WO2020120519A1 - Traitement combinatoire par voie buccale de troubles métaboliques par libération orchestrée d'entérokines - Google Patents

Traitement combinatoire par voie buccale de troubles métaboliques par libération orchestrée d'entérokines Download PDF

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WO2020120519A1
WO2020120519A1 PCT/EP2019/084531 EP2019084531W WO2020120519A1 WO 2020120519 A1 WO2020120519 A1 WO 2020120519A1 EP 2019084531 W EP2019084531 W EP 2019084531W WO 2020120519 A1 WO2020120519 A1 WO 2020120519A1
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combination
oral dosage
dosage forms
dosage form
subject
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PCT/EP2019/084531
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English (en)
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Kai Deusch
Steffen-Sebastian Bolz
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Aphaia Pharma Ag
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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to pharmaceutical packages comprising at least two different pharmaceutical oral dosage forms each containing a core and an enteric coating, the cores each containing at least one compound stimulating enteroendocrine cells to release at least one enterokine and a disintegrant leading to a burst release of the core when the respective enteric coating is substantially dissolved and/or degraded, wherein each of the
  • pharmaceutical oral dosage forms exhibit a burst release of the respective core in different parts of the small intestine of a subject and/or the dosage forms exhibit different travelling times through the small intestine of the subject.
  • the active compounds of such combination of oral dosage forms can be the same or different in each of the dosage forms.
  • the present combination of pharmaceutical oral dosage form are used for prevention and/or treatment of disorders and conditions relating to the energy household of and metabolism in the, preferably human, body, but also conditions or disorders being the consequence of or relating to, respectively, malfunction of energy household and metabolism.
  • the technical problem underlying the present invention is to provide improved preventive and therapeutic measures against metabolic and cardiovascular disorders as well as other conditions relating thereto.
  • the present invention relates to a combination of at least two pharmaceutical oral dosage forms for use in the prevention and/or treatment of a condition, disorder or disease selected from the group consisting of insulin resistance, type 2 diabetes, non alcoholic fatty liver disease, non-alcoholic steatohepatosis, microvascular dysfunction, metabolic syndrome, obesity, osteoporosis, neurodegenerative diseases, cardiovascular diseases, malabsorption conditions and conditions of impaired gastro-intestinal function in a subject
  • a condition, disorder or disease selected from the group consisting of insulin resistance, type 2 diabetes, non alcoholic fatty liver disease, non-alcoholic steatohepatosis, microvascular dysfunction, metabolic syndrome, obesity, osteoporosis, neurodegenerative diseases, cardiovascular diseases, malabsorption conditions and conditions of impaired gastro-intestinal function in a subject
  • the combination comprises at least a first and a second dosage form each comprising a core and a pH-sensitive enteric coating, wherein each core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, and at least one
  • At least one compound stimulating enteroendocrine cells to release at least one enterokine of said first and second dosage form can be the same or different.
  • the rationale of the present invention is to address a large as possible population of enteroendocrine cells in the small intestine of a subject, preferably a human subject, in particular a subject suffering or being danger of or being suspected to develop one ore more of the above conditions, diseases or disorders, to release one or more enterokines, in particular to release a substantial amount of said one or more enterokines over its/their baseline level(s) in that subject so as to improve or normalize the energy household and/or metabolism in said subject leading in return in improvement, at best cure, and/or prevention of the conditions, diseases or disorders stated above and further below.
  • A“pharmaceutical oral dosage from” according to the invention is a pharmaceutical composition typically formulated such that it is suitable for oral administration to a subject, preferably a human patient.
  • Preferred oral dosage forms for use in the invention include tablets, capsules, pellets and granules.
  • An“enteroendocrine cell” (EEC) as used in the present invention is a cell present in a subject’s, preferably, human subject’s, intestine, in particular in the small intestine’s mucosa, and secretes one or more enterokines upon receiving an appropriate trigger by a nutritional component.
  • enteroendocrine cells There are several types of enteroendocrine cells which can be addressed by the active compound or compounds released by the pharmaceutical dosage form of the invention (for a review of enteroendorine cells of the lower gastrointestinal tract, see, for example, Gunawardene et al. (2011) Int. J. Exp. Pathol. 92, 219-231 , and Latorre et al.
  • enteroendocrine cells in the context of the invention are I cells, K cells and L cells with L cells being most preferred.
  • an“enterokine” ' is a hormone secreted by EECs in the gastro intestinal system.
