WO2021122793A1 - Disaccharides sulfatés utilisés en tant qu'activateurs d'absorption transmucosale de médicaments - Google Patents

Disaccharides sulfatés utilisés en tant qu'activateurs d'absorption transmucosale de médicaments Download PDF

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WO2021122793A1
WO2021122793A1 PCT/EP2020/086490 EP2020086490W WO2021122793A1 WO 2021122793 A1 WO2021122793 A1 WO 2021122793A1 EP 2020086490 W EP2020086490 W EP 2020086490W WO 2021122793 A1 WO2021122793 A1 WO 2021122793A1
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compound
drug
compound according
sulfate groups
composition
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PCT/EP2020/086490
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Paul HASSELGREN
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Norinvent Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars

Definitions

  • the present invention relates to disaccharide compounds and their use as enhancers of transmucosal drug uptake.
  • these metabolites even when they are pharmaceutically non-effective in the human body, may end up in the environment c) Difficulty in accurate dosing due to potentially high variability in bioavailability between individuals. This results in over dosing for many patients d) Difficulty in administration, for example when the patient is nauseous such that the drug is regorged e) Adverse side effects such as nausea, diarrhea, stomach aches, and disturbance of the microbial flora of the gut.
  • Oral mucosal drug administration has been of interest for a long time. It potentially offers the convenience of the per oral treatment without the issues arising from first pass metabolism. It is also a more direct route for systemic delivery, allowing for a shorter time to onset.
  • the typical example is treatment of angina pectoris where nitroglycerin is given to patients as a tablet under the tongue, having an effect in four minutes. Nitroglycerin is however unusual in this respect and only a few other drugs are known to easily pass through the oral mucosa. In most cases the mucosa forms a daunting barrier and drug permeability is low.
  • the present invention relates to use of a compound or composition as defined herein as an enhancer of mucosal drug uptake.
  • the present invention relates to a method for delivering a drug as defined herein across a mucosal membrane, said method comprising administering the drug and a compound as defined herein to a mucosal membrane.
  • the present invention relates to a drug delivery system comprising a disaccharide for delivery of a drug across a mucosal membrane.
  • the present invention relates to a compound of formula (I):
  • R 1 is H, Ci-s alkyl, -S0 3 , or -P0 3 H 2 ;
  • R 2 is -OH, -NH 2 , -0S0 3 , or -0P0 3 H 2 ;
  • R 3 is H, -S0 3 , or -P0 3 H 2 ;
  • R 4 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ;
  • R 5 is H, -S0 3 , or -P0 3 H 2 ;
  • R 6 is H, -S0 3 , or -P0 3 H 2 ;
  • R 7 is H, -S0 3 , or -P0 3 H 2 ;
  • R 8 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a composition comprising one or more compounds as defined herein and a drug.
  • the present invention relates to a compound or composition as defined herein for use as a medicament.
  • FIG. 1 Flux of diclofenac over oesophageal mucosa (pg/cm 2 h), see Example 3. 1% (w/w) diclofenac (filled triangles) together with the disaccharides A (circles), A-LS (filled circles), B (squares) or B-HS (filled squares) were used as formulations. Two to three cells were used per formulation.
  • FIG. 3 Flux of diclofenac over oesophageal mucosa (pg/cm 2 h), see Example 4. 0.25 % (w/w) diclofenac with B-HS ammonium (filled circles), 1 % (w/w) diclofenac with B- HS ammonium (filled squares), 1 % (w/w) diclofenac with B-HS pyridinium (squares) and 0.25 % (w/w) diclofenac without B-HS were used as formulations. Two to three cells were used per formulation.
  • Figure 4 Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa (pg/cm 2 h), see Example 4. 0.25 % (w/w) diclofenac with B-HS ammonium (filled circles), 1 % (w/w) diclofenac with B-HS ammonium (filled squares), 1 % (w/w) diclofenac with B-HS pyridinium (squares) and 0.25 % (w/w) diclofenac without B-HS were used as formulations. Two to three cells were used per formulation.
