Classifications

• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • 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
  • A61K9/2806—Coating materials
• • 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
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

• the subject of the invention is an orally administerable pharmaceutical preparation containing a combination of biotechnologically produced human recombinant insulin and/or modified insulin or an analogue and/or derivative thereof, a protease inhibitor and a high molecular weight (natural) protein.
• the invention relates to a method for the production of the pharmaceutical preparation as well.
• the subject of the invention also covers the use of the pharmaceutical preparation and a method for the treatment of diabetes in mammals.
• EP 1454631 describes a pharmaceutical preparation containing a therapeutically effective quantity of insulin and crystalline dextran microparticles in aqueous suspension.
• the preparation provides a controlled insulin release that can be single-phase or multi-phase.
• the pharmaceutical preparation disclosed in international publication document No. WO0033866 contains insulin in a non-aqueous hydrophilic medium, mixed with long-chain PEG species, in the form of a suspension.
• International publication document No. WO9636352 describes an insulin preparation suitable for oral or nasal administration, containing at least two compounds promoting absorption, e.g. Na-salicylate, Na-lauryl sulphate, oleic acid, linoleic acid, lecitin, etc.
• US patent No. US5438040 is an orally administerable pharmaceutical preparation containing a conjugated insulin complex, where the insulin is covalently bound to a physiologically compatible polyalkylene glycol derivative, which is stable and water-soluble, and at the same time does not degrade in the digestive system.
• the preparation disclosed in Japanese patent application No. JP54028807 contains mucin as an additive, and an insulinase inhibitor.
• the pharmaceutical preparation described in international publication document No. WOO 166085 contains insulin, alkali metal (C8 to C22 alkyl) sulphate, water or ethanol as a solvent, a phenolic compound, an antioxidant and a protease inhibitor - e.g. bacitracin or a derivative thereof, soy trypsin or aprotinin.
• the pharmaceutical preparation disclosed in document No. EPO 127535 contains insulin, bile acid and a protease inhibitor.
• the bile acid promotes absorption, the protease inhibitor protects the insulin from proteolysis.
• the orally administered preparation quickly passes through the stomach, and it is released and quickly absorbed in the intestines.
• EP0351651 discloses a preparation suitable for oral and buccal administration containing, in addition to insulin, polyoxyethylene glycol- carboxyl acid-glyceride ester as an absorption-promoting substance, and a carrier substance.
• the preparation according to international publication document No. WO2007121318 contains insulin and sodium 4-CNAB as a carrier substance, which are lyophilized together, then the obtained powder is tabletted or filled into gelatin capsules.
• a swellable hydrogel matrix is used, which is the copolymer of methacrylic acid and polyalkylene glycol, and allows the insulin to be released only when it reaches the small intestine.
• the polymer also inhibits the activity of proteolytic enzymes in the intestines, and helps insulin to remain active for a long time before absorption.
• the preparations known so far are generally characterized by the fact that the bioavailability of insulin is low, only a small amount is absorbed from the gastrointestinal tract, it quickly degrades and fails to affect the blood sugar level.
• the aim of the invention was to develop an orally administerable pharmaceutical preparation containing insulin, with better bioavailability than those known so far.
• the set aim was achieved with a combination insulin, a protease-inhibiting substance and a high molecular weight natural protein. It is important that both the protease inhibiting substance and the protein shall have intestinal carriers, so that both can pass through the intestinal wall and with the appropriate carrier molecules can get through the insulin of peptide nature as well.
• the invention relates to an orally administerable pharmaceutical preparation containing a combination of biotechnologically produced human recombinant insulin and/or modified insulin or an analogue and/or derivative thereof, a protease inhibitor and a high molecular weight (natural) protein.
• the human insulin is an analogue with Asp. Lys, Leu, VaI or Ala at position B28 and Lys or Pro at position B29; or des(B28-B30), des(B27) or des(B30) human insulin.
• the protease inhibitor is ⁇ - amino-caproic acid and the high molecular weight natural protein is casein.
• the pharmaceutical preparation according to the invention contains 40 - 100 IU of human recombinant insulin, 100 - 1000 mg of ⁇ -amino-caproic acid and 1 - 100 mg of casein, and pharmaceutically acceptable carrier and additive substances.
• the pharmaceutical preparation according to the invention can be used for the treatment of (type 1 and 2) diabetes in mammals.
• the pharmaceutical preparation according to the invention can also be used advantageously for the treatment of diabetes in pregnancy.
• the invention also relates to the use of a combination of a therapeutically effective quantity of biotechnologically produced human recombinant insulin and/or modified insulin or an analogue and/or derivative thereof, ⁇ -amino-caproic acid and casein for the production of an orally administerable pharmaceutical preparation suitable for the treatment of (type 1 and 2) diabetes in mammals.
• the subject of the invention also covers a method for the production of the orally administerable pharmaceutical preparation, according to which 40 - 100 IU of biotechnologically produced human recombinant insulin and/or modified insulin or an analogue and/or derivative thereof, 100 - 1000 mg of ⁇ -amino-caproic acid and 1 - 100 mg of casein, mixed with pharmaceutically acceptable carrier and additive substances, are formulated into an orally administerable dosage form.
• the orally administerable pharmaceutical preparation can be a capsule, a tablet or a film-coated tablet.
• the invention also relates to a method for the treatment of (type 1 and 2) diabetes in mammals, according to which patients are given an orally administerable
• biotechnologically produced human recombinant insulin and/or modified insulin or an analogue and/or derivative thereof, ⁇ -amino-caproic acid and casein More precisely, patients are given a pharmaceutical preparation containing 40 - 100 IU of human recombinant insulin, 100 - 1000 mg of ⁇ -amino-caproic acid and 1- 100 mg of casein.
• the pharmaceutical preparation according to the invention is characterized by a bioavailability of over 30 %.
• Figure 1 Insulin (100 ⁇ M; native) stability in the presence of an equivalent quantity of insulin/ ⁇ -amino-caproic acid (acepramin, Sigma, MO) in a solution containing ⁇ -chymotrypsin (1.5 ⁇ g/10 ⁇ l).
• Example 1 The possibility of using oral insulin by means of ⁇ -amino-caproic acid carrier molecules
• mice Male Wistar rats (Charles - River Laboratories, Budapest, Hungary) were used for the experiments. Before the experiment the animals were starved for 16 hours. The experiments started between 8 and 9 h in the morning. 2 x 6 groups were formed in a random manner, with 4 animals by group.
• the animals were pretreated through a feeding probe according to the followings: group 1 : with 1 g/kg of ⁇ -amino-caproic acid; group 2: with 0.1 U/kg of insulin; group 3: with 0.1 U/kg of insulin and 1 g/kg of ⁇ -amino-caproic acid; group 4: with 1.0 U/kg of insulin; group 5: with 1.0 U/kg of insulin and 1 g/kg of ⁇ - amino-caproic acid; and group 6: with a solvent.
• the blood sugar and plasma insulin levels were determined from arterial blood drawn after 15 minutes following the treatment for the first 6 groups and after 60 minutes for the second 6 groups. The obtained results are summarized in Table 1 :
• Example 2 The effect of acepramin on the absorption of insulin with standard casein.
• In vitro stability means the biodegradation of a primitive formulation of the insulin- acepramin mixture in the presence of a protein degrading enzyme, as compared to native insulin (results of reverse-phase HPLC tests).
• the pharmaceutical preparation according to the invention is nearly equivalent to the subcutaneously administered insulin in terms of blood sugar reducing effect, it is suitable for reducing abnormally high blood sugar levels, for treating diabetic mammals.
• the pharmaceutical preparation has an insulin sensitization effect to subcutaneously administered insulin.
• the elimination half life of the pharmaceutical preparation is about 40 minutes in rats.
• the pharmaceutical preparation exhibits no subchronic toxicity.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Endocrinology (AREA)
• General Chemical & Material Sciences (AREA)
• Immunology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Zoology (AREA)
• Gastroenterology & Hepatology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Emergency Medicine (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)