  • Preferred enterokines are the incretins, i.e. hormones regulating the blood sugar level upon intake of nutrition, preferably GLP-1 , GLP-2 GIP and PYY, more preferably GLP-1 and PYY.
  • Other preferred enterokines secreted by the EEC(s) through release of the active compound(s) in the pharmaceutical dosage form are CCK and neurotensin.
  • I cells are predominantly present in the proximal small intestine, in particular in the lower duodenum and in the jejunum, and secrete cholecystokinin (CCK) upon sensing of nutrients such as amino acids and fatty acids.
  • CCK effects the release of bile acids from the gall bladder into the small intestine, but also promotes the release of digestive secrete from the pancreas.
  • GIP glycose-dependent insulinotropic peptide
  • L cells are present throughout the small intestine, i.e. duodenum, jejunum, and ileum, and release GLP-1 (glucagon-like peptide 1), GLP-2 (glucagon-like peptide 2) and PYY (peptide YY) in response to various nutrients.
  • the concentration of L cells raises from duodenum to jejunum to ileum, and the GLP-1 release from L cells shows a gradient sloping from proximal to distal small intestine with highest GLP-1 release capacity in the terminal ileum.
  • the gradient is not only a function of increasing number of L cells, but also a function of their maturation state and production rate of GLP-1 , which also increase from proximal to distal ileum.
  • GLP-1 is released from L cells in the crypts and on the villi of the mucosa.
  • L cells mature from crypt to villi, and GLP-1 release capacity is highest when the L cells reach the top of the villi.
  • L cells further secrete PYY (peptide YY) which is predominantly released in the terminal ileum.
  • PYY peptide YY
  • GLP-1 enhances nutrient-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying and feeding. GLP-1 also has proliferative, neogenic and antiapoptotic effects on pancreatic b-cells. As an intestinal trophic peptide, GLP-2 stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment,
  • GLP-2 improves intestinal barrier function. PYY inhibits gastric motility and increases water and electrolyte absorption in the colon. PYY also suppresses pancreatic secretion and has been shown to reduce appetite. PYY slows gastric emptying; whereby it increases efficiency of digestion and nutrient absorption after a meal.
  • EECs in particular L cells, are triggered to release enterokines such as GLP-1 and PYY through a variety of mechanisms being effected by the one or more active compound(s) in the pharmaceutical dosage form of the invention.
  • GLP-1 and PYY and also GLP-2; note that GLP-1 and GLP-2 are derived from a common mRNA so that these hormones are essentially co-released; cf. , for example, the review of Baggio and Drucker (2004) Best Practice & Research Clinical Endocrinology & Metabolism 18 (4), 531-554) in response to various mechanisms triggered by compounds such as nutrients.
  • One mechanism includes intake of a carbohydrate such as glucose through glucose transporters GLUT2 and/or SGLT1.
  • Other mechanisms rely on the binding to specialized G protein-coupled receptors such as taste receptors, fatty acid receptors, bile acid receptors, peptide receptors and amino acid receptors.
  • GLP-1 and PYY transmembrane calcium influx, intracellular calcium release and/or intracellular cAMP increase.
  • the various cellular mechanisms leading to release of enterokines such as GLP-1 and PYY by EECs are schematically depicted in Fig. 3.
  • the active compound(s) triggering the release of an enterokine through an EEC are preferably selected from nutrients, and more preferred active compounds include carbohydrates, fatty acids, bile acids, peptides (including oligopeptides, polypeptides and proteins), amino acids, alcohol amides and anthocyanins.
  • Preferred fatty acids are fatty acids having 2 to 6 carbon atoms.
  • Ethanolamides such as oleoylethanolamide, anandamide (N- arachidonoylethenolamide, AEA), palmitoylethanolamide, steaorylethanolamide, and derivatives of anandaminde such as prostamides, can also preferably be used as alcohol amide compounds in the inventive oral dosage forms.
  • a particularly preferred ethanolamide is oleoylethanolamide (OEA).
  • a preferred example of a peptidic active compound is the protein bovine serum albumin (BSA).
  • Carbohydrates are preferably selected from glucose and sucralose, with glucose being most preferred.
  • at least one of the first and second pharmaceutical dosage forms contains about 1 % (w/w) to about 80 % (w/w), more preferably 60 to 70 % (w/w) of active compound triggering the EECs, preferably a carbohydrate, most preferred glucose.
  • At least one of the first and second pharmaceutical oral dosage forms contains as an active compound an anthocyanin, more preferably one or more anthocyanins from Vaccinium myrtilloides Michx.
