WO2021122793A1 - Sulfated disaccharides as enhancers of transmucosal drug uptake - Google Patents

Sulfated disaccharides as enhancers of transmucosal drug uptake Download PDF

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Publication number
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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French (fr)
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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.

Abstract

The present invention relates to disaccharide compounds and their use as enhancers of transmucosal drug uptake.

Description

SULFATED DISACCHARIDES AS ENHANCERS OF TRANSMUCOSAL DRUG UPTAKE
Technical field
The present invention relates to disaccharide compounds and their use as enhancers of transmucosal drug uptake.
Background
There are several routes for administering pharmaceuticals, each with their virtues and drawbacks. Per-oral drug delivery - the ingestion of pharmaceuticals - e.g. tablet or liquid, is a convenient and largely accepted route of administration for the patients. Depending on the drug that is ingested there are however a number of drawbacks, including; a) Slow on-set, typically 30 minutes minimum. For treatment of pain, allergy, nausea time to on-set is an important factor b) Potentially low bioavailability due to first pass metabolism or poor permeability of the drug in the intestine. This requires higher per oral dosing, increasing the risk for adverse side effects in the gastro-intestinal tract. Furthermore, 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 formidable barrier and drug permeability is low. This, in conjunction with a small surface area and the constant flow of saliva, means that most of the drug that is applied is ingested rather than absorbed by the mucosa. Nevertheless, oral mucosa drug administration has become increasingly interesting from a commercial point of view. Tablets, patches, gels, and films for buccal, sublingual or sublabial application are available for certain drugs or other substances. These formulations may aim to release the drug at the mucosa at an optimized rate such that more of the drug is absorbed by the mucosa rather than ingested. A low degree of permeability is still a limiting factor and it is only when this is overcome that the true potential of oral mucosal drug administration is unlocked.
Summary
The present inventors have developed disaccharide compounds capable of enhancing drug uptake across mucosa. Hence, in one aspect, the present invention relates to use of a compound or composition as defined herein as an enhancer of mucosal drug uptake. In a further aspect, 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. In one aspect, the present invention relates to a drug delivery system comprising a disaccharide for delivery of a drug across a mucosal membrane.
In one aspect, the present invention relates to a compound of formula (I):
Figure imgf000003_0001
Formula (I) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2;
R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2;
R6 is H, -S03, or -P03H2;
R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
In one aspect, the present invention relates to a composition comprising one or more compounds as defined herein and a drug.
In one aspect, the present invention relates to a compound or composition as defined herein for use as a medicament.
Description of Drawings
Figure 1. Flux of diclofenac over oesophageal mucosa (pg/cm2h), 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.
Figure 2. Cumulative fraction of applied diclofenac penetrated (%), 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.
Figure 3. Flux of diclofenac over oesophageal mucosa (pg/cm2h), 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/cm2h), 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 5. Flux of diclofenac 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.
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. Figure 7. Flux of diclofenac over oesophageal mucosa (pg/cm2h), see Example 6. 0.25 % (w/w) diclofenac with 0.04% B-HS pyridinium (filled triangles), 0.08% B-HS pyridinium (filled circles). 0.6% B-HS pyridinium (filled squares), or 0.63% B-HS ammonium were used as formulations. Three to four cells were used per formulation. Figure 8. Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa, see Example 6. 0.25 % (w/w) diclofenac with 0.04% B-HS pyridinium (filled triangles), 0.08% B-HS pyridinium (filled circles). 0.6% B-HS pyridinium (filled squares), or 0.63% B-HS ammonium were used as formulations. Three to four cells were used per formulation.
Detailed description Compound In one aspect, the present invention relates to a compound of formula (I):
Figure imgf000005_0001
Formula (I) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2; R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2; R6 is H, -S03, or -P03H2;
R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the compound is sulfated.
