WO2007112747A1

WO2007112747A1 - Immunogen combinations

Info

Publication number: WO2007112747A1
Application number: PCT/DK2007/000161
Authority: WO
Inventors: Peter Moldt; Ove Pedersen; Dennis Matthiesen
Original assignee: Curalogic A/S
Priority date: 2006-03-31
Filing date: 2007-03-30
Publication date: 2007-10-11

Abstract

This invention relates to combinations of a first immunogen with one or more second immunogen or other active agent. The combination may be of the first immunogen and other component(s) in mixture with each other, or of the first immunogen and other components in a form that reduces or prevents contact between them. The combination may be used to deliver the first immunogen and other components to particular locations within the gastrointestinal tract to treat conditions of improper or undesirable immune responses to the immunogen(s) present in the combination. The invention also relates to methods for the preparation of the combination.

Description

IMMUNOGEN COMBINATIONS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Immunotherapy has the goal of modifying allergic immune responses. Various routes of administering allergens have been utilized in immunotherapy efforts, resulting in a selection for high dose, subcutaneous immunotherapy (SCIT) as a standard treatment to treat allergies (see ref. 3 herein). Administration by injection delivers an intact agent into the body where needed, without the possibility of degradation during passage through the digestive system. This is in contrast to non-injection routes, which include oral immunotherapy (OIT), sublingual immunotherapy (SLIT), sublingual spit immunotherapy (SLIT-spit), and sublingual swallow immunotherapy (SLIT-swallow). Oral administration must be conducted with awareness of the need for an agent to be absorbed into the body without destruction during passage through the digestive tract. Citation of documents herein is not intended as an admission that any is pertinent prior art. All statements as to the date or representation as to the contents of documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of the documents.

BRIEF SUMMARY OF THE INVENTION

The invention relates to dosage level forms of formulations of immunogens. The forms or formulations comprise a combination containing a first immunogen and one or more other immunogens, and/or other active agent. Viewed from this dosage form level, oral administration may be used to deliver additional components with a first immunogen via a single vehicle. The delivery means provided by the combination reduces the need to separately administer the first immunogen and other component(s) of the combination.

In some combinations, the first immunogen and other components are in mixture with each other. In some mixtures, the first immunogen, such as particles, beads, or granules thereof, and a second immunogen, or active agent, are free to touch each other. Contact between the molecules of the first immunogen and a second immunogen, or active agent, occurs. Reactivity between the first immunogen and the other component(s) may be low or absent such that no deleterious effect on, or degradation of, the first immunogen or other component(s) occurs due to contact between them.

In some embodiments, these combinations may be formulated into tablets, particles, beads, granules, microtablets, microparticles, microbeads, or microgranules, or placed into capsules, prior to administration. Non-limiting examples include particles, beads, granules, microparticles, microbeads, and microgranules, each in a microencapsulated form, or optionally compressed into larger aggregates or tablets. Other non-limiting examples include tablets, particles, beads, granules, and microtablets, each in a coated form. Capsules containing microencapsulated forms of the combination, as well as non-solid, liquid, or gel forms of the combination, are also included in the invention. In many cases, the microencapsulation, coating, or capsule used for a combination provides selective release or exposure of the combination in a particular region of the gastrointestinal (Gl) tract, such as the small intestine.

In other combinations, the molecules of the first immunogen and other components are partitioned from each other such that they are not in contact with each other and so do not mix. These combinations may be used in cases where the first immunogen and another component of the combination undergo a deleterious or undesirable reaction degradation if contact were allowed to occur.

In one aspect, the combination is of a first component, comprising a first immunogen within a shell or coating, and a second component, comprising a second immunogen, or an active agent. The shell or coating prevents contact between the first immunogen and second immunogen or active agent. The combination may be contained within a capsule which delivers the first immunogen and other component(s) to the small intestine after passage through the stomach. In some embodiments, the shell or coating is also selected to release or deliver the first immunogen in the small intestine. In another aspect, the combination is of a first component, comprising a first immunogen within a shell or coating for enteric release, and a second component, comprising a second immunogen, or an active agent, within a shell or coating. The shell or coating for enteric release and the second component's shell or coating prevent contact between the first immunogen and second immunogen or active agent. Non-limiting examples of a shell or coating include a film or layer that is applied to a first immunogen or a second immunogen, or active agent, as a solid material. In some embodiments, the solid material is particulate matter, including powders, crystals, beads, or granules as non-limiting examples. A coating, film or layer may be applied to various thickness by known methods, including microencapsulation, spray drying, or the Wurster process. An active agent may be a medicament, such as a biologically active chemical or complex. In some embodiments, the agent is a medicament used for the treatment of one or more symptoms associated with an immune response or allergic response. Non-limiting examples include an antihistamine, a decongestant, an antagonist of a leukotriene receptor, and a mast cell stabilizer. In some cases, the agent is active by reducing or inhibiting release or production of an immune response, or allergic response, mediator. In other embodiments, the active agent is an adjuvant, such as an immunoadjuvant. The invention further provides for a combination of two or more active agents as the second component of a combination. In some embodiments of the invention, the first and second components of the combination are contained within a capsule. The capsule is optionally of a material that permits delivery to a particular region of the Gl tract. In some embodiments, the capsule is of a material that is resistant to the acidic gastric environment of a subject's stomach but delivers the first and second components to the small intestine for release. In other embodiments, the capsule is subject to dissolution in the gastric environment, but the components comprise enteric shells or coatings such that the components are released, in whole or in part, in the stomach environment. Passage of the components to the small intestine then allows the delivery of the first immunogen and second immunogen, or active agent, to the small intestine. Therefore, the invention provides combinations in capsules for delivering either a first and second immunogens to the small intestine or a first immunogen and an active agent to the small intestine. Alternatively, a combination may comprise more than one immunogen and an active agent. Where the capsule provides for enteric delivery, the first immunogen and other component(s) are not required to be coated for delivery or release in the small intestine, but may be optionally so prepared. In other embodiments, the components of a combination may comprise a first immunogen and/or said second immunogen, or active agent, in a non-solid, liquid, or gelatinous (or gel) form. Such forms may be contained within shells or capsules, such as by gelatin, starch and similar encapsulation techniques or polymeric microencapsulation.