  • Anthocyanin to be included in the core of one or both of the at least first and second pharmaceutical oral dosage forms of the invention is delphinidin 3-rutinoside.
  • one or more of the above active compounds triggering enterokine release by EECs are combined in preferably synergistic combinations.
  • each of the at least first and second pharmaceutical oral dosage forms can comprise one or more active compounds.
  • active compounds are combined wherein one of the at least first and second pharmaceutical oral dosage forms contains an active compound as disclosed herein that is different from the active compound contained in the other (or others) of the at least first and second pharmaceutical oral dosage forms.
  • one of said first and second oral dosage forms contains a carbohydrate and the other one of said first and second oral dosage forms contains at least one compound selected from fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, alcohol amides, peptides, amino acids and anthocyanins.
  • one of said first and second oral dosage forms contains a fatty acid having 2 to 6 carbon atoms and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, oleic acid, bile acids, alcohol amides, peptides, amino acids and anthocyanins.
  • one of said first and second oral dosage forms contains oleic acid and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, fatty acids having 2 to 6 carbon atoms, bile acids, alcohol amides, peptides, amino acids and anthocyanins.
  • one of said first and second oral dosage forms contains a fatty acid having 2 to 6 carbon atoms and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, alcohol amides, peptides, amino acids and anthocyanins.
  • Another preferred embodiment is a combination of active compounds wherein one of said first and second oral dosage forms contains a peptide and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, amino acids and anthocyanins.
  • one of said first and second oral dosage forms contains an amino acid and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, alcohol amides, peptides, and anthocyanins.
  • one of said first and second oral dosage forms contains an anthocyanin and the other one of said first and second oral dosage forms contains at least one compound selected from carbohydrates, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, alcohol amides, peptides and amino acids.
  • differential targeting of EECs through the inventive combination of pharmaceutical oral dosage forms can be effected in various ways.
  • the differential targeting of EECs is effected by different sizes of the at least first and second pharmaceutical dosage forms which lead to different travelling times through the small intestine.
  • one of said first and second pharmaceutical oral dosage forms has a size of 3 mm or more, based on the largest dimension of said oral dosage form, and wherein the other of said first and second pharmaceutical dosage forms has a size of less than 3 mm, based on the largest dimension of said other oral dosage form.
  • larger oral dosage forms e.g. tablets, capsules
  • larger oral dosage forms having a largest dimension of 3 mm or more (upper encircled area in the middle diagram) behave like solid food as regards the rate of gastric emptying.
  • Such larger oral dosage forms show a lag phase after ingestion, slow gastric emptying, they travel slow through the small intestine, and are fractionated into separate boli (in the case of multiple tablets or capsules and the like, fractionation of the overall orally administered dose) through periodic pyloric sphincter opening.
  • small oral dosage forms of less than 3 mm in their largest dimension behave like fluids (lower encircled area in the middle diagram). They show no lag phase in gastric emptying which follows instantaneously after ingestion. Consequently, such small oral dosage forms travel much faster through the small intestine as compared to dosage forms having 3 mm or more in their largest dimension, and exhibit only a limited fractionation of the overall dose administered.
  • a typical range for larger pharmaceutical oral dosage forms for use in the invention are dosage forms having a largest dimension of about 3 to about 10 mm. It is to be understood that this range includes all integers of mm, namely, 3, 4, 5, 6, 7, 8, 9 and 10 mm as well as any sub-proportions thereof.
  • Preferred small pharmaceutical oral dosage forms for use in the invention are dosage forms having a largest dimension of about 0.6 mm to about 1.7 mm in the largest dimension.
  • the differential targeting of the at least first and second pharmaceutical oral dosage forms is attained by providing one of the at least first and second dosage forms with an enteric coating comprising a pH sensitive polymer being selected such that the coating substantially dissolves and/or is substantially degraded in the jejunum, preferably the terminal jejunum, of a subject, and wherein the other of said first and second dosage forms has an enteric coating comprising a pH sensitive polymer being selected such that the coating substantially dissolves and/or is substantially degraded in the ileum, preferably the terminal ileum, of a subject.
  • the pH-sensitive polymer for the oral dosage targeted to the jejunum substantially dissolves and/or degrades at a pH of from about 6.8 to about 7.4, preferably at a pH of from about 7.0 to about 7.3, more preferred at a pH of from about 7.2 to 7.3, whereas the pH sensitive polymer for the oral dosage form targeted to the ileum substantially dissolves at a pH of about 7.5 or above, preferably at a pH of from about 7.5 to 7.8.
