EP2081557A1 - Colonic delivery using zn/pectin beads with a eudragit coating. - Google Patents
Colonic delivery using zn/pectin beads with a eudragit coating.Info
- Publication number
- EP2081557A1 EP2081557A1 EP07822689A EP07822689A EP2081557A1 EP 2081557 A1 EP2081557 A1 EP 2081557A1 EP 07822689 A EP07822689 A EP 07822689A EP 07822689 A EP07822689 A EP 07822689A EP 2081557 A1 EP2081557 A1 EP 2081557A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- drug delivery
- human
- delivery system
- agent
- eudragit
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- 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
- A61P1/10—Laxatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
Definitions
- the present invention is in the area of oral drug delivery systems to administer active agents, such as metallo-specific enzymes, to the colon.
- Drug delivery systems that specifically deliver active agents to the colon have been recognized as having important therapeutic advantages.
- a large number of colonic conditions could effectively be treated more efficaciously if the active ingredient is released locally.
- Examples of such colonic disorders include Crohn's disease, ulcerative colitis, colorectal cancer and constipation.
- Colonic release can also benefit patients when, from a therapeutic point of view, a delay in absorption is necessary. Examples include the treatment of disorders such as nocturnal asthma or angor (Kinget R. et al. (1998), Colonic Drug Targeting, Journal of Drug Targeting, 6, 129).
- Colonic release can also be used to administer therapeutically active polypeptides.
- Polypeptides are typically administered by injection, because they are degraded in the stomach. Because injection is painful, research efforts have focused on using the colon as a site of absorption for active polypeptides, - including analgesics, contraceptives, vaccines, insulin, and the like. The absorption of polypeptides in the colon appears to be more effective than in other sites in the digestive tract. This is particularly due to the relatively weak proteolytic activity in the small intestine and the absence of peptidase activity associated with the membrane of the colonic epithelial cells.
- antibiotics Following their oral administration, antibiotics pass through the stomach and are then absorbed in the small intestine to diffuse in the whole organism and treat the infectious outbreak site(s) for which they have been administered. All the same, a fraction of antibiotics ingested (the importance of this fraction varies with the characteristics of each antibiotic) is not absorbed and continues its progress to the colon before being eliminated in the stool. These residual antibiotics are combined, in the large intestine, with a fraction of the antibiotics absorbed, but which are re-excreted in the digestive tract by means of biliary elimination. This fraction is of variable importance as a function of metabolism and elimination pathways for each antibiotic.
- microorganisms resistant to the antibiotic can be of various types: a) first they can be pathogenic bacteria such as for example, Clostridium difficile, a species capable of secreting toxins causing a form of colitis known as pseudomembranous colitis (Bartlett J. G. (1997) Clostridium difficile infection: pathophysiology and diagnosis, Seminar in Gastrointestinal Disease, 8, 12); b) they can also be microorganisms that are relatively weakly pathogenic, but whose multiplication can lead to an associated infection (vaginal Candidosis or Escherichia coli resistant cystitis).
- Drug delivery systems that can deliver prophylactic, therapeutic and/or diagnostic agents to the colon are disclosed.
- the systems include pectin beads crosslinked with a metal cation for instance zinc or any divalent cation of interest, which beads are then coated with Eudragit®-type polymers.
- the drag delivery systems are orally administrable, but can deliver the active agents to the colon. In some embodiments, they can administer the agents to various positions in the gastro-intestinal tract, including the colon.
- the therapeutic agent is an agent capable of reducing the residual quantity of residual antibiotics reaching the colon following oral or parenteral antibiotic therapy, such as a metallo-dependent enzyme.
- a metallo-dependent enzyme such as a metallo-dependent enzyme.
- ⁇ -lactamase Ll from Stenotrophomonas maltophilia.
- ⁇ -lactamases which are not metallo-enzymes (classes A, C or D).
- enzymes, metallo-dependent or otherwise to inactivate other classes of antibiotics such as macrolides, quinolones and fluoriquinolones, glycopeptides, lipopeptides, cyclins, oxazolidinones, and other classes of antibiotics.
- the enzymes can have the full sequence of the native enzyme, or can be truncated or otherwise modified so long as they maintain acceptable activity.
- agents capable of reducing the quantity of residual antibiotics reaching the colon following oral or parenteral antibiotic therapy one can limit the development of bacterial resistance.
- the therapeutic agents include, but are not limited to:
- peptides and proteins including, but not limited to, enzymes, hormones, cytokines, lymphokines, growth factors, antibodies, and the like) whether natural, synthetic or recombinant;
- nucleic acids and compounds including elements from nucleic acids including, but not limited to, plasmids, oligonucleotides
- viruses including DNA and RNA viruses, viruses targeting animal cells, viruses targeting vegetal cells, or viruses targeting bacteria better known as bacteriophages
- bacteria in whatever form, including spores
- mycoplasms in whatever form, including spores
- yeasts and other unicellular eucaryotes
- Colon-specific delivery is obtained by formulating a prophylactic, therapeutic, and/or diagnostic agent, such as a metallo-dependent enzyme or other agent capable of reducing the quantity of residual antibiotics reaching the colon following oral or parenteral antibiotic therapy, with specific polymers that degrade in the colon, such as pectin.
- a prophylactic, therapeutic, and/or diagnostic agent such as a metallo-dependent enzyme or other agent capable of reducing the quantity of residual antibiotics reaching the colon following oral or parenteral antibiotic therapy
- specific polymers that degrade in the colon such as pectin.
- the pectin is gelled/crosslinked with a cation such as a zinc cation.
- the formulation typically in the form of ionically crosslinked pectin beads, is subsequently coated with a specific polymer such as a Eudragit® polymer.
- the delivery can be modulated to occur at various pre-selected sites of delivery within the intestinal tract by gelling/crosslinking a mixture of the prophylactic, therapeutic, and/or diagnostic agent and pectin, with divalent metallic cations such as Ca 2+ or Zn 2+ .
- the present invention relates to coating the pectin beads with Eudragit® polymers such as FS30D, L30D (also known as L30D-55), NE30D, mixtures thereof or other desirable types of Eudragit® polymers to achieve the desired release of the prophylactic, therapeutic and/or diagnostic agent at predefined levels of the gastro-intestinal tract (GIT).
- Eudragit® polymers such as FS30D, L30D (also known as L30D-55), NE30D, mixtures thereof or other desirable types of Eudragit® polymers to achieve the desired release of the prophylactic, therapeutic and/or diagnostic agent at predefined levels of the gastro-intestinal tract (GIT).
- GIT gastro-intestinal tract
- One aspect of the invention is to provide a stable metallo-enzyme formulation for the lower intestinal or colonic delivery of such an enzyme.
- the use of zinc cations to crosslink the pectin is particularly preferred when specific metallo-dependent enzymes, which are Zn 2+ dependent, could interact with other cationic species if they were used to gel the pectin beads. Such interactions could drastically affect the activity of such metallo-dependent enzymes.
- one embodiment of the drug delivery system involves using Zn 2+ ions as a crosslinking agent for the pectin beads and in association with Zn + -dependent enzymes which are very sensitive to the presence of other competitive cations.
- Another embodiment of the invention relates to processes for preparing zinc-crosslinked and Eudragit®-coated pectin beads.
- Figure 1 is a graph showing the efficiency of water rinsing to remove excess metallic cations from a formulation of ⁇ -lacatamase Ll in pectin beads crosslinked with zinc acetate, measured in terms of conductivity (mS/cm) per sample following various washes.
- Figure 2 is a graph showing the effect of geliflcation time, rinsing process, and drying time on recovery of ⁇ -lactamase Ll activity.
- Figure 3 is a graph showing the enzymatic activity of ⁇ -lactamase Ll using CENTA as a substrate, measured in terms of response (OD/min) versus Ll concentration ( ⁇ g/ml).
- Figure 4 is a series of scanning electron micrographs showing Eudragit-coated beads prepared using the methods described herein, and a cross-section of the beads showing the approximate thickness of Eudragit layer.
- Figure 5 is a chart showing the release kinetics of ⁇ -lactamase Ll from uncoated beads, and Eudragit-coated beads with or without hydroxypropyl methyl cellulose (HPMC) pre-coating, measured in terms of activity ( ⁇ g/mg beads) versus time (minutes).
- Blue triangles represent uncoated beads; red circles represent beads coated with 40% Eudragit L30D-55 without pre-coating; green squares represent beads pre-coated with 5% HPMC and coated with 40% Eudragit L30D-55.
- Figure 6 is a chart showing the hydrolysis of amoxicillin by uncoated, and Eudragit- coated beads with or without a hydroxypropyl methylcellulose (HPMC) pre-coating, measured in terms of residual amoxicillin (%) versus time (minutes).
- Blue triangles represent uncoated beads; red circles represent beads coated with 40% Eudragit L30D-55 without pre- coating; green squares represent beads pre-coated with HPMC and coated with Eudragit L30D-55.
- Figure 7 is a chart showing the effect of Eudragit-coated pectin beads containing ⁇ - lactamase Ll on the emergence of antibiotic-resistant bacteria in piglets treated with amoxicillin, measured in terms of amoxicillin resistant bacteriacae (%) versus treatment duration (days).
- the pectin beads are formed from pectin, zinc ions, and further coating with Eudragit ® polymers and encapsulate one or more active agents.
- the Eudragit ® polymer coating ensures that they resist long enough so that their contents able to reach the colon intact.
- Pectin is a polysaccharide isolated from the cellular walls of superior plants, used widely in the agricultural food industry (as a coagulant or thickener for jams, ice creams and the like) and pharmaceutics. It is polymolecular and polydisperse. Its composition varies depending on the source, extraction conditions and environmental factors. Pectins are principally composed of linear chains of beta-l,4-(D)-galacturonic acid, at times interspersed by units of rhamnose. The carboxylic groups of galacturonic acid can be partially esterified to yield methylated pectins.
- pectins Two types are distinguished according to their degree of methylation (DM: number of methoxy groups per 100 units of galacturonic acid): - highly methylated pectin (HM: high methoxy) where the degree of methylation varies between 50 and 80%. It is slightly soluble in water and forms gels in acidic medium (pH ⁇ 3.6) or in the presence of sugars;
- pectin Treatment of pectin by ammonia transfoms some methyl carboxylate groups (-COOCH 3 ) into carboxamide groups (-CONH 2 ).
- This amidation confers novel properties to the pectins, in particular better resistance to variations in pH.
- Amidated pectins tend to be more tolerant to the variations in pH, and have also been studied for the manufacture of matricial tablets for colonic delivery (Wakerly Z. et al. (1997) Studies on amidated pectins as potential carriers in colonic drug delivery, Journal of Pharmacy and Pharmacology. 49, 622).
- Pectin is degraded by enzymes originating from higher plants and various microorganisms (fungi, bacteria, and the like) among which bacteria from the human colonic flora.
- the enzymes produced by the microflora encompass a mixture of polysaccharidases, glycosidases and esterases.
- Divalent zinc cations from various zinc salts can be used to crosslink pectin. Examples include zinc sulfate, zinc chloride, and zinc acetate.
- agents for enteric coatings are preferably methacrylic acid- alkyl acrylate copolymers, such as Eudragit® polymers.
- Eudragit® polymers such as Eudragit® polymers
- the coating of drug-loaded cores such as tablets, capsules, granules, pellets or crystals offers many advantages over uncoated counterparts, such as higher physicochemical stability, better compliance and increased therapeutic efficiency of the active ingredients. Indeed, the effectiveness of a medication depends not only on the actives it contains, but also on formulation and processing.
- Poly(meth)acrylates have proven particularly suitable as coating materials. These polymers, typically used in amounts of only a few milligrams, are pharmacologically inactive, i.e. are excreted unchanged.
- EUDRAGIT® is the trade name for copolymers derived from esters of acrylic and methacrylic acid, whose properties are determined by functional groups.
- the individual EUDRAGIT® grades differ in their proportion of neutral, alkaline or acid groups and thus in terms of physicochemical properties.
