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WO2008144690A2 - Compositions et procédés d'amélioration de l'absorption d'agents actifs - Google Patents

Compositions et procédés d'amélioration de l'absorption d'agents actifs Download PDF

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Publication number
WO2008144690A2
WO2008144690A2 PCT/US2008/064233 US2008064233W WO2008144690A2 WO 2008144690 A2 WO2008144690 A2 WO 2008144690A2 US 2008064233 W US2008064233 W US 2008064233W WO 2008144690 A2 WO2008144690 A2 WO 2008144690A2
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WIPO (PCT)
Prior art keywords
substituted
null
alkenyl
aryl
composition
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Application number
PCT/US2008/064233
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English (en)
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WO2008144690A3 (fr
Inventor
Chung Shih
Original Assignee
Nexus Pharma, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US11/805,202 external-priority patent/US8426466B2/en
Application filed by Nexus Pharma, Inc. filed Critical Nexus Pharma, Inc.
Priority to EP08755962.1A priority Critical patent/EP2150243A4/fr
Publication of WO2008144690A2 publication Critical patent/WO2008144690A2/fr
Publication of WO2008144690A3 publication Critical patent/WO2008144690A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • a composition for enhancing transmucosal absorption of an active agent can comprise a) at least one active agent; and b) an absorption enhancer having the formula:
  • Ri can be null, C 1 -Ci 2 alkylene, C 2 -Ci 2 alkenylene, arylene, or substituted alkylene, alkenylene, or arylene.
  • the substituted alkylene, alkenylene, or arylene can be substituted with N, O, S, or P.
  • R 2 can be hydrogen, C ⁇ -C ] 2 alkyl, C 2 -Ci 2 alkenyl, aryl, or cycloalkyl; and each R 3 can independently be hydrogen, C]-Ci 2 alkyl, C 2 -Ci 2 alkenyl, or aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P.
  • X can be a tertiary amine, quaternary amine, tertiary sulfur, carboxylic acid, sulfide, sulfonic acid, sulfenic acid, sulfoxide, phosphoric acid, phosphonic acid, poly(ethylene glycol), saccharide, oligosaccharide, polyol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, chitosan, or a combination thereof.
  • A can be null or CONH, wherein A and R] are not simultaneously null; and Z can be O, S, NH, or NR wherein R is lower alkyl, or wherein Z is joined with R 2 to form a heterocyclic ring.
  • R 3 , Z-R 2 and/or X-Ri-A possess labile linkages such as ester linkages, or peptide bonds that are subjected to hydrolysis by a variety of peptidases.
  • the composition of the present invention may be formulated into various dosage forms configured to bring the composition into effective contact with a mucosal surface of a subject, which includes external and internal mucosal surfaces of the body.
  • Oral or administration can be used to contact the composition with the mucosal surfaces of the intestines, whereas a buccal administration can be used to transmucosally deliver the composition through the mucosal surfaces within the oral cavity.
  • Exemplary dosage forms for delivery include tablets, capsules, powders, suspensions, creams, and suppositories.
  • the present invention is also drawn to methods of enhancing transmucosal absorption of active agents in a subject, which comprises administering a composition to the subject so that the composition comes into effective contact with a mucosal surface of the subject.
  • the composition can be the same as that described above.
  • the present invention also is drawn to the use of absorption enhancers in the manufacture of a medicament for enhancing transmucosal absorption of an active agent, in which the
  • administering refers to the manner in which a drug, formulation, or composition is introduced into the body of a subject. Administration can be accomplished by various art-known routes such as oral, parenteral, transdermal, inhalation, implantation, etc. Thus, an oral administration can be achieved by swallowing, chewing, or sucking an oral dosage form comprising active agent(s).
  • Parenteral administration can be achieved by injecting a composition intravenously, intra- arterially, intramuscularly, intrathecally, or subcutaneous Iy, etc.
