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WO2008132731A2 - Procédés et compositions pour administration rectale d'insuline - Google Patents

Procédés et compositions pour administration rectale d'insuline Download PDF

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Publication number
WO2008132731A2
WO2008132731A2 PCT/IL2008/000546 IL2008000546W WO2008132731A2 WO 2008132731 A2 WO2008132731 A2 WO 2008132731A2 IL 2008000546 W IL2008000546 W IL 2008000546W WO 2008132731 A2 WO2008132731 A2 WO 2008132731A2
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WO
WIPO (PCT)
Prior art keywords
another embodiment
insulin
composition
acid
amount
Prior art date
Application number
PCT/IL2008/000546
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English (en)
Other versions
WO2008132731A3 (fr
Inventor
Miriam Kidron
Original Assignee
Oramed Pharmaceuticals, Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oramed Pharmaceuticals, Inc filed Critical Oramed Pharmaceuticals, Inc
Publication of WO2008132731A2 publication Critical patent/WO2008132731A2/fr
Publication of WO2008132731A3 publication Critical patent/WO2008132731A3/fr

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Classifications

    • 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

Definitions

  • the insulin is regular-acting insulin. In another embodiment, the insulin is fast-acting insulin. In another embodiment, the insulin is lente insulin. In another embodiment, the insulin is semilente insulin. In another embodiment, the insulin is Ultralente insulin. In another embodiment, the insulin is NPH insulin. In another embodiment, the insulin is glargine insulin. In another embodiment, the insulin is lispro insulin. In another embodiment, the insulin is aspart insulin. In another embodiment, the insulin is a combination of two or more of any of the above types of insulin. In another embodiment, the insulin is any other type of insulin known in the art. Each possibility represents a separate embodiment of the present invention.
  • the crystalline insulin of the present invention is modified insulin synthesised by mutation of the genes used in E. coli or S. cerevisiae.
  • recombinant human insulin produced in insect cells is used for crystalline preparations.
  • recombinant human insulin produced in a cell line is used for crystalline preparations:
  • recombinant human insulin produced in CHO cells is used for crystalline preparations.
  • insulin of the present invention exists in rhombohedral crystals as hexamers.
  • the crystalline insulin of the present invention is crystalline insulin-zinc.
  • crystalline insulin comprises insulin-protamine complexes, such as neutral protamine Hagedorn (NPH) insulin.
  • the amount of insulin utilized in methods and compositions of the present invention is 0.5-3 units (u)/kg in humans.
  • the units used to measure insulin in methods and compositions of the present invention are USP Insulin Units.
  • the units used to measure insulin are milligrams.
  • another USP Insulin Unit is equivalent to 45.5 mg insulin.
  • the amount of insulin is 0.1-1 u/kg.
  • the amount is 0.2-1 u/kg.
  • the amount is 0.3-1 u/kg.
  • the amount is 0.5-1 u/kg.
  • the amount is 0.1-2 u/kg.
  • the amount is 0.2-2 u/kg.
  • the amount is 0.3-2 u/kg.
  • the amount is 0.5-2 u/kg.
  • the amount is 0.7-2 u/kg.
  • the amount is 1-2 u/kg.
  • the amount of insulin is 0.1 u/kg. In another embodiment, the amount is 0.2 u/kg. In another embodiment, the amount is 0.3 u/kg. In another embodiment, the amount is 0.4 u/kg. In another embodiment, the amount is 0.5 u/kg. In another embodiment, the amount is 0.6 u/kg. In another embodiment, the amount is 0.8 u/kg. In another embodiment, the amount is 1 u/kg. In another embodiment, the amount is 1.2 u/kg. In another embodiment, the amount is 1.4 u/kg. In another embodiment, the amount is 1.6 u/kg. In another embodiment, the amount is 1.8 u/kg. In another embodiment, the amount is 2 u/kg. In another embodiment, the amount is 2.2 u/kg. In another embodiment, the amount is 2.5 u/kg. In another embodiment, the amount is 3 u/kg.
  • the amount is 20-30 u. In another embodiment, the amount is 10-50 u. In another embodiment, the amount is 20-50 u. In another embodiment, the amount is 30-50 u. In another embodiment, the amount is 20-100 u. In another embodiment, the amount is 30-100 u. In another embodiment, the amount is 100-150 u. In another embodiment, the amount is 100-250 u. In another embodiment, the amount is 100-300 u. In another embodiment, the amount is 200-300 u. In another embodiment, the amount is 100-500 u. In another embodiment, the amount is 200-500 u. In another embodiment, the amount is 300-500 u. In another embodiment, the amount is 200-1000 u. In another embodiment, the amount is 300-1000 u. In another embodiment, the amount is 200-1000 u. In another embodiment, the amount is 300-1000 u.
  • the amount is 50 u. hi another embodiment, the amount is 80 u. In another embodiment, the amount is 100 u. In another embodiment, the amount is 120 u. In another embodiment, the amount is 140 u. hi another embodiment, the amount is 160 u. In another embodiment, the amount is 180 u. In another embodiment, the amount is 200 u. In another embodiment, the amount is 300 u. In another embodiment, the amount is 500 u.
  • sustained release dosage forms e.g. sustained release microencapsulation
  • the use of sustained release dosage forms enables the treatment frequency to be reduced to once or twice a day.
  • the insulin dosage is increased correspondingly with decreasing frequency of administration.
