WO2022195152A1 - Système d'administration en de multiples endroits pour l'administration différentielle dans le tractus gastro-intestinal - Google Patents

Système d'administration en de multiples endroits pour l'administration différentielle dans le tractus gastro-intestinal Download PDF

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Publication number
WO2022195152A1
WO2022195152A1 PCT/ES2022/070159 ES2022070159W WO2022195152A1 WO 2022195152 A1 WO2022195152 A1 WO 2022195152A1 ES 2022070159 W ES2022070159 W ES 2022070159W WO 2022195152 A1 WO2022195152 A1 WO 2022195152A1
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Prior art keywords
capsule
administration
digestive
protease
present
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PCT/ES2022/070159
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English (en)
Spanish (es)
Inventor
Massiel Esther CEPEDA MOLERO
Miguel Angel POZA VILLALBA
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Aora Health S.L.
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Publication of WO2022195152A1 publication Critical patent/WO2022195152A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals

Definitions

  • the present invention refers to the field of food, nutrition and medicine, more specifically to the field of supplements that help in the digestion and assimilation of food and nutrients, even more specifically, to a delivery system for the administration of adjuvants in the digestion and assimilation of food and nutrients (for example, different types of enzymes).
  • Digestive enzymes derived from microbes have been used in food production areas and in therapeutic applications for many years, especially in Asia. Varieties of lipase, amylase, protease and lactase have been developed from microbial species and have been used in the treatment of enzyme deficiencies. Microbial digestive enzymes have intrinsic advantages, being heat stable and resistant to gastric acid inactivation, unlike animal-derived digestive enzymes (porcine pancreatin), which is conventionally used for the treatment of pancreatic digestive disorders. Furthermore, microbially derived enzymes are more efficient, more stable, and have a broader pH range of activity.
  • microbial enzymes comprise different enzymes, which work in different pH conditions and this gives the option to select more specific enzymes for the pH of the stomach or intestine (de Souza, IA, et.al. (2019)
  • Enzymatic hydrolysis of starch into sugars is influenced by microgel assembly Biotechnol Rep 22, e00342, Vishwanatha KS, Appu Rao AG and Singh SA (2009) Characterization of acid protease expressed from Aspergillus oryzae MTCC 5341.
  • stomach and small intestine are necessary or desirable for proper treatment of digestive disorders.
  • the subject or patient is provided only with tablets or capsules comprising digestive enzymes (either porcine pancreatin, plant enzymes or microbial enzymes) and providing for administration of the digestive enzymes to one site, stomach or intestine.
  • digestive enzymes either porcine pancreatin, plant enzymes or microbial enzymes
  • the inventors of the present invention after extensive and exhaustive research, have surprisingly discovered a system that solves all the problems present in the state of the art and mentioned above.
  • the solution found by the present inventors comprises the appropriate combination of enzymes and/or digestive adjuvants that is provided in a multi-site administration system that ensures the administration of each digestive and/or enzyme adjuvant at the desired or required site in the digestive tract.
  • gastrointestinal In a first aspect, the present invention relates to a multi-site delivery system that provides for the delivery of digestive aids to at least two different sites in the gastrointestinal tract.
  • the present invention relates to a nutraceutical comprising the multi-site delivery system of the present invention.
  • the present invention relates to a pharmaceutical composition comprising the multi-site delivery system of the present invention.
  • the present invention relates to the use of a multi-site administration system or a pharmaceutical composition, both in accordance with the present invention, as a medicament, preferably for the prevention, treatment or improvement of a digestive disease, more preferably pancreatic secretion problems (preferably cystic fibrosis or chronic pancreatitis, more preferably digestive symptoms thereof), exocrine pancreatic disorders, symptoms associated with pancreatectomy (more preferably digestive symptoms associated with pancreatectomy, even more preferably, digestive enzyme support after pancreatectomy), Crohn's disease, functional dyspepsia, bloating, indigestion symptoms, digestive disorders, irritable bowel syndrome, high cholesterol, diarrhea (most preferably antibiotic-associated diarrhea), or excessive production of gases.
  • pancreatic secretion problems preferably cystic fibrosis or chronic pancreatitis, more preferably digestive symptoms thereof
  • exocrine pancreatic disorders symptoms associated with pancreatectomy (more preferably digestive symptoms associated with pancreatectomy, even more preferably, digestive enzyme support after pancreatectomy),
  • the present invention relates to the use of a multi-site delivery system or a pharmaceutical composition, both in accordance with the present invention, for the manufacture of a medicament for the treatment of a digestive disease.
  • the present invention relates to a method for treating a digestive disease in a subject in need thereof, comprising the administration of a therapeutically effective amount of a multi-site delivery system or a pharmaceutical composition, both in accordance with the present invention, to the subject.
  • the present invention relates to the use of a multi-site delivery system or a nutraceutical, both in accordance with the present invention, to improve digestion in a subject.
  • the present invention relates to the use of a multi-site delivery system or a nutraceutical, both in accordance with the present invention, to restore intestinal flora in a subject.
  • protease or its plural is accompanied by one or more numbers (eg, 3.0, 4.5, or 6.0), such number or numbers refer to the optimum pH. for the activity of said protease(s).
  • Granulate and its plural take on their usual meaning in the prior art, that is, free-flowing, small spherical particles made by agglomerating fine powders or granules of active substances. and excipients using appropriate processing equipment.
  • Granules are a type of multiparticulate system that have become an important and successful dosage form for immediate or modified active release.
  • the granules have a size in the range between 0.5 mm and 1.5 mm.
  • microencapsulated and its plural acquire the meaning that they normally have in the state of the art, that is, microparticles made up of a porous membrane containing an active substance.
  • the sealed microencapsulated can release their contained at controlled rates under specific conditions.
  • the materials used for encapsulation in microencapsulates can be, for example and without limitation, gelatin, fats, oils, gum arabic, calcium alginate, waxes, wheat starch, corn , rice, potato, nylon, cyclodextrin, maltodextrin, sodium caseinate, lecithin, whey protein or proteins from different sources
  • the microencapsulates have a size in the range between 50 nm and 1.5 mm.
  • liposome As used herein, the term "liposome” and its plural take on the meaning they normally have in the art, that is, extraordinarily small spherical vesicles composed primarily of phospholipids. Liposomes are a widely used type of system because they modify the pharmacokinetics of the active ingredient that they encapsulate, improving its solubility, bioavailability and stability in vitro and in vivo. The liposomes have a size in the range between 5 nm and 200 mm.
  • a capsule comprises a body and a cap.
  • the present invention refers to a multi-site administration system comprising: a first capsule, and an additional administration means, characterized in that the first capsule encapsulates the delivery means additional administration; in that each of the first capsule and the additional delivery means deliver at least one digestive aid; and in that the first capsule and the additional administration medium release their contents at a different pH.
  • Each of the first capsule and the additional delivery means directly deliver at least one digestive aid.
  • the multi-site delivery system of the present invention provides for differential delivery or delivery of digestive aids to at least two different sites in the gastrointestinal tract. That is, the digestive aids delivered by the first capsule are released into the medium (and thus provide their activity) at a site in the gastrointestinal tract and the digestive aids delivered by the additional delivery medium are released into the medium (and, therefore, they provide their activity) elsewhere in the gastrointestinal tract. It will be understood by the person skilled in the art that the above statement contemplates that a residual amount of the digestive aids from the additional administration medium will be released and perform their action at the administration site of the first capsule.
  • the additional means of administration may be any means known in the art to be suitable for the administration of the desired substance(s).
  • the additional means of administration is at least one tablet, at least one mini-tablet, at least one capsule, at least one microencapsulate, at least one liposome or at least one granulate, more preferably, the additional means of administration is a tablet, one or a plurality of mini-tablets, a capsule, one or a plurality of granules, one or a plurality of microencapsulates, or one or a plurality of liposomes.