- the skillful use and combination of different EUDRAGIT® polymers offers ideal solutions for controlled drug release in various pharmaceutical and technical applications.
- EUDRAGIT® provides functional films for sustained-release tablet and pellet coatings. The polymers are described in international pharmacopeias such as Ph.Eur., USP/NF, DMF and JPE.
- EUDRAGIT® polymers can provide the following possibilities for controlled drug release: • Gastrointestinal tract targeting (gastroresistance, release in the colon)
- EUDRAGIT® polymers are available in a wide range of different concentrations and physical forms, including aqueous solutions, aqueous dispersion, organic solutions, and solid substances.
- EUDRAGIT® polymers are determined by the chemical properties of their functional groups. A distinction is made between: • poly(meth)acrylates, soluble in digestive fluids (by salt formation) EUDRAGIT® L (Methacrylic acid copolymer), S (Methacrylic acid copolymer), FS and E (basic butylated methacrylate copolymer) polymers with acidic or alkaline groups enable pH-dependent release of the active ingredient. Applications: from simple taste masking via resistance solely to gastric fluid, to controlled drug release in all sections of the intestine.
- EUDRAGIT® RL and RS ammonio methacrylate copolymers
- EUDRAGIT® NE polymers with neutral groups enable controlled time release of the active by pH-independent swelling.
- Enteric EUDRAGIT® coatings provide protection against drug release in the stomach and enable controlled release in the intestine.
- Targeted drug release in the gastrointestinal tract is recommended for particular applications or therapeutic strategies, for example when the drug is sparingly soluble in the upper digestive tract, or when the drug may be degraded by gastric fluid.
- this dosage form is very patient-friendly as it does not stress the stomach and the number of doses of the therapeutic drug can be considerably reduced, thanks to prolonged delivery.
- the dominant criterion for release is the pH-dependent dissolution of the coating, which takes place in a certain section of the intestine (pH 5 to over 7) rather than in the stomach (pH 1-5).
- anionic EUDRAGIT® grades containing carboxyl groups can be mixed with each other.
- EUDRAGIT® L and S grades are suitable for enteric coatings.
- EUDRAGIT® FS 30 D aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid is specifically used for controlled release in the colon.
- enteric EUDRAGIT® coatings include: pH-dependent drug release protection of actives sensitive to gastric fluid protection of the gastric mucosa from aggressive actives increase in drug effectiveness good storage stability controlled release in the colon/GI targeting
- the active agent can be an anti-infectious, for example antibiotics, anti-inflammatory compounds, anti-histamines, anticholinergics, antivirals, antimitotics, peptides, proteins, enzymes, nucleic acids (RNA or DNA), peptide nucleic acids, plasmids, genes, anti-sense oligonucleotides, interfering RNAs, ribozymes, small molecules with specific binding capacities or activities (such as targeted chemotherapeutics), diagnostic agents, immunosuppressive agents, viruses, bacteria, other micro-organisms or eukaryotic cells.
- antibiotics for example antibiotics, anti-inflammatory compounds, anti-histamines, anticholinergics, antivirals, antimitotics, peptides, proteins, enzymes, nucleic acids (RNA or DNA), peptide nucleic acids, plasmids, genes, anti-sense oligonucleotides, interfering RNAs, ribozymes, small molecules with specific binding
- the active agent can be introduced into the drug delivery system as a powder, a solution, a suspension, or complexed with a solubilizing agent, such as a cyclodextrin or any other suitable compound.
- a solubilizing agent such as a cyclodextrin or any other suitable compound.
- Some of the active agents described herein can be administered in the form of prodrugs.
- Prodrugs have been widely studied for the colonic targeting of various active ingredients (such as steroid and non-steroid anti-inflammatory drugs, and spasmolytics).
- the prodrugs can be based on the action of bacterial azoreductases, so that the active agents are targeted to the colon with the drug delivery systems described herein, and the active agents are formed by reaction of the prodrug with a bacterial azoreductase, which provides a dual mechanism for ensuring that the drugs are administered to the colon.
- Representative chemistry for forming such prodrugs is described, for example, in Peppercorn M. A. et al. (1972) The role of intestinal bacteria in the metabolism of salicylazosulfapyridin, The Journal of Pharmacology and Experimental Therapeutics, 181, 555 and 64, 240.
- Another approach consists in using bacterial hydrolases such as glycosidases and polysaccharidases (Friend D.R. (1995) Glycoside prodrugs: novel pharmacotherapy for colonic diseases, S. T.P.Pharma Sciences, 5, 70; Friend D.R. et al. (1984) A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria,
- Prodrugs have thus been developed by coupling, for example, sugar with steroids (glucose, galactose, cellobiose, dextrane (international application WO 90/09168)), cyclodextrins Hirayama F. et al. (1996) In vitro evaluation of Biphenylyl Acetic Acid-beta - Cyclodextrin conjugates as colon-targeting prodrugs: drug release behavior in rat biological media, Journal of Pharmacy and Pharmacology, 48, 27).
- the active agent is an enzyme capable of inactivating antibiotics in the colon. Any agent that inactivates an antibiotic can be administered.
- ⁇ -lactamases can be used.
- the selected enzyme i.e. ⁇ -lactamase Ll, a Zn 2+ -dependent ⁇ -lactamase from Stenotrophomonas maltophilia, was chosen from a series of ⁇ -lactamases because its characteristics showed the best profile for the targeted application. Also, it has been demonstrated to have an excellent stability profile. The characteristics of various ⁇ -lactamases evaluated are described hereafter.
- the cation used to crosslink the pectin comprises the cation on which the enzyme depends.
- ⁇ -lactamase Ll a Zn + -dependent ⁇ -lactamase from Stenotrophomonas maltophilia
- Stenotrophomonas maltophilia a Zn + -dependent ⁇ -lactamase from Stenotrophomonas maltophilia
- antibiotics When the antibiotic is from another class of antibiotics, enzymes or other molecules that inactivate such antibiotics can be used.
- One such example would be to use an erythromycin esterase to inactivate macrolide antibiotics.
- the active agent can be one capable of inactivating quinolones.
- Representative agents include those disclosed by Chen, Y et al. ((1997) “'Microbicidal models of soil metabolisms biotransformations of danofioxacin,” Journal of Industrial Microbiology and Biotechnology 19:378).
- Patients can be treated with combinations of these agents.
- any type of antitumor agent can be used.
- the anti-tumor agents can be, for example, antiproliferative agents, agents for DNA modification or repair, DNA synthesis inhibitors, DNA/RNA transcription regulators, RNA processing inhibitors, agents that affect protein expression, synthesis and stability, agents that affect protein localization or their ability to exert their physiological action, agents that interfere with protein- protein or protein-nucleic acid interactions, agents that act by RNA interference, receptor binding molecules of any chemical nature (including small molecules and antibodies), targeted toxins, enzyme activators, enzyme inhibitors, gene regulators, HSP-90 inhibitors, molecules interfering with microtubules or other cytoskeletal components or cell adhesion and motility , agents for phototherapy, and therapy adjuncts.
- Representative antiproliferative agents include N-acetyl-D-sphingosine (C 2 ceramide), apigenin, berberine chloride, dichloromethylenediphosphonic acid disodium salt, loe-emodine, emodin, HA 14-1, N-hexanoyl-D-sphingosine (C 6 ceramide), 7b-hydroxycholesterol, 25-hydroxycholesterol, hyperforin, parthenolide, and rapamycin.
- C 2 ceramide N-acetyl-D-sphingosine
- apigenin apigenin
- berberine chloride dichloromethylenediphosphonic acid disodium salt
- loe-emodine emodin
- HA 14-1 HA 14-1
- N-hexanoyl-D-sphingosine C 6 ceramide
- 7b-hydroxycholesterol 25-hydroxycholesterol
- hyperforin parthenolide, and rapamycin.
- Representative agents for DNA modification and repair include aphidicolin, bleomycin sulfate, carboplatin, carmustine, chlorambucil, cyclophosphamide monohydrate, cyclophosphamide monohydrate ISOP AC®, cis-diammineplatinum(II) dichloride (Cisplatin), esculetin, melphalan, methoxyamine hydrochloride, mitomycin C, mitoxantrone dihydrochloride, oxaliplatin, and streptozocin.
- Representative DNA synthesis inhibitors include ( ⁇ )amethopterin (methotrexate), 3-amino-l,2,4-benzotriazine 1,4-dioxide, aminopterin, cytosine b-D- arabinofuranoside (Ara-C), cytosine b-D-arabinofuranoside (Ara-C) hydrochloride, 2- fluoroadenine-9-b-D-arabinofuranoside (Fludarabine des-phosphate; F-ara-A), 5- fluoro-5'-deoxyuridine, 5-fluorouracil, ganciclovir, hydroxyurea, 6-mercaptopurine, and 6-thioguanine.
- DNA/RNA transcription regulators include actinomycin D, daunorubicin hydrochloride, 5,6-dichlorobenzimidazole 1-b-D-ribofuranoside, doxorubicin hydrochloride, homoharringtonine, and idarubicin hydrochloride.
- Representative enzyme activators and inhibitors include forskolin, DL- aminoglutethimide, apicidin, Bowman-Birk Inhibitor, butein, (S)-(+)-camptothecin, curcumin, (-)-deguelin, (-)-depudecin, doxycycline hyclate, etoposide, formestane, fostriecin sodium salt, hispidin, 2-imino-l-imidazolidineacetic acid (Cyclocreatine), oxamflatin, 4-phenylbutyric acid, roscovitine, sodium valproate, trichostatin A, tyrphostin AG 34, tyrphostin AG 879, urinary trypsin inhibitor fragment, valproic acid (2-propylpentanoic acid), and XK469.
- Representative gene regulators include 5-aza-2'-deoxycytidine, 5-azacytidine, cholecalciferol (Vitamin D3), ciglitizone, cyproterone acetate, 15-deoxy-D 12 ' 14 - prostaglandin J 2> epitestosterone, flutamide, glycyrrhizic acid ammonium salt (glycyrrhizin), 4-hydroxytamoxifen, mifepristone, procainamide hydrochloride, raloxifene hydrochloride, all trans-retinal (vitamin A aldehyde), retinoic acid (vitamin A acid), 9-cis-retinoic acid, 13-cis-retinoic acid, retinoic acid p-hydroxyanilide, retinol (Vitamin A), tamoxifen, tamoxifen citrate salt, tetradecylthioacetic acid, and troglita
- HSP-90 inhibitors include 17-(allylamino)-17- demethoxygeldanamycin and geldanamycin.
- microtubule inhibitors include colchicines, dolastatin 15, nocodazole, taxanes and in particular paclitaxel, podophyllotoxin, rhizoxin, vinblastine sulfate salt, vincristine sulfate salt, and vindesine sulfate salt and vinorelbine (Navelbine) ditartrate salt.
- Representative agents for performing phototherapy include photoactive porphyrin rings, hypericin, 5-methoxypsoralen, 8-methoxypsoralen, psoralen and ursodeoxycholic acid.
- Representative agents used as therapy adjuncts include amifostine, 4-amino-
- agents can also be anti-VEGF (vascular endothelial growth factor) agents, as such are known in the art.
- VEGF vascular endothelial growth factor
- the agents can also be directed against growth factor receptors such as those of the EGF/Erb-B family such as EGF Receptor (Iressa or Gefitinib, and Tarceva or Erlotinib), Erb-B2, receptor (Herceptin or Trastuzumab), other receptors (such as Rituximab or Rituxan/MabThera), tyrosine kinases, non-receptor tyrosine kinases, cellular serine/threonine kinases (including MAP kinases), and various other proteins whose deregulation contribute to oncogenesis (such as small/Ras family and large/heterotrimeric G proteins).