In further embodiments, the first immunogen and second immunogen, or first immunogen and active agent, are each in a shell or coating suitable for oral administration. Non-limiting coated forms include powder, particle, bead, granule, tablet, microbead, microgranule, and microtablet as well as combinations thereof. In some embodiments, a combination comprises first and second immunogens, both of which are in a shell or coating for enteric release. In other embodiments, a combination comprises a first immunogen, in a shell or coating for enteric release, and an active agent. The agent may also be coated for enteric delivery or may be coated for delivery to another part of the Gl tract. In alternative embodiments, the first immunogen and second immunogen, or first immunogen and active agent, are each in a shell or coating and within a capsule suitable for oral administration. In some embodiments, the shell or coating simply prevents contact between the first and second immunogens, or between the first immunogen and active agent, while the capsule is of a material for enteric delivery. In other embodiments, the shell or coating for immunogen(s) is for enteric delivery, the shell or coating for an active agent (if present) is optionally for enteric delivery, but the capsule is not limited to enteric delivery.

In further embodiments, a combination comprising a particle, a bead, a granule, a tablet, a microbead, a microgranule, a microtablet, or a combination of any two or more of these forms, may comprise a first immunogen, a second immunogen, and an active agent. Such solids may be optionally compressed into a larger aggregate or tablet for use in the invention.

In yet another aspect, the invention provides a layered composition wherein one or more first immunogen is part of a core which is within a first shell or coating that partitions the first immunogen from a second immunogen and/or one or more active agent. The second immunogen and/or one or more active agent is thus layered upon the coated core to form a larger particle. The larger particle is then optionally within a capsule or second shell or coating. Alternatively, the core comprises one or more active agent as described herein, optionally within a first shell or coating as described above, and an immunogen is layered upon that shell or coating. This alternative larger particle is also optionally within a capsule or second shell or coating. The first shell or coating, as well as the capsule or second shell or coating may be individually selected to permit delivery or release of the contained materials in the small intestine.

The combinations of the invention comprise a first immunogen which may be an allergen that produces an allergic response in some individuals. In some embodiments, the allergen is that of an insect, mold, fungus (including of the genus Altemaria and Helminthosporium), dust mite (D. farinae), ragweed, grass or grass pollen (including timothy grass and Bermuda grass), tree or tree pollen (including olive, white oak, and box elder), a weed (including Russian thistle or tumbleweed), plantain (Plantago), epithelia, animal dander, a dog, a cat, or venom. Other allergens include a cockroach allergen, ragweed pollen, birch pollen, Japanese cedar pollen, dog hair, and cat hair. Where more than one immunogen is present in a combination, the additional immunogen may be an allergen that is different or distinct from the first immunogen, and optionally selected from an allergen of an insect, mold, fungus, dust mite, ragweed, grass or grass pollen, tree or tree pollen, a weed, epithelia, a cat, or venom. Examples of combinations are:

one immunogen from grass, the additional immunogen from ragweed one immunogen from grass, the additional immunogen from tree pollen one immunogen from cat, the additional immunogen from dust mite one immunogen from one insect, the additional immunogen from another insect.

In embodiments of the invention where immunogens are in contact with each other, mixtures of allergens from plant species, as well as allergens of dust mites, epithelia, and cats, may be used in the practice of the invention. The mixtures may comprise a combination of any two or more allergens from those listed above. Other combinations of allergens are preferably combined with reduced or the absence of contact between them.

So embodiments of the invention where immunogens are not in contact with each other may be advantageously used where one of the immunogens is a non-dust mite insect or insect bite allergen, a mold or fungal allergen, or a venom allergen. As non-limiting examples, the allergens of cockroach, Altemaria, Helminthosporium, and venoms should be prevented from contacting other immunogens or allergens in a combination of the invention. Of course allergens that may be combined may also be kept apart as described herein. The invention includes the preferred separation of all immunogens and allergens in the combinations described herein. The benefits of such partitioning include the minimizing of degradation of materials due to the presence of proteases, phosphatases, glycosidases, and other enzymatic activities, as present with some immunogens, without the need for extraction or fractionation to remove such activities. Thus the invention includes the partitioning of immunogens and allergens to impede degradation and loss of immunoreactivity. An immunogen or allergen may be present in a combination of the invention in a unit dosage, or dosage level, form. A variety of allergens may be used in the practice of the invention as described herein. Administration of the immunogen(s)/allergen(s) may be used to reduce or decrease, via immunotherapy, immune responses to the immunogen(s) and/or allergic responses to the allergen(s). The invention thus includes methods of immunotherapy, or desensitization, by oral administration of a combination of the invention. The immunogen containing combination is orally administered, such as regularly or semi-regularly over time, to a subject, such as a human being, to reduce the immune response to the immunogen. The administration may be self administration by a subject. In many embodiments, the administration is over weeks, months, or years. The administration may be to prevent or reduce the strength or severity of an immune or allergic response of a subject upon later exposure to an immunogen or allergen. Alternatively, the administration may be to treat or reduce the strength or severity of an immune or allergic response of a subject exhibiting an acute immune or allergic response to an immunogen or allergen. The subject may be any that has been determined to be in need of immunotherapy. One non-limiting example is a human subject that has been diagnosed with an undesirable level of immune response to an immunogen or an allergic response to an allergen. The diagnosis may be made by a skilled clinician or other medical worker by use of routine methodology and recognized standards. Non-limiting examples of possible diagnoses include seasonal and non-seasonal allergies.

In one aspect, the immunogen/allergen is administered as part of a pre-treatment or conditioning of a subject. In some embodiments, the administration is prior to exposure of the subject to the allergen in the subject's environment. Non-limiting examples include pre-seasonal treatment in the case of seasonal allergies, such as those resulting from plant pollens. In other embodiments, the administration is to a subject that is previously untreated by immunotherapy, such as individuals not previously treated with clinical or other intentional administration of allergen. Non-limiting examples include unsensitized individuals, such as those not previously exposed to the allergen in their environment. The administered dose of an immunogen or allergen is optionally increased during the pre-treatment or conditioning period.

The invention also includes methods for preparing the combinations described herein. In some embodiments, the methods provide for the coating or encapsulating of immunogen(s) to prepare a component of a combination described herein.

DEFINITIONS

The term "immunogen" refers to material capable of inducing an immune response in a subject, such as a human being. An immune response is the physiological reaction of an organism's immune system to a non-self, or foreign, substance that results in the formation of sensitized lymphocytes and antibodies against the substance. The substance may be described as an antigen, such as a molecule to which a cognate binding antibody may be produced.