  • Figure 6 Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa, normalized to reference 0.25% (w/w) diclofenac, see Example 5. 0.25 % (w/w) diclofenac together with 0.15% B-HS (filled circles), 0.59% B-HS (filled squares), or 2.37% B-HS (squares) were used as formulations. Seven cells were used per formulation.
  • R 1 is H, Ci-s alkyl, -S0 3 , or -P0 3 H 2 ;
  • R 2 is -OH, -NH 2 , -0S0 3 , or -0P0 3 H 2 ;
  • R 3 is H, -S0 3 , or -P0 3 H 2 ;
  • R 4 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ;
  • R 5 is H, -S0 3 , or -P0 3 H 2 ;
  • R 6 is H, -S0 3 , or -P0 3 H 2 ;
  • R 7 is H, -S0 3 , or -P0 3 H 2 ;
  • R 8 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ; or a pharmaceutically acceptable salt thereof.
  • the compound is sulfated.
  • the compound is of formula (II):
  • R 1 is H, Ci-s alkyl, -S0 3 , or -P0 3 H 2 ;
  • R 2 is -OH, -NH 2 , -0S0 3 , or -0P0 3 H 2 ;
  • R 3 is H, -S0 3 , or -P0 3 H 2 ;
  • R 4 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ;
  • R 5 is H, -S0 3 , or -P0 3 H 2 ;
  • R 6 is H, -S0 3 , or -P0 3 H 2
  • R 7 is H, -S0 3 , or -P0 3 H 2 ;
  • R 8 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ; or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (III):
  • R 1 is H, Ci-s alkyl, -S0 3 , or -P0 3 H 2 ;
  • R 2 is -OH, -NH 2 , -0S0 3 , or -0P0 3 H 2 ;
  • R 3 is H, -S0 3 , or -P0 3 H 2 ;
  • R 4 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ;
  • R 5 is H, -S0 3 , or -P0 3 H 2
  • R 6 is H, -S0 3 , or -P0 3 H 2 ;
  • R 7 is H, -S0 3 , or -P0 3 H 2 ;
  • R 8 is -CH 2 OH, -CH 2 0S0 3 , -CH 2 0P0 3 H 2 , -OH, -0S0 3 , or -OP0 3 H 2 ; or a pharmaceutically acceptable salt thereof.
  • R 2 is -NH 2 . In another embodiment, R 2 is -OH. In yet another embodiment, R 2 is -0S0 3 .
  • R 3 is H. In another embodiment, R 3 is -S0 3 . In one embodiment, R 4 is -CH2OH. In another embodiment, R 4 is -CH 2 0S0 3 . In yet another embodiment, R 4 is -OH. In yet another embodiment, R 4 is -0S0 3 .
  • R 5 is H. In another embodiment, R 5 is -S0 3 .
  • R 6 is H. In another embodiment, R 6 is -S0 3 .
  • R 7 is H. In another embodiment R 7 is -S0 3 .
  • the compound is of Formula (V): wherein R 16 is H or -S0 3 ;
  • R 17 is H or -S0 3 ;
  • R 18 is H or -S0 3 ;
  • R 19 is H or -S0 3 ;
  • R 20 is H or -S0 3 ;
  • R 21 is H or -S0 3 ;
  • R 22 is H or -S0 3 ; or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VI):
  • R 16 is H or -S0 3 ;
  • R 17 is H or -S0 3 ;
  • R 18 is H or -S0 3 ;
  • R 19 is H or -S0 3 ;
  • R 20 is H or -S0 3 ;
  • R 21 is H or -S0 3 ;
  • R 22 is H or -S0 3 ; or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VII):
  • R 16 is H or -S0 3 ;
  • R 17 is H or -S0 3 ;
  • R 18 is H or -S0 3 ;
  • R 19 is H or -S0 3 ;
  • R 20 is H or -S0 3 ;
  • R 21 is H or -SO 3 ; and R 22 is H or -SO 3 ; or a pharmaceutically acceptable salt thereof.
  • At least one of R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 is -SO 3 .