- EGF Receptor Iressa or Gefitinib, and Tarceva or Erlotinib
- Erb-B2 receptor
- Herceptin or Trastuzumab such as Rituximab or Rituxan/MabThera
- tyrosine kinases such as
- paclitaxel docetaxel
- tamoxifen vinorelbine
- gemcitabine gemcitabine
- cisplatin etoposide
- topotecan irinotecan
- anastrozole rituximab
- trastuzumab rituximab
- fludarabine cyclophosphamide
- gentuzumab carboplatin, interferons
- doxorubicin doxorubicin.
- the most commonly used anticancer agent is paclitaxel, which is used alone or in combination with other chemotherapy drugs such as: 5 -FU, doxorubicin, vinorelbine, Cytoxan, and cisplatin.
- Combination therapy can be provided by combining two or more of the above compounds.
- Immunosuppressive agents are also used to treat Crohn's disease. Most commonly prescribed are 6-mercaptopurine and a related drug, azathioprine. Immunosuppressive agents work by blocking the immune reaction that contributes to inflammation.
- Infliximab brand name, Remicade
- Infliximab is an anti-tumor necrosis factor alpha (TNF-alpha) antibody. This and other anti-TNF-alpha agents can be used to remove TNF-alpha from the colon, thereby preventing inflammation, without the side effects that might result if TNF- alpha were removed from the blood stream outside of the colon.
- Antidiarrheal agents are often also administered, including diphenoxylate, loperamide, and codeine.
- agents that are used to treat ulcerative colitis overlap with those used to treat Chrohn's Disease.
- examples include aminosalicylates, drugs that contain 5- aminosalicyclic acid (5-ASA), to help control inflammation, such as sulfasalazine, olsalazine, mesalamine, and balsalazide. They also include corticosteroids such as prednisone and hydrocortisone, and immunomodulators such as azathioprine and 6- mercapto-purine (6-MP), cytokines, interleukins, and lymphokines. Cyclosporine A may be used with 6-MP or azathioprine to treat active, severe ulcerative colitis.
- Anti- TNF-alpha agents, the thiazolidinediones or glitazones, including rosiglitazone and pioglitazone, can also be used.
- Constipation/Irritable Bowel Syndrome Constipation such as that associated with irritable bowel syndrome, is often treated using stimulant laxatives, osmotic laxatives such as Lactulose and MiraLax, stool softeners (such as mineral oil or Colace), bulking agents (such as Metamucil or bran).
- Agents such as Zelnorm (also called tegaserod) can be used to treat IBS with constipation.
- anticholinergic medications such as Bentyl ® and Levsin ® have been found to be helpful in alleviating the bowel spasms of IBS.
- Protein and Peptide Drugs such as Bentyl ® and Levsin ® have been found to be helpful in alleviating the bowel spasms of IBS.
- the drug delivery systems can be used to orally administer proteins and peptides that might otherwise be degraded if orally administered, and which might otherwise have to be administered intramuscularly or intravenously.
- protein and peptide drugs useful in the present invention include:
- Adrenocorticotropic hormone (ACTH) peptides including, but not limited to, ACTH, human; ACTH 1-10; ACTH 1-13, human: ACTH 1-16, human; ACTH 1-17; ACTH 1-24, human; ACTH 4-10; ACTH 4-11; ACTH 6-24; ACTH 7-38, human; ACTH 18-39, human; ACTH, rat; ACTH 12-39, rat; beta-cell tropin (ACTH 22-39); biotinyl-ACTH 1-24, human; biotinyl-ACTH 7-38, human; corticostatin, human; corticostatin, rabbit; [Met(02) 4 , DLys 8 , Phe 9 ] ACTH 4-9, human; [Met(0) 4 ,DLys 8 , Phe 9 ] ACTH 4-9, human; N-acetyl, ACTH 1-17, human; and ebiratide.
- ACTH Adrenocorticotropic hormone
- Adrenomedullin peptides including, but not limited to, adrenomedullin, adrenomedullin 1-52, human; adrenomedullin 1-12, human; adrenomedullin 13-52, human; adrenomedullin 22-52, human; pro-adrenomedullin 45-92, human; pro- adrenomedullin 153-185, human; adrenomedullin 1-52, porcine; pro-adrenomedullin (N-20), porcine; adrenomedullin 1-50, rat; adrenomedullin 11-50, rat; and pro AM- N20 (proadrenomedullin N-terminal 20 peptide), rat.
- Adrenomedullin peptides including, but not limited to, adrenomedullin, adrenomedullin 1-52, human; adrenomedullin 1-12, human; adren
- Allatostatin peptides including, but not limited to, allatostatin I; allatostatin II; allatostatin III; and allatostatin IV.
- Amylin peptides including, but not limited to, acetyl-amylin 8-37, human; acetylated amylin 8-37, rat; AC 187 amylin antagonist; AC253 amylin antagonist; AC625 amylin antagonist; amylin 8-37, human; amylin (IAPP), cat; amylin (insulinoma or islet amyloid polypeptide ⁇ APP)); amylin amide, human; amylin 1-13 (diabetes-associated peptide 1-13), human; amylin 20-29 (IAPP 20-29), human; AC625 amylin antagonist; amylin 8-37, human; amylin (IAPP), cat; amylin, rat; amylin 8-37, rat; biotinyl-amylin, rat; and biotinyl-amylin amide, human.
- Amyloid beta-protein fragment peptides including, but not limited to, Alzheimer's disease beta-protein 12-28 (SP17); amyloid beta-protein 25-35; amyloid beta/A4-protein precursor 328-332; amyloid beta/A4 protein precursor (APP) 319- 335; amyloid beta-protein 1-43; amyloid beta-protein 1-42; amyloid beta-protein 1-40; amyloid beta-protein 10-20; amyloid beta-protein 22-35; Alzheimer's disease beta- protein (SP28); beta-amyloid peptide 1-42, rat; beta-amyloid peptide 1-40, rat; beta- amyloid 1-11; beta-amyloid 31-35; beta-amyloid 32-35; beta-amyloid 35-25; beta- amyloid/ A4 protein precursor 96-110; beta-amyloid precursor protein 651-616; beta- amyloid 1-38; [Gln u ]-Alzheimer's disease beta-protein; [GIn 1 1 ]
- Angiotensin peptides including, but not limited to, A-779; Ala-Pro-Gly- angiotensin II; [Ile 3 ,Val 5 ]-angiotensin II; angiotensin III antipeptide; angiogenin fragment 108-122; angiogenin fragment 108-123; angiotensin I converting enzyme inhibitor; angiotensin I, human; angiotensin I converting enzyme substrate; angiotensin 11-7, human; angiopeptin; angiotensin II, human; angiotensin II antipeptide; angiotensin II 1-4, human; angiotensin II 3-8, human; angiotensin II 4-8, human; angiotensin II 5-8, human; angiotensin III ([Des- Asp 1 ] -angiotensin II), human; angiotensin III inhibitor ([He 7 ] -angiotensin III); angiotensin-converting enzyme inhibitor (Ne
- Antibiotic peptides including, but not limited to, Ac-SQNY; bactenecin, bovine; CAP 37 (20-44); carbormethoxycarbonyl-DPro-DPhe-OBzl; CD36 peptide P 139-155; CD36 peptide P 93-110; cecropin A-melittin hybrid peptide [CA(1-7)M(2- 9)NH2]; cecropin B, free acid; CYS(Bzl)84 CD fragment 81-92; defensin (human) HNP-2; dermaseptin; immunostimulating peptide, human; lactoferricin, bovine (BLFC); and magainin spacer.
- Antigenic polypeptides which can elicit an enhanced immune response, enhance an immune response and or cause an immunizingly effective response to diseases and/or disease causing agents including, but not limited to, adenoviruses; anthrax; Bordetella pertussus; botulism; bovine rhinotracheitis; Branhamella catarrhalis; canine hepatitis; canine distemper; Chlamydiae; cholera; coccidiomycosis; cowpox; cytomegalovirus; Dengue fever; dengue toxoplasmosis; diphtheria; encephalitis; enterotoxigenic Escherichia coli; Epstein Barr virus; equine encephalitis; equine infectious anemia; equine influenza; equine pneumonia; equine rhinovirus; Escherichia coli; feline leukemia; flavivims; globulin; haemophilus influenza type b; Haemophilus influenzae
- Anti-microbial peptides including, but not limited to, buforin I; buforin II; cecropin A; cecropin B; cecropin Pl, porcine; gaegurin 2 (Rana rugosa); gaegurin 5 (Rana rugosa); indolicidin; protegrin-(PG)-I; magainin 1; and magainin 2; and T-22 [Tyr 5 ' 12 , Lys 7 ]-poly-phemusin II peptide.
- Apoptosis related peptides including, but not limited to, Alzheimer's disease beta-protein (SP28); calpain inhibitor peptide; capsase-1 inhibitor V; capsase-3, substrate IV; caspase-1 inhibitor I, cell-permeable; caspase-1 inhibitor VI; caspase-3 substrate III, fluorogenic; caspase-1 substrate V, fluorogenic; caspase-3 inhibitor I, cell-permeable; caspase-6 ICE inhibitor III; [Des-Ac, biotin]-ICE inhibitor III; IL-I B converting enzyme (ICE) inhibitor II; IL-I B converting enzyme (ICE) substrate IV; MDL 28170; and MG-132.
- SP28 Alzheimer's disease beta-protein
- calpain inhibitor peptide including, but not limited to, Alzheimer's disease beta-protein (SP28); calpain inhibitor peptide; capsase-1 inhibitor V; capsase-3, substrate IV; caspase-1 inhibitor I, cell-permeable; caspas
- Atrial natriuretic peptides including, but not limited to, alpha-ANP (alpha- chANP), chicken; anantin; ANP 1-11, rat; ANP 8-30, frog; ANP 11-30, frog; ANP-21 (fANP-21), frog; ANP-24 (fANP-24), frog; ANP-30, frog; ANP fragment 5-28, human, canine; ANP-7-23, human; ANP fragment 7-28, human, canine; alpha-atrial natriuretic polypeptide 1-28, human, canine; A71915, rat; atrial natriuretic factor 8-33, rat; atrial natriuretic polypeptide 3-28, human; atrial natriuretic polypeptide 4-28, human, canine; atrial natriuretic polypeptide 5-27; human; atrial natriuretic aeptide (ANP), eel; atriopept
- Bag cell peptides including, but not limited to, alpha bag cell peptide; alpha- bag cell peptide 1-9; alpha-bag cell peptide 1-8; alpha-bag cell peptide 1-7; beta-bag cell factor; and gamma-bag cell factor.
- Bombesin peptides including, but not limited to, alpha-sl casein 101-123 (bovine milk); biotinyl-bombesin; bombesin 8-14; bombesin; [Leu 13 -psi (CH2NH)Leu 14 ]-bombesin; [D-Phe 6 , Des-Met 14 ] -bombesin 6-14 ethylamide; [DPhe 12 ] bombesin; [DPhe 12 ,Leu 14 ]-bombesin; [Tyr 4 ] -bombesin; and [Tyr 4 ,DPhe !2 ] -bombesin.
- alpha-sl casein 101-123 bovine milk
- biotinyl-bombesin bombesin 8-14
- bombesin [Leu 13 -psi (CH2NH)Leu 14 ]-bombesin
- Bone GLA peptides including, but not limited to, bone GLA protein; bone GLA protein 45-49; [GIu , GIa ' 4 ] -osteocalcin 1-49, human; myclopeptide -2 (MP-2); osteocalcin 1-49 human; osteocalcin 37-49, human; and [Tyr 38 , Phe 42 ' 46 ] bone GLA protein 38-49, human.
- Bradykinin peptides including, but not limited to, [Ala ' , des-Pro 3 ]- bradykinin; bradykinin; bradykinin (Bowfin.