As used herein, an immunogen includes a proteinaceous molecule, such as a peptide or polypeptide, or proteinaceous complex, such as a peptide or polypeptide containing complex, or an extract or isolate containing an immunogen. An extract or isolate may contain more than one immunogen. Non-limiting examples of an immunogen containing extract or isolate include an extract or fraction of naturally occurring substances, such as fractions of a virus or bacterium, as well as an isolated viral particle or bacterial cell. An extract, fraction, or isolate may be of material from one source, or of material from multiple (2 or more) sources. A peptide or polypeptide immunogen may be naturally occurring, or produced by artificial or synthetic means, including de novo synthesis or recombinant production. An immunogen may also have one or more carbohydrate component or moiety. The term "allergen" refers to an immunogen that results in an allergic reaction or response in a subject. The allergic reaction or response commonly does not follow the first exposure to an immunogen, but rather occurs on subsequent exposure(s) to that immunogen, which is thus an allergen. An allergic reaction or response is a misdirected or undesirable immune response because the immunogen is generally harmless and does not cause an immune response in most people. In many instances, an allergic reaction or response occurs in a sensitized immune system, where histamine and other chemicals are released upon exposure to the allergen. The reaction or response includes results in itching, swelling, mucus production, muscle spasms, hives, rashes (such as of the skin), nasal congestion, itchy nose and throat, cough, wheezing, nausea, vomiting, abdominal pain, cramping, and diarrhea as non- limiting examples. Non-limiting examples of an allergen containing extract or isolate include an extract or fraction of naturally occurring substances, such as an extract or fraction of pollen, as well as isolated pollen itself. An extract, fraction, or isolate may be of material from one biological source, such as one species of organism, or of material from multiple (2 or more) sources.

DETAILED DESCRIPTION OF MODES OF PRACTICING THE INVENTION This invention describes combinations comprising one or more immunogens or allergens for oral administration. In some aspects, the invention relates to the delivery of the one or more immunogens to the small intestine via enteric delivery and release of the immunogen(s). The combinations may comprise a mixture comprising an immunogen in contact with another immunogen or an active agent. Alternatively, the combinations may comprise an immunogen that is prevented from contacting another immunogen or an active agent. In some embodiments, the combination comprises a coated or encapsulated immunogen with one or more other immunogen and/or an active agent. In other embodiments, the combination is in the form of a coated tablet, microtablet, or other solid form. In further embodiments, the combination comprises encapsulated immunogen(s) or allergen(s), optionally with an active agent, contained within a capsule. The combinations may also comprise an immunogen or active agent in a liquid or non-solid form.

Additional embodiments of the invention include combinations that are resistant to gastric environment of the stomach. Thus compositions that reduce contact between the immunogen(s) or allergen(s) and the gastric mucosa of the stomach lining are described.

In embodiments where capsule is used to contain materials for enteric delivery, the capsule may be susceptible to dissolution in a gastric environment at low pH, such as in the case of a gelatin capsule for use with the invention. Other non-limiting examples of such capsule material include polymers that are unstable in the low pH environment of the gastric mucosa. Representative examples of such polymers include those that may be considered a "gastric coating" in that they are not soluble or subject to dissolution until exposed to low pH conditions of about 1.0 to 3.0 such as in the gastric environment of the stomach. Such polymers are known to the skilled person and may be used to encapsulate an immunogen or allergen as described herein. A "gastric coating" provides little to no resistance against the gastric mucosa. The invention thus also describes compositions that comprise a material that provides resistance against the gastric environment to protect or shield an immunogen and other agents until they are beyond the stomach. In some embodiments, the material is a layer that reduces or prevents degradation of an immunogen or allergen in low pH environments, such as in the mammalian stomach and proximal part of the small intestines. This layer may also be used to reduce or prevent release of the immunogen or allergen in the gastric environment. The immunogen or allergen thus avoids exposure to acid and proteolytic digestion. This preserves the antigenic structure and the ability to immunize in a form more similar to that of the immunogen or allergen in the environment and/or as encountered by a subject.

As described herein, this layer may be used to coat or encapsulate an immunogen of the invention. The coated or encapsulated material may optionally be in a capsule composed of the "gastric coating" described above such that with dissolution of the "gastric coating", the gastric mucosa resistant layer is exposed. In some embodiments, the gastric mucosa resistant layer is an enteric layer which is resistant to low pH but is subject to dissolution under higher pH conditions such as that of the small intestine. So while stable at low pH, the coating releases the allergen in higher pH environments, such as the duodenum, jejunum and ileum. In some embodiments, an immunogen or allergen may be part of a core particle or layered onto a core. One or more binders may be present in the core in an amount within the range of from about 0 to about 10% and preferably about 1 % by weight of the composition. Sodium carboxymethylcellulose is the preferred binder most suitable for use herein. Non-limiting examples of other binders which may be used include Avicel a PH101 ; Avicel a RC 591 ; Avicel a CL-611 ; Methocel a E-5 (Dow Corp.); Starch 1500 (Colorcon, Ltd.); Hydroxypropyl Methylcellulose (HPMC) (Shin-Etsu Chemical Co., Ltd.); polyvinylpyrrolidone; potassium alginate; and sodium alginate. Where the gastric mucosa resistant layer is an enteric layer, non-limiting materials that may be used include a water emulsion of ethylacrylate methylacrylic acid copolymer, or hydroxypropyl methyl cellulose acetate succinate (HPMAS). Other coatings may be used, including those comprising macrogol 6000 and those described in JP 93059098 B; JP 83055125 B; JP 96013748 B2; and US Patent 4,377,568. Other materials may be used to coat or encapsulate (or microencapsulate), optionally in the absence of a "gastric coating", include a solution of Eudragit L-30-D 55 (an aqueous acrylic resin dispersion of an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ester of approximately 1 :1 , and a mean molecular weight of approximately 250,000) containing 30% w/w of dry lacquer substance; hydroxypfopylmethyl cellulose acetate succinate; Eudragit F30D; hydroxypropyl methylcellulose phthalate HP50 (HPMCP-HP50) (USP/NF 220824); HP55 (HPMCP-HP55) (USP/NF type 200731 ); HP55S available from Shin Etsu

Chemical; CoatericD (polyvinyl acetate phthalate) (Colorcon Ltd.); SuretericD (polyvinyl acetate phthalate) (Colorcon, Ltd.); and AquatericD (cellulose acetate phthalate) (FMC

Corp.).

In some embodiments, the coating material is used in combination with a plasticizer to improve the continuity of the coating. Non-limiting examples include triethylcitrate

(TEC) sold by Morfley Inc. While plasticizers can be liquid, they are not considered to be solvents because they remain within the coating material to alter its physical characteristics. Plasticizers do not act to dissolve the immunogen or allergen. Of course plasticizers which dissolve or denature the allergen may be. used in the invention if such modified allergens were desired.

In compositions comprising a coating, the coating may optionally be in the form of a film that is applied to the composition. The invention also provides for the selection of the thickness of a coating, film, or encapsulating layer. In most embodiments, a coating or film is selected to be sufficiently thick to prevent contact between two materials, such as a first immunogen and a second immunogen or active agent as described herein.