  • Such pH sensitive polymers are preferably selected from hydroxypropylmethyl celluloses (also called hereinafter“hypromelloses”) and anionic copolymers of methacrylic acid and methacrylmethacrylate.
  • the pH sensitive enteric coating containing or being made of hydroxypropylmethyl cellulose is hydroxypropylmethyl cellulose acetate succinate.
  • a highly preferred commercially available product of this kind is AQOAT®, particularly preferred AQOAT®-HF (Shin-Etsu Chemical Co., Chiyoda, Japan).
  • AQOAT® particularly preferred AQOAT®-HF (Shin-Etsu Chemical Co., Chiyoda, Japan).
  • Eudragit® polymers may also be used.
  • Eudragit® is commercially available from Evonik Healthcare & Nutrition GmbH, Essen, Germany.
  • Eudragit® FS30D is used as the pH sensitive polymer of the coating, or at least a part thereof.
  • the coating comprises or is made of a combination of a hydroxypropylmethyl cellulose and an anionic copolymer of methacrylic acid and methacrylmethacrylate.
  • a combination of coatings is applied such that typically a sub-coating of one pH sensitive polymer is applied as a first layer and a coating of a second pH sensitive polymer is applied on the sub-coating as a second layer.
  • the pH sensitive coating can comprise a sub-coating of or comprising, respectively, a hydroxypropylmethyl cellulose as a first layer, and a second coating comprising or being made of an anionic copolymer of methacrylic acid and methacrylmethacrylate provided as a second layer on the sub-coating.
  • the coating of the pharmaceutical oral dosage form of the invention comprises a coating comprising a first layer (sub-coating) comprising or being made of an anionic polymer of methacrylic acid and methacrylmethacrylate such as an Eudragit®, more preferably Eudragit® FS30D, and a second layer comprising or being made of a hydroxypropylmethyl cellulose such as
  • AQOAT® more preferably AQOAT®-HF. More preferably, the anionic copolymer of methacrylic acid and methacrylmethacrylate, e.g. an Eudragit®, preferably Eurdragit®
  • FS30D is present in less amount than the hydroxypropylmethyl cellulose such as AQOAT®, more preferably AQOAT® ⁇ HF.
  • the thickness of the first layer of this type of combination is lower then the thickness of the second layer in this combination.
  • the ratio of amount or thickness, respectively, between first layer and second layer typically ranges from about 1 :10 to about 1 :50, particularly preferred from about 1 :20 to about 1 :30.
  • the active compound(s) in the core part of the pharmaceutical oral dosage forms are preferably further combined with active ingredients having various functions.
  • EEC maturation agents typically enhance the release capacity of the EECs, such as L cells, for the relevant enterokine, in the case of L cells GLP-1 and/or PYY and/or GLP-2.
  • Preferred EEC maturation agents include human milk oligosaccharides (HMO) and inhibitors of NOTCH signalling such as y- secretase inhibitors, preferably dibenzazepine.
  • HMOs are commercially available (Jennewein Biotechnologie GmbH, Rheinbreitbach, Germany) and preferred HMOs in the context of the invention include, but are not limited t, e.g. 2’-fucosyllactose, 3-fucosyllactose, 6’-sialyllactose and lacto-N-neotetraose as well as mixtures thereof.
  • the pharmaceutical oral dosage forms for use in the invention are designed to burst release the active ingredient(s) at the targeted area of the small intestine of a subject, preferably the duodenum, jejunum and/or ileum, more preferably the jejunum (particularly preferred the terminal jejunum) and/or the ileum (more preferably the terminal ileum), of the, preferably human, subject.
  • the core contains a disintegrant.
  • Disintegrants for use in the present invention are generally known in the art as rapidly expanding and dissolving when coming into contact with the targeted environment, typically, an aqueous environment as in the present invention, namely, the small intestine of a subject, preferably a human.
  • Disintegrants lead to rapid breakdown of the core of the pharmaceutical oral dosage forms for use in the invention when the core comes into contact of the aqueous medium present in the subject’s small intestine.
  • the disintegrant in the pharmaceutical dosage forms for use in the invention is selected such that more than 70 % of the core is released within two minutes or less or more than 85 % of the core is released within 5 minutes or less, following contact with water or an aqueous medium like the small intestine of a human subject.
  • a typical time line of a burst release of a pharmaceutical dosage form of the invention is depicted in Fig. 7.