  • Transdermal administration can be accomplished by applying, pasting, rolling, attaching, pouring, pressing, rubbing, etc., of a transdermal preparation onto a skin surface.
  • transmucosal administration can be accomplished by applying, pasting, rolling, attaching, pouring, pressing, rubbing, etc., of a transmucosal preparation onto a mucosal surface, as well as by spraying, irrigating the surface with the preparation.
  • an effective amount refers to an amount of an ingredient which, when included in a composition, is sufficient to achieve an intended compositional or physiological effect.
  • a “therapeutically effective amount” refers to a non-toxic, but sufficient amount of an active agent, to achieve therapeutic results in treating a condition for which the active agent is known to be effective.
  • an "effective amount” or a “therapeutically effective amount” may be dependent on such biological factors.
  • the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision.
  • a "therapeutically effective amount" of an active agent can achieve a therapeutic effect that is measurable by the subject receiving the active agent. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical, medicinal, and health sciences.
  • effective contact refers to contact of a nature and duration sufficient to allow a desired effect to be achieved, e.g. effective contact of a preparation with a surface into which it is to be absorbed will allow a measurable amount, preferably also an effective amount, of an agent in the preparation to enter the tissues or bloodstream of a subject, depending on the application target.
  • carrier or “inert carrier” refers to typical compounds or compositions used to carry active ingredients, such as polymeric carriers, liquid carriers, or other carrier vehicles with which a bioactive agent, such as insulin, may be combined to achieve a specific dosage form.
  • a bioactive agent such as insulin
  • carriers do not substantially react with the bioactive agent in a manner which substantially degrades or otherwise adversely affects the active agent or its therapeutic potential.
  • alkyl alkylene, alkenyl, alkenylene, or the like
  • these terms include either linear or branched hydrocarbon chains. These hydrocarbon chains can optionally be substituted with N, O, S, or P, for example.
  • null is used herein to describe variables that, though included in a compound formulation, can be removed from the formulation.
  • a formulation is described as including a variable "B” and “B” is said to be null, -CH 2 — , O, S, or NH
  • the variable "B” can be removed from the formulation, or can be substituted with -CH 2 -, O, S, or NH.
  • the mechanism of adjuvants is mostly unknown.
  • theories including transport via paracellular routes by opening the tight junctions, or by transcellular routes via perturbing the lipid bilayers of the epithelial cells have been proposed.
  • the use of adjuvants can present particular risks.
  • the adjuvant could be toxic, e.g. it can cause damage barriers such as lipid bilayers, other membranes, and selective transport systems, both at the point of absorption or located elsewhere in the body.
  • the instant invention addresses this problem by generally providing adjuvants into which labile linkages may be optionally introduced so that the beneficial permeation enhancing activity can be preserved and the adverse effects can be eliminated.
  • a composition for achieving enhanced absorption of a drug or other active agent can comprise an effective amount of the active agent itself and an absorption enhancer or a pharmaceutically acceptable salt thereof.
  • the absorption enhancer may have the general formula:
  • Ar can be an aromatic structure such as benzene or naphthalene
  • can be null, a saturated or unsaturated linear, branched or cyclic alkylene, or arylene, and optionally may be substituted with functional groups containing hetero-atoms such as N, O, S, or P (Ri can be coupled to Ar through a coupling moiety); and
  • absorption enhancers in accordance with the present invention can comprise a functional fragment of a small molecule adjuvant, a lipophilic component, and a hydrophilic component.
  • such an enhancer can have the following formula:
  • Ri can be null, linear, or branched C 1 -C 12 alkylene, C 2 -C] 2 alkenylene, arylene, or substituted alkylene, alkenylene, or arylene, said substituted alkylene, alkenylene, or arylene being substituted with N, O, S, or P;
  • R 2 can be hydrogen or an aliphatic chain such as CrCi 2 alkyl, C 2 -Ci 2 alkenyl, or an aryl or cycloalkyl functional group; each R 3 can independently be hydrogen, Ci-C t 2 alkyl, C 2 -Ci 2 alkenyl, or aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P;
  • X can be tertiary amine, quaternary amine, tertiary sulfur, carboxylic acid, sulfon
  • A can be null or a coupling moiety such as amide or ester.