  • compositions of the present invention further comprise tolmetin.
  • tolmetin acts as an absorption enhancer.
  • tolmetin of the present invention comprise tolmetin salt.
  • the compositions of the present invention further comprise sodium caprate.
  • sodium caprate acts as an absorption enhancer.
  • the compositions of the present invention further comprise salicylic acid.
  • salicylic acid acts as an absorption enhancer.
  • the compositions of the present invention further comprise oleic acid.
  • oleic acid acts as an absorption enhancer.
  • the compositions of the present invention further comprise linoleic acid.
  • compositions of the present invention further comprise a nitric oxide (NO) donor.
  • the compositions of the present invention further comprise a bile acid, glycine-conjugated form of a bile acid, or an alkali metal salt.
  • the compositions of the present invention further comprise an ascorbic acid.
  • the ascorbic acid is sodium ascorbate or potassium ascorbate.
  • the compositions of the present invention further comprise a salicyclic acid.
  • compositions of the present invention further comprise sodium salicylate, potassium salicylate, acetyl-salicylic acid, salicylosalicylic acid, aluminum acetylsalicylate, choline salicylate, salicylamide, or lysine acetylsalicylate.
  • compositions of the present invention further comprise exalamide.
  • the compositions of the present invention further comprise diflunisal.
  • the compositions of the present invention further comprise ethenzamide.
  • NO donors of the present invention comprise 3-(2-Hydroxy-l-(l- methylethyl)-2-nitrosohydrazino)- 1 -propanamine, N-ethyl-2-( 1 -ethyl -hydroxy-2- nitrosohydrazino)-ethanamine, or S-Nitroso-N-acetylpenicillamine
  • the bile acid of the present invention is a 5 beta-cholanic acid. In another embodiment, the bile acid of the present invention is a 3 , 12-diol-7-another-5 beta-cholanic acid. In another embodiment, the bile acid of the present invention is a 3 alpha-hydroxy-12-ketocholic acid. In another embodiment, the bile acid of the present invention is a 3 beta-hydroxy-12-ketocholic acid. In another embodiment, the bile acid of the present invention is a 12 alpha-3 beta-dihydrocholic acid. In another embodiment, the bile acid of the present invention is an ursodesoxycholic acid.
  • compositions of the present invention further comprise a nonionic surfactant.
  • compositions of the present invention further comprise a nonionic surfactant.
  • compositions of the present invention further comprise a nonionic polyoxyethylene ether surface active agent (e.g. another having an HLB value of 6 to 19, wherein the average number of polyoxyethylene units is 4 to 30).
  • the compositions of the present invention further comprise anionic surface active agents.
  • the compositions of the present invention further comprise a cationic surface active agent.
  • the compositions of the present invention further comprise an ampholytic surface active agent.
  • zwitteruionic surfactants such as acylcarnitines serve as absorption enhancers.
  • the amount of an absorption enhancer utilized in methods and compositions of the present invention is 0.1 mg/dosage unit. In another embodiment, the amount of enhancer is 0.2 mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage unit. In another embodiment, the amount is 0.4 mg/dosage unit. In another embodiment, the amount is 0.6 mg/dosage unit. In another embodiment, the amount is 0.8 mg/dosage unit. In another embodiment, the amount is 1 mg/dosage unit. In another embodiment, the amount is 1.5 mg/dosage unit. In another embodiment, the amount is 2 mg/dosage unit. In another embodiment, the amount is 2.5 mg/dosage unit.
  • the amount is 3 mg/dosage unit. In another embodiment, the amount is 5 mg/dosage unit. In another embodiment, the amount is 7 mg/dosage unit. In another embodiment, the amount is 10 mg/dosage unit. In another embodiment, the amount is 12 mg/dosage unit. In another embodiment, the amount is 15 mg/dosage unit. In another embodiment, the amount is 20 mg/dosage unit. In another embodiment, the amount is 30 mg/dosage unit. In another embodiment, the amount is 50 mg/dosage unit. In another embodiment, the amount is 70 mg/dosage unit. In another embodiment, the amount is 100 mg/dosage unit. In another embodiment, the absorption enhancer of the present invention is a chelating agent.
  • the amount is 1-10 mg/dosage unit, hi another embodiment, the amount is 2-10 mg/dosage unit. In another embodiment, the amount is 3-10 mg/dosage unit. In another embodiment, the amount is 5-10 mg/dosage unit. In another embodiment, the amount is 1-20 mg/dosage unit. In another embodiment, the amount is 2-20 mg/dosage unit. In another embodiment, the amount is 3-20 mg/dosage unit. In another embodiment, the amount is 5-20 mg/dosage unit. In another embodiment, the amount is 10-20 mg/dosage unit. In another embodiment, the amount is 10-100 mg/dosage unit, hi another embodiment, the amount is 20- 100 mg/dosage unit.
  • the amount is 30- 100 mg/dosage unit. In another embodiment, the amount is 50-100 mg/dosage unit. In another embodiment, the amount is 10-200 mg/dosage unit. In another embodiment, the amount is 20-200 mg/dosage unit. In another embodiment, the amount is 30-200 mg/dosage unit. In another embodiment, the amount is 50-200 mg/dosage unit. In another embodiment, the amount is 100- 200 mg/dosage unit. In another embodiment, the absorption enhancer of the present invention is a chelating agent.
  • the absorption enhancer of the present invention is a chelating agent.