The invention also provides a method of reducing a subject's immune response to an immunogen or allergen, such as an environmental allergen. The immune response may be symptoms of allergic rhinitis and/or allergic conjunctivitis. The method may comprise administering a first combination of the invention, comprising one or more allergens, to the subject. The administrating may be during a pre-treatment or "pre- seasonal" treatment phase. The administering may be followed by maintaining administration of said one or more allergens by a second combination comprising said one or more allergens to said subject during said exposure of the subject to said allergen in the subject's environment. This is during the maintenance, or "in season", phase. The first and second combinations may be administered orally to reduce said subject's immune response, such as symptoms of allergic rhinitis and/or allergic conjunctivitis, to the allergen.

Where a combination comprises an active agent, the activity of the agent may be simultaneously provided to the treated subject. This provides an added feature even in case of "pre-treatment" or "pre-seasonal" treatment as well as treatment of an unsensitized (previously unexposed) individual.

Other immune responses that may be reduced by the practice of the invention include, but are not limited to, nasal stuffiness/congestion, nasal discharge/postnasal drip, nasal itching, sneezing, itchy/burning eyes, tearing/watering eyes, redness of eyes, and itchy throat and/or ears. In some embodiments, such benefits may be provided by the antihistamine, decongestant, antagonist of a leukotriene receptor, and mast cell stabilizer present as an active agent in a combination. Non-limiting examples of these agents include cetirizin, fexofenadine, acrivastine, azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, diphenhydramine, loratadine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, or triprolidine as an antihistamine; pseudoephedrine hydrochloride or phenylephrine as a decongestant; an antagonist of a cysteinyl leukotriene CysLTI receptor; an inhibitor of an immune response mediator formation or release; montelukast sodium ([R-(E)]-1-[[[1-[3-[2-(7- chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1 -hydroxy- 1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt]) and Zafirlukast (^(δ-cyclopentyloxy-carbonylamino-i-methyl-indol-S-ylmethyO-S-methoxy- N-o-tolylsulfonylbenzamide) as an antagonist of a leukotriene receptor; an inhibitor of mediator formation which inhibits 5-lipooxygenase, such as Zileuton((±)-1-(1- Benzo[b]thien-2-ylethyl)-l-hydroxyurea), which inhibits leukotriene formation, especially LTB1 , LTC1 , LTD1 , LTE1 ; and Cromolyn sodium (disodium 5,5'-[(2- hydroxytrimethylene)dioxylbis[4-oxo-4H-1 -benzopyran-2-carboxylate]) or Nedocromil sodium (4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4,6-dioxo- 10-propyl-, disodium salt) as a mast cell stabilizer. The allergen in the subject's environment includes, but is not limited to, airborne or atmospheric allergens such as pollens. Embodiments of the invention include those wherein the allergen is selected from a cockroach allergen, ragweed pollen, grass pollen, tree pollen, birch pollen, Japanese cedar pollen, dog hair, cat hair or a dust mite allergen. Other allergens include those of an insect or insect bite, mold, fungus (including of the genus Alternaria and Helminthosporium), dust mite (D. farinae), ragweed or ragweed pollen, weed or weed pollen (including Russian thistle or tumbleweed), grass or grass pollen (including timothy grass and Bermuda grass), tree or tree pollen (including olive, white oak, and box elder), plantain (Plantago), epithelia, animal (such as dog, cat, horse, and other mammals) dander, dust, a dog or dog hair, a cat or cat hair, venom or foodstuffs, such as peanuts, shellfish, shrimp, and crustaceans. Compositions comprising one or more of these allergens, in any combination, may also be used.

Thus in some embodiments, the invention may be advantageously used with subject having a history of seasonal allergic rhinitis, such as to ragweed, grass, or tree pollen. The invention provides the benefit of reduces the seasonal increase of IgE in such subjects during the respective pollen season.

Administration may be by oral means and by use of doses and dosing regimens, such as unit dosing, that result in the reduction of immune responses to the allergen in the subject. The invention also provides particular allergen doses for use in the disclosed methods. The daily doses may be from about 1 to about 30 times the maintenance injection dose used in SCIT expressed in microgram major allergen units as defined in reference 41 herein, which is readily determined by routine methods known in the field. The dose may be from about 2 to about 25 times, from about 3 to about 10 times, from about 4 to about 15, or from about 5 to about 20 times the SCIT maintenance dose. Using ragweed pollen extract as a non-limiting example, about 40 microgram Amb a 1 major allergen or more may be used in the practice of the invention. Doses of about 10, about 15, about 20, about 25, about 30, about 35, and about 40 microgram Amb a 1 major allergen may also be used. The doses may be increased during the conditioning or pre-seasonal treatment phases of the methods described herein.

Alternatively, and with respect to ragweed, doses of about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, to about 24 microgram Amb a 1 (a major allergenic protein of ragweed) allergen may be used. Of course use of ragweed pollen extract that is equivalent to these Amb a 1 doses may also be used. The invention further includes a method of preparing one or more immunogens for oral administration. In some embodiments, a method comprises coating the immunogen(s), in tablet or microtablet form, to form a coated tablet or microtablet of the invention. In other embodiments, a method comprises encapsulating or microencapsulating the immunogen(s) to form a capsule or microcapsule of the invention. In certain embodiments, the administering of the invention may be by use of a microencapsulated allergen as described herein. In some embodiments, the encapsulating is by use of aqueous conditions without employing non-aqueous solvents. In other embodiments, non-aqueous solvents may be used. In some embodiments, the allergen(s) are dispersed in an aqueous solution. The solution is then sprayed onto a core particle, such as a nonpareil composed of sugar and/or starch. This results in the formation of a microsphere, which may then be coated or encapsulated as described herein. In some embodiments, the microsphere is coated with a polymer in solution which solidifies to become an acid resistant coating. A non-limiting example of the solution is a water based emulsion of the polymer. The coating should protect the allergen as it passes through the stomach even if the coating was within a gastric coating as described above. The dissolution of the gastric coating in the stomach allows the enteric coating to sequester an allergen from the gastric mucosa and the low pH environment to allow release of the allergen into the small intestines where it can act upon the lymphoid tissue. The allergen may be in the form of pollen or pollen extract, optionally in lyophilized form.