In one embodiment of the present invention, the compound is of formula (II):
Figure imgf000006_0001
Formula (II) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2;
R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2;
R6 is H, -S03, or -P03H2; R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the compound is of Formula (III):
Figure imgf000007_0001
Formula (III) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2;
R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2;
R5 is H, -S03, or -P03H2; R6 is H, -S03, or -P03H2;
R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
In one embodiment, R2 is -NH2. In another embodiment, R2 is -OH. In yet another embodiment, R2 is -0S03.
In one embodiment, R3 is H. In another embodiment, R3 is -S03. In one embodiment, R4 is -CH2OH. In another embodiment, R4 is -CH20S03. In yet another embodiment, R4 is -OH. In yet another embodiment, R4 is -0S03.
In one embodiment, R5 is H. In another embodiment, R5 is -S03.
In one embodiment, R6 is H. In another embodiment, R6 is -S03.
In one embodiment, R7 is H. In another embodiment R7 is -S03.
In one embodiment, the compound is of Formula (V):
Figure imgf000008_0001
wherein R16 is H or -S03;
R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03; R21 is H or -S03; and
R22 is H or -S03; or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is of Formula (VI):
Figure imgf000009_0001
Formula (VI) wherein
R16 is H or -S03;
R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03; R21 is H or -S03; and
R22 is H or -S03; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is of Formula (VII):
Formula (VII) wherein
R16 is H or -S03; R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03;
R21 is H or -SO3; and R22 is H or -SO3; or a pharmaceutically acceptable salt thereof.
In one embodiment, at least one of R16, R17, R18, R19, R20, R21, and R22 is -SO3. In one embodiment, at least two, such as at least three, such as at least four, such as at least five, such as at least six of R16, R17, R18, R19, R20, R21, and R22 is -SO3. In one embodiment, 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 R16, R17, R18, R19, R20, R21, and R22 is -SO3. In one embodiment, R18 and R22 are -SO3. In one embodiment, R16, R17, R19, R20, and R21 are H and R18 and R22 are -SO3.
In one embodiment, the compound is of Formula (IV): wherein R9 is H or -S03; R10 is H or -S03;
R11 is H or -S03;
R12 is H or -S03;
R13 is H or -S03;
R14 is H or -S03; and R15 is H or -S03; or a pharmaceutically acceptable salt thereof.
In one embodiment, at least one of R9, R10, R11, R12, R13, R14, and R15 is -S03. In one embodiment, at least two, such as at least three, such as at least four, such as at least five, such as at least six of R9, R10, R11, R12, R13, R14, and R15 is -S03. In one embodiment, 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 R9, R10, R11, R12, R13, R14, and R15 is -S03.
In one embodiment, 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.
In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, the compound is sulfated with 2 to 5 equivalents of sulfate units per disaccharide molecule.
Drug
As used herein "drug" includes any bioactive agent having a therapeutic effect in an animal. The term “drug” may be used interchangeably with the term active pharmaceutical ingredients (API).
In one embodiment, the drug is a small molecule. As used herein, the term "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. In one embodiment, the drug has a molecular weight of less than 500 g/mol. In one embodiment, the drug is negatively charged at neutral pH. As used herein, the general use of the term "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. One of skill the art will appreciate that minor fluctuations (e.g., tenths or hundredths) can occur when measuring with a pH meter.
In one embodiment, the drug is diclofenac, i.e. [2-(2,6-Dichloroanilino)phenyl]acetic acid.
Composition
In one aspect, the present invention relates to a composition comprising one or more compounds as defined herein and a drug. Preferably, the composition is a pharmaceutical composition. In one embodiment, the composition further comprises one or more excipients, such as excipients that are pharmaceutically acceptable. The choice of excipient depends to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The term "excipient" encompasses for example diluents, carriers or adjuvants.