- bradykinin potentiating peptide bradykinin 1-3; bradykinin 1-5; bradykinin 1-6; bradykinin 1-7; bradykinin 2-7; bradykinin 2-9; [DPhe 7 ] bradykinin; [Des-Arg 9 ] -bradykinin; [Des-Arg 10 ]-Lys- bradykinin ( [Des-Arg 10 ]-kallidin); [D-N-Me-Phe 7 ] -bradykinin; [Des-Arg 9 , Leu 8 ]- bradykinin; Lys-bradykinin (kallidin); Lys- [Des-Arg ,Leu ] -bradykinin ([Des--
- BNP Brain natriuretic peptides
- BNP Brain natriuretic peptides
- BNP canine; BNP-like Peptide, eel; BNP-32, human; BNP-45, mouse; BNP-26, porcine; BNP-32, porcine; biotinyl-BNP-32, porcine; BNP-32, rat; biotinyl-BNP-32, rat; BNP-45 (BNP 51-95, 5K cardiac natriuretic peptide), rat; and [Tyr°]-BNP 1-32, human.
- C-peptides including, but not limited to, C-peptide; and [Tyr°]-C-peptide, human.
- C-type natriuretic peptides including, but not limited to, C-type natriuretic peptide, chicken; C-type natriuretic peptide-22 (CNP -22), porcine, rat, human; C-type natriuretic peptide-53 (CNP-53), human; C-type natriuretic peptide-53 (CNP-53), porcine, rat; C-type natriuretic peptide-53 (porcine, rat) 1-29 (CNP-53 1- 29); prepro-CNP 1-27, rat; prepro-CNP 30-50, porcine, rat; vasonatrin peptide (VNP); and [Tyr°]-C-type natriuretic peptide-22 ([Tyr°]-CNP-22).
- CNP C-type natriuretic peptides
- Calcitonin peptides including, but not limited to, biotinyl-calcitonin, human; biotinyl-calcitonin, rat; biotinyl-calcitonin, salmon; calcitonin, chicken; calcitonin, eel; calcitonin, human; calcitonin, porcine; calcitonin, rat; calcitonin, salmon; calcitonin 1-7, human; calcitonin 8-32, salmon; katacalcin (PDN-21) (C- procalcitonin); and N-proCT (amino-terminal procalcitonin cleavage peptide), human.
- Calcitonin gene related peptides including, but not limited to, acetyl- alpha-CGRP 19-37, human; alpha-CGRP 19-37, human; alpha-CGRP 23-37, human; biotinyl-CGRP, human; biotinyl-CGRP II, human; biotinyl-CGRP, rat; beta-CGRP, rat; biotinyl-beta-CGRP, rat; CGRP, rat; CGRP, human; calcitonin C-terminal adjacent peptide; CGRP 1-19, human; CGRP 20-37, human; CGRP 8-37, human; CGRP II, human; CGRP, rat; CGRP 8-37, rat; CGRP 29-37, rat; CGRP 30-37, rat; CGRP 31-37, rat; CGRP 32-37, rat; CGRP 33-37, rat; CGRP 31-37, rat; CG
- CART peptides including, but not limited to, CART, human; CART 55-102, human; CART, rat; and CART 55- 102, rat.
- Casomorphin peptides including, but not limited to, beta-casomorphin, human; beta-casomorphin 1-3; beta-casomorphin 1-3, amide; beta-casomorphin, bovine; beta- casomorphin 1-4, bovine; beta-casomorphin 1-5, bovine; beta-casomorphin 1-5, amide, bovine; beta-casomorphin 1-6, bovine; [DAIa 2 ] -beta-casomorphin 1-3, amide, bovine; [DAla 2 ,Hyp 4 ,Tyr 5 ]-beta-casomorphin 1-5 amide; [DAla 2 ,DPro 4 ,Tyr 5 ]-beta- casomorphin 1-5, amide; [D Ala 2 ,Tyr 5 ] -beta-casomorphin 1-5, amide, bovine; [DAla 2 ' 4 ,Tyr 5 ]-beta-casomorphin 1
- Chemotactic peptides including, but not limited to, defensin 1 (human) HNP-I (human neutrophil peptide- 1 ); and N-formyl-Met-Leu-Phe.
- Cholecystokinin (CCK) peptides including, but not limited to, caerulein; cholecystokinin; cholecystokinin-pancreozymin; CCK-33, human; cholecystokinin octapeptide 1-4 (non-sulfated) (CCK 26-29, unsulfated); cholecystokinin octapeptide (CCK 26-33); cholecystokinin octapeptide (non-sulfated) (CCK 26-33, unsulfated); cholecystokinin heptapeptide (CCK 27-33); cholecystokinin tetrapeptide (CCK 30- 33); CCK-33, porcine; CR 1 409, cholecystokinin antagonist; CCK flanking peptide (unsulfated); N-acetyl cholecys
- Colony-stimulating factor peptides including, but not limited to, colony- stimulating factor (CSF); GM-CSF; M-CSF; and G-CSF.
- Corticotropin releasing factor (CRF) peptides including, but not limited to, astressin; alpha-helical CRF 12-41; biotinyl-CRF, ovine; biotinyl-CRF, human, rat; CRF, bovine; CRF, human, rat; CRF, ovine; CRF, porcine; [Cys 21 ]-CRF, human, rat; CRF antagonist (alpha-helical CRF 9-41); CRF 6-33, human, rat; [DPro 5 ]-CRF, human, rat; [D-Phe 12 , Nle 21 ' 38 ]-CRF 12-41, human, rat; eosinophilotactic peptide; [Met(0) 2I ]-CRF, ovine; [Nle 21
- Cortistatin peptides including, but not limited to, cortistatin 29; cortistatin 29 (1-13); [Tyr 0 ] -cortistatin 29; pro-cortistatin 28-47; and pro-cortistatin 51-81.
- Cytokine peptides including, but not limited to, tumor necrosis factor alpha (TNF- ⁇ ); and tumor necrosis factor- ⁇ (TNF- ⁇ ).
- Interleukins including but not limited to IL-l ⁇ , IL-I ⁇ , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, and IL-13.
- Interleukin peptides including, but not limited to, interleukin-1 beta 165-181, rat; and interleukin-8 (IL-8, CINC/gro), rat.
- Chemokines including but not limited to RANTES, MCP-I, MIP- l ⁇ , MIP- l ⁇ .
- Dermorphin peptides including, but not limited to, dermorphin and dermorphin analog 1-4.
- Dynorphin peptides including, but not limited to, big dynorphin (prodynorphin 209-240), porcine; biotinyl-dynorphin A (biotinyl-prodynorphin 209-225); [DAIa 2 ,
- Endorphin peptides including, but not limited to, alpha-neo-endorphin, porcine; beta-neo-endorphin; Ac-beta-endorphin, camel, bovine, ovine; Ac-beta- endorphin 1-27, camel, bovine, ovine; Ac-beta-endorphin, human; Ac-beta-endorphin 1-26, human; Ac-beta-endorphin 1-27, human; Ac-gamma-endorphin (Ac-beta- lipotropin 61-77); acetyl-alpha-endorphin; alpha-endorphin (beta-lipotropin 61-76); alpha-neo-endorphin analog; alpha-neo-endorphin 1-7; [Arg 8 ] -alpha-neo-endorphin 1- 8; beta-endorphin (beta-lipotropin 61-91), camel, bovine, ovine; beta-endor
- Endothelin peptides including, but not limited to, endothelin-1 (ET-I); endothelin-l [Biotin-Lys 9 ]; endothelin-1 (1-15), human; endothelin-1 (1-15), amide, human; Ac-endothelin-1 (16-21), human; Ac-[DTrp 16 ]-endothelin-l (16-21), human; [Ala 3 ' ⁇ ]-endothelin-l; [Dprl, Asp 15 ]-endothelin-l; [Ala 2 ]-endothelin-3, human; [Ala 18 ]-endothelin-l, human; [Asn 18 ] -endothelin-1, human; [Res-701-l]-endothelin B receptor antagonist; Suc-[Glu 9 , Ala u ' 15 ]-endothelin-l (8-21), IRL-1620; endothelin-C
- ETa receptor antagonist peptides including, but not limited to, [BQ- 123]; [BE18257B]; [BE-18257A]/[W-7338A]; [BQ-485]; FR139317; PD-151242; and TTA-386.
- ETb receptor antagonist peptides including, but not limited to, [BQ-3020]; [RES-701-3]; and [IRL- 1720].
- Enkephalin peptides including, but not limited to, adrenorphin, free acid; amidorphin (proenkephalin A (104-129)-NH2), bovine; BAM- 12P (bovine adrenal medulla dodecapeptide); BAM-22P (bovine adrenal medulla docosapeptide); benzoyl- Phe- Ala-Arg; enkephalin; [D-AIa 2 , D-Leu 5 ]-enkephalin; [D-AIa 2 , D-Met 5 ]- enkephalin; [DAla 2 ]-Leu-enkephalin, amide; [DAla 2 ,Leu 5 ,Arg 6 ]-enkephalin; [Des- Ty ⁇ DPen ⁇ j-enkephalin; [Des-Tyr',DPen 2 ,Pen 5 ]-enkephalin; [Des-Tyr']-Leu- enkephalin; [D-Pen '
- Ephrin B its analogues and antagonists.
- Fibroneetin peptides including, but not limited to platelet factor-4 (58-70), human; echistatin (Eehis carinatus); E, P ,L selectin conserved region; fibroneetin analog; fibronectin-binding protein; fibrinopeptide A, human; [Tyr°]-fibrinopeptide A, human; fibrinopeptide B, human; [GIu 1 ] -fibrinopeptide B, human; [Tyr 15 ]- fibrinopeptide B, human; fibrinogen beta-chain fragment of 24-42; fibrinogen binding inhibitor peptide; fibroneetin related peptide (collagen binding fragment); fibrinolysis inhibiting factor; FN-C/H-1 (fibroneetin heparin-binding fragment); FN-C/H-V (fibroneetin heparin-binding fragment); heparin-binding peptide; laminin penta peptide, amide
- Galanin peptides including, but not limited to, galanin, human; galanin 1-19, human; preprogalanin 1-30, human; preprogalanin 65-88, human; preprogalanin 89- 123, human; galanin, porcine; galanin 1-16, porcine, rat; galanin, rat; biotinyl-galanin, rat; preprogalanin 28-67, rat; galanin 1-13-bradykinin 2-9, amide; M40, galanin 1-13- Pro-Pro-( Ala-Leu) 2- Ala-amide; C7, galanin 1-13-spantide-amide; GMAP 1-41, amide; GMAP 16-41, amide; GMAP 25-41, amide; galantide; and entero-kassinin.
- Gastrin peptides including, but not limited to, gastrin, chicken; gastric inhibitory peptide (GIP), human; gastrin I, human; biotinyl-gastrin I, human; big gastrin- 1, human; gastrin releasing peptide, human; gastrin releasing peptide 1-16, human; gastric inhibitory polypeptide (GIP), porcine; gastrin releasing peptide, porcine; biotinyl-gastrin releasing peptide, porcine; gastrin releasing peptide 14-27, porcine, human; little gastrin, rat; pentagastrin; gastric inhibitory peptide 1-30, porcine; gastric inhibitory peptide 1-30, amide, porcine; [Tyr°] -gastric inhibitory peptide 23-42, human; and gastric inhibitory peptide, rat.
- GIP gastric inhibitory peptide
- GIP gastric inhibitory peptide
- gastrin I human
- Glucagon peptides including, but not limited to, [Des-His',Glu 9 ]-glucagon, extendin-4, glucagon, human; biotinyl-glucagon, human; glucagon 19-29, human; glucagon 22-29, human; Des-His 1 - [GIu 9 ] -glucagon, amide; glucagon-like peptide 1, amide (preproglucagon 72-107, amide); glucagon-like peptide 1 (preproglucagon 72- 108), human; glucagon-like peptide 1 (7-36) (preproglucagon 78-107, amide); glucagon-like peptide II, rat; biotinyl-glucagon-like peptide- 1 (7-36) (biotinyl- preproglucagon 78-107, amide); glucagon-like peptide 2 (preproglucagon 126-159), human; oxynto
- Gn-RH associated peptides including, but not limited to, Gn-RH associated peptide 25-53, human; Gn-RH associated peptide 1-24, human; Gn-RH associated peptide 1-13, human; Gn-RH associated peptide 1-13, rat; gonadotropin releasing peptide, follicular, human; [Tyr°]-GAP ([Tyr°] -Gn-RH Precursor Peptide 14-69), human; and proopiomelanocortin (POMC) precursor 27-52, porcine.