  • the additional administration means is a capsule (second capsule within the system of the present invention) and, therefore, in this most preferred embodiment, the multi-site administration system of the present invention comprises: at least two capsules (more preferably two capsules), in which a first capsule encloses a second capsule, characterized in that both the first capsule and the second capsule each encapsulate at least one digestive aid and in that the first and second capsules release their content at a different pH.
  • the first capsule has a size between 00 and 1; most preferably a size of 00, 0 (body length 18.44mm and cap length 10.72mm) or 1 (body length 16.61mm and cap length 9.78mm). mm); more preferably 00 (body length 22.22 mm and cover length 11.74 mm).
  • the first capsule has a body length of between 16 and 25 mm and a cap length of between 9.5 and 12 mm; more preferably, the first capsule has a body length of 22.22 mm and a cap length of 11.74 mm.
  • the additional means of administration is at least one mini-tablet (preferably one or a plurality of mini-tablets)
  • said at least one mini-tablet has a diameter between 1.5 mm and 4 mm, more preferably between 1.5 mm and 3mm, even more preferably, said at least one mini-tablet has a diameter of 1.5mm, 2mm or 3mm.
  • the additional administration means is a capsule (second capsule), it is preferably 2 or more in size; more preferably it has a size between 2 and 5; more preferably, size 2 (body length 15.27mm and cap length 8.94mm), 3 (body length 13.59mm and cap length 8.08mm ), 4 (body length 12.19 mm and cap length 7.21 mm) or 5 (body length 9.30 mm and cap length 6.20 mm); even more preferably it has a size 2. Therefore, preferably the second capsule has a body length between 9 mm and 15.5mm and a cap length of between 6mm and 9mm, more preferably a body length of 15.27mm and a cap length of 8.94mm.
  • the at least one digestive adjuvant administered by the first capsule is encapsulated within said first capsule.
  • the at least one digestive aid delivered by the first capsule refers to at least one digestive aid directly encapsulated by the first capsule and not comprised or encapsulated by the additional delivery means. That is, the first capsule directly encapsulates the additional delivery medium and the at least one digestive aid to be delivered by the first capsule.
  • the location of the at least one digestive adjuvant administered by the additional administration means depends on the format of said additional administration means, that is, if the additional administration means is in the form of a tablet, a granule or a granule. a mini-tablet, the at least one digestive aid is comprised in said tablet, granules or mini-tablet; and if the additional means of administration is a capsule, microencapsulate or liposome, the at least one digestive adjuvant is encapsulated within the capsule, microencapsulate or liposome.
  • the first capsule and the additional delivery medium have the composition and structure required to provide delivery of their contents (each of at least one digestive aid) at a different pH.
  • first capsule and the additional administration medium release their contents at a different pH provides a differential release in the gastrointestinal tract, that is, the first capsule and the additional administration medium release their contents at different places in the gastrointestinal tract . More preferably, the first capsule releases its contents in the stomach and the further delivery means releases its contents in the intestine, more preferably the small intestine. It is contemplated that the first capsule releases all of its contents in the stomach and the additional delivery means releases most of its contents in the small intestine (the remainder of its contents may be delivered to another site or point in the gastrointestinal tract). It is also contemplated within the present invention that the first capsule releases all of its contents into the stomach and environment. Further administration releases its entire contents into the intestine (preferably the small intestine).
  • the system of the present invention allows the digestive adjuvants to be released in the place of the digestive tract where they optimally perform their activity. Therefore, in a preferred embodiment, the first capsule releases in the stomach at least one digestive adjuvant whose activity is optimal in the stomach; and the additional administration medium releases in the intestine (preferably small intestine) at least one digestive adjuvant whose activity is optimal in said intestine (preferably small intestine).
  • the first capsule releases its content at a pH between 1 and 4.9, more preferably at a pH of 3.
  • the additional administration medium releases its content at a pH between 5 and 7, more preferably at a pH of 6.2.
  • the above pH differential release ensures differential release in the stomach (first capsule) and intestine (preferably small intestine) (further delivery medium) of the multi-site delivery system of the present invention.
  • the first capsule and the second capsule are made of the material required to provide delivery at the desired pH.
  • the additional means of administration is at least one tablet, at least one granule, at least one microencapsulate, at least one liposome and/or at least one mini-tablet
  • said at least one tablet, at least one granule, at least a microencapsulate, at least one liposome and/or at least one mini-tablet have the required structure and/or composition to provide administration at the desired pH, that is, they provide the required gastroresistance (resistance to the pH conditions of the stomach) and administration (by degradation and release) in the intestine, more preferably the small intestine.
  • the at least one tablet, at least one granules and/or at least one mini-tablet comprise a coating suitable for providing the aforementioned administration.
  • the at least one tablet, at least one granules and/or at least one mini-tablet comprise gastro-resistant coating excipients such as shellac, Nutrateric II, Eudragit®, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or combinations thereof; more preferably Eudragit®.
  • gastro-resistant coating excipients such as shellac, Nutrateric II, Eudragit®, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate or combinations thereof; more preferably Eudragit®.
  • Nutratric II Cosmetic and characteristics
  • said Nutrateric II coating comprises purified water, ethylcellulose, ammonium hydroxide, medium chain triglycerides, oleic acid, sodium carboxymethylcellulose, talc and polydextrose.
  • Eudragit® (Evonik) The composition and characteristics of Eudragit® (Evonik) are known in the state of the art. Briefly, said Eudragit® comprises a mixture of methyl acrylate, methyl methacrylate and methacrylic acid (30% dispersion, 62.5% w/w, w/w), polysorbate 80 (33% aqueous solution) (3, 1% p/p), micronized talc (31.3% p/p), plasticizer (triethyl citrate, 3.1% p/p) and diluent.
  • the first capsule is preferably a protein capsule or a vegetable polymer capsule.
  • the first capsule is a protein capsule, ie a capsule made of one or more proteins.
  • the first capsule is made of gelatin, which can be any gelatin available in the state of the art, more preferably it is of bovine, porcine, fish or vegetable origin or combinations thereof, even more preferably bovine gelatin .
  • the moisture content of the first capsule is between 1% and 20%, more preferably between 13% and 16%.
  • the first capsule is a vegetable polymer capsule, that is, a capsule made of one or more vegetable polymers. More preferably, the vegetable polymer is cellulose or a derivative thereof, more preferably a cellulose or a derivative thereof with a low moisture content, preferably a moisture content of between 1% and 20%, even more preferably less than 14%, even more preferably 9%.
  • the plant polymer is hydroxypropylmethylcellulose (HPMC), preferably HPMC, preferably with a moisture content between 1% and 20%, even more preferably less than 14%, even more preferably 9%.
  • HPMC hydroxypropylmethylcellulose
  • the capsule does not contain a gelling agent.
  • the first capsule consists essentially of one or more vegetable polymers, more preferably cellulose or a derivative thereof, more preferably cellulose or a derivative thereof with a low moisture content, preferably a moisture content of between 1% and 20%, even more preferably less than 14%, even more preferably 9%, even more preferably, the vegetable polymer is hydroxypropylmethylcellulose (HPMC), preferably with a moisture content of between 1% and 20%, even more preferably less than 14%, even more preferably 9%.
  • HPMC hydroxypropylmethylcellulose
  • the additional delivery means is preferably a capsule (second capsule within the multi-site delivery system of the present invention), which is preferably made from a plant polymer (more preferably, one or more plant polymers). More preferably, the vegetable polymer is cellulose or a derivative thereof, more preferably a cellulose or a derivative thereof with a low moisture content, preferably a moisture content of between 1% and 20%, even more preferably less than 14%, more preferably less than 6%, even more preferably 5.6%. In a more preferred embodiment, the plant polymer is hydroxypropylmethylcellulose (HPMC), preferably HPMC with low water content, more preferably less than 6% water content, even more preferably 5.6%.