In one embodiment, the pharmaceutical composition is formulated for administration across a mucosal membrane. In one embodiment, the mucosal membrane is in the oral cavity. In one embodiment, the mucosal membrane is buccal and/or sublingual mucosa. In one embodiment, the administration is buccal, sublingual and/or sublabial administration.
In one embodiment, the pharmaceutical composition if formulated as a gel, a film, a tablet or a patch. In a preferred embodiment, 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.
Penetration enhancer
In one aspect, the present invention relates to use of a compound or composition as defined herein as an enhancer of mucosal drug uptake. In other words, 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. Thus, in one embodiment, the compound as defined herein is a penetration enhancer of the drug as defined herein. In one embodiment, the penetration enhancer accelerates the delivery of a substance through the mucosa. In one embodiment, the compound as defined herein function as/is an enhancer of transmucosal drug uptake.
In one embodiment, 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. In one embodiment, 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.
Administration
In one aspect, 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 phrase “delivering a drug across a mucosal membrane” is equal to the phrase “transmucosal drug delivery”.
As used herein, "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.
As used herein, the term “mucosa” or “mucosal membrane” 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. In general the mucosa is composed of two types of layers, the outer epithelial layer and inner lamina propria. Different mucosal tissues contain specialized tissues. The mucosa may for example be oral mucosa, rectal mucosa, vaginal mucosa, nasal mucosa or ophthalmic mucosa.
In one embodiment, 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. Thus, in one embodiment, the mucosal membrane is in the oral cavity. Thus, the mucosal membrane may be an "oromucosal membrane", which, as used herein, refers to buccal, buccomaxillary sublingual, gingival, buccogingival and palatal membranes.
In one embodiment, 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.
In one embodiment, 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. For example, 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.
In one embodiment, the compound and the drug are administered simultaneously. In one embodiment, the drug and the compound are in a composition, such as in a composition as defined herein.
In one embodiment, the compound and the drug are administered sequentially. In one embodiment, the drug is administered within 1 h of the administration of the compound. In one embodiment, 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. In one embodiment, the method results in a therapeutically relevant concentration of the drug in the blood.
In one embodiment, 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. In one embodiment, 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. As used herein, the term, "flux" is defined as the absorption of the drug through the mucosa, and may be described by Fick's first law of diffusion: J=-D(dCm/dx), where J is the flux in g/cm2/sec, D is the diffusion coefficient of the drug through the skin or mucosa in cm2/sec and dcm/dx is the concentration gradient of the drug across the mucosa.
Drug delivery system
In one aspect, 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. The term "transmucosal," as used herein, refers to any route of administration via a mucosal membrane. Examples include, but are not limited to, buccal, sublingual, nasal, vaginal, and rectal. In one embodiment, mucosal membrane is buccal mucosa, and hence, the administration is buccal. In one embodiment, the mucosal membrane is sublingual mucosa, and hence, the administration is sublingual.
In one embodiment, 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.
In one embodiment, 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. Medical use
In one aspect, the present invention relates to a compound or composition as defined herein for use as a medicament. In one embodiment, the composition is suitable to use in the treatment of the same indications as the drug encompassed in the composition. For example, when the drug is diclofenac, which may be used to treat pain, then the composition as defined herein comprising diclofenac may be used in the treatment of pain.
Examples
Example 1 - Synthesis of two sulfated disaccharides
Two different disaccharides, A) Methyl 4-0-^-D-galactopyranosyl)-D-glucopyranoside, CAS No. 2152-98-9, and B) 4-0-^-D-Galactopyranosyl)-D-glucosamine, CAS No. 13000-25-4, were used as starting material acquired from Carbosynth Ltd as well as to use as reference material in the NMR characterisation.
Synthesis of sulfated methyl 4-0-(3-D-galactopyranosyl)-D-glucopyranoside (A-LS); Under argon atmosphere, methyl 4-0-(3-D-galactopyranosyl)-D-glucopyranoside (200 mg, 0.56 mmol) was dissolved in dry DMF and the resulting solution was cooled to - 20°C. Sulfur trioxide pyridine complex (125 mg, 0.78 mmol, 1.4 eq) was added in portions. The reaction mixture was stirred at -20°C overnight, evaporated to dryness. 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, 1H-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.