  • A is an amide such that X-Ri-A is X- R ⁇ -CONH-, i.e. this chain is attached to the ring via nitrogen.
  • B can be null, -CH 2 — , O, S, or NH; and Z can be null, O, S, NH, or NR where R is lower alkyl, or wherein Z is joined with R 2 to form a heterocyclic ring.
  • the aromatic ring can also be naphthalene or another fused aromatic ring structure.
  • a and R t are not simultaneously null, that is, if A is null, then Ri is other than null, and if R] is null, then A is other than null.
  • R 3 , Z-R 2 and/or X-Ri-A may possess labile linkages such as amide or ester linkages, or peptide bonds that are subjected to hydrolysis by a variety of peptidases.
  • the absorption enhancer has the formula:
  • Rj, R 2 , R 3 , Z, A, and X represent the same groups as with Formula II and where A and R] are not simultaneously null.
  • R 3 , Z-R 2 and/or X-Rj-A possess labile linkages.
  • the absorption enhancer may have the formula:
  • Ri, R 2 , R 3 , A, and X represent the same groups as with Formula II and where A and R t are not simultaneously null.
  • R 3 , Z-R 2 and/or X-Ri-A possess labile linkages.
  • R is attached to the aromatic ring by an amide or ester linkage.
  • A is an amide such that X-R t -A is X-Ri-CONH, i.e. this chain is attached to the aromatic ring via nitrogen.
  • X is COOH.
  • any combination of R 3 , Z-R 2 , and X-RrA contain linkages that are labile under conditions where breakdown of the enhancer would be advantageous.
  • linkages can be broken by enzymatic or other chemical action, such as hydrolysis.
  • such linkages include amide linkages or ester linkages.
  • the activity of the enhancers can also be affected by the overall lipophilicity of the molecule contributed by R] and R 2 as well as substitution(s) on the aromatic ring.
  • a more optimal length of R 2 can provide the maximal enhancement, while a shorter or longer chain length may provide a lesser benefit in some circumstances.
  • enhancement may be affected by the position of the moiety containing Ri and the amide group of the moiety containing R 2 .
  • the basic structure of salicylic acid is preserved to the extent that an OH group is present at carbon 2 of the ring (and therefore is ortho to the carbonyl carbon at position 1).
  • the lipophilic functionality R 2 extends from the carbonyl, ester, or amide group at position 1, while Ri is linked to the ring at any one of carbons 3-6.
  • other structural arrangements that will provide both lipophilic and hydrophilic properties are considered within the scope of this invention.
  • R 3 may be attached, directly or through an ether, ester, or amide linkage, at any of carbons 3-6 instead of Ri, with an alkyl or alkenyl group providing lipophilicity and a polar group (such as carbonyl, nitro, cyano, tri-chloro- or tri-fluoro- substituted groups) providing polarity.
  • a polar group such as carbonyl, nitro, cyano, tri-chloro- or tri-fluoro- substituted groups
  • the relative orientation of the hydro xyl and carbonyl remains the same (i.e. ortho), as in Formulas II-IV.
  • the length of the carbon chain in R 2 may be adjusted to provide the maximal enhancement.
  • Biologically and chemically active agents that can be made more useful by enhancing their absorption are exemplified, without limitation, by the following: growth hormones, including human growth hormones (hGH), bovine growth hormones, and porcine growth hormones; growth hormone releasing hormones; interferons; cytokines; naturally occurring or recombinant insulins, including porcine, bovine, and human, optionally having counter ions including sodium, zinc, calcium, and ammonium; insulin- like growth factors, including IGF-I; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, and ultra-low molecular weight heparin; calcitonin, including salmon, eel, and human; erythropoetin; granulocyte-colony stimulating factor; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; proteas
  • compositions of the present invention are particular useful for Type III agents, that is, highly water soluble but poorly gastrointestinal membrane permeable agents, as classified by Biopharmaceutics Classification System set forth by the United States Food and Drug Administration.