  • Preferred disintegrants in the context of the invention are crosslinked polyvinylpyrrolidones, crosslinked carboxymethyl celluloses and modified starchs. Particularly preferred crosslinked
  • polyvinylpyrrolidones for use in the invention include Polyplasdones, in particular
  • Polyplasdone XL, Polyplasdone XL-10 and Polyplasdone INF-10 commercially available from Ashland Inc., Covington, KY, USA.
  • Other useful disintegrants include, but are not limited to, polyvinylpolypyrrolidone, croscarmellose and carboxymethylcellulose (preferably, the sodium salt thereof).
  • the burst release of the core’s ingredients in particular the active compound(s) such as glucose, establishes a steep gradient between intracellular and extracellular levels of the respective active compound(s), preferably glucose, sucralose, ethanolamides, BSA and/or an anthocyanine such as delphinidin 3-rutinoside, in the targeted EEC, preferably L cells, at the site of release of the core ingredients.
  • the active compound(s) such as glucose
  • the burst release of the active ingredient(s) from the pharmaceutical oral dosage forms of the invention in the different targeted areas of the small intestine a subject provides an improved triggering of EECs, in particular L cells, since the compound(s) sensed by the EECs can access the target cells, preferably L cells, over the whole small intestine such that more enterokines, in particular GLP-1 and PYY, are produced and released by the EECs (see also Fig. 2 and its further description herein below).
  • a tracer substance is caffeine.
  • One example of a preferred combination of active compound and tracer substance is glucose and caffeine, preferably, about 60 to about 70 % (w/w) glucose and about 2 to about 4 % (w/w) caffeine, most preferred about 67 % (w/w) glucose and about 3.2 % (w/w) caffeine, based on the total weight of the core.
  • the release of the tracer substance from the pharmaceutical oral dosage form in the small intestine can be conveniently monitored by analytical methods generally known in the art.
  • analytical methods generally known in the art.
  • blood samples are taken from the subject before and at suitable time intervals after oral administration of the oral dosage form. After centrifugation of the blood sample, the caffeine content in the serum fraction of the sample is measured by ELISA testing using commercially available test kits (e.g. Caffeine ELISA Kit, BioVision Inc., Milpitas, CA, USA) according to the manufacturer’s instructions.
  • the pharmaceutical oral dosage forms for use in the invention may contain further ingredients typically present in oral dosage forms such as tablets, capsules, granules and pellets, for providing and/or improving various parameters.
  • Typical additional ingredients for use in the present invention include excipients, carriers, fillers, glidants, dispersants, plasticizers, wetting agents, anti-tacking agents, neutralization agents and the like.
  • the person skilled in the art of formulating pharmaceutical oral dosage forms is readily able to identify specific compounds and substances of the above and other types as well as their combinations and amounts to be used. Further guidance can be found in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, in particular pages 1289-1329.
  • the present invention further relates to a pharmaceutical package comprising at least a first pharmaceutical oral dosage form and a second oral dosage form wherein said first and second oral dosage forms are as defined as described above-
  • a further embodiment of the invention is a method for the prevention and/or treatment of a condition or disease selected from the group consisting of insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatosis, microvascular dysfunction, metabolic syndrome, obesity, osteoporosis, neurodegenerative diseases, cardiovascular diseases, malabsorption conditions and conditions of impaired gastro-intestinal function in a subject comprising the step of orally administering an effective amount of at least a first and a second pharmaceutical oral dosage form to the subject in need thereof wherein said at least first and second pharmaceutical oral dosage forms are as defined and described above.
  • the therapeutic and preventive, respectively aspect of the invention relating to impaired gastro-intestinal function is based on the known proliferative and antiapoptotic effect of enterokines as described herein, specifically GLP-1 and GLP-2, on cells of the gastro intestinal tract, especially of the gastro-intestinal mucosa (see, for example, Sigalet (2012) J. Anim. Sci. 90, 1224-1232; Aw et al. (2017) Asia-Pac. J. Clin. Oncol. 14, 23-31 ; and Kissow et al. (2012) Cancer Chemother. Pharmacol. 70, 39-48).
  • pharmaceutical oral dosage forms of the invention it is possible not only to prevent and/treat malabsorption disorders in affected subjects, but also to treat subjects, in particular human subjects, suffering from disorders, diseases and/or conditions of impaired gastro-intestinal function due to irregular gastro-intestinal growth (including reduced intestinal length and impaired/reduced formation of intestinal mucosa and villi, especially, and preferably, in neonatal and infant children, and/or due to disorders of the intestinal mucosa such as mucositis, preferably resulting from chemotherapy, radiotherapy and/or infections, especially in tumour and/or cancer patients.