Nonpareils are small, round particles of pharmaceutically inert, or acceptable, materials. Commercially available nonpareils include Nupareils which is sold by Ingredient Technology Corporation. In some embodiments, the nonpareils are coated with an amount of the allergen containing solution to provide a coating of 1-10% allergen by weight on a solids basis. Coating conditions and times may vary based on the apparatus and coating viscosity. In many embodiments, the coating steps are conducted at less than 50⁰C, such as less than 35°C. A microsphere comprising a nonpareil and a first immunogen may also be used as a core particle upon which a first shell or coating is applied. The first shell or coating may be selected in material or thickness to prevent contact with a layer of a second immunogen or active agent applied to the core particle as described herein. The larger particle with the second immunogen or active agent may then be coated or encapsulated, such as with an enteric coating, to form a combination with a second shell or coating. The second shell or coating may be for enteric delivery. The larger particle, with or without a second shell or coating, may of course be formulated within a capsule, optionally for enteric delivery, of the invention for oral administration. Where the second shell or coating is for enteric delivery, the capsule is optionally acid unstable to release the combination in the stomach and subsequent enteric delivery of the combination.

In order to protect one immunogen from another active ingredient, the thickness of the shell or coating is preferably at least 5 μm, such as in the range of from 10 μm to 60 μm, such as in the range of from 15 μm to 60 μm, such as in the range of from 15 μm to 50 μm, such as in the range of from 20 μm to 50 μm, such as in the range of from 25 μm to 50 μm.

The thickness may be determined by cutting the object, for example the microbead and examine the object by acquiring a scanning electron micrograph (image)using a scanning electron microscope.

Multiple coating and encapsulating methods may be used in the practice of the invention. As a non-limiting example, the Wurster process is a coating technique may be used to uniformly coat or encapsulate individual particulate materials. This method utilizes a spray nozzle below a fluidized bed of solid particles. A fluidizing air stream is used to suspend the particles in a cyclic flow of the particles past the spray nozzle. The nozzle sprays an atomized flow of coating solution or other coating suspension. The coating solution may comprise dissolved polymer, sugar, inorganic salts, sol gels, and/or other dissolved materials. The atomized coating material contacts the particles as they move away from the nozzle. The coating material evaporates or solidifies, under the temperature of the fluidizing air, shortly after contacting the particles. In the process, the coating solids are left on the particles as part of a film or coat. The process may continue until the particles are coated to a desired thickness. The Wurster process may be used to apply a film or coat to particulates such as powders, crystals, or granules of immunogens and active agents as described herein. The process can encapsulate materials with diameters ranging from about 50μm to several millimeters and above. The process may be used to coat small particles without agglomeration. Coating properties can be optimized without undue experimentation by adjusting coat formulation parameters, processing conditions, and layering. As described herein, the coatings and capsules used may serve the purpose of regulating or controlling solubility, such as in the stomach or the small intestine, and reactivity, but reducing or limiting contact between immunogens. The coatings and capsules may also serve to mask flavors, odor, and color. Microencapsulation can be used to prepare particles as small as about 8 microns and as large as about 2 millimeter. Microencapsulation may be used to coat immunogens and other components when they are in a gelatinous form. In cases of encapsulating a liquid, up to 85% of the capsule may be liquid filled. Alternatively, methods such as spray drying may be used for microencapsulating immunogens and/or active agents as described herein. Where microencapsulation disperses an immunogen and/or active agent throughout a particle, a subsequent coating process can be used to shield or protect the particle.

Spray drying are well known methods for coating particles. In both processes, the particle to be coated is added to the melt or solution. Coating occurs during atomization. Smaller coating materials may be separated in a subsequent step. An immunogen or allergen may be used or formulated in combination with a stabilizing agent, such as one which provides physical protection for the immunogen or allergen. Non-limiting examples of such agents include therapeutically inactive water soluble sugars such as lactose, mannitol and trehalose. These agents may also protect the therapeutic antigen during the coating process. In some embodiments of the invention, about 1 to about 10% polyvinylpyrrolidone is used to aid the binding of allergen to a nonpareil.

Allergen coated microspheres that have been coated may be processed by any standard methods known in the field. Talc (up to about 3.0% of coating composition) may also be added to prevent sticking between the microsphere particles as needed. Similarly, an antifoaming agent (such as about 0.0025% of coating composition) like sorbitan sesquioleate (Nikko Chemicals Company Limited) or silicone can be included as needed. In some embodiments of the invention, a suitable adjuvant may be used with administration of an allergen or allergen containing composition to a subject. Suitable adjuvants are known to the skilled person and may be selected as desired. The adjuvant may be formulated to be part of an allergen containing composition of the invention.

As described herein, enteric coated microspheres are placed in gel capsules prior to use in the practice of the invention. Alternative formulations of the microspheres, such as non-capsulated combinations, may also be used in the practice of the invention.

The invention further provides for a plurality of doses, of immunogen(s) or allergen(s), for oral administration in methods as described herein. The plurality of doses may comprise individual compositions of the same, or increasing, amounts of an allergen, such as an environmental allergen. In some embodiments, the increasing amounts of an allergen may range from about 5 to about 40 units of one or more ragweed antigen. The composition of allergen may optionally comprise ragweed pollen extract.

Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified.

EXAMPLES Example 1 : Combinations of pollen

Grass pollen suitable for oral immunotherapy is prepared and microencapsulated as described herein. The microencapsulation is with a monosaccharide containing coating that envelopes the pollen to prevent its exposure to external contact. The microencapsulated pollen is combined with uncoated ragweed pollen suitable for oral immunotherapy and encapsulated within a capsule for enteric delivery after oral administration.

Alternatively, the microencapsulation is with an enteric coating followed by combination with ragweed pollen and encapsulation within a capsule for enteric delivery.

Example 2: Double microencapsulation of pollen

Grass and ragweed pollen suitable for oral immunotherapy are prepared and separately microencapsulated by a method as described herein. The microencapsulation is with an monosaccharide containing coating that envelopes each pollen to prevent its exposure to external contact. The two separately microencapsulated pollens are combined and encapsulated within a capsule for enteric delivery after oral administration.

Alternatively, each microencapsulation is with an enteric coating followed by encapsulation within a gelatin capsule for oral administration.

Example 3: Layered particle

Grass pollen suitable for oral immunotherapy is prepared and microencapsulated by a method as described herein. The microencapsulation is with an monosaccharide containing coating that envelopes the pollen to prevent its exposure to external contact. Extracted or isolated ragweed allergen (Amb a 1 ) is layered or coated onto the microencapsulated pollen as described herein. The ragweed allergen coated particle is then optionally layered or coated again with a second monosaccharide containing coating to form a final particle. The final particle is encapsulated within a capsule for enteric delivery after oral administration.

Alternatively, the ragweed allergen coated particle is layered or coated with an enteric coating to form a final particle which is encapsulated within a gelatin capsule for oral administration.