Synthesis of 4-0-(3-D-galactopyranosyl)-D-glucosamine (B-HS): Under Argon atmosphere, 4-0-(3-D-galactopyranosyl)-D-glucosamine (100 mg, 0.29 mmol) was dissolved in dry DMF and the resulting solution was cooled to -20°C. Sulfur trioxide pyridine complex (260 mg, 1.64 mmol, 5.6 eq) was added in portions. The reaction mixture was stirred at -20°C overnight, evaporated to dryness. The resulting material was subjected to ion exchange procedure, carried out similarly to the synthesis of A- LS, to afford target material, 1H-NMR showing absence of pyridine.
Estimation of sulfate incorporation into disaccharides by NMR: Two-dimensional (2D) proton-carbon (1H-13C) HSQC spectra recorded on a 500 MHz NMR spectrometer were used to estimate the degree of sulfation. With respect to the degree of the overall sulfation of C2, C3, C4 and C6, in respective sugar unit, an estimate was obtained from integration of the 2D peaks. For A-LS the overall estimate was 0.5-0.6 equivalents of sulfate per disaccharide molecule with more than half of these incorporated sulfate groups attached to the 6-positions of the galactose and glucose rings. For B-HS the overall estimate was 2.5 equivalents of sulfate per disaccharide molecule with more than half of these incorporated sulfate groups attached to the 6-positions of the galactose and glucoseamine rings.
This Example demonstrate preparation of compounds of Formula (I), such as compounds of Formulas (IV) and (V) as defined herein.
Example 2 - Interactions between sulfated disaccharides and drug molecules
Using a 1 D 1H NMR assay interactions between the drug molecule diclofenac and the two sulfated disaccharides, 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 Na2HP04 . 2H20, and 88.16 mg NaCI in 12 mL of D20. 30 pL 10 mM DSS (4,4- dimethyl-4-silapentane-1 -sulfonic acid) in D20 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 D20 up to a total volume of 15 mL.
A 500 MHz Varian Inova spectrometer equipped with a 5 mm 1H/13C/15N triple resonance probe was used for the performed NMR experiments. Spectra were recorded at 25°C.
The 1 D 1H spectra were recorded using a standard 1D experiment with the sequence “s2pul” in VnmrJ 2.3. DSS (4, 4-dimethyl-4-silapentane-1 -sulfonic acid) was used chemical shift reference standard for 1H chemical shifts with the dimethyl signal set to 0 ppm. NMR data were processed and analysed using MestReNova 12.0.1 (Mestrelab Research S.L.). Chemical shifts of the drug molecule were compared before and after addition of the sulfated disaccharides. No change in chemical shift or broadening effects was observed for diclofenac in combination with each of the two sulfated disaccharides. Furthermore, no change in chemical shifts or broadening effects could be observed for the disaccharides in combination with diclofenac. Thus, it can be concluded that no interactions between diclofenac and the studied disaccharides can be detected at millimolar concentrations. Example 3 - Permeation enhancing effect in porcine oesophagus
In vitro penetration of diclofenac was determined using 14 Bronaugh diffusion cells. Oesophageal mucosa from pig were used as membranes, PBS was used as receptor solution. Five donor formulations (1-5) were prepared using human saliva, diclofenac and the four disaccharides, A, A-LS, B and B-HS as described in Example 1 , see table
1.
Table 1. Compositions in % (w/w).
Figure imgf000019_0001
Three cells for each donor formulation 1-4 were used, and two cells for the control (donor formulation 5). The cells were occluded and sodium azide was used in the receptor solution to avoid bacterial growth. The receptor solution was collected between 0-4, 4-8, 8-12 and 12-24 h and diclofenac content was analysed by HPLC. The flux of diclofenac over the membranes can be seen in Table 2 and Figure 1, while the cumulative fraction penetrated can be seen in Table 3 and Figure 2.