  • HPMC hydroxypropylmethylcellulose
  • HPMC provides a capsule with gastroresistance (resistance to the pH conditions of the stomach) and delivery (by degradation of the capsule) to the small intestine.
  • the second capsule further comprises a gelling agent, which helps to ensure the proper behavior of the second capsule, i.e. to be resistant to acidic conditions and therefore to withstand the conditions of the stomach and deliver its contents to the intestine (preferably , small intestine).
  • the gelling agent is preferably gellan gum. Therefore, the second capsule is made from a plant polymer and a gelling agent, both as explained above.
  • the second capsule preferably comprises from 85 to 98% by weight of a vegetable polymer and from 2 to 10% by weight of gelling agent, more preferably from 90 to 95% by weight of a vegetable polymer and from 3 to 6% in weight. weight of gelling agent, even more preferably 93.08% by weight of a vegetable polymer and 5% by weight of gelling agent, both as explained above.
  • the % by weight of the vegetable polymer and the gelling agent in the second capsule are given with respect to the weight of the second capsule without considering or taking into account the content of said second capsule, that is, with respect to the weight of the second capsule per se.
  • the at least one digestive aid may be the same or different in the first capsule and in the additional administration medium.
  • the digestive aids in the first capsule and the additional delivery means may be entirely the same, partially the same, or entirely different.
  • the at least one digestive aid mentioned above can be any digestive aid known in the state of the art (currently or discovered in the future). It is contemplated that the at least one digestive aid is selected from: at least one enzyme, at least one probiotic, at least one prebiotic, at least one synbiotic, at least one postbiotic, at least one parabiotic, or combinations thereof. Said enzyme, probiotic, prebiotic, synbiotic, postbiotic or parabiotic can be any of those known in the state of the art.
  • the digestive aid or the combination of digestive aids in the first capsule and in the additional means of administration are selected to provide the activities or effects required or desired (taking into account the disease to be prevented, ameliorated or treated). , or the condition or characteristic to be modulated or resolved).
  • the enzyme is preferably at least one microbial digestive enzyme, at least one animal digestive enzyme, at least one plant enzyme, at least one fungal digestive enzyme, or combinations thereof; more preferably, bacterial enzyme, fungal enzyme, plant enzyme, or combinations thereof; even more preferably at least one microbial digestive enzyme from bacteria (preferably from Bacillus subtilis, Bacillus licheniformis or bacterial Amyloquefaciens; more preferably from Bacillus subtilis), at least one fungal digestive enzyme (preferably from Aspergillus oryzae, Aspergillus niger, Rhizopus oryzae, Aspergillus melleus, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea, more preferably Aspergillus oryzae, Aspergillus niger, Rhizopus oryzae, Candida rugosa or Candida cylindracea) or combinations thereof.
  • bacteria preferably from Bacillus subtilis, Bacillus
  • the at least one selected enzyme is preferably of the type required for food digestion, more preferably, it is selected from lipase, protease, amylase, glucoamylase, galactosidase, cellulase, lactase, hemicellulase, phytase, xylanase or combinations thereof, more preferably, acid stable protease, alpha galactosidase, amylase, protease, lipase, neutral protease, glucoamylase, cellulase, lactase, hemicellulase, xylanase or combinations thereof, even more preferably:
  • the enzymes selected for the first capsule are preferably more active in the stomach, ie, they are active at the pH (and other conditions) of the stomach (optimal activity in the stomach); and the enzymes selected for the additional means of administration are preferably more active in the intestine, more preferably, the small intestine, ie, they are active at the pH (and other conditions) of the intestine (most preferably, the small intestine) (optimal activity in the intestine, preferably the small intestine).
  • the prebiotic is preferably GOS (galactooligosaccharide), IMOS (isomaltooligosaccharide), MOS (mannan oligosaccharide), inulin and/or FOS (fructooligosaccharide), more preferably FOS.
  • the probiotic is preferably at least one lactic acid and/or bifidobacterial bacterium, more preferably at least one lactic acid bacterium, more preferably at least one Lactobacillus bacterium, even more preferably Lactobacillus plantarum.
  • the synbiotic is preferably the combination of the prebiotic and the probiotic as explained above.
  • the postbiotic is preferably a soluble substance or combination of substances generated by the metabolism of lactic acid bacteria and/or bifidobacteria and released into the extracellular medium, with beneficial activity on health.
  • They can be, for example, extracellular proteins, extracellular polysaccharides, acids or supernatant.
  • the parabiotic is preferably non-viable microbial cells (preferably bacteria) or cell extracts of at least one lactic acid bacteria and/or bifidobacteria which, when administered in adequate amounts, confer a health benefit.
  • microbial cells preferably bacteria
  • cell extracts of at least one lactic acid bacteria and/or bifidobacteria which, when administered in adequate amounts, confer a health benefit.
  • These bacteria or extracts thereof can be inactivated by heat or ultraviolet light, for example.
  • the first capsule preferably encapsulates at least one digestive adjuvant selected from lipase, protease, amylase, glucoamylase, galactosidase, cellulase, lactase, hemicellulase, phytase, xylanase or combinations thereof; more preferably selected from: lipase, amylase, 4.5 protease, 3.0 protease, 6.0 protease, neutral bacterial protease, amylase, glucoamylase, alpha galactosidase or combinations thereof; more preferably 1-100 mg lipase, 1-100 mg amylase, 1-100 mg protease 4.5, 1-100 mg protease 3.0, 1- 100 mg protease 6.0, 1-100 mg neutral bacterial protease, 1-100 mg amylase, 1-100 mg glucoamylase, 1-100 mg alpha galactosidase, or combinations thereof.
  • lipase prote
  • the additional administration means comprises at least one lipase, protease, amylase, glucoamylase, galactosidase, cellulase, lactase, hemicellulase, phytase, xylanase, prebiotic, probiotic, postbiotic, parabiotic or combinations thereof; more preferably, selected from: lipase, protease 4.5, protease 3.0, protease 6.0, neutral bacterial protease, amylase, glucoamylase, alpha galactosidase, prebiotic (preferably FOS), probiotic, postbiotic, parabiotic or combinations of the themselves; more preferably 1-100 mg lipase, 1-100 mg amylase, 1-100 mg protease 4.5, 1-100 mg protease 3.0, 1-100 mg protease 6.0, 1-100 mg neutral bacterial protease, 1-100 mg amylase, 1-100 mg glucoamylase, 1-100 mg al
  • the at least one digestive adjuvant encapsulated in the first capsule is at least one fungal and/or bacterial digestive enzyme (preferably from Aspergillus oryzae , Aspergillus niger, Rhizopus oryzae, Aspergillus melleus, Bacillus licheniformis, bacterial Amyloquefaciens, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea ); more preferably it is selected from lipase, protease, amylase, glucoamylase or combinations thereof; more preferably, it is selected from lipase, 4.5-protease, 3.0-protease, amylase, glucoamylase, or combinations thereof; more preferably it is lipase, protease 4.5, protease 3.0, amylase and glucoamy
  • the at least one digestive adjuvant is selected from amylase, glucoamylase, lipase, alpha-galactosidase, protease, Lactobacillus bacteria, FOS or combinations thereof; more preferably it is selected from amylase, glucoamylase, lipase, alpha-galactosidase, protease 4.5, protease 6.0, neutral bacterial protease, Lactobacillus plantarum, FOS or combinations thereof, where the enzymes are preferably of bacterial or fungal origin .