- GAP Gn-RH associated peptides
- Growth factor peptides including, but not limited to, cell growth factors; epidermal growth factors; tumor growth factor; TGF-alpha, human; TGF-alpha, from other mammalian species TGF-beta; alpha-TGF 34-43; human EGF (epidermal growth factor); acidic fibroblast growth factor; basic fibroblast growth factor; basic fibroblast growth factor 13-18; basic fibroblast growth factor 120-125; brain derived acidic fibroblast growth factor 1-11; brain derived basic fibroblast growth factor 1-24; brain derived acidic fibroblast growth factor 102-111; [Cys(Acm 20 ' 31 )] -epidermal growth factor 20-31; epidermal growth factor receptor peptide 985-996; insulin-like growth factor (IGF)-I, chicken; IGF-I, rat; IGF-I, human; Des (1-3) IGF-I, human; R3 IGF-I, human; R3 IGF-I, human; long R3 IGF-I
- Growth hormone peptides including, but not limited to, growth hormone (hGH), human; growth hormone 1-43, human; growth hormone 6-13, human; growth hormone releasing factor, human; growth hormone releasing factor, bovine; growth hormone releasing factor, porcine; growth hormone releasing factor 1-29, amide, rat; growth hormone pro-releasing factor, human; biotinyl-growth hormone releasing factor, human; growth hormone releasing factor 1-29, amide, human; [D-AIa 2 ] -growth hormone releasing factor 1-29, amide, human; [N-Ac-Tyr 1 , D-Arg 2 ]-GRF 1-29, amide; [His , NIe 27 ] -growth hormone releasing factor 1-32, amide; growth hormone releasing factor 1-37, human; growth hormone releasing factor 1-40, human; growth hormone releasing factor 1-40, amide, human; growth hormone releasing factor 30-44, amide, human; growth hormone releasing factor, mouse; growth hormone releasing factor, ovine; growth hormone releasing factor
- GTP -binding proteins and fragment peptides thereof including, but not limited to, [Arg 8 ]-GTP-binding protein fragment, Gs alpha; GTP-binding protein fragments, of the G beta family; GTP-binding protein fragments, of the Ggamma family; GTP- binding protein fragment, Galpha; GTP-binding protein fragments, Go alpha a and b; GTP-binding protein fragment, Gs alpha; and GTP-binding protein fragments, G alpha il, G alpha i2, G alpha i3; GTP-binding protein fragment, Golf alpha; GTP- binding protein fragment, Gz alpha; GTP-binding protein fragment, Gq alpha.
- Guanylin peptides including, but not limited to, guanylin, human; guanylin, rat; and uroguanylin.
- Inhibin peptides including, but not limited to, inhibin, bovine; inhibin, alpha- subunit 1-32, human; [Tyr ]-inhibin, alpha-subunit 1-32, human; seminal plasma inhibin-like peptide, human; [Tyr°]-seminal plasma inhibin-like peptide, human; inhibin, alpha-subunit 1-32, porcine; and [Tyr 0 ] -inhibin, alpha-subunit 1-32, porcine.
- Interferon peptides including, but not limited to, alpha interferon species (e.g., alphal, alpha2, alpha2a, alpha2b, alpha2c, alpha2d, alpha3, alpha4, alpha4a, alpha4b, alpha5, alpha ⁇ , alpha74, alpha76, alphaA, alphaB, alphaC,, alphaCl, alphaD, alphaE, alphaF, alphaG, alphaG, alphaH, alphal, alphaJl, alphaJ2, alphaK, alphaL); interferon beta species (e.g., betala); interferon gamma species (e.g., gammala, gammalb); interferon epsilon; interferon tau; interferon omega or any analogues of interferon omega.
- alpha interferon species e.g., alphal, alpha2, alpha2a, alpha2b, alpha2c, alpha2d
- Insulin peptides including, but not limited to, insulin, human; insulin, porcine; IGF-I, human; insulin-like growth factor II (69-84); pro-insulin-like growth factor II (68-102), human; pro-insulin-like growth factor II (105-128), human; [Asp B28 ]- insulin, human; [Lys ]-insulin, human; [Leu ]-insulin, human; [VaI ]-insulin, human; [Ala B28 ] -insulin, human; [Asp B28 , Pro B29 ]-insulin, human; [Lys B28 , Pro B29 ]- insulin, human; [Leu B28 , Pro B29 ]-insulin, human; [Val B28 , Pro B29 ]-insulin, human; [Ala B28 , Pro B29 ]-insulin, human; [Gl/ 2 ⁇ -insulin, human; [Gl/ 21 Gln B3 ]-insulin, human
- Laminin peptides including, but not limited to, laminin; alpha 1 (I)-CB3 435- 438, rat; and laminin binding inhibitor.
- Leptin peptides including, but not limited to, leptin 93-105, human; leptin 22- 56, rat; Tyr-leptin 26-39, human; and leptin 116-130, amide, mouse.
- Leucokinin peptides including, but not limited to, leucomyosuppressin (LMS); leucopyrokinin (LPK); leucokinin I; leucokinin II; leucokinin III; leucokinin IV; leucokinin VI; leucokinin VII; and leucokinin VIII.
- LMS leucomyosuppressin
- LPK leucopyrokinin
- leucokinin I leucokinin II
- leucokinin III leucokinin IV
- leucokinin VI leucokinin VI
- leucokinin VII leucokinin VII
- leucokinin VIII leucokinin VIII.
- Luteinizing hormone-releasing hormone peptides including, but not limited to, antide; Gn-RH II, chicken; luteinizing hormone-releasing hormone (LH-RH) (GnRH); biotinyl-LH-RH; cetrorelix (D-20761); [D-Ala 6 ]-LH-RH; [Ghi 8 ]-LH-RH (Chicken
- Mastoparan peptides including, but not limited to, mastoparan; mas7; mas8; mas 17; and mastoparan X.
- Mast cell degranulating peptides including, but not limited to, mast cell degranulating peptide HR-I; and mast cell degranulating peptide HR-2.
- MSH Melanocyte stimulating hormone
- alpha-melanocyte stimulating hormone [Ac-Cys 4 ,DPhe 7 ,Cys 10 ] alpha-MSH 4-13, amide; alpha-melanocyte stimulating hormone; alpha-MSH, free acid; beta-MSH, porcine; biotinyl-alpha-melanocyte stimulating hormone; biotinyl-[Nle , D-Phe 7 ] alpha-melanocyte stimulating hormone;
- MSH amide
- beta-MSH human
- gamma-MSH gamma-MSH
- Morphiceptin peptides including, but not limited to, morphiceptin (beta- casomorphin 1-4 amide); [D-Pro ] -morphiceptin; and [N-MePhe 3 ,D-Pro 4 ]- morphiceptin.
- Motilin peptides including, but not limited to, motilin, canine; motilin, porcine; biotinyl-motilin, porcine; and [Leu 13 ]-motilin, porcine.
- Neuro-peptides including, but not limited to, Ac-Asp-Glu; achatina cardio- excitatory peptide- 1 (ACEP-I) (Achatina fulica); adipokinetic hormone (AKH) (Locust); adipokinetic hormone (Heliothis zea and Manduca sexta); alytesin; Tabanus atratus adipokinetic hormone (Taa-AKH); adipokinetic hormone II (Locusta migratoria); adipokinetic hormone II (Schistocera gregaria); adipokinetic hormone III (AKH-3); adipokinetic hormone G (AKH-G) (Gryllus bimaculatus); allatotropin (AT) (Manduca sexta); allatotropin 6-13 (Manduca sexta); APGW amide (Lymnaea stagnalis); buccalin; cerebellin; [Des-Ser'j-cere
- Neuropeptide Y (NPY) peptides including, but not limited to, [Leu 31 ,Pro 34 ]- neuropeptide Y, human; neuropeptide F (Moniezia expansa); B1BP3226 NPY antagonist; Bis (31/31') ⁇ [Cys 31 , Trp 32 , Nva 34 ] NPY 31-36 ⁇ ; neuropeptide Y, human, rat; neuropeptide Y 1-24 amide, human; biotinyl-neuropeptide Y; [D-Tyr 27 ' 36 , D- ThT 32 J-NPY 27-36; Des 10-17 (cyclo 7-21) [Cys 7 ' 21 , Pro 34 ]-NPY; C2-NPY; [Leu 31 ,
- neuropeptide Y human; neuropeptide Y, free acid, human; neuropeptide Y, free acid, porcine; prepro NPY 68-97, human; N-acetyl-[Leu 28 , Leu 31 ] NPY 24-36; neuropeptide Y, porcine; [D-Trp 32 ] -neuropeptide Y, porcine; [D-Trp 32 ] NPY 1-36, human; [Leu 17 ,DTrp 32 ] neuropeptide Y, human; [Leu 31 , Pro 34 ]-NPY, porcine; NPY 2- 36, porcine; NPY 3-36, human; NPY 3-36, porcine; NPY 13-36, human; NPY 13-36, porcine; NPY 16-36. porcine; NPY 18-36, porcine; NPY 20-36; NFY 22-36; NPY 26-
- Neurotropic factor peptides including, but not limited to, glial derived neurotropic factor (GDNF); brain derived neurotropic factor (BDNF); and ciliary neurotropic factor (CNTF).
- GDNF glial derived neurotropic factor
- BDNF brain derived neurotropic factor
- CNTF ciliary neurotropic factor
- Ligands of the Notch receptor including, but not limited to the Delta-like- 1,
- Orexin peptides including, but not limited to, orexin A; orexin B, human; orexin B, rat, mouse.
- Opioid peptides including, but not limited to, alpha-casein fragment 90-95;
- BAM- 18P casomokinin L; casoxin D; crystalline; DALDA; dermenkephalin (deltorphin) (Phylomedusa sauvagei); [D-AIa 2 ] -deltorphin I; [D-AIa 2 ] -deltorphin II; endomorphin-1; endomorphin-2; kyoto ⁇ hin; [DArg 2 ]-kyotorphin; morphin tolerance peptide; morphine modulating peptide, C-terminal fragment; morphine modulating neuropeptide (A-18-F-NH2); nociceptin [orphanin FQ] (ORLl agonist); TIPP; Tyr- MIF-I; Tyr- W-MIF-I ; valorphin; LW-hemo ⁇ hin-6, human; Leu-valorphin-Arg; and Z-Pro-D-Leu.
- Oxytocin peptides including, but not limited to, [Asu 6 ]-oxytocin; oxytocin; biotinyl-oxytocin; [Thr , GIy ]-oxytocin; and tocinoic acid ([He ]-pressinoic acid).
- PACAP pituitary adenylating cyclase activating peptide
- PACAP 1-27, human, ovine, rat PACAP (l-27)-Gly-Lys-Arg- NH2, human; [Des-Gln 16 ] -PACAP 6-27, human, ovine, rat; PACAP38, frog; PACAP27-NH2, human, ovine, rat; biotinyl-PACAP27-NH2, human, ovine, rat; PACAP 6-27, human, ovine, rat; PACAP38, human, ovine, rat; biotinyl-PACAP38, human, ovine, rat; PACAP 6-38, human, ovine, rat; PACAP27-NH2, human, ovine, rat; biotinyl-PACAP27-NH2, human, ovine, rat; PACAP 6-27, human, ovine, rat; PACAP 6-27, human, ovine, rat; PA
- Pancreastatin peptides including, but not limited to, chromostatin, bovine; pancreastatin (hPST-52) (chromogranin A 250-301, amide); pancreastatin 24-52 (hPST-29), human; chromogranin A 286-301, amide, human; pancreastatin, porcine; biotinyl-pancreastatin, porcine; [NIe 8 ] -pancreastatin, porcine; [Tyr°,Nle 8 ]- pancreastatin, porcine; [Tyr 0 ] -pancreastatin, porcine; parastatin 1-19 (chromogranin A 347-365), porcine; pancreastatin (chromogranin A 264-314-amide, rat; biotinyl- pancreastatin (biotinyl-chromogranin A 264-314-amide; [Tyr 0 ] -pancreastatin, rat; pancreastat
- Pancreatic polypeptides including, but not limited to, pancreatic polypeptide, avian; pancreatic polypeptide, human; C-fragment pancreatic polypeptide acid, human; C-fragment pancreatic polypeptide amide, human; pancreatic polypeptide (Rana temporaria); pancreatic polypeptide, rat; and pancreatic polypeptide, salmon.