  • This treatment aspect of the invention also comprises the prevention of the above gastro-intestinal disorders and diseases.
  • the at least first and second oral dosage forms can be administered sequentially or simultaneously. Simultaneous administration is preferred.
  • the combined administration of the pharmaceutical oral dosage forms as described and defined herein leads to a substantial increase of the addressed at least one enterokine, preferably GLP-1 , GLP-2, GIP, PYY, CCK and/or neurotensin, particularly preferred GLP-1 and/or GLP-2 and/or PYY, above the respective base-line level of the enterokine, in particular the level of the enterokine in the blood serum/plasma of the subject being treated.
  • enterokine preferably GLP-1 , GLP-2, GIP, PYY, CCK and/or neurotensin, particularly preferred GLP-1 and/or GLP-2 and/or PYY
  • the level of the respective enterokine in the subject’s blood serum/plasma increases by at least about 50 % or more, preferably about 50 % to about 200 % or even more such as about 300 %, as compared to the level in the blood plasma/serum of the subject before administration of the
  • the increase in enterokine concentration in the subject’s blood plasma/serum typically occurs within about 3 to about 6 hours post administration, preferably simultaneous administration, of the combination of pharmaceutical oral dosage forms as described herein.
  • the term“effective amount of the pharmaceutical oral dosage form(s)” depends on various factors such as the specific condition, disorder or disease to be treated and/or prevented, the age and sex of the subject as well as the general condition of the subject. Furthermore, the“effective amount of the pharmaceutical oral dosage form(s)” depends on the type of active compound(s) used. Typically, however, pharmaceutical oral dosage forms used in the invention are preferably administered once daily in one or more unit dosages, more preferably in the fasted state of the subject, particularly preferred at least about 30 min, more preferred at least about 45 min, even more preferred at least 1 hour before the first meal of the day.
  • the effective amount is preferably a daily dose of about 0.5 to about 6 g glucose orally administered in one or more unit dosages in the fasted state of the subject as outlined before.
  • a dose of about 1 to about 5.5 g once daily is more preferred, and about 5 g glucose once daily may be given as a particularly preferred regimen.
  • a typical unit dosage of glucose within a pharmaceutical oral dosage form as described herein is about 0.5 g to about 2 g, more preferably about 0.75 to about 1.5 g glucose such as ca. 1 g glucose per unit dosage.
  • the dosage form is formulated such that the at least one compound stimulating enteroendocrine cells to release an enterokine stimulates said cells present in the intestine of the subject from the jejunum to the ileo-cecal valve of the, preferably human, subject.
  • Fig. 1 illustrates GLP-1 and PYY release by L cells along the small intestine.
  • the left panel is a schematic representation of the gastro-intestinal tract of a human.
  • the human’s small intestine comprises, from gastric side to colon side, the three parts duodenum, jejunum and ileum.
  • L cells are present in the human small intestine from duodenum to ileum with the concentration and maturation of L cells increasing from proximal to distal small intestine. The highest concentration of L cells is found in the terminal (i.e. distal) ileum.
  • Panels on the right show the time dependency of GLP-1 and PYY, respectively, output of L cells in the jejunum (upper right panel) and in the ileum (lower right panel).
  • L cells Upon stimulation by nutrients, here exemplified by glucose, L cells release the enterokines GLP-1 and PYY, whereby GLP-1 is released from L cells throughout the small intestine (i.e. duodenum, jejunum and ileum), however, substantial release of GLP-1 starts in the jejunum and increases from proximal to distal small intestine with peak release in the terminal ileum.
  • PYY release is much lower in the jejunum and increases strongly only in the ileum where GLP-1 and PYY are co-released to substantially equal extend.
  • Fig. 2 shows a schematic representation of a cross-section of a villus in the mucosa of the small intestine of a human subject.
  • GLP-1 is released from L cells in the crypts and on the villi.
  • the GLP-1 release capacity per L cells increases with the maturation state of the L cell, i.e. it is highest when the L cells reach the top of the villi.
  • L cells start to synthesize PYY only at a higher maturation state.
  • the maturation of L cells can be accelerated by substances such as human milk oligosaccharides (HMO) and a variety of pathway inhibitors (e.g. NOTCH signalling inhibitors).
  • HMO human milk oligosaccharides
  • NOTCH signalling inhibitors e.g. NOTCH signalling inhibitors
  • L cell maturation enhancing substances with a nutrient like glucose or other active compound (such as anthocyanin) in the at least one of the combined oral dosage forms leads to a synergistic increase of GLP-1 and PYY by L cells.