  • the at least one digestive aid encapsulated in the first capsule is at least one fungal and/or bacterial digestive enzyme (preferably of Aspergillus oryzae, Aspergillus niger, Rhizopus oryzae, Aspergillus melleus, Bacillus licheniformis, bacterial Amyloquefaciens, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea), more preferably it is selected from lipase, protease, amylase, glucoamylase or combinations thereof; more preferably, it is selected from lipase, 4.5-protease, 3.0-protease, amylase, glucoamylase, or combinations thereof; more preferably it is lipase, protease 4.5, protease 3.0, amylase and glucoamylase; more preferably it is lipase, protease 4.5, protease 3.0, amylase
  • the at least one digestive adjuvant is selected from at least one fungal digestive enzyme (preferably from Aspergillus oryzae, Aspergillus niger, Rhizopus oryzae, Aspergillus melleus, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea) and at least one bacterial enzyme (preferably from Bacillus licheniformis, bacterial Amyloquefaciens or Bacillus subtilis), preferably selected from amylase, glucoamylase, lipase, alpha-galactosidase, protease or combinations thereof; more preferably it is selected from amylase, glucoamylase, lipase, alpha-galactosidase, 4.5 protease, 6.0 protease, neutral bacterial protease or combinations thereof; more preferably, it is amylase, glucoamylase,
  • the total amount of each of the digestive aids provided by the system of administration in multiple sites is, preferably: 58.3 mg of lipase, 51.5 mg of amylase, 40.5 mg of glucoamylase, 12.5 mg of alpha-galactosidase, 7.5 mg of protease 3.0, 6 6.0 protease, 6.0 mg neutral bacterial protease, and 5.6 mg 4.5 protease.
  • the additional delivery means is preferably a capsule (ie, the second capsule within the multi-site delivery system of the present invention).
  • the multi-site administration system of the present invention in this first most preferred embodiment due to the differential administration at different points or sites in the gastrointestinal tract and the combination of enzymes, is useful for the prevention, treatment and/or improvement of exocrine pancreatic insufficiency (pancreatic secretion problems) and/or to provide faster digestion. More preferably, the exocrine pancreatic insufficiency is cystic fibrosis or chronic pancreatitis.
  • the multi-site delivery system of the present invention in this first most preferred embodiment is for use in the prevention, treatment, and/or amelioration of digestive symptoms associated with pancreatic secretion problems (more preferably, digestive symptoms associated therewith), cystic fibrosis (more preferably, digestive symptoms associated therewith) or chronic pancreatitis (more preferably, digestive symptoms associated therewith), even more preferably it is for use in the prevention, treatment and/or the improvement of cystic fibrosis (more preferably, digestive symptoms associated therewith).
  • the at least one digestive aid encapsulated in the first capsule is at least one fungal and/or bacterial digestive enzyme (preferably of Aspergillus oryzae, Aspergillus niger, Aspergillus melleus, Bacillus licheniformis, Bacterial Amyloquefaciens, Rhizopus oryzae, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea); more preferably it is selected from lipase, protease, amylase, glucoamylase or combinations thereof; more preferably, it is selected from lipase, 4.5-protease, 3.0-protease, amylase, glucoamylase, or combinations thereof; more preferably it is lipase, protease 4.5, protease 3.0, amylase and glucoamylase;
  • the at least one digestive adjuvant is a synbiotic (that is, at least one probiotic and at least one prebiotic; preferably a probiotic and a prebiotic); more preferably a lactic acid bacterium and a prebiotic (preferably FOS); more preferably, a Lactobacillus bacteria and FOS; more preferably Lactobacillus plantarum and FOS bacteria; even more preferably 5 billion CFUs (colony forming units) of Lactobacillus plantarum and 140 mg FOS.
  • a synbiotic that is, at least one probiotic and at least one prebiotic; preferably a probiotic and a prebiotic
  • more a lactic acid bacterium and a prebiotic preferably FOS
  • FOS lactic acid bacterium and a prebiotic
  • Lactobacillus bacteria and FOS more preferably Lactobacillus bacteria and FOS
  • Lactobacillus plantarum and FOS bacteria even more preferably 5 billion CFUs (colony forming units) of Lactobacillus plant
  • the total amount of each of the digestive adjuvants provided by the multi-site administration system is preferably: 13.3 mg of lipase, 21.5 mg of amylase , 13.8 mg glucoamylase, 7.5 mg protease 3.0, 3.9 mg protease 4.5, 5 billion Lactobacillus plantarum CFUs, and 140 mg FOS.
  • the additional delivery means is preferably a capsule (ie, the second capsule within the multi-site delivery system of the present invention).
  • the multi-site administration system of the present invention in this second most preferred embodiment due to the differential administration at different points or sites in the gastrointestinal tract and the combination of digestive adjuvants, is useful for the prevention, treatment and/or the improvement of pancreatic problems (exocrine pancreatic disorders, preferably associated digestive symptoms), Crohn's disease, dyspepsia, digestive disorders, indigestion symptoms, irritable bowel syndrome, high cholesterol or diarrhea (preferably associated digestive symptoms) , more preferably antibiotic-associated diarrhea) and/or for the restoration of the intestinal flora; even more preferably, for the prevention, treatment and/or improvement of pancreatic problems (exocrine pancreatic disorders, preferably associated digestive symptoms), Crohn's disease, functional dyspepsia, indigestion symptoms, digestive disorders, high cholesterol, irritable bowel syndrome or diarrhea (eg, travel- or antibiotic-associated diarrhea, more preferably,
  • the at least one digestive aid encapsulated in the first capsule is at least one fungal and/or bacterial digestive enzyme (preferably, Aspergillus oryzae, Aspergillus niger, Rhizopus oryzae, Aspergillus melleus, Bacillus licheniformis, bacterial Amyoquefaciens, Bacillus subtilis, Bacillus amyloliquefaciens, Candida rugosa or Candida cylindracea); more preferably it is selected from lipase, protease, amylase, glucoamylase or combinations thereof; more preferably, it is selected from lipase, 4.5-protease, 3.0-protease, amylase, glucoamylase, or combinations thereof; more preferably it is lipase, protease 4.5, protease 3.0, amylase and glucoamylase; more preferably
  • the at least one digestive adjuvant is at least one fungal digestive enzyme (preferably from Aspergillus niger), preferably alpha-galactosidase, more preferably alpha-galactosidase from Aspergillus niger, even more preferably 600 GalU of alpha-galactosidase from Aspergillus niger.
  • fungal digestive enzyme preferably from Aspergillus niger
  • alpha-galactosidase more preferably alpha-galactosidase from Aspergillus niger, even more preferably 600 GalU of alpha-galactosidase from Aspergillus niger.
  • the additional delivery means is preferably a capsule (ie, the second capsule within the multi-site delivery system of the present invention).
  • the multi-site administration system of the present invention in this third most preferred embodiment due to the differential administration at different points or sites in the gastrointestinal tract and the combination of digestive adjuvants, is useful for the prevention, treatment and/or improvement of pancreatic problems (exocrine pancreatic disorders, preferably digestive symptoms associated with them), functional dyspepsia, bloating, symptoms of indigestion or excessive gas production (preferably due to ingestion of grains, vegetables and/or beans, flatulence or bloating abdominal) (preferably associated digestive symptoms).
  • pancreatic problems exocrine pancreatic disorders, preferably digestive symptoms associated with them
  • functional dyspepsia bloating
  • symptoms of indigestion or excessive gas production preferably due to ingestion of grains, vegetables and/or beans, flatulence or bloating abdominal
  • the additional administration medium which is encapsulated within the first capsule, is suspended within said first capsule, preferably, it is suspended in a solid powder medium, in a semi-liquid medium or in a medium of solid granules. This determines the form in which the contents of the first capsule are (except or apart from the additional delivery medium) (including the at least one digestive aid delivered by and encapsulated in the first capsule).