  • at least two, such as at least three, such as at least four, such as at least five, such as at least six of R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 is -SO 3 .
  • no more than six, such as no more than five, such as no more than four, such as no more than three, such as no more than two of R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 is -SO 3 .
  • R 18 and R 22 are -SO 3 .
  • R 16 , R 17 , R 19 , R 20 , and R 21 are H and R 18 and R 22 are -SO 3 .
  • the compound is of Formula (IV): wherein R 9 is H or -S0 3 ; R 10 is H or -S0 3 ;
  • R 11 is H or -S0 3 ;
  • R 12 is H or -S0 3 ;
  • R 13 is H or -S0 3 ;
  • R 14 is H or -S0 3 ; and R 15 is H or -S0 3 ; or a pharmaceutically acceptable salt thereof.
  • At least one of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is -S0 3 .
  • at least two, such as at least three, such as at least four, such as at least five, such as at least six of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is -S0 3 .
  • no more than six, such as no more than five, such as no more than four, such as no more than three, such as no more than two of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is -S0 3 .
  • the compound is a sulfated 4-0- ⁇ -D-galactopyranosyl)-D- glucosamine. In one embodiment, the compound is a sulfated methyl 4-0- ⁇ -D-galactopyranosyl)-D- glucopyranoside.
  • the compound comprises at least one sulfate group, such as at least two sulfate groups, such as at least three sulfate groups, such as at least four sulfate groups, such as at least five sulfate groups, such as at least six sulfate groups, such as at least seven sulfate groups, such as at least eight sulfate groups.
  • the compound comprises no more than eight sulfate groups, such as no more than seven sulfate groups, such as no more than six sulfate groups, such as no more than five sulfate groups, such as no more than four sulfate groups, such as no more than three sulfate groups, such as no more than two sulfate groups, such as no more than one sulfate group.
  • the compound comprises one to eight sulfate groups, such as one sulfate group, such as two sulfate groups, such as three sulfate groups, such as four sulfate groups, such as five sulfate groups, such as six sulfate groups, such as seven sulfate groups, such as eight sulfate groups. In one embodiment, the compound comprises two to five sulfate groups.
  • the compound of the present invention is a disaccharide.
  • the compound is sulfated with 0.5 to 7 equivalents of sulfate units per disaccharide molecule, such as 0.5 equivalent, such as 1 equivalent, such as 2 equivalents, such as 3 equivalents, such as 4 equivalents, such as 5 equivalents, such as 6 equivalents, such as 7 equivalents of sulfate units per disaccharide molecule.
  • the compound is sulfated with 2 to 5 equivalents of sulfate units per disaccharide molecule.
  • drug includes any bioactive agent having a therapeutic effect in an animal.
  • drug may be used interchangeably with the term active pharmaceutical ingredients (API).
  • the drug is a small molecule.
  • small molecule is used to refer to molecules that have a relatively low molecular weight, typically less than about 1500 g/mol, such as less than 1000 g/mol, such as less than 750 g/mol, such as less than 500 g/mol.
  • the drug has a molecular weight of less than 500 g/mol.
  • the drug is negatively charged at neutral pH.
  • neutral pH refers to a pH range between about pH 5.5 and about pH 8, and in one embodiment, between about pH 6 and about 8, such as about pH 6 to 7.5.
  • the drug is diclofenac, i.e. [2-(2,6-Dichloroanilino)phenyl]acetic acid.
  • the present invention relates to a composition
  • a composition comprising one or more compounds as defined herein and a drug.
  • the composition is a pharmaceutical composition.
  • the composition further comprises one or more excipients, such as excipients that are pharmaceutically acceptable.
  • excipient encompasses for example diluents, carriers or adjuvants.
  • the pharmaceutical composition is formulated for administration across a mucosal membrane.
  • the mucosal membrane is in the oral cavity.
  • the mucosal membrane is buccal and/or sublingual mucosa.
  • the administration is buccal, sublingual and/or sublabial administration.
  • the pharmaceutical composition if formulated as a gel, a film, a tablet or a patch.