Priority Applications (13)

Applications Claiming Priority (2)

Publications (1)

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Citations (15)

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• 2009
  • 2009-08-03 HU HU0900482A patent/HUP0900482A2/hu unknown
• 2010
  • 2010-08-02 WO PCT/IB2010/053499 patent/WO2011015984A1/en not_active Ceased
  • 2010-08-02 US US13/387,212 patent/US20120129769A1/en not_active Abandoned
  • 2010-08-02 BR BR112012002413A patent/BR112012002413A2/pt not_active IP Right Cessation
  • 2010-08-02 KR KR1020127005524A patent/KR20120088660A/ko not_active Withdrawn
  • 2010-08-02 RU RU2012109006/15A patent/RU2012109006A/ru unknown
  • 2010-08-02 CA CA2769620A patent/CA2769620A1/en not_active Abandoned
  • 2010-08-02 CN CN201080038764XA patent/CN102791282A/zh active Pending
  • 2010-08-02 MX MX2012001461A patent/MX2012001461A/es not_active Application Discontinuation
  • 2010-08-02 JP JP2012523416A patent/JP2013501043A/ja active Pending
  • 2010-08-02 AU AU2010280418A patent/AU2010280418B2/en not_active Expired - Fee Related
  • 2010-08-02 UA UAA201202346A patent/UA106506C2/uk unknown
  • 2010-08-02 EP EP10757272A patent/EP2461820A1/en not_active Withdrawn
• 2012
  • 2012-01-31 IL IL217856A patent/IL217856A0/en unknown
  • 2012-02-29 ZA ZA2012/01519A patent/ZA201201519B/en unknown

Patent Citations (15)

Non-Patent Citations (2)

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