  • the additional means of administration is at least one tablet (preferably a tablet), preferably said additional administration medium is suspended within the first capsule in a solid powder medium or semi-liquid medium.
  • the additional delivery medium is at least one mini-tablet (preferably one mini-tablet or a plurality of mini-tablets), preferably said additional delivery medium is suspended within the first capsule in a solid powder medium.
  • the additional administration medium is at least one granulate (preferably a granule)
  • said additional administration medium is preferably suspended within the first capsule in a solid powder medium or in a semi-liquid medium.
  • said additional delivery medium is preferably suspended within the first capsule in a solid powder medium or semi-liquid medium.
  • said additional delivery medium is preferably suspended within the first capsule in a solid powder medium or semi-liquid medium.
  • said additional administration medium is suspended within the first capsule in a solid powder medium, semi-liquid medium or solid granule medium; more preferably in a semi-liquid medium.
  • the content of said at least one capsule is preferably a solid powder.
  • the additional means of administration is a granule, tablet, or mini-tablet
  • said tablet, granule, or mini-tablet further comprises additional ingredients or compounds (in addition to of at least one digestive adjuvant).
  • Said additional ingredients or compounds can be any of those known in the state of the art as long as they do not alter the activity of the at least one digestive adjuvant used and its release or administration.
  • said additional ingredient or compound is selected from diluent, binder, lubricant, glidant, disintegrant, wetting agent, buffering agent, coloring agent, flavoring agent, adsorbents or combinations thereof.
  • the diluent can be any diluent known in the state of the art, more preferably the diluent is a sugar, maltodextrin, starch, microcrystalline cellulose or combinations thereof.
  • the binder can be any binder known in the art, more preferably, the binder is gum arabic, gelatin, polyvinylpyrrolidone, cellulose derivatives (for example, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose) or combinations thereof.
  • the binder is gum arabic, gelatin, polyvinylpyrrolidone, cellulose derivatives (for example, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose) or combinations thereof.
  • the lubricant can be any lubricant known in the state of the art, more preferably the lubricant is magnesium stearate.
  • the disintegrant can be any disintegrant known in the state of the art, more preferably, the disintegrant is corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate or a combination thereof.
  • the multi-site delivery system of the present invention allows for delivery to different sites in the gastrointestinal tract (preferably the stomach and small intestine). Therefore, it can effectively administer a different set of digestive adjuvants to the stomach and the small intestine, allowing to solve the problems or needs present in the state of the art and mentioned above.
  • the provision of particular sets of digestive aids in the multi-site delivery system of the present invention provides the treatment effective for various digestive indications.
  • the multi-site delivery system of the present invention can be prepared by procedures known in the art and using equipment (filling machines, for example) known in the art with appropriate considerations.
  • the present invention relates to a nutraceutical comprising the multi-site delivery system of the present invention.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the nutraceutical is the multi-site delivery system of the present invention.
  • the multiple administration system of the present invention is as explained in the first preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably at least 1 capsule per day, more preferably 1 to 6 capsules, more preferably 1 to 2 capsules 1 to 3 times per day (preferably with each of the three meals of the day), even more preferably 1 capsule per day with the main meal. Also preferably, the nutraceutical is ingested with water.
  • the multiple administration system of the present invention is as explained in the second preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably 1 capsule per day (preferably with the main meal). Also preferably, the nutraceutical is ingested with water.
  • the multiple administration system of the present invention is as explained in the third preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably 1 or 2 capsules per day (preferably with food) major). Also preferably, the nutraceutical is ingested with water.
  • the present invention relates to a pharmaceutical composition comprising the multi-site delivery system of the present invention.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the pharmaceutical composition is the multi-site delivery system of the present invention.
  • the multiple administration system of the present invention is as explained in the first preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably at least 1 per day, more preferably 1 to 6 capsules, more preferably 1 to 2 capsules 1 to 3 times per day (preferably with each of the three meals of the day), even more preferably 1 capsule per day with the main meal. Also, preferably, the nutraceutical is ingested with water.
  • the multiple administration system of the present invention is as explained in the second preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably 1 capsule per day (preferably with the main meal). Also preferably, the nutraceutical is ingested with water.
  • the multiple administration system of the present invention is as explained in the third preferred embodiment of the first aspect of the present invention and, in this case, the dose of the nutraceutical of the present invention is preferably 1 or 2 capsules per day (preferably with the main meal). Also preferably, the nutraceutical is ingested with water.
  • the present invention relates to a multi-site delivery system or a pharmaceutical composition, both in accordance with the present invention, for use as a medicament.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the pharmaceutical composition of the present invention is as explained above in the third aspect of the present invention.
  • the dosage is as explained above in the third aspect of the present invention.
  • the use as a medicament described in this fourth aspect of the present invention is for a subject in need thereof.
  • said subject in need is a mammal, more preferably a human.
  • the multi-site administration system or the pharmaceutical composition is for use in the prevention, treatment and/or improvement of a digestive disease , more preferably, for use in the prevention, treatment and/or improvement of pancreatic secretion problems (preferably cystic fibrosis or chronic pancreatitis, more preferably digestive symptoms associated therewith), pancreatic exocrine disorders (preferably, associated digestive symptoms), Crohn's disease, functional dyspepsia, bloating, indigestion symptoms, digestive disorders, irritable bowel syndrome, high cholesterol, diarrhea (most preferably antibiotic-associated diarrhea) or excessive gas production; even more preferably, pancreatic secretion problems, pancreatic exocrine disorders, cystic fibrosis, chronic pancreatitis, Crohn's disease, functional dyspepsia, indigestion symptoms, digestive disorders, high cholesterol, irritable bowel syndrome, diarrhea (eg, travel-associated diarrhea or antibiotics, more preferably antibiotic-associated diarrhea), blo
  • the multi-site delivery system or the pharmaceutical composition is for use in the prevention, treatment and/or the amelioration of digestive symptoms associated with a digestive disease, more preferably, for use in the prevention, treatment and/or amelioration of digestive symptoms associated with pancreatic secretion problems (preferably, cystic fibrosis or chronic pancreatitis) , exocrine, pancreatic disorders, Crohn's disease, functional dyspepsia, bloating, symptoms of indigestion, digestive disorders, irritable bowel syndrome, high cholesterol, diarrhea (most preferably antibiotic-associated diarrhoea) or excessive gas production (for example , flatulence, bloating); even more preferably digestive symptoms associated with pancreatic secretion problems, exocrine pancreatic disorders, cystic fibrosis, chronic pancreatitis, Crohn's disease, functional dyspepsia, indigestion symptoms, digestive disorders, high cholesterol, irritable bowel syndrome, diarrhea
  • pancreatic secretion problems preferably, cystic fibrosis or chronic pan
  • the multi-site delivery system is as described in the first most preferred embodiment explained above in the first aspect of the present invention.
  • the multi-site delivery system or pharmaceutical composition is for use in the prevention, treatment and/or amelioration of pancreatic secretion problems (preferably cystic fibrosis or chronic pancreatitis, more preferably digestive symptoms associated to them), even more preferably, the prevention, treatment and/or improvement of digestive symptoms associated with pancreatic secretion problems, cystic fibrosis (more preferably, digestive symptoms associated with it) or chronic pancreatitis (more preferably, symptoms digestive disorders associated with it). More preferably, in this case the multi-site delivery system or pharmaceutical composition is for use in the prevention, treatment and/or amelioration of cystic fibrosis (more preferably digestive symptoms associated therewith).
  • the multi-site delivery system is as described in the second most preferred embodiment explained above in the first aspect of the present invention.