  • the pharmaceutical formulation of the composition does not lower or interferes with the primary therapeutic effect of the active pharmaceutical ingredients (API), i.e. the drug.
  • API active pharmaceutical ingredients
  • the present invention relates to use of a compound or composition as defined herein as an enhancer of mucosal drug uptake.
  • the compound as defined herein function as a penetration enhancer, such as a pharmaceutically acceptable penetration enhancer.
  • the term "penetration enhancer” and “pharmaceutically acceptable penetration enhancer” as used herein is a non-toxic agent that improves bioavailability of a drug as defined herein.
  • the compound as defined herein is a penetration enhancer of the drug as defined herein.
  • the penetration enhancer accelerates the delivery of a substance through the mucosa.
  • the compound as defined herein function as/is an enhancer of transmucosal drug uptake.
  • the use results in an increase of at least two times of the concentration of the drug in the blood compare to the mucosal drug uptake in the absence of the compound or composition.
  • the mucosal drug uptake is increased by at least 50%, such as at least 75%, such as at least 100%, such as at least 150%, such as at least 200%, such as at least 250%, such as at least 300%, such as at least 400%, such as at least 500% compared to the mucosal drug uptake in the absence of the compound or composition.
  • the present invention relates to a method for delivering a drug as defined herein across a mucosal membrane, said method comprising administering the drug and a compound as defined herein to a mucosal membrane.
  • administering refers to placing a compound, a drug or a composition as defined herein in physical contact with the mucosal membrane of a subject in need of the drug.
  • mucosa refers to a tissue comprising a mucous membranes, i.e. the moist layer that lines the internal passages of the body exposed to the outside environment, such as the mouth, nose, throat, esophagus and lungs, the inside of the eyelids, the gastrointestinal tract and the vagina.
  • the mucosa is composed of two types of layers, the outer epithelial layer and inner lamina basement. Different mucosal tissues contain specialized tissues.
  • the mucosa may for example be oral mucosa, rectal mucosa, vaginal mucosa, nasal mucosa or ophthalmic mucosa.
  • the composition, compound and/or drug as defined herein is placed under the tongue or anywhere else in the oral cavity to allow the active ingredient to come in contact with the mucosa of the oral cavity of the patient in order to obtain a local or systemic effect of the active pharmaceutical ingredient.
  • the mucosal membrane is in the oral cavity.
  • the mucosal membrane may be an "oromucosal membrane", which, as used herein, refers to buccal, buccomaxillary sublingual, gingival, buccogingival and palatal membranes.
  • the mucosal membrane is buccal and/or sublingual mucosa.
  • the term “buccal mucosa” refers to the mucosa in the cheek.
  • the term “sublingual mucosa” refers to the mucosa under the tongue.
  • the composition, compound and/or drug as defined herein is administered via oromucosal administration, which refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract.
  • oromucosal administration refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract.
  • sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism.
  • the compound and the drug are administered simultaneously.
  • the drug and the compound are in a composition, such as in a composition as defined herein.
  • the compound and the drug are administered sequentially.
  • the drug is administered within 1 h of the administration of the compound.
  • the drug is administered within 45 minutes, such as within 30 minutes, such as within 15 minutes, such as within 5 minutes, such as within 1 minute, of the administration of the compound.
  • the method results in a therapeutically relevant concentration of the drug in the blood.
  • the method of delivering a drug results in an enhanced mucosal uptake of the drug as compared to mucosal uptake of the drug in absence of the compound.
  • administration of the drug together with the compound results in that the flux of the drug is increased by at least two times, such as at least three times, such as at least four times as compared to mucosal uptake of the drug in absence of the compound.
  • the present invention relates to a drug delivery system comprising a disaccharide for delivery of a drug across a mucosal membrane. Said delivery across a mucosal membrane may also be referred to as a transmucosal delivery.
  • transmucosal refers to any route of administration via a mucosal membrane. Examples include, but are not limited to, buccal, sublingual, nasal, vaginal, and rectal.
  • mucosal membrane is buccal mucosa, and hence, the administration is buccal.