Example 4: Production of two microencapsulated allergens in one capsule

A ragweed solution was formed by dissolving 203 grams of polyvinylpyrrolidone and 203 grams lactose in 2439.6 grams of sterile water (50⁰C). Next, 34.4 grams of lyophilized short ragweed extract was added and dissolved at room temperature. The coating solution was formulated by combining 4068 grams of Eudragit L30D (30% solids) with 122 gram triethyl citrate. The microspheres were formed in a Glatt model GPCG-5 Wurster spray dryer. The Wurster chamber was loaded with 2000 grams of

30-35 mesh nonpareils. The inlet air pressure was adjusted such that the microspheres reached a "f luidized" state. The inlet air temperature was increased till the product temperature was between 40-45⁰C and the antigen solution was sprayed onto the nonpareils. The variables of air flow ("outlet flap"), inlet air temperature, and spray rate were adjusted in order to maintain a free "fluidized" state of the microspheres. When all of the antigen solution was sprayed, the enteric coating (Eudragit L30D) was sprayed (initially at around 30 g/min) adjusting variables of inlet air temperature and air flow to achieve maximum spray rate while maintaining a product temperature of 29-32°C. At the end of the coating process, the fluidized particles cured for 1 hour.

Microencapsulated grass pollen extract was prepared similarly. The two microencapsulated allergen extracts are combined in a capsule. The enteric coating prevents contact between the allergen extracts

Example 5: a shell or coating for enteric release

A ragweed solution was formed by dissolving 150 grams of mannitol in 1000 g of sterile water. Next, 10 grams of lyophilized short ragweed extract was added and dissolved at room temperature. The solution is freeze dried to give free flowing powder which is filled into capsule together with microencapsulated grass pollen extract manufactured as described in example 1. The enteric coat on the microencapsulated grass pollen extract prevents contact between the allergens

Example 6: Production of two allergens in one capsule produced as layers

A ragweed solution was formed by dissolving 203 grams of polyvinylpyrrolidone and 203 grams lactose in 2439.6 grams of sterile water (50⁰C). Next, 34.4 grams of lyophilized short ragweed extract was added and dissolved at room temperature. A second allergen solution was prepared consisting of 203 grams of polyvinylpyrrolidone, 203 grams lactose and 30 grams of grass pollen extract in 2439.6 grams of sterile water. The microspheres were formed in a Glatt model GPCG-5 Wurster spray dryer. The Wurster chamber was loaded with 2000 grams of nonpareils. The inlet air pressure was adjusted such that the microspheres reached a "fluidized" state. The inlet air temperature was increased till the product temperature was between 40-45⁰C and the antigen solution was sprayed onto the nonpareils. The variables of air flow ("outlet flap"), inlet air temperature, and spray rate were adjusted in order to maintain a free "fluidized" state of the microspheres. When all of the ragweed solution was sprayed, a layer of polyvinylpyrrolidone was sprayed on top of the ragweed pollen extract layer. The grass was sprayed onto the polyvinylpyrrolidone layer followed by an enteric coat layer prepared from 4068 grams of Eudragit L30D (30% solids) combined with 122 gram triethyl citrate. At the end of the coating process, the fluidized particles cured for 1 hour. The polyvinylpyrrolidone layer applied to the microbead after application of the ragweed pollen extract layer but before the grass pollen extract layer great a barrier separating the two allergen layers. The microbeads are filled in capsules.

Example 7: Production of two allergens in a tablet

A ragweed solution was formed by dissolving 203 grams of polyvinylpyrrolidone and 203 grams lactose in 2439.6 grams of sterile water (50⁰C). Next, 34.4 grams of lyophilized short ragweed extract was added and dissolved at room temperature. A second solution was prepared from 203 grams lactose in 2439.6 grams of sterile water. The microspheres were formed in a Glatt model GPCG-5 Wurster spray dryer. The Wurster chamber was loaded with 2000 grams of nonpareils. The inlet air pressure was adjusted such that the microspheres reached a "fluidized" state. The inlet air temperature was increased till the product temperature was between 40-45⁰C and the antigen solution was sprayed onto the nonpareils. The lactose solution was sprayed on top of the allergen layer. Similarly, microbeads with microencapsulated grass pollen extract ware prepared. The two extract microbeads were mixed and compressed into a tablet and the tablet was enteric coated with a layer of Eudragit L30D. The finishing lactose layer on the microbeads ensures that the two allergen extract do not get into contact.

REFERENCES:

I Litwin et al. "Oral immunotherapy with short ragweed extract in a novel encapsulated preparation: a double-blind study" J Allergy Clin Immunol. 1997 Jul;100(1):30-8. 2 Van Deusen et al. "Efficacy and safety of oral immunotherapy with short ragweed extract" Ann Allergy Asthma Immunol. 1997 Jun;78(6):573-80.

3 Ledford, DK "Is oral immunotherapy too good to be true? Ann Allergy Asthma Immunol. 2004 Jan;92(1):1-2.

4 TePas et al. "Clinical efficacy of microencapsulated timothy grass pollen extract in grass-allergic individuals." Ann Allergy Asthma Immunol. 2004 Jan;92(1):25-

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5 Litwin et al. "Immunologic effects of encapsulated short ragweed extract: a potent new agent for oral immunotherapy" Ann Allergy Asthma Immunol. 1996 Aug;77(2): 132-8. 6 Bagnasco et al. "Absorption and distribution kinetics of the major

Parietaria judaica allergen (Parj 1) administered by noninjectable routes in healthy human beings" J Allergy Clin Immunol. 1997 Jul;100(1):122-9.

7 Walter et al. "Functionalisation of allergen-loaded microspheres with wheat germ agglutinin for targeting enterocytes." Biochem Biophys Res Commun. 2004 Mar 5;315(2):281-7.

8 Roth-Walter et al. "M cell targeting with Aleuria aurantia lectin as a novel approach for oral allergen immunotherapy." J Allergy Clin Immunol. 2004

Dec; 114(6): 1362-8.

9 Wang et al. "Management of allergic rhinitis: a common part of practice in primary care clinics." Allergy. 2004 Mar;59(3):315-9.

10 Canonica et al. "Noninjection routes for immunotherapy." J Allergy Clin Immunol. 2003 Mar;111 (3):437-48.

I 1 Patriarca et al. "Oral desensitizing treatment in food allergy: clinical and immunological results." Aliment Pharmacol Ther. 2003 Feb;17(3):459-65. 12 Oppenheimer et al. "Safety and efficacy of oral immunotherapy with standardized cat extract" J Allergy Clin Immunol. 1994 Jan;93(1 Pt 1):61-7.

13 Swarbrick et al. "Absorption of antigens after oral immunisation and the simultaneous induction of specific systemic tolerance." Gut. 1979 Feb;20(2):121-5.