  • the multi-site delivery system or the pharmaceutical composition is for use in the prevention, treatment and/or improvement of pancreatic problems (exocrine pancreatic disorders, preferably digestive symptoms associated with them), Crohn's disease, functional dyspepsia, symptoms of indigestion, digestive disorders, irritable bowel syndrome, high cholesterol or diarrhea ( eg travel or antibiotic associated diarrhoea, more preferably antibiotic associated diarrhoea); more preferably the prevention, treatment and/or improvement of digestive symptoms associated with pancreatic problems (exocrine pancreatic disorders), Crohn's disease, functional dyspepsia, symptoms of indigestion, digestive disorders, high cholesterol, irritable bowel syndrome or diarrhea (eg travel or antibiotic associated diarrhoea, more preferably antibiotic associated diarrhoea); even more preferably pancreatic problems (exocrine pancreatic problems (exocrine pancreatic disorders
  • the multi-site delivery system is as described in the third most preferred embodiment explained above in the first aspect of the present invention.
  • the multi-site delivery system or pharmaceutical composition is for use in the prevention, treatment and/or amelioration of pancreatic problems (exocrine pancreatic disorders, preferably digestive symptoms associated therewith), functional dyspepsia, bloating, symptoms of indigestion or excessive gas production (preferably from eating grains, vegetables and/or beans, flatulence or bloating); more preferably the prevention, treatment and/or improvement of digestive symptoms associated with pancreatic problems (exocrine pancreatic disorders), functional dyspepsia, bloating, symptoms of indigestion or excessive gas production (preferably from ingestion of grains, vegetables and /or beans, flatulence or bloating); even more preferably, pancreatic problems (exocrine pancreatic disorders, preferably digestive symptoms associated with them), functional dyspepsia, abdominal dyspepsia, symptoms of indigestion or excessive gas production (preferably due to in
  • the present invention relates to use of a multi-site delivery system or a pharmaceutical composition, both in accordance with the present invention, in the manufacture of a medicament for the treatment of a digestive disease.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the pharmaceutical composition of the present invention is as explained above in the third aspect of the present invention.
  • the dosage is as explained above in the third aspect of the present invention.
  • the digestive disease is as explained above in the fourth aspect of the present invention.
  • the present invention relates to a method for treating a digestive disease in a subject in need thereof, comprising the administration of a therapeutically effective amount of a multi-site delivery system or a pharmaceutical composition, both in accordance with the present invention, to the subject.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the pharmaceutical composition of the present invention is as explained above in the third aspect of the present invention.
  • the dosage is as explained above in the third aspect of the present invention.
  • the digestive disease and the subject are as explained above in the fourth aspect of the present invention.
  • the present invention relates to the use of a multi-site delivery system or a nutraceutical, both in accordance with the present invention, to improve digestion in a subject.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the nutraceutical of the present invention is as explained above in the second aspect of the present invention.
  • the dosage is as explained above in the second aspect of the present invention.
  • the improvement in digestion can be any known in the state of the art.
  • the improvement in digestion is a non-therapeutic improvement of digestion.
  • the improvement in digestion is an improvement in protein absorption, an improvement in fat absorption, a reduction in the production of gas or flatulence, or combinations thereof.
  • the improvement in digestion is the prevention of gas production, preferably the prevention of gas production with the ingestion of grains, vegetables and/or beans, the prevention of flatulence and/or the prevention of swelling.
  • the multi-site delivery system is as described in the third most preferred embodiment explained above in the first aspect of the present invention.
  • the improvement in digestion provides a higher rate of digestion, ie faster digestion.
  • the multi-site delivery system is as described in the first most preferred embodiment explained above in the first aspect of the present invention.
  • the subject is preferably a subject in need of improved digestion, more preferably a mammal, even more preferably a human.
  • the present invention relates to the use of a multi-site delivery system or a nutraceutical, both in accordance with the present invention, to restore intestinal flora in a subject.
  • the multi-site delivery system of the present invention is as explained above in the first aspect of the present invention.
  • the nutraceutical of the present invention is as explained above in the second aspect of the present invention.
  • the multi-site delivery system is as described in the second most preferred embodiment explained above in the first aspect of the present invention.
  • the subject is preferably a subject in need of restoration of their intestinal flora, more preferably a mammal, even more preferably a human.
  • Figure 1 shows the degree of lipolysis (% digested fat, relative to initial lipid content) after simulated in vitro digestion in Example 2 below using a model feed with two treatment groups: Kreon® 10,000 ( black bars) or a capsule system of the present invention (according to Example 1) (white bars).
  • the letters at the top of the bars represent the homogeneous groups obtained by statistical analysis of variance (p >0.05); the same letters mean no difference and different letters mean a statistically significant difference).
  • the x-axis shows the different times analyzed and each group of two adjoining bars (one black and one white) corresponds, from left to right, to: 0 minutes of the gastric stage, 60 minutes of the gastric stage, 120 minutes of the gastric stage.
  • the y axis refers to the percentage of lipolysis (that is, the percentage of fat digested with respect to the initial fat content).
  • Figure 2 shows the hydrolyzed sugars (% reducing sugars, this is the percentage of monosaccharides and disaccharides obtained after the digestion of complex sugars, with respect to the initial content of complex sugars) after the simulated in vitro digestion in Example 2 included then using a model food with two treatment groups: Kreon® 10,000 (black bars) or a capsule system of the present invention (according to Example 1) (white bars).
  • Kreon® 10,000 black bars
  • a capsule system of the present invention accordinging to Example 1 (white bars).
  • the letters represent the homogeneous groups obtained by statistical analysis of variance (p > 0.05); the same letters mean that there are no differences and different letters mean a statistically significant difference).
  • the x-axis shows the different times analyzed and each group of two adjoining bars (one black and one white) corresponds, from left to right, to: 0 minutes of the gastric stage, 20 minutes of the gastric stage, 120 minutes of the gastric stage. gastric, 0 minutes of the duodenal stage, 20 minutes of the duodenal stage and 120 minutes of the duodenal stage.
  • the y axis refers to the percentage of glycolysis (that is, the percentage of digested sugars (monosaccharides and disaccharides, which are reducing sugars) with respect to the initial content of sugars (which are complex sugars)).
  • Figure 3 shows the percentage of proteins soluble in trichloroacetic acid (TCA) (hydrolyzed proteins are soluble in TCA, while non-hydrolyzed proteins precipitate in TCA) after simulated in vitro digestion in Example 2 using a model food.
  • TCA trichloroacetic acid
  • Kreon® 10,000 black bars
  • a capsule system of the present invention accordinging to Example 1 (white bars).
  • the assigned letters represent the homogeneous groups obtained by statistical analysis of variance (p >0.05); the same letters mean that there are no differences and the different letters mean a difference statistically significant).
  • the x-axis shows the different times analyzed and each group of two adjoining bars (one black and one white) corresponds, from left to right, to: 0 minutes of the gastric stage (stomach), 20 minutes of the gastric stage (stomach) , 120 minutes of the gastric stage (stomach), 0 minutes of the duodenal stage (small intestine), 20 minutes of the duodenal stage (small intestine), and 120 minutes of the duodenal stage (small intestine).
  • the y-axis refers to the percentage of soluble protein in TCA (with respect to total protein).
  • Figure 4 shows the results obtained in example 3 for the FAS questionnaire (Fatigue Questionnaire).
  • the three groups each includes 4 bars
  • the three groups reflected from top to bottom are: difference in mental fatigue, difference in physical fatigue and total difference FAS.
  • Each of these 3 groups or variables on the y-axis has 4 bars that refer to the 4 working groups, from top to bottom: supplement with the system of the present invention for 180 days, supplement with the system of the present invention for 90 days, supplementation with the system of the present invention for 30 days and supplementation with Creon® 25,000 (pancreatin).
  • the x-axis refers to or reflects the mean score.
  • Figure 5 shows the results obtained in example 3 for the PAC-SYM questionnaire (Patient Constipation Assessment Questionnaire).