  • the mucosal membrane is sublingual mucosa, and hence, the administration is sublingual.
  • the disaccharide is a compound as defined herein. In one embodiment, the disaccharide is a sulfated 4-0- ⁇ -D-galactopyranosyl)-D-glucosamine. In one embodiment, the disaccharide is a sulfated methyl 4-0- ⁇ -D-galactopyranosyl)- D-glucopyranoside.
  • the drug delivery system comprises a diclofenac and a disaccharide selected from the group consisting of sulfated 4-0-(b-0- galactopyranosyl)-D-glucosamines and sulfated methyl 4-0- ⁇ -D-galactopyranosyl)-D- glucopyranosides.
  • the present invention relates to a compound or composition as defined herein for use as a medicament.
  • the composition is suitable to use in the treatment of the same indications as the drug encompassed in the composition.
  • the drug is diclofenac, which may be used to treat pain
  • the composition as defined herein comprising diclofenac may be used in the treatment of pain.
  • This material was dissolved in water : methanol (1 : 1) and injected into the basic ion exchange column (Varian mega bond elut NH2, pH 9.8). The column was washed (3 x 10mL methanol) and eluted with ammonia solution in water : methanol (1 : 1) (3 x 20mL). The resulting solution was lyophilized to afford target material, 1 H-NMR showing absence of pyridine. The material was re-dissolved in 5 mL of water, filtered through a syringe filter and lyophilized afford target material.
  • A-LS and B-HS as described in Example 1 were investigated. All samples were prepared in a 0.1 M deuterated phosphate buffer with 0.1 M NaCI, pD 7.8.
  • the buffer was prepared by dissolving 38.35 mg KH2PO4, 217.34 mg Na 2 HP0 4 . 2H 2 0, and 88.16 mg NaCI in 12 mL of D20.
  • 30 pL 10 mM DSS (4,4- dimethyl-4-silapentane-1 -sulfonic acid) in D 2 0 was added as internal chemical shift calibration standard.
  • the pH was adjusted by adding 14 pL 0.6 M DCI until pD 7.8 was reached.
  • the buffer was subsequently diluted with D 2 0 up to a total volume of 15 mL.
  • the experiment shows the disaccharides to have a penetration enhancing effect of diclofenac through oesophageal mucosa. Furthermore, sulfation is important for the permeation enhancing effect, and the most efficient enhancer, B-HS, increases the penetration of diclofenac more than 10 times at the first two measuring points.
  • Example 4 Permeation enhancing effect with different counter ion and vehicle
  • a new batch of B-HS was prepared similarly to the description in Example 1.
  • the overall estimate of sulfation (by NMR) was 2.6 equivalents per disaccharide molecule. Ion change was performed for some of the material, creating two preparations differing only in counter ion; one with pyridine, one with ammonium.
  • Permeation of diclofenac was investigated similarly to Example 3, although the receptor solution was collected at shorter intervals; between 0-0.5, 0.5-1, 1-2, 2-4 and 4-8 h.
  • Four donor formulations were prepared using PBS, diclofenac and the two preparations of B-HS, see table 4.
  • the experiment shows that counter ion does not affect the permeation enhancing effect of diclofenac through oesophageal mucosa due to B-HS. Furthermore, saliva is not important for the permeation enhancing effect as it remains when PBS is used as vehicle.
  • Example 5 Permeation enhancing effect at lower concentrations of B-HS Permeation of diclofenac was investigated similarly to Example 3, although the receptor solution was collected at different intervals; between 0-1, 1-2, 2-4, 4-8 and 8- 24 h.
  • Four donor formulations were prepared using PBS, diclofenac and the pyridine preparation of B-HS, see table 7. Table 7. Compositions in % (w/w).
  • a new batch of B-HS with ammonium as counter ion was prepared similarly to the description in Example 1.
  • the overall estimate of sulfation (by NMR) was 4.8 equivalents per disaccharide molecule.
  • Permeation of diclofenac was investigated similarly to Example 3, although the receptor solution was collected at different intervals; between 0-1, 1-2, 2-4, 4-8 and 8-24 h.