Table 2. Flux of diclofenac over oesophageal mucosa (pg/cm2h).
Figure imgf000019_0002
Table 3. Cumulative fraction of applied diclofenac penetrated (%).
Figure imgf000020_0001
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 For this experiment, 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.
Table 4. Compositions in % (w/w).
Figure imgf000020_0002
The flux of diclofenac over the membranes can be seen in Table 5 and Figure 3, while the cumulative fraction penetrated can be seen in Table 6 and Figure 4. Table 5. Flux of diclofenac over oesophageal mucosa (pg/cm2h).
Figure imgf000021_0001
Table 6. Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa (pg/cm2h).
Figure imgf000021_0002
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).
Figure imgf000022_0001
Oesophageal mucosa from two pigs where used, with 3+4 Bronaugh cells for each of the donor formulations 1-4
Normalized to reference, the flux of diclofenac over the membranes can be seen in Table 8 and Figure 5, while the cumulative fraction penetrated can be seen in Table 9 and Figure 6. Table 8. Flux of diclofenac over oesophageal mucosa, normalized to reference 0.25% (w/w) diclofenac.
Figure imgf000022_0002
Table 9. Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa, normalized to reference 0.25% (w/w) diclofenac.
Figure imgf000022_0003
The experiment shows that there is little or no difference in the permeation enhancing effect of diclofenac through oesophageal mucosa due changes in the concentration of B-HS in the range 0.15-2.37 % (w/w). Furthermore, the enhancing effect is most prominent during the early phase of the experiment. Example 6 - Permeation enhancing effect with higher sulfation level of B-HS
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.
Table 10. Compositions in % (w/w).
Figure imgf000023_0001
The flux of diclofenac over the membranes can be seen in Table 11 and Figure 7, while the cumulative fraction penetrated can be seen in Table 12 and Figure 8.
Table 11. Flux of diclofenac over oesophageal mucosa (pg/cm2h).
Figure imgf000023_0002
Table 12. Cumulative fraction of applied diclofenac penetrated over oesophageal mucosa.
Figure imgf000024_0001
The experiment shows that B-HS with a higher degree of sulfation has a similar permeation enhancing effect of diclofenac through oesophageal mucosa. Furthermore, it shows a concentration dependency and combined with Example 5 it makes 0.15% a likely lower limit to maintain the effect for the permeation of 0.25% diclofenac.

Claims

Claims
1. A compound of formula (I):
Figure imgf000025_0001
Formula (I) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2;
R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2;
R6 is H, -S03, or -P03H2;
R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
2. The compound according to any one of the preceding claims, wherein the compound is of formula (II):
Formula (II) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2;
R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2;
R6 is H, -S03, or -P03H2;
R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
3. The compound according to any one of the preceding claims, wherein the compound is of Formula (III):
Formula (III) wherein
R1 is H, Ci-s alkyl, -S03, or -P03H2; R2 is -OH, -NH2, -0S03, or -0P03H2;
R3 is H, -S03, or -P03H2;
R4 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; R5 is H, -S03, or -P03H2;
R6 is H, -S03, or -P03H2; R7 is H, -S03, or -P03H2; and
R8 is -CH2OH, -CH20S03, -CH20P03H2, -OH, -0S03, or -OP03H2; or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of the preceding claims, wherein R2 is - NH2.