  • the four groups (each includes 4 bars) reflected from top to bottom are: difference in abdominal symptoms, difference in rectal symptoms, difference in fecal symptoms, and total difference PAC SYM.
  • Each of said 4 groups or variables on the y-axis has 4 bars that refer to the 4 working groups, from top to bottom: supplement with the system of the present invention for 180 days, supplement with the system of the present invention for 90 days, supplementation with the system of the present invention for 30 days and supplementation with Creon® 25,000 (pancreatin).
  • the x-axis refers to or reflects the mean score.
  • Figure 6 shows the results obtained in Example 3 for the PAGI-SYM (Patient Assessment Index of Upper Gastrointestinal Symptoms) questionnaire.
  • the seven groups (each includes 4 bars) reflected from top to bottom are: difference in gastroesophageal discomfort/reflux, difference in upper abdominal pain, difference in nausea-vomiting, difference in regurgitation, difference in early fullness postprandial satiety, difference in lower abdominal pain, and difference in total PAGI-SYM.
  • Each of said 7 groups or variables on the y-axis has 4 bars that refer to the 4 working groups, from top to bottom: supplement with the system of the present invention for 180 days, supplement with the system of the present invention for 90 days, supplementation with the system of the present invention for 30 days and supplementation with Creon® 25,000 (pancreatin).
  • the multi-site delivery systems of the present invention were prepared by means known in the art and using equipment known in the art with the appropriate settings (filling machine). Briefly:
  • the second capsule or inner capsule is prepared with the appropriate content or dose (as indicated below).
  • the second capsule or inner capsule was an HPMC capsule of HPMC with a water content of 5.6% and with a gelling agent (gellan gum).
  • the second capsule or internal capsule was of size 2 (body length 15.27mm and cap length 8.94mm).
  • the second capsule cap or inner capsule weighed 24 mg of which: 0.4604 mg was titanium dioxide, 1.2 mg was gellan gum and 22.3396 mg was HPMC; and the second capsule body or inner capsule weighed 36 mg of which: 0.6906 mg was titanium dioxide, 1.8 mg gellan gum, 33.5094 mg HPMC.
  • This capsule maintains its mechanical stability in changing temperatures and low relative humidity. This capsule is very slow release and resistant to gastric fluids.
  • the body of the first capsule or outer capsule was dosed with the appropriate content in semi-liquid form (see dosage below) and then the second capsule or inner capsule was placed therein.
  • the first capsule or outer capsule was a gelatin capsule with bovine gelatin and a moisture content of between 13% and 16%.
  • the first capsule or outer capsule was size 00 (22.22mm long body and 12.95mm long cap).
  • the cap of the first capsule or outer capsule weighed 50.4 mg of which: 0.756 mg was red iron oxide, 0.166 mg was titanium dioxide, 7.308 mg was water, and 42.169 mg was bovine gelatin; and the first capsule body or outer capsule weighed 75.6 mg of which: 1.134 mg was red iron oxide, 0.249 mg was titanium dioxide, 10.962 mg water, 63.254 mg bovine gelatin.
  • the lid of the first capsule or external capsule was placed and sealed with the body.
  • the sealing procedure involves bonding the interface of the cap to the body with a thin film of gelatin. The sealing was done by taping with bands. The taping involved several tasks, first the gelatin bath was prepared and its viscosity checked continuously. Then, sealing was done with a gelatin band.
  • the entire procedure took less than 1 minute and turned the two-piece hard capsule into a leak-free dosing unit. Once sealed, the capsule meets tamper-evident guidelines as it cannot be opened without visibly altering the capsule.
  • the sealing procedure must be carried out within the indicated period and with special care since the gelatin band can cause physical defects in the capsule such as bubbles in the gelatin band or the capsules can take a "banana" shape and this is due to a long drying cycle.
  • the condition of the filling room of the capsule filling machine is from 20°C to
  • First capsule or external capsule it is 4000 FIP (International Fungal Lipase Unit) of lipase from the fungi Rhizopus oryzae, Candida rugosa or Candida cylindracea; 3120 HUT (Hemoglobin Unit Tyrosine Base) of Aspergillus oryzae protease 4.5; 15 SAPU (Acid Stable Protease Unit) of Aspergillus niger protease 3.0, 2150 DU (Alpha-Amylase Dextrinizing Units) of Aspergillus oryzae amylase; and 14 AGU (Amyloglucosidase Unit) of glucoamylase from Aspergillus niger.
  • FIP International Fungal Lipase Unit
  • SAPU Acid Stable Protease Unit
  • Aspergillus niger protease 3.0, 2150 DU Alpha-Amylase Dextrinizing Units
  • AGU Amyloglucosidase Unit
  • Second capsule or internal capsule 4500 DU of Aspergillus oryzae amylase; 12 AGU of glucoamylase from Aspergillus niger, 9000 FIP of lipase from the fungi Candida rugosa, Candida cylindracea or Rhizopus oryzae-, 125 GalU (Alpha-Galactosidase Unit) of alpha-galactosidase from Aspergillus niger, 1000 HUT of protease 4.5 from Aspergillus oryzae; 3000 Aspergillus oryzae Protease 6.0 HUT; and 3000 PC of neutral bacterial protease from Bacillus subtilis.
  • First capsule or external capsule 4000 FIP (International Fungal Lipase Unit) of lipase from the fungi Candida rugosa, Candida cylindracea or Rhizopus oryzae-, 3120 HUT (Hemoglobin Unit Tyrosine Base) of protease 4.5 from Aspergillus oryzae -, 15 SAPU (Acid-Stable Protease Unit) of protease 3.0 from Aspergillus niger, 2150 DU (Alpha-Amylase Dextrinizing Units) of amylase from Aspergillus oryzae-, and 14 AGU (Amyloglucosidase Unit) of glucoamylase from Aspergillus niger.
  • FIP International Fungal Lipase Unit
  • SAPU Acid-Stable Protease Unit
  • Amylase from Aspergillus oryzae-
  • AGU Amyloglucosidase Unit
  • Second capsule or inner capsule 5 billion CFUs (colony-forming units) of Lactobacillus plantarum and 140 mg of FOS.
  • First capsule or outer capsule 4000 FIP (International Fungal Lipase Unit) of lipase from the fungi Candida rugosa, Candida Cylindracea or Rhizopus oryzae; 3120 HUT (Hemoglobin Unit Tyrosine Base) of Aspergillus oryzae protease 4.5; 15 SAPU (Acid Stable Protease Unit) of Aspergillus niger protease 3.0, 2150 DU (Alpha-Amylase Dextrinizing Units) of Aspergillus oryzae amylase; and 14 AGU (Amyloglucosidase Unit) of glucoamylase from Aspergillus niger.
  • FIP International Fungal Lipase Unit
  • SAPU Acid Stable Protease Unit
  • Aspergillus niger protease 3.0, 2150 DU Alpha-Amylase Dextrinizing Units
  • AGU Amyloglucosidase Unit
  • Second capsule or internal capsule 600 GalU of alpha-galactosidase from Aspergillus niger.
  • Example 2 Analysis of the delivery pattern provided by a multi-site delivery system of the present invention This example was performed to determine the hydrolytic efficiency of the first multi-site delivery system obtained according to Example 1 (lipid hydrolysis, carbohydrates and proteins), comparing the enzymatic activity of the supplement with that of a reference drug (Kreon® 10,000, which is porcine pancreatin), using a food model. Details of such a model feed are provided in Table 1, below:
  • a standard portion of the model food (55.6 g) was digested with a dose of a Creon® capsule (2500 Lipase Units (LU)/g of fat) or a capsule system according to Example 1 (3250 LU/g of fat).