  • compositions of the present invention are useful for administering biologically or chemically active agents to animals, including but not limited to birds such as chickens, and mammals such as cows, pigs, dogs, cats, primates, and particularly humans.
  • the present invention may also be utilized to deliver agents such as pesticides and hormone disruptors to insects.
  • compositions of the present invention can be particularly useful in enhancing the absorption of active agents across mucosal surfaces outside of the small and large intestines, so as to provide a viable alternate delivery route to a subject's system other than by oral routes.
  • transmucosal administration can be a less invasive alternative to oral administration, due to the relatively easy access to a number of mucosal surfaces, such as in the buccal cavity, nose, vagina, and rectum.
  • Other possible transmucosal routes include the sublingual, ocular, intraduodenal, intraco Ionic, pulmonary mucosa, jejunum mucosa, and ileum mucosa.
  • compositions of the present invention also encompass both traditional oral delivery routes as well as through oral mucosa.
  • the present invention also provides methods of enhancing absorption of active agents in a subject by administering a composition comprising an active agent and an enhancer so that it comes into effective contact with a mucosal surface of the subject, such as any of the surfaces listed above.
  • the dosage form utilized in such a method will depend on the mucosal surface involved, and the manner of access provided to the surface.
  • dosage forms for providing enhanced absorption of active agents by any of these routes can comprise the active agent(s) and any absorption enhancer in accordance with the present invention.
  • dosage forms include liquid suspensions or elixirs, capsules, coated and uncoated tablets, quick dissolving formulations, lozenges, gels, pastes, etc.
  • Buccal administration can include buccal patches, tablets, lozenges, gels, pastes, etc.
  • Rectal and vaginal dosage forms include liquids, gels, pastes, creams, and suppositories.
  • Nasal administration may be accomplished with liquids, gels, pastes, or dry powders.
  • these dosage forms may each also comprise excipients in addition to the active agent and enhancer.
  • liquid oral dosage forms may include diluents, solubilizers, flavorants, taste masking agents, surfactants, buffering agents, preservatives, antioxidants, colorants, ethanol, propylene glycol, saccharides, and polyethylene glycol, as well as other appropriate additives known to those skilled in the art, and any combination thereof.
  • Solid oral dosage forms such as tablets, coated tablets, capsules, and powders may be prepared by conventional skills in the art, and include excipients such as fillers, diluents, disintegrants, lubricants, glidents, plasticizers, colorants, flavorants, taste masking agents, saccharides, surfactants, binders, buffering agents, preservatives, antioxidants, colorants, polymer coatings, pore formers, and any combination thereof.
  • Formulations for nasal administration may require a propellant.
  • Suppositories may also contain suppository bases to provide proper consistency, such as coconut butter, polyethylene glycol, etc. Any of these dosage forms may optionally include any of a number of enzyme inhibitors known in the art such as actinonin or epiactinonin, and derivatives thereof; aprotinin; and Bowman-Birk inhibitor.
  • 4-Aminosalicylic acid (12.3 g) is placed in a round bottom flask. The flask is charged with 150 mL of methanol and 20 niL of concentrated sulfuric acid. The reaction mixture is brought to gentle reflux for 1 day, and then allowed to cool to room temperature. The mixture is further chilled in a freezer and methyl 4-aminosalicylate bisulfate is crystallized. The crystals are collected and washed with cold methanol to afford 15.8 g of the product as off-white needles.