5. The compound according to any one of the preceding claims, wherein R2 is - OH.
6. The compound according to any one of the preceding claims, wherein R2 is - 0S03.
7. The compound according to any one of the preceding claims, wherein R3 is H.
8. The compound according to any one of the preceding claims, wherein R3 is - S03.
9. The compound according to any one off the preceding claims, wherein R4 is - CH2OH.
10. The compound according to any one off the preceding claims, wherein R4 is - CH2OSO3.
11. The compound according to any one off the preceding claims, wherein R5 is H.
12. The compound according to any one off the preceding claims, wherein R5 is - S03.
13. The compound according to any one off the preceding claims, wherein R6 is H.
14. The compound according to any one off the preceding claims, wherein R6 is - S03.
15. The compound according to any one off the preceding claims, wherein R7 is H.
16. The compound according to any one off the preceding claims, wherein R7 is - S03.
17. The compound according to any one off the preceding claims, wherein R4 is - OH.
18. The compound according to any one off the preceding claims, wherein R4 is - OSOs.
19. The compound according to any one of the preceding claims, wherein the compound is of Formula (V): Formula (V) wherein
R16 is H or -S03; R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03;
R21 is H or -SO3; and R22 is H or -SO3; or a pharmaceutically acceptable salt thereof.
20. The compound according to any one of the preceding claims, wherein the compound is of Formula (VI):
Formula (VI) wherein
R16 is H or -S03;
R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03;
R21 is H or -SO3; and R22 is H or -SO3; or a pharmaceutically acceptable salt thereof.
21. The compound according to any one of the preceding claims, wherein the compound is of Formula (VII):
Formula (VII) wherein
R16 is H or -S03;
R17 is H or -S03;
R18 is H or -S03;
R19 is H or -S03;
R20 is H or -S03;
R21 is H or -SO3; and R22 is H or -SO3; or a pharmaceutically acceptable salt thereof.
22. The compound according to any one of the preceding claims, wherein at least one of R16, R17, R18, R19, R20, R21, and R22 is -SO3.
23. The compound according to any one of the preceding claims, wherein at least two, such as at least three, such as at least four, such as at least five, such as at least six of R16, R17, R18, R19, R20, R21, and R22 is -SO3.
24. The compound according to any one of the preceding claims, wherein 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 R16, R17, R18, R19, R20, R21, and R22 is -SO3.
25. The compound according to any one of the preceding claims, wherein R18 and R22 are -S03.
26. The compound according to any one of the preceding claims, wherein R16, R17,
R19, R20, and R21 are H and R18 and R22 are -S03.
27. The compound according to any one of the preceding claims, wherein the compound is of Formula
Figure imgf000032_0001
Formula (IV) wherein
R9 is H or -S03;
R10 is H or -S03;
R11 is H or -S03;
R12 is H or -S03;
R13 is H or -S03;
R14 is H or -S03; and R15 is H or -S03; or a pharmaceutically acceptable salt thereof.
28. The compound according to any one of the preceding claims, wherein at least one of R9, R10, R11, R12, R13, R14, and R15 is -S03.
29. The compound according to any one of the preceding claims, wherein at least two, such as at least three, such as at least four, such as at least five, such as at least six of R9, R10, R11, R12, R13, R14, and R15 is -S03.
30. The compound according to any one of the preceding claims, wherein 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 R9, R10, R11, R12, R13, R14, and R15 is -S03.
31. The compound according to any one of the preceding claims, wherein the compound is sulfated.
32. The compound according to any one of the preceding claims, wherein the compound is a sulfated 4-0-^-D-galactopyranosyl)-D-glucosamine.
33. The compound according to any one of the preceding claims, wherein the compound is a sulfated methyl 4-0-^-D-galactopyranosyl)-D-glucopyranoside.
34. The compound according to any one of the preceding claims, wherein 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.
35. The compound according to any one of the preceding claims, wherein 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.
36. The compound according to any one of the preceding claims, wherein 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.
37. The compound according to any one of the preceding claims, wherein the compound comprises two to five sulfate groups.
38. The compound according to any one of the preceding claims, wherein 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.
39. The compound according to any one of the preceding claims, wherein the compound is sulfated with 2 to 5 equivalents of sulfate units per disaccharide molecule.