14 Cooper et al. "A controlled trial of oral hyposensitization in pollen asthma and rhinitis in children." Clin Allergy. 1984 Nov;14(6):541-50. 15 Giovane et al. "A three-year double-blind placebo-controlled study with specific oral immunotherapy to Dermatophagoides: evidence of safety and efficacy in paediatric patients." Clin Exp Allergy. 1994 Jan;24(1):53-9.

16 Mosbech et al. "High dose grass pollen tablets used for hyposensitization in hay fever patients. A one-year double blind placebo-controlled study." Allergy. 1987

Aug;42(6):451-5.

17 Moller et al. "Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. A double blind study." Allergy. 1986 May;41 (4):271-9.

18 Taudorf et al. "Oral administration of grass pollen to hay fever patients. An efficacy study in oral hyposensitization." Allergy. 1985 Jul;40(5):321-35.

19 Litwin et al. "Microencapsulation: The furture of oral immunotheraphy?" BioDrugs 1998 Apr.9 261-270.

20 Barone et al. "Abrogation of oral tolerance by feeding encapsulated antigen." Cell Immunol. 2000 Feb 1 ;199(2):65-72. 21 Mayer et al. "Therapeutic potential of oral tolerance." Nat Rev Immunol.

2004 Jun;4(6):407-19.

22 "Induction of oral tolerance in TGF-beta 1 null mice." J Immunol. 1998 JuI 1 ;161 (1):154-60.

23 Jain et al. "Activation patterns of murine B cells after oral administration of an encapsulated soluble antigen." Vaccine. 1996 Sep;14(13):1291-7.

24 Hong et al. "Pepsin-digested peanut contains T-cell epitopes but no IgE epitopes." J Allergy Clin Immunol. 1999 Aug; 104(2 Pt 1):473-8.

25 Taudorf et al. "Oral immunotherapy in birch pollen hay fever." J Allergy Clin Immunol. 1987 Aug;80(2): 153-61. 26 Bagnasco et al. "Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers." Clin Exp Allergy. 2001

Jan;31 (1):54-60.

27 Van Wilsem et al. "Dendritic cells of the oral mucosa and the induction of oral tolerance. A local affair." Immunology. 1994 Sep;83(1): 128-32 28 Marcucci et al. "Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications."

Allergy. 2001 Nov;56(11):1091-5.

29 Bousquet et al. "Characteristics of patients with seasonal allergic rhinitis and concomitant asthma." Allergy. 2004 Jun;34(6):897-903. 30 Canonica et al. "Sublingual and oral immunotherapy." Immunol Allergy Clin North Am. 2004 Nov;24(4):685-704.

31 Passalacqua et al. "Articles 3 Oral and sublingual immunotherapy in paediatric patients." Curr Opin Allergy Clin Immunol. 2003 Apr;3(2): 139-45.

32 Guerin et al. "Microsphere entrapped bee-venom phospholipase A2 retains specific IgE binding capacity: a possible use for oral specific immunotherapy." J Microencapsul. 2002 Nov-Dec;19(6):761-5.

33 Criado Molina et al. "Immunotherapy with an oral Alternaria extract in childhood asthma. Clinical safety and efficacy and effects on in vivo and in vitro parameters" Allergol lmmunopathol (Madr). 2002 Nov-Dec;30(6):319-30.

34 Martorell Aragones "New administration routes for immunotherapy. A.AIIergol lmmunopathol (Madr). 2000 May-Jun;28(3):93-102.

35 Creticos et al. "Responses to ragweed-pollen nasal challenge before and after immunotherapy" J. Allergy Clin Immunol. 1989 Aug;84(2):197-205.

36 Creticos et al. "Efficacy safety and kinetics of oral ragweed immunotherapy in the treatment of allergic seasonal rhinitis" J. Allergy Clin Immunol. 1990;85(1 , part 2):165, abstract 85.

37 Aramaki et al. "Induction of oral tolerance after feeding of ragweed pollen extract in mice" Immunol. Lett. 1994; 40(1):21-25.

38 Li et al. "Allergen immunotherapy: a practice parameter". Ann. Allergy Asthma Immunol. 2003; 90:1-40.

39 Nelson, 'The use of standardized extracts in allergen immunotherapy". J. Allergy Clin. Immunol. 2000; 106 (1): 41-45.

All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entireties, whether previously specifically incorporated or not. Having now fully described this invention, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation.

While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.

Claims

1. A composition for oral administration, said composition comprising a capsule for enteric delivery or release of a combination of a first component comprising a first immunogen within a shell or coating and a second component comprising a second immunogen, or active agent, wherein the shell or coating prevents contact between the first immunogen and second immunogen or active agent.

2. The composition of claim 1 wherein said second immunogen, or active agent, is also within a shell or coating to prevent contact between the first immunogen and second immunogen or active agent.

3. A composition for oral administration, said composition comprising a combination of a first component comprising a first immunogen within a shell or coating for enteric release and a second component comprising a second immunogen, or active agent, wherein the shell or coating for enteric release prevents contact between the first immunogen and second immunogen or active agent.

4. The composition of claim 3 wherein said first immunogen and second immunogen or active agent, are microencapsulated and the combination is contained within a capsule.

5. The composition of any of the preceding claims, wherein said combination comprises first and second immunogens, both microencapsulated for enteric release.

6. The composition of any of the preceding claims, wherein said combination comprises a first immunogen and a microencapsulated active agent.

7. The composition of any of the preceding claims, wherein said active agent is an antihistamine, a decongestant, an antagonist of a leukotriene receptor, a mast cell stabilizer, an immuno-adjuvant, or any combination of two or more thereof.

8. The composition of claim 7 wherein said active agent is an antihistamine selected from cetirizin, fexofenadine, acrivastine, azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, diphenhydramine, loratadine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, and triproiidine.

9. The composition of claim 7 wherein said active agent is a decongestant selected from pseudoephedrine hydrochloride and phenylephrine.

10. The composition of claim 7 wherein said active agent is an antagonist of a cysteinyl leukotriene CysLTI receptor or an inhibitor of mediator formation or release.

11. The composition of claim 7 wherein said active agent is an antagonist of a leukotriene receptor selected from montelukast sodium ([R-(E)]-1-[[[1-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(1 -hydroxy-1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt]) and Zafirlukast (4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy- N-o-tolylsulfonylbenzamide).

12. The composition of claim 10 wherein said active agent is an inhibitor of mediator formation which inhibits 5-lipooxygenase, such as Zileuton ((±)-1-(1-

Benzo[b]thien-2-ylethyl)-l-hydroxyurea), which inhibits leukotriene formation, especially LTB1 , LTC1 , LTD1. LTE1.

13. The composition of claim 7 wherein said active agent is a mast cell stabilizer, such as an inhibitor of mediator formation, selected from Cromolyn sodium (disodium 5,5'-[(2-hydroxytrimethylene)dioxylbis[4-oxo-4H-1-benzopyran-2- carboxylate]) and Nedocromil sodium (4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, disodium salt).