  • composition of this invention may further include a surface- active agent, preservative, and coloring agent, which are ordinarily used in suppositories.
  • the unit dosage forms of the pharmaceutical composition of this invention include a solid suppository having as a base a solid fat which when administered to the rectum, becomes flowable within the rectum, such as cacao butter and WITEPSOL, a solid suppository having as a base a hydrophilic solid substance which becomes flowable in the rectum in the same way, such as macrogol, and a gelatin capsule suppository having a nomally liquid substance (liquid at room temperature) such as neutral fatty acid triglycerides and vegetable oils as a base and coated with a gelatin film.
  • a nomally liquid substance liquid at room temperature
  • a gelatin capsule shell of the present invention comprises 0.5-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 10-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 15-30 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 1-10 mg titanium oxide. In another embodiment, a gelatin capsule shell of the present invention comprises 3-6 mg titanium oxide.
  • a gelatin capsule shell of the present invention comprises 0.1- 1.5 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.5-1.5 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 1 - 1.5 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.1-1 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.2-1 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.1-0.6 mg D&C yellow No. Quinoline Yellow.
  • a gelatin capsule shell of the present invention comprises 0.2-0.6 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.3-0.6 mg D&C yellow No. Quinoline Yellow. In another embodiment, a gelatin capsule shell of the present invention comprises 0.4-0.5 mg D&C yellow No. Quinoline Yellow.
  • the capsule fill comprises 50-5000 mg soybean oil. In another embodiment, the capsule fill comprises 500-5000 mg soybean oil. In another embodiment, the capsule fill comprises 50-500 mg soybean oil. In another embodiment, the capsule fill comprises 500-3000 mg soybean oil. In another embodiment, the capsule fill comprises 50-5000 mg soybean oil. hi another embodiment, the capsule fill comprises 500-2500 mg soybean oil. In another embodiment, the capsule fill comprises 1000-1500 mg soybean oil. In another embodiment, the capsule fill comprises 500-1000 mg soybean oil. In another embodiment, the capsule fill comprises 700- 1200 mg soybean oil . In another embodiment, the capsule fill comprises 700- 1000 mg soybean oil. In another embodiment, the capsule fill comprises 600-900 mg soybean oil.
  • the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 300- 1000 mg SNAC. In another embodiment, the capsule fill comprises 500-1000 mg SNAC. In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 10-500 mg SNAC. In another embodiment, the capsule fill comprises 10-300 mg SNAC. In another embodiment, the capsule fill comprises 50-250 mg SNAC. In another embodiment, the capsule fill comprises 10-1000 mg SNAC. In another embodiment, the capsule fill comprises 50-150 mg SNAC. In another embodiment, the capsule fill comprises 80-120 mg SNAC.
  • the capsule fill comprises 1-50 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 10-50 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 15-50 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 30-50 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 1-30 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 10-30 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 1-20 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 2-15 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 2-10 mg RD-T recombinant human insulin. In another embodiment, the capsule fill comprises 3-5 mg RD-T recombinant human insulin.
  • composition of the present invention is formulated into insertable liquids for use as retention enemas.
  • the present invention comprises rectal ointments that incorporate the composition of the present invention.
  • the present invention comprises rectal creams that incorporate the composition of the present invention.
  • ointments and creams of the invention further comprise rectal insertion and delivery tips.
  • administration of internal rectal medicated cream or ointment requires placement of the applicator's lubricated tip at the rectal opening.
  • the correct dosage of the composition of the present invention is squeezed into the rectum.
  • the present invention comprises rectal aerosol foams (oil-in- water emulsions resembling light creams, non-greasy) that incorporate the composition of the present invention.
  • the present invention comprises rectal coherent gel matrix that incorporate the composition of the present invention.
  • the present invention comprises a non-dissolving, non- disintegrating slow-release suppository base consisting essentially of a linear polymer, such as methyl cellulose, and water in an amount of more than 35 parts by weight and less than 65 parts by weight of linear polymer.
  • the present invention comprises a non-dissolving, non- disintegrating, slow-release, shaped suppository consisting essentially of polyvinyl pyrrolidanother and water, wherein the water is present in an amount of more than 35 parts by weight wherein the suppository has flexibility and becomes slippery when moistened.