  • Four donor formulations were prepared using PBS, diclofenac and the pyridine preparation of B-HS at 2.6 equivalents of sulfation (as used in Examples 4 and 5) or the new ammonium preparation of B-HS, see table 10.

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Abstract

La présente invention concerne des composés disaccharides et leur utilisation en tant qu'activateurs d'absorption transmucosale de médicaments.
PCT/EP2020/086490 2019-12-17 2020-12-16 Disaccharides sulfatés utilisés en tant qu'activateurs d'absorption transmucosale de médicaments WO2021122793A1 (fr)

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JP3418423B2 (ja) * 1993-03-03 2003-06-23 久光製薬株式会社 経粘膜投与用薬剤組成物
WO2011036521A2 (fr) * 2009-09-25 2011-03-31 Dr. Reddy's Laboratories Limited Formulations comprenant des composés triptan
WO2012045009A2 (fr) * 2010-09-30 2012-04-05 Normoxys, Inc. Dérivés de saccharides polyphosphatés et pyrophosphatés
WO2012068147A1 (fr) * 2010-11-15 2012-05-24 The Ohio State University Research Foundation Systèmes mucoadhésifs à libération contrôlée
WO2017072774A1 (fr) * 2015-10-29 2017-05-04 Solubest Ltd Compositions pharmaceutiques pour administration par voie transmuqueuse
WO2018035050A1 (fr) * 2016-08-16 2018-02-22 Opko Pharmaceuticals, Llc Disaccharides heptasulfatés purs à biodisponibilité orale améliorée
WO2018054959A1 (fr) * 2016-09-20 2018-03-29 Aarhus Universitet Composés destinés au traitement de troubles du métabolisme des lipoprotéines

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Publication number Priority date Publication date Assignee Title
JP3418423B2 (ja) * 1993-03-03 2003-06-23 久光製薬株式会社 経粘膜投与用薬剤組成物
WO1996039129A1 (fr) * 1995-06-06 1996-12-12 Queen's University At Kingston Procede permettant d'accroitre le depot de plaques amyloides
WO2011036521A2 (fr) * 2009-09-25 2011-03-31 Dr. Reddy's Laboratories Limited Formulations comprenant des composés triptan
WO2012045009A2 (fr) * 2010-09-30 2012-04-05 Normoxys, Inc. Dérivés de saccharides polyphosphatés et pyrophosphatés
WO2012068147A1 (fr) * 2010-11-15 2012-05-24 The Ohio State University Research Foundation Systèmes mucoadhésifs à libération contrôlée
WO2017072774A1 (fr) * 2015-10-29 2017-05-04 Solubest Ltd Compositions pharmaceutiques pour administration par voie transmuqueuse
WO2018035050A1 (fr) * 2016-08-16 2018-02-22 Opko Pharmaceuticals, Llc Disaccharides heptasulfatés purs à biodisponibilité orale améliorée
WO2018054959A1 (fr) * 2016-09-20 2018-03-29 Aarhus Universitet Composés destinés au traitement de troubles du métabolisme des lipoprotéines

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CEDENO-LAURENT FILIBERTO ET AL: "Development of a Nascent Galectin-1 Chimeric Molecule for Studying the Role of Leukocyte Galectin-1 Ligands and Immune Disease Modulation", THE JOURNAL OF IMMUNOLOGY, vol. 185, no. 8, 15 September 2010 (2010-09-15), US, pages 4659 - 4672, XP055792023, ISSN: 0022-1767, Retrieved from the Internet <URL:https://www.jimmunol.org/content/jimmunol/185/8/4659.full.pdf?with-ds=yes> DOI: 10.4049/jimmunol.1000715 *
CONSORTIUM FOR FUNCTIONAL GLYCOMICS: "Core H -Printed Array Version 4", 1 December 2008 (2008-12-01), pages 1 - 21, XP055792059, Retrieved from the Internet <URL:http://glycomics.scripps.edu/CoreH/CoreHarray112608v4.pdf> [retrieved on 20210331] *
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