40. A composition comprising one or more compounds according to any one of the preceding claims and a drug.
41. The composition according to any one of the preceding claims, wherein the composition is a pharmaceutical composition.
42. The composition according to any one of the preceding claims, wherein the drug is a small molecule.
43. The composition according to any one of the preceding claims wherein the drug has a molecular weight of less than 500 g/mol.
44. The composition according to any one of the preceding claims wherein the drug is negatively charged at neutral pH.
45. The composition according to any one of the preceding claims, wherein the drug is diclofenac.
46. The composition according to any one of the preceding claims, further comprising one or more excipients.
47. The composition according to any one of the preceding claims, wherein the pharmaceutical composition is formulated for administration across a mucosal membrane.
48. The composition according to any one of the preceding claims, wherein the mucosal membrane is in the oral cavity.
49. The composition according to any one of the preceding claims, wherein the mucosal membrane is buccal and/or sublingual mucosa.
50. The composition according to any one of the preceding claims, wherein the administration is buccal, sublingual and/or sublabial administration.
51. The composition according to any one of the receding claims, wherein the pharmaceutical composition if formulated as a gel, a film, a tablet or a patch.
52. The compound or composition according to any one of the preceding claims for use as a medicament.
53. A drug delivery system comprising a disaccharide for delivery of a drug across a mucosal membrane.
54. The drug delivery system according to any one of the preceding claims, wherein the mucosal membrane is in the oral cavity.
55. The drug delivery system according to any one of the preceding claims, wherein the mucosal membrane is buccal and/or sublingual mucosa.
56. The drug delivery system according to any one of the preceding claims, wherein the disaccharide is a compound according to any one of the preceding claims.
57. The drug delivery system according to any one of the preceding claims, wherein the disaccharide is a sulfated 4-0-^-D-galactopyranosyl)-D-glucosamine.
58. The drug delivery system according to any one of the preceding claims, wherein the disccharide is a sulfated methyl 4-0-^-D-galactopyranosyl)-D- glucopyranoside.
59. The drug delivery system according to any one of the preceding claims, wherein the drug is diclofenac.
60. A method for delivering a drug across a mucosal membrane, said method comprising administering a drug and the compound according to any one of the preceding claims to the mucosal membrane.
61. The method according to any one of the preceding claims, wherein the mucosal membrane is in the oral cavity.
62. The method according to any one of the preceding claims, wherein the mucosal membrane is a buccal and/or sublingual mucosa.
63. The method according to any one of the preceding claims, wherein the compound and the drug are administered simultaneously.
64. The method according to any one of the preceding claims, wherein the compound and the drug are administered sequentially.
65. The method according to any one of the preceding claims, wherein the drug is administered within 1 h of the administration of the compound.
66. The method according to any one of the preceding claims, wherein 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.
67. The method according to any one of the preceding claims, wherein the drug and the compound are in a composition.
68. The method according to any one of the preceding claims, wherein the drug is a small molecule.
69. The method according to any one of the preceding claims wherein the drug has a molecular weight of less than 500 g/mol.
70. The method according to any one of the preceding claims wherein the drug is negatively charged at neutral pH.
71. The method according to any one of the preceding claims, wherein the drug is diclofenac.
72. The method according to any one of the preceding claims, wherein the method results in an enhanced mucosal uptake of the drug as compared to mucosal uptake of the drug in absence of the compound or composition according to any one of the preceding claims.
73. The method according to any one of the preceding claims, wherein the method results in a therapeutically relevant concentration of the drug in the blood.
74. The method according to any one of the preceding claims, wherein the administration of the drug and 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 or composition according to any one of the preceding claims.
75. Use of a compound or composition according to any one of the preceding claims as an enhancer of mucosal drug uptake.
76. The use according to any one of the preceding claims, wherein the use of the compound 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.
77. The use according to any one of the preceding claims, wherein 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.
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