- Parathyroid hormone peptides including, but not limited to, [Asp 76 ]- parathyroid hormone 39-84, human; [Asp 76 ] -parathyroid hormone 53-84, human; hormone 64-84, human; [Asn , Leu 18 ] -parathyroid hormone 1-34, human; [Cys 5>28 ] -parathyroid hormone 1-34, human; hypercalcemia malignancy factor 1-40; [Leu ]-parathyroid hormone 1-34, human; [Lys(biotinyl) 13 , NIe 8 ' 18 , Tyr 34 ] -parathyroid hormone 1-34 amide; [NIe 8 ' 18 , Tyr 34 ] -parathyroid hormone 1-34 amide; [NIe 8 ' 18 , Tyr 34 ] -parathyroid hormone 3-34 amide, bovine; [NIe 8 ' 18 , Tyr 34 ] -parathyroid hormone 1-34, human; [NIe 8 ' 18 , Tyr 34 ]
- Parathyroid hormone (PTH)-related peptides including, but not limited to, PTHrP ([Tyr 36 ]-PTHrP 1-36 amide), chicken; hHCF-(l-34)-NH2 (humoral hypercalcemic factor), human; PTH-related protein 1-34, human; biotinyl-PTH-related protein 1-34, human; [Tyr 0 ] -PTH-related protein 1-34, human; [Tyr 34 ] -PTH-related protein 1-34 amide, human; PTH-related protein 1-37, human; PTH-related protein 7- 34 amide, human; PTH-related protein 38-64 amide, human; PTH-related protein 67- 86 amide, human; PTH-related protein 107-111, human, rat, mouse; PTH-related protein 107-111 free acid; PTH-related protein 107-138, human; and PTH-related protein 109- 111 , human.
- PTHrP [Tyr 36
- Peptide T peptides including, but not limited to, peptide T; [D-Ala']-peptide T; and [D-AIa 1 ]-peptide T amide.
- Prolactin-releasing peptides including, but not limited to, prolactin-releasing peptide 31 , human; prolactin-releasing peptide 20, human; prolactin-releasing peptide
- Peptide YY (PYY) peptides including, but not limited to, PYY, human; PYYY
- Renin substrate peptides including, but not limited to, acetyl, angiotensinogen
- Secretin peptides including, but not limited to, secretin, canine; secretin, chicken; secretin, human; biotinyl-secretin, human; secretin, porcine; and secretin, rat.
- Somatostatin GEF peptides including, but not limited to, BIM-23027; biotinyl-somatostatin; biotinylated cortistatin 17, human; cortistatin 14, rat; cortistatin
- NTB NTB (Naltriben); [NIe 8 ] -somatostatin 1-28; octreotide (SMS 201-995); prosomatostatin 1-32, porcine; [Tyr°]-somatostatin; [Tyr'j-somatostatin; [Tyr 1 ]- somatostatin 28 (1-14); [Tyr n ]-somatostatin; [Tyr°, D-Trp 8 ] -somatostatin; somatostatin; somatostatin antagonist; somatostatin-25; somatostatin-28; somatostatin
- biotinyl-somatostatin-28 [Tyr°]-somatostatin-28; [Leu 8 , D-Trp 22 , Tyr 25 ]- somatostatin-28; biotinyl-[Leu 8 , D-Trp 22 , Tyr 25 ]-somatostatin-28; somatostatin-28 (1-
- Substance P peptides including, but not limited to, G protein antagonist-2; Ac-
- Tachykinin peptides including, but not limited to, [Ala , beta-Ala ] neurokinin A 4-10; eledoisin; locustatachykinin I (Lom-TK-I) (Locusta migratoria); locustatachykinin II (Lom-TK-II) (Locusta migratoria); neurokinin A 4-10; neurokinin A (neuromedin L, substance K); neurokinin A, cod and trout; biotinyl-neurokinin A (biotinyl-neuromedin L, biotinyl-substance K); [Tyr°] -neurokinin A; [Tyr 6 ]-substance K; FR64349; [Lys 3 , Gly 8 -(R)-gamma-lactam-Leu 9 ]-neurokinin A 3-10; GR83074; GR87389; GR94800; [Beta- Ala 8
- Thyrotropin-releasing hormone (TRH) peptides including, but not limited to, biotinyl-thyrotropin-releasing hormone; [GIu ]-TRH; His-Pro-diketopiperazine; [3- Me-His 2 ]-TRH; pGlu-Gln-Pro-amide; pGlu-His; [Phe 2 ]-TRH; prepro TRH 53-74; prepro TRH 83-106; prepro-TRH 160-169 (Ps4, TRH-potentiating peptide); prepro- TRH 178-199; thyrotropin-releasing hormone (TRH); TRH, free acid; TRH-SH Pro; and TRH precursor peptide.
- TRH Thyrotropin-releasing hormone
- Toxin peptides including, but not limited to, omega-agatoxin TK; agelenin, (spider, Agelena opulenta); apamin (honeybee, Apis mellifera); calcicudine (CaC) (green mamba, Dedroaspis angusticeps); calciseptine (black mamba, Dendroaspis polylepis polylepis); charybdotoxin (ChTX) (scorpion, Leiurus quinquestriatus var.
- Immunotoxins consist in toxins covalently linked to an antibody which acts as a homing system, specifically targeting the toxin to those cells which one wishes to eliminate by the means of an antibody (polyclonal or monoclonal) directed against a molecule, or a group of molecules, carried at the surface of the targeted cells.
- Toxins including, but not limited to those cited above, can be used to this effect.
- the invention described in this patent application may be used to deliver such immunotoxins to the colon.
- the antibody may be replaced by a small molecule that similarly acts to target the toxin to a chosen group of cells.
- Vasoactive intestinal peptides including, but not limited to, VIP, human, porcine, rat, ovine; VIP-Gly-Lys-Arg-NH2; biotinyl-PHI (biotinyl-PHI-27), porcine; [GIp 16 ] VIP 16-28, porcine; PHI (PHI-27), porcine; PHI (PHI-27), rat; PHM- 27 (PHI), human; prepro VIP 81-122, human; preproVIP/PHM 111-122; prepro VIP/PHM 156-170; biotinyl-PHM-27 (biotinyl-PHI), human; vasoactive intestinal contractor (endothelin-beta); vasoactive intestinal octacosa-peptide, chicken; vasoactive intestinal peptide, guinea pig; biotinyl-VIP, human, porcine, rat; vasoactive intestinal peptide 1-12, human
- Virus related peptides including, but not limited to, fluorogenic human CMV protease substrate; HCV core protein 59-68; HCV NS4A protein 18-40 (JT strain);
- HCV NS4A protein 21-34 JT strain
- hepatitis B virus receptor binding fragment hepatitus B virus pre-S region 120-145
- herpes virus inhibitor 2 HIV envelope protein fragment 254-274
- HIV gag fragment 129-135 HIV substrate
- R15K HIV-I inhibitory peptide T20; T21; V3 decapeptide P 18-110; and virus replication inhibiting peptide.
- Proteins of the Wnt family and fragments thereof. While certain analogs, fragments, and/or analog fragments of the various polypeptides have been described above, it is to be understood that other analogs, fragments, and/or analog fragments that retain all or some of the activity of the particular polypeptide, or on the contrary that act as an antagonist thereby preventing its action, may also be useful in embodiments of the present invention. Analogs may be obtained by various means, as will be understood by those skilled in the art. For example, certain amino acids may be substituted for other amino acids in a polypeptide without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules.
- polypeptide drug As the interactive capacity and nature of a polypeptide drug defines its biological functional activity, certain amino acid sequence substitutions can be made in the amino acid sequence and nevertheless remain a polypeptide with like properties, or on the contrary confer to this analogue antagonistic activity that interferes with or blocks the action of the natural product.
- small molecules whether peptidomimetic or not, natural or synthetic, may be able to substitute for the proteins and peptides cited above and have similar activity by binding to their receptors. On the contrary, such small molecules may block or interfere with the activity of the proteins and peptides cited above by various mechanisms, including, but not limited to, preventing their interaction with their cognate receptors. Additionally, many of the proteins cited above act as initiators of signaling pathways.
- An embodiment of this invention is the use of chemical molecules (peptides, peptidomimetics, or any other natural or synthetic molecule of any chemical nature) as activators or inhibitors of these signaling pathways.
- Examples of this strategy are the use of inhibitors of gamma-secretase to inhibit the Notch signaling pathway, or inhibitors of the interaction between beta-catenin and Tcf transcription factors to inhibit the Wnt-beta-catenin pathway, both of which are involved in colorectal cancer.
- the active agents can also be in the form of oligonucleotides, including oligoribonucleotides, oligodeoxyribomicleotides and derivatives thereof useful for prophylactic, palliative or therapeutic purposes, including gene therapy and the treatment of cancer, such as colon cancer.
- An oligonucleotide is a polymer of a repeating unit generically known as a nucleotide.
- An unmodified (naturally occurring) nucleotide has three components: (1) a nitrogen-containing heterocyclic base linked by one of its nitrogen atoms to (2) a 5- pentofuranosyl sugar and (3) a phosphate esterified to one of the 5' or 3' carbon atoms of the sugar.
- the phosphate of a first nucleotide is also esterified to an adjacent sugar of a second, adjacent nucleotide via a 3 '-5' phosphate linkage.
- Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside.
- the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. The respective ends of this linear polymeric structure can be further joined to form a circular structure, however, within the context of the invention, open linear structures are generally preferred.
- Oligonucleotides can include nucleotide sequences sufficient in identity and number to effect specific hybridization with a particular nucleic acid. Such oligonucleotides which specifically hybridize to a portion of the sense strand of a gene are commonly described as “antisense.”
- antisense means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleotides.
- adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds.
- oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position.
- the oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other.
- oligonucleotide refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent intersugar (backbone) linkages as well as oligonucleotides having non-naturally- occurring portions which function similarly. They may be single or double stranded.
- oligonucleotides formulated in the compositions of the invention may be from about 8 to about 100 nucleotides in length, more preferably from about 10 to about so nucleotides in length, and most preferably from about 10 about 25 nucleotides in length.
- Oligonucleotides that are formulated in the compositions of the invention include antisense compounds and other bioactive oligonucleotides. A discussion of antisense oligonucleotides and some desirable modifications can be found in De Mesmaeker et al. (Ace. Chem. Res., 1995, 28, 366).
- antisense compounds include antisense oligonucleotides, antisense peptide nucleic acids (PNAs), small interfering RNAs, short hairpin RNAs, ribozymes and external guide sequences (EGSs).
- PNAs antisense peptide nucleic acids
- small interfering RNAs small interfering RNAs
- short hairpin RNAs short hairpin RNAs
- ribozymes external guide sequences
- mRNA to be interfered with include all vital functions such as translocation of the RNA to the site for protein translation, actual translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, turnover or degradation of the mRNA and possibly even independent catalytic activity which may be engaged in by the RNA.
- the overall effect of such interference with mRNA function is modulation of the expression of a protein, wherein “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of the protein. In the context of the present invention, inhibition is the preferred form of modulation of gene expression.
- Antisense compounds can exert their effect by a variety of means.
- One such means is the antisense-mediated direction of an endogenous nuclease, such as RNase H in eukaryotes or RNase P in prokaryotes, to the target nucleic acid (Chiang et al., J. Biol. Chem., 1991, 266, 18162; Forster et al., Science, 1990, 249, 783).