  • a urethral suppository comprises i) a relatively long, relatively small diameter shaft, ii) a bulbous head extending from a rounded nose through a relatively gradually outwardly curving insertion surface having an axial length equaling about two thirds of the overall length of the head and a relatively sharply curving retention surface extending from the intersection with the insertion surface which is the maximum diameter of the head to an intersection with the shaft, the intersection between the retention surface and the insertion surface not comprising a sharp edge or corner, and iii) a conical tail including an outwardly tapered retaining surface extending from the shaft to a base having a diameter substantially greater than the maximum diameter of the bulbous head, wherein shaft, head, and tail comprises predetermined dimensions and a unitary structure and are formed entirely from insulin.
  • insulin is combined in a dissolvable element containing an agent material that is used for local administration of an agent material in an internal body area.
  • the dissolvable element is made of a dissolvable polymer material and/or complex carbohydrate material which dissolve due to human body temperatures and moisture during use to release the agent material in a desired timed release and dosage.
  • the present invention comprises a sustained release suppository comprising a fat having a melting range of from 29°C to 4O 0 C.
  • the sustained release suppository further comprises a physiologically acceptable organic substance that is swellable in contact with water.
  • the organic substance that is swellable in contact with water is hydroxypropylmethylcellulose.
  • the sustained release suppository further comprises hydrophobic silicium dioxide.
  • the present invention comprises a suppository for use in the vaginal or rectal cavity comprising insulin and a mixture of triglycerides of fatty acids.
  • the vaginal or rectal suppository further comprises a gel forming agent and a gel dispersing agent.
  • the present invention comprises an effervescent vaginal suppository composition containing a stabilizer.
  • the stabilizer is selected from compounds such as anhydrous sodium sulfate, anhydrous silica gel, dried magnesium silicate, dried aluminum silicate, dried calcium carboxymethylcellulose, dried microcrystalline cellulose, dried starch and dried calcium phosphate, or mixtures thereof.
  • the present invention comprises an insulin capsule.
  • the insulin capsule is formed of a hard capsule shell.
  • hard capsule shell is made of a mixed ester of cellulose ether, e.g. alkyl-, hydroxyalkyl- and hydroxyalkyl alkylcelluloses, esterified with aliphatic monacyl groups and acidic succinyl groups.
  • the capsule is inserted into the rectum.
  • the capsule shell is disintegrated and the rectally absorbable effective insulin is released into the rectum.
  • the suppository of the present invention comprises a biocompatible material in the form of a polymer.
  • the biocompatible polymer is polyurethane.
  • the polymer is cellulose acetate.
  • the biocompatible polymer is polyamide.
  • the polymer is polyethylene.
  • the polymer is polyethylene terephthalate.
  • the polymer is polypropylene.
  • the polymer is polyvinyl acetate.
  • the polymer is polyvinyl chloride.
  • the polymer is silicanother rubber.
  • the polymer is latex.
  • the polymer is polyhydroxybutyrate.
  • the polymer is polyhydroxyvalerate.
  • the polymer is Teflon.
  • the polymer is polylactic acid.
  • the polymer is polyglycolic acid.
  • the biocompatible polymer erodes at a substantially slower rate than the rest of the matrix.
  • the biocompatible polymer comprises a matrix of another or more substantially water soluble crystalline polymers.
  • the pharmaceutical composition of this invention may be prepared by uniformly mixing predetermined amounts of the active ingredient, the absorption aid and optionally the base, etc. in a stirrer or a grinding mill, if required at an elevated temperature.
  • the resulting composition may be formed into a suppository in unit dosage form by, for example, casting the mixture in a mold, or by forming it into a gelatin capsule using a capsule filling machine.
  • the coating is a gelatin coating.
  • microencapsulation is used to protect the insulin against decomposition in the rectum.
  • methods for applying a gelatin coating and for microencapsulation are well known in the art. Each method represents a separate embodiment of the present invention.
  • the coating is a film-coating.
  • the coating is ethylcellulose.
  • the coating is a water-based dispersion of ethylcellulose, e.g. hydroxypropylmethylcellulose (HPMC) El 5.
  • the coating is a monolithic matrix.
  • the coating is cellulose ether (e.g. hypromellose (HPMC).
  • HPMC hypromellose
  • compositions of the present invention have the advantage of more closely mimicking physiological insulin secretion by the pancreas.
  • the liver is exposed to a greater insulin concentration than peripheral tissues.
  • insulin administered according to the present invention reaches the intestine and is absorbed in the body through the intestine and through the portal system to the liver. This absorption route thus resembles the physiological secretion of insulin by the pancreas, enabling, in this embodiment, delicate control of the blood glucose level and the metabolic activities of the liver and the peripheral organs controlled by insulin.
  • compositions of the present composition are absorbed at different rates into the blood stream.
  • a treatment protocol of the present invention is therapeutic.
  • the protocol is prophylactic.
  • Each possibility represents a separate embodiment of the present invention.
  • cornstarch potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidanother, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants
  • buffers e.g., Tris-HCL, acetate, phosphate
  • additives such as albumin or gelatin to prevent absorption to surfaces
  • detergents e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts
  • senorbic acid e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole
  • stabilizers e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose
  • viscosity increasing agents e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum
  • sweeteners e.g. aspartame, citric acid
  • preservatives e.g., Thimerosal, benzyl alcohol, parabens
  • lubricants e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate
  • flow-aids e.g. colloidal silicon dioxide
  • plasticizers e.g.
  • diethyl phthalate, triethyl citrate emulsifiers
  • emulsifiers e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
  • polymer coatings e.g., poloxamers or poloxamines
  • coating and film forming agents e.g. ethyl cellulose, acrylates, polymethacrylates
  • adjuvants e.g. ethyl cellulose, acrylates, polymethacrylates
  • the dosage forms of the present invention are formulated to achieve an immediate release profile, an extended release profile, or a delayed release profile.
  • the release profile of the composition is determined by using specific excipients that serve for example as binders, disintegrants, fillers, or coating materials.
  • the composition will be formulated to achieve a particular release profile as known to another skilled in the art.
  • compositions also include, in another embodiment, incorporation of crystalline insulin into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
  • particulate compositions of the active ingredients are coated with polymers (e.g. poloxamers or poloxamines)
  • compositions containing crystalline insulin and an absorption enhancer are delivered in a vesicle, e.g. a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • a vesicle e.g. a liposome
  • the term “treating” refers to curing a disease. In another embodiment, “treating” refers to preventing a disease. In another embodiment, “treating” refers to reducing the incidence of a disease. In another embodiment, “treating” refers to ameliorating symptoms of a disease. In another embodiment, “treating” refers to inducing remission. In another embodiment, “treating” refers to slowing the progression of a disease.
  • compositions of the present enable direct absorption of rectally administered insulin.
  • intra-rectal insulin preparations of the present invention are effective in lowering blood glucose levels ( Figure 1). Additionally, the intra- rectal insulin preparations of the present invention have comparable efficacy in lowering blood glucose levels to the oral insulin formulations presented in Example 2.
  • the capsules were mechanically cleaned from lubricating oil in a tumble dryer for about 20 minutes. Last, the capsules were coated and stored in polyethylene boxes at 2-8 0 C.
  • enhancers are compared for their ability to facilitate absorption of insulin following rectal administration in methods and compositions of the present invention.
  • Insulin rectal capsules and suppositories are formulated as described, except that the alternate enhancers are substituted for EDTA or SNAC.
  • Amounts of the enhancers are also varied, to determine the optimal amounts. The most effective enhancer/amount is used in subsequent experiments.
  • Insulin rectal capsules and suppositories are formulated as described hereinabove, except that the type and amount of insulin is varied. The most effective type/amount of insulin is used in clinical trials.
  • Formulations comprising EDTA or SNAC and crystalline insulin were formulated as follows: (1) formulation containing 200 mg EDTA, 100 U (4mg) crystalline insulin, 876 mg soybean oil in a rectal gelatin capsule composed of 186 mg gelatin, 102.3 mg glycerol (98%), 5 mg titanium oxide, and 36.7 mg water; (2) formulation containing 100 mg SNAC, 100 U (4 mg) crystalline insulin, 876 mg soybean oil in a rectal gelatin capsule composed of 186 mg gelatin, 102.3 mg glycerol (98%), 5 mg titanium oxide, and 36.7 mg water.
  • Formulations (1) and (2) are administered rectally to 8 healthy volunteers divided to two groups (4 healthy volunteers in each group) entering the clinic on the morning of dosing after an 8 hour overnight fast. No food is allowed until the last blood sample is collected (approximately 3.0 hours post study drug administration).
  • Blood samples are collected 15 minutes prior to study drug administration, at 0 min, and then every 10 min for the first 60 min and every 15 minutes after drug administration up to 180 minutes. Treatment Phase will consist of two periods and will be approximately 10 days in duration.
  • Glucose tests (another-drop) to monitor real-time glucose values are performed using 2 gluco-meters.
  • the Treatment Phase consists of two periods and is 10 days in duration. At each study period prior to study drug administration an indwelling catheter is inserted for blood sample collection; glucose test (another drop) is performed 15 minutes prior to study drug administration; vital signs (blood pressure, heart rate) are recorded 20 minutes prior to study drug administration. Vital signs are measured in the sitting position after at least 5 minutes of rest; blood samples for insulin, plasma glucose and C-peptide analysis are collected 15 minutes prior to study drug administration; vital signs (blood pressure, heart rate) are recorded at approximately 1 and 3 hours post study drug administration. Vital signs are measured in the sitting position.