  • Fig. 3 is a schematic representation showing the various molecular mechanisms by which a stimulus to an L cell is translated in the cell to a release of enterokines GLP-1 and PYY.
  • GLP-1 and PYY are released in response to stimuli that activate glucose transporters (GLUT2, SGLT1) and G protein-coupled receptors such as taste receptors, fatty acid receptors, amino acid receptors and bile acid receptors.
  • the signals generated by the glucose transporters or G-protein-coupled receptors are transmitted by three main mechanisms: transmembrane calcium influx, intracellular calcium release and intracellular cAMP release.
  • signalling events in L cells can be separated into three segments: (i) glucose transporter (GLUT2 and SGTL1) levels and levels of G protein-coupled receptors; (ii) the intracellular signalling pathway level (calcium and cAMP-dependent pathways); and (iii) the amount of fusion events of vesicles with the plasma membrane to release their content (release level).
  • glucose transporter GLUT2 and SGTL1
  • intracellular signalling pathway level calcium and cAMP-dependent pathways
  • release level the amount of fusion events of vesicles with the plasma membrane to release their content
  • release level the nature of the released enterokine does not depend on the stimulus or signalling pathways involved but exclusively on (a) the location of the L cell in the small intestine (duodenum, jejunum or ileum) and (b) on the maturation state of the L cell (corresponding to its position in the crypts or on the villi of the mucosa).
  • Fig. 4 illustrates the impact of the dimensions of pharmaceutical dosage forms on their behaviour in the gastrointestinal tract: larger oral dosage forms (e.g. tablets, capsules) having a largest dimension of 3 mm or more (upper encircled area in the middle diagram) behave like solid food as regards the rate of gastric emptying. Such larger oral dosage forms show a lag phase after ingestion, slow gastric emptying, they travel slow through the small intestine, and are fractionated into separate boli (in the case of multiple tablets or capsules and the like, fractionation of the overall orally administered dose) through periodic pyloric sphincter opening. On the contrary, small oral dosage forms of less than 3 mm in their largest dimension behave like fluids (lower encircled area in the middle diagram). They show no lag phase in gastric emptying which follows instantaneously after ingestion.
  • larger oral dosage forms e.g. tablets, capsules
  • larger oral dosage forms having a largest dimension of 3 mm or more (upper encircled area in the middle diagram) behave like solid
  • the differential targeting of the combination of small and larger oral dosage forms leads to an optimisation of the release of entorkines by the targeted EECs, in the present example GLP- 1 and PYY released by L cells.
  • Fig. 6 illustrates the combinatorial approach of the invention using different pharmaceutical oral dosage forms with different active compounds (here three oral dosage forms with three different active compounds A, B and C).
  • Fig. 7 shows a graphic representation depicting the data of online UV/VIS
  • spectrophotometric measurement of caffeine released from the core of a pharmaceutical oral dosage form of the invention in an aqueous buffer as indicated over time The data show a burst release of the core components: almost 70 % of the core contents are released into the buffer solution within less than 2 min, and more than 85 % are released within 5 min.
  • Fig. 8 shows graphical representations of experimental data obtained from GLUTag cells (as a cell culture model of human L cells, especially in terms of their stimulation properties to secrete enterokines; cf; Kuhre et al. (2016) J. Mol. Endocrinol.
  • A Data of GLP-1 release are expressed as fold increase in comparison to negative control (stimulation medium supernatant of cells without treatment by any stimulus)
  • B Data of GLP-1 release are expressed as GLP-1 concentration in the stimulation medium supernatant with signal of negative control (stimulation medium supernatant of cells without treatment by any stimulus) subtracted. Numbers in brackets above the columns indicate the number of independent experiment for each stimulant or control, respectively.
  • Fig. 9 shows graphical representations of dose response data of GLUTag cells stimulated with glucose (Fig. 9A), ethanolamide (Fig. 9B) or delphinidin 3-rutinoside (Fig. 9C) at the indicated concentrations.
  • Fig. 10 shows a graphical representation of experimental data obtained from GLUTag cells (as a cell culture model of L cells) stimulated by BSA at 0.5 % (w/v). GLP-1 concentration was measured in the stimulation medium supernatant.
  • the phosphodiesterase inhibitor 3- isobutyl-1 -methylxanthine (IBMX) was used as positive control. Negative control was stimulation medium supernatant only.