  • Example 2 Synthesis of methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate
  • Methyl 4-aminosalicylate bisulfate from Example 1 (5 g) is placed in a 50-mL round bottom flask. The flask is charged with 20 mL of methylene chloride and 15 mL of triethylamine. Finally, succinic anhydride (2.75 g) is added. The reaction mixture is then allowed to stir at ambient conditions overnight. Solvents are removed under reduced pressure, yielding a viscous residue, to which 1 N HCl is added. Methyl (3-carboxy- propionylamino)-2-hydroxybenzoate is yielded as tan powder. The powders are collected by filtration, washed with water, and dried.
  • Example 3 Synthesis ofN-n-hexyl 4-(3-carboxy-propionylamino)-2- hydroxybenzamide
  • Methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate from Example 2 (1 g) is dissolved in 15 mL of methanol.
  • n-Hexylamine (5 mL) is added to this solution, and the reaction mixture is brought to mild reflux for 2 days. Solvents are removed under vacuum and residue acidified using 1 N HCl.
  • N-n-hexyl 4-(3-carboxy-propionylamino)- 2-hydroxybenzamide precipitate is collected, washed with water, and dried,
  • Methyl 4-aminosalicylate bisulfate from Example 1 (5 g) is suspended in 20 mL of methanol. To the solution, 20 mL of 28% ammonium hydroxide is added slowly until all solid is dissolved. The reaction mixture is stirred at ambient conditions overnight. Solvent is removed under reduced pressure and water is lyophilized. The residue is collected, washed with minimum amount of ice water and dried to yield 2.5 g of the product as off-white powders.
  • Example 6 Synthesis of4-(9-carboxy-nonanoylamino)-2-hydroxybenzamide 4-aminosalicylamide (2 g) from Example 5 is charged with 20 mL of methylene chloride. To the solution, 3.3 g of methyl 10-chloro-lO-oxodecanoate is added. The reaction is initiated by addition of 2.6 mL of triethylamine. The reaction mixture is allowed to stir at ambient conditions for 2 days. Solvent is removed and the residue is acidified using 1 N HCl. The precipitate is extracted into ethyl acetate. The organic layer is further extracted with 1 N NaOH and saturated NaCl solutions. After drying over anhydrous sodium sulfate, solvent is removed.
  • Example 7 Synthesis ofn-butyl 4-aminosalicylate 4-Aminosalicylic acid (12.3 g) is placed in a round bottom flask. The flask is charged with 150 mL of n-butanol and 20 mL of concentrated sulfuric acid. The reaction mixture is brought to gentle reflux for 1 day, and then allowed to cool to room temperature. The mixture is further chilled in a freezer and n-butyl 4-aminosalicylate bisulfate is crystallized. The crystals are collected and washed with cold methanol to afford 15.8 g of the product as off-white needles.
  • Example 8 Synthesis ofn-butyl 4-(3-carboxy'propionylamino)-2-hydroxybenzoate
  • n-Butyl 4-aminosalicylate bisulfate (5 g) is placed in a 50-mL round bottom flask. The flask is charged with 20 mL of methylene chloride and 15 mL of triethylamine. Finally, succinic anhydride (2.75 g) is added. The reaction mixture is then allowed to stir at ambient conditions overnight. Solvents are removed under reduced pressure, yielding a viscous residue, to which 1 N HCl is added. n-Butyl (3-carboxy-propionylamino)-2- hydroxybenzoate is yielded as tan powder. The powders are collected by filtration, washed with water, and dried.
  • N-n-hexyl 4-(3-carboxy-propionylamino)-2-hydroxybenzamide from Example 3 is suspended in 2 mL of water. It is neutralized by 1 equivalent of sodium hydroxide. The pH is adjusted to 7-8 by IN HCl and saturated sodium bicarbonate. Bovine pancreatic insulin (1.75 mL; Sigma, 10 mg/niL; in pH 8.2 HEPES buffer) is added and mixed by gentle swirling. The solution density is determined so that the required dose may be calculated.