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Abstract

Compositions comprenant de l'insuline et un activateur d'absorption, procédés de traitement du diabète de type 2, consistant à administrer ces compositions, et procédés d'administration rectale d'insuline
PCT/IL2008/000546 2007-04-26 2008-04-27 Procédés et compositions pour administration rectale d'insuline WO2008132731A2 (fr)

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US92400407P 2007-04-26 2007-04-26
US60/924,004 2007-04-26

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WO2008132731A3 WO2008132731A3 (fr) 2010-02-25

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018087298A1 (fr) * 2016-11-14 2018-05-17 University Of Copenhagen Insuline rectale pour le traitement de maladies intestinales inflammatoires
WO2025068976A1 (fr) * 2023-09-28 2025-04-03 Biotts Inc. Compositions contenant des agonistes de l'insuline destinées à être utilisées dans le traitement du diabète ou de l'obésité

Family Cites Families (3)

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WO2018087298A1 (fr) * 2016-11-14 2018-05-17 University Of Copenhagen Insuline rectale pour le traitement de maladies intestinales inflammatoires
US11400137B2 (en) 2016-11-14 2022-08-02 University Of Copenhagen Rectal insulin for treatment of inflammatory bowel diseases
WO2025068976A1 (fr) * 2023-09-28 2025-04-03 Biotts Inc. Compositions contenant des agonistes de l'insuline destinées à être utilisées dans le traitement du diabète ou de l'obésité

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