  • Example 1 Burst release tablet core
  • a core for a pharmaceutical oral dosage form for use in the invention has been developed to provide a burst release kinetic of disintegration in tap water or aqueous buffer of less than 2 min.
  • Glucose has been selected as an example of the active compound.
  • a glucose gentle direct compression process was used employing specific functional excipients to enable a good followability as well as processability and tablet properties on the one hand side and a fast disintegration and dissolution behaviour of glucose on the other hand. More specifically, the following excipients were selected:
  • lubricant and glidant agents selected as lubricant and glidant agents, respectively.
  • Breaking strength 245 N +/- 7 %
  • the tablet core of Example 1 was coated with AQOAT®-HF to provide an enteric coating and drug please at a specific pH value of >6.8, specifically at pH 7.3.
  • the tablet core of Example 1 was spray-coated using the following coating composition:
  • Example 1 The above coating was applied on the tablet core of Example 1 by using a LCH 25 Lodige lab-coater (Gebruder Lodige Maschinenbau GmbH, Paderborn, Germany).
  • the tablet core of Example 1 was coated with Eudragit® FS30D to provide an enteric coating and drug release at a pH value of >7.0, specifically at pH 7.3.
  • the tablet core of Example 1 was spray-coated using the following coating composition:
  • Example 1 The above coating was applied on the tablet core of Example 1 by using a LCH 25 Lodige lab-coater (Gebruder Lodige Maschinenbau GmbH, Paderborn, Germany).
  • Example 4 GLP-1 release of GLUTag cells in response to different active compounds
  • Murine GLUTag cells ATCC, Manassas, VA, USA
  • T25 T25 into 6 wells of a 12-well plate.
  • the resulting cells were 40-50% confluent and on day 2 the cells were 50-60% confluent.
  • the cells were mostly single cells or very small aggregates; with no large aggregates observable.
  • 300 pi of stimulation medium either non-supplemented PBS as negative control or PBS supplemented with 10mM FSK/IBMX (positive control), 10 mM glucose, 50 mM sucralose, 10 mM delphinidin 3-rutinoside or 100 mM oleoylethanolamide, were added to the cells. The cells were then incubated for 2 hours at 37°C.
  • the 300 mI of stimulation medium were removed from the well and centrifuged for 5 minutes. 200 mI of the supernatant were transferred to a fresh test tube and the samples were stored at -80°C until subjected to GLP-1 measurement. The cells were discarded.
  • GLP-1 in the supernatant was measured using a commercially available ELISA (Mouse GLP- 1 Elisa Kit, Chrystal Chem (Europe), Zaandam, The Netherlands) according to the manufacturer’s instructions.
  • Fig. 8 A: data expressed as fold increase of measured GLP-1 concentration in the sample over negative control; B: data expressed as GLP-1 concentration in the supernatant after subtraction of signal measured in negative control).
  • BSA (at a concentration of 0.5 % (w/v)) was used as a peptidic stimulant of GLP-1 release by GLUTag cells.
  • stimulation medium alone PBS
  • IBMX served as the positive control. The results are shown in Fig. 10.

Abstract

La présente invention concerne des emballages pharmaceutiques comprenant au moins deux formes différentes posologiques pharmaceutiques par voie buccale contenant chacune un cœur et un enrobage entérique, les cœurs contenant chacun au moins un composé stimulant les cellules entéroendocriniennes pour libérer au moins une entérokine et un agent délitant conduisant à une libération par poussée du cœur lorsque l'enrobage entérique respectif est sensiblement dissous et/ou dégradé, chacune des formes posologiques pharmaceutiques par voie buccale faisant preuve d'une libération par poussée du cœur respectif dans différentes parties de l'intestin grêle d'un sujet et/ou les formes posologiques faisant preuve de différents temps de déplacement à travers l'intestin grêle du sujet. Les composés actifs d'une telle combinaison de formes posologiques par voie buccale peuvent être identiques ou différents dans chacune des formes posologiques. La présente combinaison des formes posologiques pharmaceutiques par voie buccale est utilisée pour la prévention et/ou le traitement de troubles et d'états liés au ménage énergétique et au métabolisme, préférablement, dans le corps humain, mais également aux états ou troubles qui sont la conséquence ou qui sont liés, respectivement, au dysfonctionnement du ménage énergétique et du métabolisme.
PCT/EP2019/084531 2018-12-10 2019-12-10 Traitement combinatoire par voie buccale de troubles métaboliques par libération orchestrée d'entérokines WO2020120519A1 (fr)

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