  • Lipolysis was measured by a colorimetric assay to measure the presence of free fatty acids as explained in Lamothe, S. et al (Influence of cheese matrix on lipid digestion in a simulated gastro-intestinal environment). lipid digestion in a simulated gastrointestinal environment]; Food Funct., 2012, 3, 724-731). Briefly:
  • a sample of the digestion was taken and diluted 100-fold with a solution of Triton X-100 5.6% and ethanol 6% in water. This solution was used to solubilize free fatty acids and stop lipase activity.
  • the fatty acids released during digestion were measured in the diluted samples using a free fatty acid colorimetric assay kit (Roche Diagnostics, Indianapolis, IN, USA) in which the free fatty acids reacted with the substrate to form a colored compound and then the absorbance was measured by spectrophotometer.
  • the oleic acid standard was used for the quantitative determination of free fatty acids (FFA). FFAs were expressed as percentage of total fatty acids that could theoretically be released after complete digestion.
  • the porcine pancreatin capsule (Kreon® 10,000), as is known in the state of the art, is designed for release in the duodenal stage, which is confirmed by the results obtained ( Figure 1).
  • a small lipolytic activity was already observed at the end of the gastric (stomach) stage, a result of its first release of enzymes.
  • the enzymatic release of the two supplements can be observed, being significantly faster in the case of the capsule system according to Example 1 (multi-site administration system of the present invention), although at the end of duodenal digestion there are no significant differences in the percentage of lipolysis reached between the two groups tested.
  • Reducing sugars have the property of reducing many of the reactants.
  • One of these reagents is 3,5-dinitrosalicylic acid (DNS). DNS in alkaline solution is reduced to 3-amino, 5-nitrosalicylic acid.
  • Sodium and potassium tartrate 45 g of sodium and potassium tartrate were dissolved in 75 ml of H2O.
  • DNS solution 1.5 g of DNS reagent was dissolved in 30 ml of a 2 M NaOH solution (2 M NaOH: 80 g of NaOH dissolved in 1 liter of water).
  • DNS Reagent Prepare fresh by mixing reagents (1) and (2) to make up the volume to 150 ml with water.
  • Standard sodium sugar stock 250 mg of glucose in water and make up the volume to 100 ml.
  • Dry test tubes were used. A standard sugar solution in the range of 0 to 3 ml was pipetted into different test tubes and the volume of all test tubes was made up to 3 ml with distilled water, resulting in concentrations ranging from 0 to 750 ml. mg. Tubes with 3 ml of the samples to be analyzed were also prepared. 1 ml of DNS reagent was added to all test tubes, and the test tubes were mixed with cotton or marble stoppers and kept in a boiling water bath for 5 minutes. The tubes were then cooled to room temperature. Subsequently, the excitations were read at 540 mm against the model.
  • Standard curves were prepared and used to estimate reducing sugars and glycolysis.
  • Figure 3 shows the results of the percentage of hydrolyzed protein (% protein soluble in TCA with respect to the total protein of the sample) reached throughout the simulated digestion process for each one of the supplements studied.
  • the proteolysis observed in the presence of Creon® 10,000 during the gastric stage is the result of the activity of the pepsin present in the simulated gastric fluids.
  • the first enzymatic release of the multi-site delivery system of the present invention throughout the gastric stage leads to significant differences in hydrolyzed protein after 120 minutes of gastric digestion (p > 0.05). (stomach).
  • the soluble protein values achieved in the gastric stage remain constant after the second release of the multi-site delivery system of the present invention, while the release of Creon® 10,000 throughout duodenal digestion causes a significant increase in the amount of soluble protein in TCA (p > 0.05).
  • the efficacy of the first multi-site administration system of the present invention described in Example 1 was evaluated.
  • a study was carried out in 10 cystic fibrosis patients with a total study duration of 180 days. .
  • Patients were asked to compare self-reported gastrointestinal, constipation and fatigue symptoms while taking porcine pancreatic digestive enzymes - active in the gut - and then while taking the food supplement of the present invention.
  • Weight and stool were also analyzed as indicators of fat absorption.
  • the Upper Gastrointestinal Symptoms Assessment (PAGI-SYM), Constipation Assessment (PAC-SYM), and Fatigue Assessment Scale (FAS) questionnaires were used to measure patient-reported symptoms.
  • Creon® 25,000 (porcine enzymes, pancreatin) for 30 days. Patients reported their gastrointestinal symptoms, constipation, and fatigue using each of the 3 questionnaires mentioned. Over the next 30 days, patients switched to the multi-site delivery system of the present invention with microbially derived enzymes selected to be more active under the different pH conditions of the gastrointestinal tract. The patients received a reduced initial dose, based on their weight, which was adjusted according to the needs of each patient as the days passed. After 30, 90, and 180 days of dietary supplement treatment, patients returned to report gastrointestinal, constipation, and fatigue symptoms to their physicians using each again. of the 3 questionnaires mentioned above.
  • Table 1 Values obtained for t-test of paired samples.
  • the system of the present invention is a valid and safer alternative than the current porcine-derived enzyme supplementation due to a significant reduction in the consumption of digestive enzymes together with a significant improvement in symptoms in patients with cystic fibrosis, mental fatigue and physical, constipation, and other upper gastrointestinal symptoms.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un système d'administration multiple pour l'administration différentielle dans le tractus gastro-intestinal, lequel système d'administration en de multiples endroits comprend: une première capsule et un moyen d'administration additionnel, caractérisé en ce que la première capsule encapsule le moyen d'administration additionnel; en ce que la première capsule et le moyen d'administration additionnel administrent au moins un adjuvant digestif; et en ce que la première capsule et le moyen d'administration additionnel libèrent leur contenu à un pH différent.
PCT/ES2022/070159 2021-03-18 2022-03-18 Système d'administration en de multiples endroits pour l'administration différentielle dans le tractus gastro-intestinal WO2022195152A1 (fr)

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ES202130247A ES2924573B2 (es) 2021-03-18 2021-03-18 Sistema de administracion en multiples sitios para administracion diferencial en el tracto gastrointestinal

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US4853230A (en) * 1986-04-30 1989-08-01 Aktiebolaget Hassle Pharmaceutical formulations of acid labile substances for oral use
ES2524345T3 (es) * 2007-04-04 2014-12-05 Sigmoid Pharma Limited Composición farmacéutica oral

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4786505A (en) * 1986-04-30 1988-11-22 Aktiebolaget Hassle Pharmaceutical preparation for oral use
US4853230A (en) * 1986-04-30 1989-08-01 Aktiebolaget Hassle Pharmaceutical formulations of acid labile substances for oral use
ES2524345T3 (es) * 2007-04-04 2014-12-05 Sigmoid Pharma Limited Composición farmacéutica oral

Non-Patent Citations (3)

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Title
ANONYMOUS: "Combodart 0.5 mg / 0.4 mg hard capsules - Summary of Product Characteristics (SmPC) - (emc)", GLAXOSMITHKLINE, 8 April 2020 (2020-04-08), pages 1 - 19, XP055972732, Retrieved from the Internet <URL:https://www.medicines.org.uk/emc/product/507/smpc#gref> [retrieved on 20221019] *
C.G. WILSON, P.J. CROWLEY: "Controlled Release in Oral Drug Delivery", 1 January 2011, SPRINGER, ISBN: 978-1-4614-1003-4, article STEGEMANN, SVEN: "Chapter 14: Capsules as a Delivery System for Modified-Release Products", pages: 277 - 298, XP009540080, DOI: 10.1007/978-1-4614-1004-1_14 *
MOAWIA M AL-TABAKHA: "HPMC capsules: current status and future prospects", JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIÉTÉ CANADIENNE DES SCIENCES PHARMACEUTIQUES, CANADA, 1 January 2010 (2010-01-01), Canada , pages 428 - 442, XP055198323, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/21092714> DOI: 10.18433/J3K881 *

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