- EVS External Guide Sequences
- Another means involves covalently linking a synthetic moiety having nuclease activity to an oligonucleotide having an antisense sequence, rather than relying upon recruitment of an endogenous nuclease.
- Synthetic moieties having nuclease activity include, but are not limited to, enzymatic RNAs, lanthanide ion complexes, and the like (Haseloff et al., Nature, 1988, 334, 585; Baker et al., J. Am. Chem. Soc, 1997, 119, 8749).
- antisense compound also includes ribozymes, synthetic RNA molecules and derivatives thereof that catalyze highly specific endoribonuclease reactions (see, generally, U.S. Pat. No. 5,543,508 to Haseloff et al. and U.S. Pat. No. 5,545,729 to Goodchild et al.).
- RNAs or DNAs that encode such RNAs leading to the modulation of gene expression by the mechanism of RNA interference.
- RNAs include, but are not limited to, short interfering RNAs, consisting of double stranded RNAs of less than 50 base pairs, typically 21 or 29 nucleotides in length with the addition at either of their extremities of other chemical molecules (including deoxyribonucleotides, natural or modified), as well as short hairpin RNAs (or DNA molecules including plasmids and viruses of any nature leading to their production, in vitro or in vivo) that act by RNA interference.
- This also includes any DNA or RNA molecule, single or double strand, that leads in cells to RNA interference.
- the antisense compounds formulated in the compositions of the invention (1) can be from about 8 to about 100 nucleotides in length, more preferably from about 10 to about 30 nucleotides in length, (2) single or double stranded, (3) are targeted to a nucleic acid sequence required for the expression of a gene from a mammal, including a human, and (4), when contacted with cells expressing the target gene, modulate its expression. Due to the biological activity of the gene product encoded by the target gene, modulation of its expression has the desirable result of providing specific prophylactic, palliative and/or therapeutic effects.
- nucleobase sequence of an oligonucleotide or other antisense compound need not be 100% complementary to its target nucleic acid sequence to be specifically hybridizable.
- An antisense compound is specifically hybridizable to its target nucleic acid when there is a sufficient degree of complementarity to avoid non-specific binding of the oligonucleotide to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, or, in the case of in vitro assays, under assay conditions.
- bioactive oligonucleotides include aptamers and molecular decoys.
- the term is meant to refer to any oligonucleotide (including a peptide- nucleic acid or PNA) that (1) provides a prophylactic, palliative or therapeutic effect to an animal in need thereof and (2) acts by a non-antisense mechanism, i.e., by some means other than by hybridizing to a nucleic acid.
- PNA peptide- nucleic acid
- the name aptamer has been coined by Ellington et al.
- nucleic acids and oligonucleotides that may be classified as aptamers may be readily purified or isolated via affinity chromatography using columns that bear immobilized ligand.
- Aptamers may be nucleic acids that are relatively short to those that are as large as a few hundred nucleotides.
- RNA aptamers that are 155 nucleotides long and that bind dyes such as Cibacron Blue and Reactive Blue 4 with good selectivity have been reported (Ellington et al., Nature, 1990, 346, 818). While RNA molecules were first referred to as aptamers, the term as used in the present invention refers to any nucleic acid or oligonucleotide that exhibits specific binding to small molecule ligands including, but not limited to, DNA, RNA, DNA derivatives and conjugates, RNA derivatives and conjugates, modified oligonucleotides, chimeric oligonucleotides, and gapmers (see, e.g., U.S. Pat. No. 5,523,3B9, to Ecker et al., issued Jun. 4, 1996 and incorporated herein by reference).
- Molecular decoys are short double-stranded nucleic acids (including single- stranded nucleic acids designed to "fold back" on themselves) that mimic a site on a nucleic acid to which a factor, such as a protein, binds. Such decoys are expected to competitively inhibit the factor; that is, because the factor molecules are bound to an excess of the decoy, the concentration of factor bound to the cellular site corresponding to the decoy decreases, with resulting therapeutic, palliative or prophylactic effects. Methods of identifying and constructing decoy molecules are described in, e.g., U.S. Pat. No. 5,716,780 to Edwards et al.
- Another type of bioactive oligonucleotide is an RNA-DNA hybrid molecule that can direct gene conversion of an endogenous nucleic acid (Cole-Strauss et al., Science, 1996, 273, 1386).
- Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphoro-dithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'- alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalklyphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'.
- oligonucleotides can be formulated into the drug delivery system of the invention and used for prophylactic or therapeutic purposes.
- the oligonucleotides can be stabilized through complexation, for example, with cationic lipids such as Lipoplexe or cationic polymers such as Polyplexe.
- Medical imaging is the non-invasive or non-surgical visualization of internal organs or processes.
- Representative diagnostic methods include X-rays, magnetic resonance imaging (MRI), radionuclides or nuclear medicine, and ultrasound.
- Radionuclides are nuclei that decay by dissipating excess energy (parent) to become stable (daughter) by energy emission in form of particulate or electromagnetic radiation.
- Fluoroscopy is a fluorescent screen that detects gamma or X-rays, which are imaged by a TV camera to afford real time images of organs in motion by using contrast agents, such as PCTA.
- CAT - Computed axial tomography - takes advantage of small differences in tissue radiographic density to create an image. The colon is often imaged using a lower GI series of a barium enema to conduct a radiographic study of the large bowel colon and rectum.
- Radiolabeled compounds include iodine radiolabels, such as iobenguane sulfate 1 I, sodium 123 iodine, sodium 131 iodine, and indium labels, such as 111 In radiolabels, indium chloride, and indium satumomabpendetide.
- Imaging contrast agents include iron-containing contrast agents such as ferumoxides and dentritic gadolinium.
- the present invention can be used to deliver to the colon agents that enable or facilitate the visualization of structures, lesions, cells carrying defined cell surface or intracellular molecules by any imagining technique including, but not restricted to, radiograph ⁇ " , radio-tomography, magnetic resonance imaging (MRI), ultrasonic, positron emission tomography (PET scan), or any other form of imaging technique using radio-magnetic waves of whatever wavelength.
- radiograph ⁇ radio-tomography
- MRI magnetic resonance imaging
- PET scan positron emission tomography
- small molecules or antibodies that recognize ccil-surface structures of colon cancer cells can be labeled with radionuclides such as "Technecium and used to detect tumor cells and metastases of ⁇ arious sizes Including micro-metastases.
- Pectin beads can be prepared using methods known to those of skill in the art, including by mixing the active agent(s) in a pectin solution, and gelling the pectin anionic moieties with a divalent cation such as divalent zinc, for example, in the form of a zinc acetate solution.
- the gellation is typically done by stirring a solution, suspension or dispersion of the active agent, in one embodiment, ⁇ -lactamase Ll, and pectin, adjusting the pH of the solution if necessary, and adding this solution dropwise to a zinc acetate solution under agitation.
- the active agent(s) are not adversely affected by other metal ions
- divalent or trivalent metal ions other than zinc can be used.
- Suitable technologies for adding the pectin solution dropwise to the zinc acetate solution are known to those of skill in the art; and include the multi-nozzle system from Nisco Engineering AG and other relevant technologies to produce drops from a pectin solution.
- the pectin drops undergo a gelification process, ideally during a predetermined time to obtain the best encapsulation yield and subsequent release efficiency.
- the concentration of the pectin solution is advantageously from around 4 to around 10% (w/v), preferably around 4 to around 7%
- the metal cation, such as zinc acetate, solution is advantageously from about 2 to about 20% (w/v), preferably from about 5 to about 15%. More preferably, the pectin solution is about 5% (w/v), the zinc acetate solution is about 12% (w/v).
- the pectin beads are advantageously stirred in the metal cation, such as zinc acetate, solution, at a pH of about 6, at room temperature, under slow agitation, for at least around 12 minutes up to around 20 hours, preferably from around 20 minutes to around 2 hours.
- the metal cation such as zinc acetate, solution
- the beads can then then be recollected and rinsed in distilled water, ideally until the conductivity of the rinsing solution reaches a plateau.
- Rinsing is preferably done at least twice or under a continuous process to minimize the amount of residual zinc acetate recovered in the rinsing solution.
- the rinsed beads can then be collected and can be subjected to a drying process using methods known to those of skill in the art, including heated incubator or fluidized bed technologies.
- the beads are typically dried at a temperature of between around 20 and around 40 0 C for around 30 min to around 24 hours, preferably at around 35 0 C overnight. Drying is preferably performed until the weight of the beads reaches a plateau.
- the diameter of the particles can be finely tuned using needles of appropriate internal diameter to form the pectin drops added to the zinc acetate solution.
- the beads are preferably between about 600 and 1500 ⁇ m in diameter.
- the encapsulation yields are typically between 50 and 100%, measured in terms of enzymatic activity.
- the pectin beads can be collected, and combined with appropriate excipients and formulated into a variety of oral drug delivery systems.
- the beads can be combined with a solid excipient, and tableted, or included in a capsule.
- the pectin beads can also be combined with liquid/gel excipients which do not degrade the pectin beads, and the mixture/dispersion can be incorporated into a capsule, such as a gel-cap.
- the tablets or capsules can be coated, if desired, with a suitable enteric coating so as to assist in passing through the stomach without degradation.
- the pH in the stomach is of the order of 1 to 3 but it increases in the small intestine and the colon to attain values close to 7 (Hovgaard L. et al. (1996) Current Applications of Polysaccharides in Colon Targeting, Critical Reviews in Therapeutic Drug Carrier Systems, 13, 185).
- the drug delivery systems in the form of tablets, gelatin capsules, spheroids and the like, can reach the colon, without being exposed to these variations in pH, by coating them with a pH-dependent polymer, insoluble in acidic pH but soluble in neutral or alkaline pH (Kinget et al. op. eit).
- the polymers most currently used for this purpose are derivatives of methaerylic acid, Eudragit ® L and S (Ashford M. et al. (1993), An in vivo investigation of the suitability of pH-dependent polymers for colonic targeting, International Journal of Pharmaceutics, 95, 193 and 95, 241; and David A. et a (1997) Acrylic polymers for colon-specific drug delivery, S.T.P.
- the drug delivery systems are administered in an effective amount suitable to provide the adequate degree of treatment or prevention of the disorders for which the compounds are administered.
- the efficient amounts of these compounds are typically below the threshold concentration required to elicit any appreciable side effects.
- the compounds can be administered in a therapeutic window in which some the disorders are treated and certain side effects are avoided.
- the effective dose of the compounds described herein is sufficient to provide the desired effects in the colon but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects elsewhere in the body.
- effective doses are at very low concentrations, where maximal effects are observed to occur, with minimal side effects, and this is optimized by targeted colonic delivery of the active agents.
- the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24-hour period.
- the drug delivery systems described herein can be used to treat those types of conditions and disorders for which colonic delivery is appropriate.
- the disorders are those that result from exposure of the colon to antibiotics, such as diarrhea, modification of the commensal flora and the development of bacterial resistance to antibiotics.
- the drug delivery systems contain agents which inactivate antibiotics, and the active principles can be administered in a therapeutically effective dosage to a patient who has been, is being, or will be treated with one or several antibiotics.
- the metallo-dependent enzyme is an enzyme other than one which inactivates antibiotics
- such enzyme can be administered to treat the specific disorders treated by such enzymes.
- the drug delivery systems are administered to a patient who suffers from colon cancer.
- the drug delivery systems include one or more antitumor agents, and the systems are administered in a therapeutically effective dosage to a patient who is suffering from colon cancer.
- the cancer can be present at another location in the body, and the drug delivery systems can be used to by-pass the stomach and its concomitant degradation of certain antitumor agents, so as to avoid the need to use intramuscular or intravenous administration of these agents.
- the drug delivery systems are administered to a patient who suffers from a colonic disorder such as Chrohn's disease, ulcerative colitis, irritable bowel syndrome, diarrhea, or constipation.
- the drug delivery systems include agents which treat or prevent these disorders, and the systems can be administered in a therapeutically effective dosage to a patient who is suffering from such a disorder.