14. The composition of any of the preceding claims, wherein either said first immunogen and/or said second immunogen, or active agent, are in non-solid, liquid, or gel form, and where the second immunogen is optionally contained within a shell or coating.

15. The composition of any of the preceding claims, wherein said combination comprises a first immunogen, a second immunogen, and a microencapsulated active agent.

16. The composition of any of the preceding claims, wherein said first immunogen is an allergen from an insect or insect bite, mold, fungus, dust mite, ragweed or ragweed pollen, weed or weed pollen, grass or grass pollen, tree or tree pollen, a weed, epithelia, dander, dust, a cat or cat hair, venom, or foodstuffs, such as peanuts, shellfish, shrimp, and crustaceans.

17. The composition of any of the preceding claims, wherein said second immunogen is different from the first immunogen and is an allergen of an insect or insect bite, mold, fungus, dust mite, ragweed or ragweed pollen, grass or grass pollen, tree or tree pollen, weed or weed pollen, epithelia, a cat or cat hair or cat dander, or venom.

18. The composition of claim 17 wherein said second immunogen is different from the first immunogen and is an allergen of an insect or insect bite, mold, fungus, or venom.

19. The composition of claim 1 or 2 wherein said first immunogen and second immunogen, or active agent, are in a form selected from powder, particle, bead, granule, tablet, microbead, microgranule, microtablet, or combinations thereof.

20. The composition of claim 3 or 4 wherein said first immunogen and second immunogen, or active agent, are in a form selected from powder, particle, bead, granule, tablet, microbead, microgranule, microtablet, or combinations thereof, optionally compressed together into a larger aggregate.

21. The composition of claim 20 wherein said combination comprises first and second immunogens, both in a shell or coating for enteric release.

22. The composition of claim 20 wherein said combination comprises a first immunogen and an active agent.

23. The composition of claim 20, 21 or 22 wherein said microbead, microgranule, microtablet, or combination thereof is contained within a capsule.

24. The composition of claim 22 wherein said active agent is an antihistamine, a decongestant, an antagonist of a leukotriene receptor, a mast cell stabilizer, or any combination of two or more thereof.

25. The composition of claim 24 wherein said active agent is an antihistamine selected from cetirizin, fexofenadine, acrivastine, azatadine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, diphenhydramine, loratadine, pheniraminei phenyltoloxamine, promethazine, pyrilamine, and triprolidine.

26. The composition of claim 24 wherein said active agent is a decongestant selected from pseudoephedrine hydrochloride and phenylephrine.

27. The composition of claim 24 wherein said active agent is an antagonist of a cysteinyl leukotriene CysLTI receptor or an inhibitor of mediator formation or release. 28. The composition of claim 24 wherein said active agent is an antagonist of a leukotriene receptor selected from montelukast sodium ([R-(E)]-1-[[[1-[3-[2-(7-chloro- 2-quinolinyl)ethenyl]phenyl]-3-[2-(1 -hydroxy- 1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt]) and Zafirlukast (4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy- N-o-tolylsulfonylbenzamide).

29. The composition of claim 27 wherein said active agent is an inhibitor of mediator formation which inhibits 5-lipooxygenase, such as Zileuton ((±)-1-(1- Benzo[b]thien-2-ylethyl)-l-hydroxyurea), which inhibits leukotriene formation, especially LTB1 , LTC1 , LTD1 , LTE1.

30. The composition of claim 24 wherein said active agent is a mast cell stabilizer, such as an inhibitor of mediator formation, selected from Cromolyn sodium (disodium 5,5'-[(2-hydroxytrimethylene)dioxylbis[4-oxo-4H-1-benzopyran-2- carboxylate]) and Nedocromil sodium (4H-Pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-, disodium salt).

31. The composition of claim 20 or 21 wherein said combination comprises a first immunogen, a second immunogen, and an active agent.

32. The composition of claim 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 wherein said first immunogen is an allergen from an insect or insect bite, mold, fungus, dust mite, ragweed or ragweed pollen, weed or weed pollen, grass or grass pollen, tree or tree pollen, a weed, epithelia, dander, dust, a cat or cat hair, venom, or foodstuffs, such as peanuts, shellfish, shrimp, and crustaceans.

33. The composition of claim 20, 21 , or 32 wherein said second immunogen is different from the first immunogen and is an allergen of an insect or insect bite, mold, fungus, dust mite, ragweed or ragweed pollen, grass or grass pollen, tree or tree pollen, weed or weed pollen, epithelia, a cat or cat hair or cat dander, or venom.

34. The composition of claim 31 wherein said second immunogen is different from the first immunogen and is an allergen of an insect or insect bite, mold, fungus, or venom.

35. The composition of any of the preceding claims comprising a core comprising a first immunogen within a first shell or coating, and a second immunogen or active agent layered upon said first shell or coating.

36. The composition of claim 35, further comprising a capsule which contains said composition.

37. The composition of claim 35, further comprising a second shell or coating upon said second immunogen or active agent.

38. The composition of claim 37, wherein said second shell or coating is for enteric delivery or release of said second immunogen or active agent.

40. The composition of claim 35 wherein said core comprises a particle comprising a pharmaceutically acceptable substance and said first immunogen.

41. The composition of claim 40 wherein said particle comprising a pharmaceutically acceptable substance is a nonpareil.

42. The composition of claim 41 wherein said first immunogen is coated or layered on said nonpareil.

43. A method for producing a composition for oral administration comprising a capsule for enteric delivery or release of a combination of a first component comprising a first immunogen within a shell or coating and a second component comprising a second immunogen

said method comprising the steps of

establishing a first component comprising a first immunogen within a shell or coating, and

establishing a second component comprising a second immunogen, or active agent,

combining the first component and the second component in a capsule for enteric delivery or release, wherein the shell or coating prevents contact between the first immunogen and second immunogen or active agent.

44. A method for producing a composition for oral administration for enteric delivery or release of a combination of a first component comprising a first immunogen within a shell or coating and a second component comprising a second immunogen

said method comprising the steps of

establishing a first component comprising a first immunogen within a shell or coating for enteric release , and

establishing a second component comprising a second immunogen, or active agent, combining the first component and the second component, wherein the shell or coating prevents contact between the first immunogen and second immunogen or active agent.

45. The method according to claim 43 or 44, wherein the method and/or the composition comprises one or more features of the claims 1-42.

46. Use of a composition as defined in any of the claims 1-42 for the production of a pharmaceutical composition for the treatment and/or prevention of allergy.

47. A pharmaceutical composition comprising the composition as defined in any of claims 1 -42.