  • Example 12 The general procedure followed in Example 12 above is followed in Examples 13- 26 (using different compounds and different dosages as set forth below, given intracolonically or by oral gavage), with the following results.
  • C Colonically O: By oral gavage. It is noted that though Examples 10, 11, 17, and 18 are shown as "negative,” that does not mean that no enhancement occurred. It only means that a 50% reduction in glucose levels was not reached in 60 minutes. As insulin reduces glucose levels in the blood, a depression in glucose levels indicates insulin reaching the blood efficaciously.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne des compositions et procédés d'amélioration de l'absorption d'agents actifs à travers la muqueuse de sujets animaux. Des compositions ayant des liaisons biodégradables sont incluses, conférant une diminution de probabilité de toxicité. L'invention concerne également des procédés d'utilisation et des formes galéniques appropriées.
PCT/US2008/064233 2007-05-21 2008-05-20 Compositions et procédés d'amélioration de l'absorption d'agents actifs WO2008144690A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08755962.1A EP2150243A4 (fr) 2007-05-21 2008-05-20 Compositions et procédés d'amélioration de l'absorption d'agents actifs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11/805,202 2007-05-21
US11/805,202 US8426466B2 (en) 2006-05-22 2007-05-21 Compositions and methods for enhancing active agent absorption
US409907P 2007-11-21 2007-11-21
US61/004,099 2007-11-21

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WO2008144690A2 true WO2008144690A2 (fr) 2008-11-27
WO2008144690A3 WO2008144690A3 (fr) 2009-02-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015020113A1 (fr) * 2013-08-07 2015-02-12 国立大学法人京都大学 Méthode de production de cellule productrice d'hormone pancréatique
CN104906592A (zh) * 2011-02-25 2015-09-16 隆萨有限公司 用于蛋白质药物偶联物的支链联接体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773647A (en) 1997-02-07 1998-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817624A (en) * 1995-06-05 1998-10-06 Alza Corporation Permeation enhancer compositions for increased absorption of therapeutic proteins through the colonic membrane
CA2396711A1 (fr) * 2000-01-27 2001-08-02 Aqua Solution Inc. Composition pour administration intestinale
US20030198666A1 (en) * 2002-01-07 2003-10-23 Richat Abbas Oral insulin therapy
CN100522243C (zh) * 2006-03-13 2009-08-05 新疆维吾尔自治区畜牧科学院兽医研究所 动物皮肤渗透剂

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773647A (en) 1997-02-07 1998-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Absorption Enhancement of Cromolyn Sodium Through Noncovalent Complexation", PHARMACEUTICAL RESEARCH, vol. 21.12, 2004, pages 2196 - 206
FAUST, JOHN A.; LEONARD H. JULES; MELVILLE SAHYUN: "Derivatives of Salicylamide", JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION, vol. 45.8, 1956, pages 514 - 17, XP008115755, DOI: doi:10.1002/jps.3030450803
MASUKAZU, NAITO ET AL.: "Chemotherapeutics for Mycobacterium Tuberculosis. XI 1. Antibacterial Activity of Derivatives of Esters of Aminosalicylic Acid on Mycobacterium Tuberculosis", PHARMACEUTICAL SOCIETY OF JAPAN, vol. 78.6, 1958, pages 682 - 83, XP008115756
See also references of EP2150243A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104906592A (zh) * 2011-02-25 2015-09-16 隆萨有限公司 用于蛋白质药物偶联物的支链联接体
WO2015020113A1 (fr) * 2013-08-07 2015-02-12 国立大学法人京都大学 Méthode de production de cellule productrice d'hormone pancréatique
JPWO2015020113A1 (ja) * 2013-08-07 2017-03-02 国立大学法人京都大学 膵ホルモン産生細胞の製造法
US9796962B2 (en) 2013-08-07 2017-10-24 Kyoto University Method for generating pancreatic hormone-producing cells

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