- the drug delivery systems are used to administer peptide or protein-based active agents, such as insulin, antibodies, and the like, or oligonucleotide-based therapeutics, such as antisense or RNA interference therapy, so that the agents pass through the stomach without being digested.
- the drug delivery systems include these protein/peptide/oligonucleotide-based agents, and the systems can be administered in a therapeutically effective dosage to a patient in need of treatment with these agents, without the need to administer these agents via subcutaneous or intravenous injection.
- the drug delivery systems are used to administer diagnostic agents to the colon.
- the drug delivery systems include diagnostic agents, such as imaging contrast agents, and the systems are administered in a diagnostically effective dosage to a patient who will be subjected to a diagnostic assay for diagnosis of a colonic disorder.
- a stock solution of nitrocefin was obtained by dissolving nitrocefin dried powder at a concentration of 10 mM in dimethylsulfoxide (DMSO). The stock solution was stored at -20 0 C and diluted 100-fold immediately prior to use in 50 mM sodium phosphate buffer (Hepes buffer) pH 7.0 containing 0.1 mg/ml bovine serum albumin (BSA). Buffer selection is described in Table I.
- Example 2 Instability of ⁇ -lactamase Ll In Original Pectin Mix and Effect of Metallic Counter-Ion
- ⁇ -lactamase Ll (Eurogentec, Belgium, approx. lOmg/mL as determined by ⁇ BCA assay) was mixed to 1Og of a 6% pectin solution (Low methoxylated amidated pectin (Unipectine), Texturant Systems, cat# OGl 75C) made in water; the pH of the pectin solution was not adjusted.
- the pectin/ ⁇ -lactamase Ll mixture was added drop- wise over a period of 2 minutes using a peristaltic pump and a needle of 0.8 mm inner diameter to a beaker containing 40 ml of calcium chloride (6%) under agitation (200 rpm) at room temperature.
- beads were recovered by filtration and washed 3 times in 200 ml of purified water to eliminate excess of free calcium. At this stage, beads are referred to as "geUed beads".
- Example 3 Optimization of Metallic Ion Used to Gel the Pectin, and the Effect of pH of the Pectin Solution.
- Beads were prepared as described in Example 2. However, the concentration of the pectin solution was decreased from 6% to 4% due to the decrease in solubility of pectin with increased pH.
- the encapsulation yield was measured by assaying the enzymatic activity of ⁇ - Lactamase Ll as described in Example 1.
- the positive control was prepared by diluting the same amount of ⁇ -lactamase
- Ll as should be contained in 5 beads in 20 ml of 10 mM Hepes, 145 mM NaCl, 0.1 mg/ml BSA pH 7.4.
- ⁇ -lactamase Ll was inactivated irrespective of the cation used for pectin gelification when the pectin solution was at pH 4.0 (4.3 % residual activity in calcium and 3.8 % in zinc), whereas nearly full activity was retained after buffering the pectin solution to pH 7.0 (86.7% in calcium and 64.0% in zinc).
- Table 5 summarizes the experimental design Table 5 : Experimental design for the optimization of critical parameters involved in ⁇ -Lactamase Ll formulation
- Pectin B C: pH of E:
- Beads were prepared as described in example 2 except that the gelification time in the cation bath was reduced from 20 min to 10 min to allow a smart timing of the experiments.
- a pectinase should be used to quantify formulated ⁇ -lactamase Ll.
- Example 5 Improvement of Stability of the Beads Comprising ⁇ -Laetamase Ll in Simulated Intestinal Media (SIM) by Increased Zinc Ion Concentration and Duration of Drying Beads containing ⁇ -lactamase Ll were prepared as described in example 4. Increasing zinc acetate concentrations (6, 8, 10 and 12%) were tested. Further coating with or without PEI were compared.
- SIM Simulated Intestinal Media
- Drying of beads was also increased from 2 hours to overnight. Efficiency of washing to remove excess metallic ion used for gelif ⁇ cation was also monitored by measuring the conductivity of the water rinsing solution.
- Beads containing ⁇ -lactamase Ll were prepared as previously described, and gelled with 6 or 12 % Zinc acetate solutions (see Example 5).
- Table 8 Stability of beads in Simulated Intestinal Medium for 5 h at 37°C.
- the numbers represent the number of beads still apparently intact in solution.
- SCM Simulated colonic medium
- Example 7 Effect of Gelification Time, Rinsing Process, and Drying Time on Recovery of ⁇ -Lactamase Ll Activity
- Hydrolysis of CENTA is a well known technique used to quantify ⁇ -lactamase activity.
- the usual format is in single tubes and is not adapted for analysis of a large number of samples. This example describes the development and fit for purpose qualification of this assay in 96 wells microplate format
- a stock solution of CENTA was obtained by solubilization of the CENTA dried powder at a concentration of 25 mM in water; it was stored in 25 ⁇ l aliquots at - 20 0 C.
- the assay mix was done by diluting 22 ⁇ l of CENTA stock solution in the following assay buffer: 10 ml 30 mM Hepes buffer pH 7.5 containing 50 ⁇ m ZnCl 2 , hence yielding a CENTA concentration of 1 10 ⁇ M.
- 20 ⁇ l containing the enzyme to be assayed were added to 180 ⁇ l of assay mix, hence using a final concentration of 100 ⁇ M CENTA In the assay.
- Example 9 Release of ⁇ -lactamase Ll from uncoated beads, and Eudragit-coated beads with or without HPMC pre-coating.
- a batch of pectin beads containing ⁇ -lactamase Ll was manufactured under the following conditions: beads were formed by adding dropwise through a 0.5 mm internal diameter needle a solution of 5% pectin containing 300 mg/1 purified recombinant ⁇ -lactamase Ll (Eurogentec, Belgium) to a 12% bath of Zn acetate, 2H 2 O. Beads were gelified for 90 min in the Zn acetate bath, collected, washed with water untill the water conductivity had reached a stable plateau, signifying that rinsing is optimal and finally dried at 35 0 C under vacuum.
- Dried beads obtained were 0.8- 1.25 mm diameter, weighed on average 0.6 mg and contain approx 5 to 6 ⁇ g ⁇ - lactamase Ll per mg of beads. They were either left uncoated, or coated using a Glatt GPC 1.1 with Top spray according to the following formulas shown in Table 9.
- Pre-coating of beads was performed with HPMC using same material as for the coating with Eudragit.
- coated and uncoated beads were incubated under gentle mixing at 37 0 C in 50 mM Hepes buffer pH 7.4 containing 0.1 M NaCl and 100 PG/ml pectinases from Aspergillus aculeatus (Sigma).
- Example 10 Efficiency of released Ll to hydrolyze antibiotics in vitro.
- simulated gastric medium 0.1N HCl
- 3h at 37 0 C in simulated intestinal medium (50 niM Na/K phosphate buffer pH 6.8 containing 0.1 M NaCl)
- simulated colonic medium 50 mM Hepes buffer pH 7.4, 0.1 M NaCl
- 100 PG/ml pectinases from Aspergillus aculeatus Sigma Aldrich
- Example 11 Effect of ⁇ -lactamase Ll containing beads on the emergence of bacterial resistance in piglets treated with amoxicillin.
- piglets were either untreated, or orally treated with 20 mg/kg amoxicillin per day for 7 days.
- Half of the treated animals received, together with the daily dose of antibiotics, a gelatin capsule filled with 320 mg pectin beads containing ⁇ -lactamase Ll 5 pre-coated with 5% HPMC and coated with 40% Eudragit L3OD-55 (batch 100); the other half received similarly coated placebo pectin beads.
- Feces were collected 3 days before the onset of treatment, and each day during 7 days of treatment and analyzed for their content of total and amoxicillin-resistant enterobacteria on MacConkey agar plates containing 0 or 100 ⁇ g/ml amoxicillin.
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US85960006P | 2006-11-17 | 2006-11-17 | |
PCT/EP2007/062475 WO2008059062A1 (en) | 2006-11-17 | 2007-11-16 | Colonic delivery using zn/pectin beads with a eudragit coating. |
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JP (1) | JP2010510196A (ja) |
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WO2009040030A1 (en) * | 2007-09-11 | 2009-04-02 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2009033707A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
US20100184680A1 (en) * | 2007-09-11 | 2010-07-22 | Dorian Bevec | Therapeutic uses of b-type natriuretic peptide and human growth hormone 1-43 |
CZ302789B6 (cs) | 2009-11-25 | 2011-11-09 | Zentiva, K. S. | Zpusob zvýšení rozpustnosti farmaceuticky aktivních látek a cílený (kontrolovaný) transport do streva |
US9572856B2 (en) | 2009-12-16 | 2017-02-21 | The George Washington University a Congressionally Chartered Not-for-Profit Corporation | Method of treating low blood pressure |
PT2538930T (pt) | 2010-02-23 | 2016-08-05 | Da Volterra | Formulações para administração oral de adsorventes no intestino |
BR112012024877A2 (pt) * | 2010-04-08 | 2016-06-14 | Merz Pharma Gmbh & Co Kgaa | preenchedor, processo para o preparo de um preenchedor e dispositivo de injeção |
GB201202433D0 (en) | 2012-02-13 | 2012-03-28 | Diurnal Ltd | Controlled drug release |
US9907755B2 (en) * | 2013-03-14 | 2018-03-06 | Therabiome, Llc | Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents |
JP6522584B2 (ja) * | 2013-04-26 | 2019-05-29 | ラ ホヤ ファーマシューティカル カンパニーLa Jolla Pharmaceutical Company | 腎不全を処置するための組成物及び方法 |
US20160279187A1 (en) * | 2013-10-31 | 2016-09-29 | University Of Hawaii | Calpain inhibitors for ibd and colorectal cancer treatment |
HUE047062T2 (hu) | 2013-12-18 | 2020-04-28 | The George Washington Univ A Congressionally Chartered Not For Profit Corporation | Angiotenzin II alacsony vérnyomás kombinációs kezelésére |
EP3083031B1 (en) | 2013-12-20 | 2019-10-16 | Fresenius Kabi Deutschland GmbH | Microcapsules with polymeric coating comprising a lipid and an active agent |
CN107072950B (zh) * | 2014-09-11 | 2020-11-03 | 嘉利达股份有限公司 | 明胶/果胶粒子 |
US20160158174A1 (en) * | 2014-12-09 | 2016-06-09 | Intercontinental Great Brands Llc | Enteric-Coated Functional Food Ingredients And Methods For Making The Enteric-Coated Functional Food Ingredients |
AU2017205168A1 (en) | 2016-01-07 | 2018-08-16 | La Jolla Pharma, Llc | Methods for administering angiotensin II |
WO2018005606A1 (en) * | 2016-06-28 | 2018-01-04 | Synthetic Biologics, Inc. | Microbiome protection from oral antibiotics |
US11771656B2 (en) * | 2016-11-17 | 2023-10-03 | Shanghai Jiaotong University School Of Medicine | Oral colon-targeted delivery system and preparation method and application thereof |
DE102017000896A1 (de) * | 2017-02-01 | 2018-08-02 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Selektives Freisetzungssystem für Tumortherapeutika und Tumordiagnostika sowie Biosensor für Tumorgewebe |
WO2018191678A1 (en) | 2017-04-14 | 2018-10-18 | La Jolla Pharmaceutical Company | Methods for administering angiotensin ii |
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US5840332A (en) * | 1996-01-18 | 1998-11-24 | Perio Products Ltd. | Gastrointestinal drug delivery system |
RU2375047C2 (ru) * | 2004-03-26 | 2009-12-10 | Лек Фармасьютиклз Д.Д. | Фармацевтическая лекарственная форма, устойчивая к действию желудочного сока, включающая n-(2-(2-фталимидоэтокси)ацетил)-l-аланил-d-глутаминовую кислоту (lk 423) |
DK1883396T3 (da) * | 2005-05-18 | 2013-10-07 | Centre Nat Rech Scient | Afgivelse af adsorptionsmidler til tyktarmen |
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