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WO2021029467A1 - Forme posologique solide pour administration orale - Google Patents

Forme posologique solide pour administration orale Download PDF

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Publication number
WO2021029467A1
WO2021029467A1 PCT/KR2019/010364 KR2019010364W WO2021029467A1 WO 2021029467 A1 WO2021029467 A1 WO 2021029467A1 KR 2019010364 W KR2019010364 W KR 2019010364W WO 2021029467 A1 WO2021029467 A1 WO 2021029467A1
Authority
WO
WIPO (PCT)
Prior art keywords
granule
insulin
formulation
dosage form
mixing
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2019/010364
Other languages
English (en)
Inventor
Hyung-Kyun Jun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sam Chun Dang Pharm Co Ltd
Original Assignee
Sam Chun Dang Pharm Co Ltd
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 Sam Chun Dang Pharm Co Ltd filed Critical Sam Chun Dang Pharm Co Ltd
Priority to PCT/KR2019/010364 priority Critical patent/WO2021029467A1/fr
Publication of WO2021029467A1 publication Critical patent/WO2021029467A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • the present invention relates to the field of oral pharmaceutical formulations, especially the solid dosage form of insulin.
  • SNEDDS Self-Nano Emulsified Drug Delivery System
  • protein eg. insulin
  • peptide eg. liraglutide
  • hormone drugs eg. somatropin
  • SNEDDS Self-Nano Emulsified Drug Delivery System
  • SNEDDS can be used to protect the drug against degradation.
  • SNEDDS can also increases the solubilization and dissolution of the drug to have quick onset, and enhances drug absorption through structural or fluidity changes in the intestinal membrane.
  • Diabetes is a metabolic disease that causes high blood glucose level.
  • the high blood glucose level is due to either failure to produce enough insulin or to the development of insulin resistance. Failure to produce enough insulin results in diabetes Type 1.
  • Type 2 diabetes results from insulin resistance.
  • Type 1 diabetes is typically treated with insulin or synthetic insulin analogs.
  • Type 2 diabetes may require insulin if other medications fail.
  • the present invention provides a solid oral pharmaceutical formulation of insulin with high stability, efficiency and low-cost for preparation. Besides, this formulation is suitable for both type 1 diabetes and type2 diabetes, and the efficacy in blood glucose-lowing can be achieved for more than 4 hours after single dose administration.
  • the present invention provides the method for preparing this formulation as well.
  • the solid dosage form for orally administering comprising insulin, microcrystalline cellulose, stearic acid, magnesium aluminometasilicate, labraso, polyvinyl alcohol and titanium dioxide.
  • the magnesium aluminometasilicate includes Neusilin ® US2 and Neusilin ® UFL2.
  • a method of preparing the solid dosage form for orally administering comprising the steps of: (a)weighting granule 1, comprising insulin, microcrystalline cellulose, and stearic acid, and passing through a #35 sieve; (b) mixing granule 1 for at least 5 minutes, next tableting it to 7 ⁇ 8 KP intensity, and then passing through #16 mesh sieve and granulation; (c) weighting granule 2, comprising magnesium aluminometasilicate, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide; and passing through a #30 sieve; (d) mixing granule 2 for at least 5 minutes, pouring the labrasol on the mixing granule 2 and waiting for overnight; (e) coating mixing granule 2 by fluid bed granulation; and (f) forming the dosage form by final mixing granule 1 and granule 2.
  • the formulation is a solid dosage form and does not contain any antacid, it is very stable when stored in vitro.
  • the formulation of this invention is automatically emulsified to form colloid micelle with insulin loading inside under the participation of gastric juice.
  • the insulin is stable inside the micelle.
  • FIG.1 is a graph of blood glucose levels (% of initial) over time, calculated as a percent of initial blood glucose values, for streptozotocin (STZ)-induced diabetic mice to which were orally administered 200 IU/kg of insulin(filled circles), or orally administered of water (open circles).
  • STZ streptozotocin
  • FIG.2 is a graph of blood glucose levels (% of control) over time, calculated as a percent of control blood glucose values, for streptozotocin (STZ)-induced diabetic mice to which were orally administered 200 IU/kg of insulin.
  • FIG.3 is a graph of blood glucose levels (% of initial) over time, calculated as a percent of initial blood glucose values, for genetic-deficient diabetic mice to which were orally administered 200 IU/kg of insulin (filled circles), or orally administered of water (open circles).
  • the present invention provides a pharmaceutical formulation which is effective in adjusting blood glucose levels by providing suitable amount of insulins in a subject, when administered to said subject's gastrointestinal tract by oral administration of a pharmaceutical formulation according to the present invention.
  • a formulation that includes insulin, microcrystalline cellulose, stearic acid, magnesium aluminometasilicate, labraso, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide.
  • the formulation comprises at least 1.18% w/w insulin, at least 7.5% microcrystalline cellulose, at least 0.14% w/w stearic acid, at least 14.7% w/w magnesium aluminometasilicate, at least 44.12% w/w labraso, at least 8.46% w/w polyvinyl alcohol and at least 0.29% w/w titanium dioxide.
  • the magnesium aluminometasilicate includes Neusilin ® US2 and Neusilin ® UFL2.
  • a method of preparing the solid dosage form for orally administering comprising the steps of: (a)weighting granule 1, comprising insulin, microcrystalline cellulose, and stearic acid, and passing through a #35 sieve; (b) mixing granule 1 for at least 5 minutes, next tableting it to 7 ⁇ 8 KP intensity, and then passing through #16 mesh sieve and granulation; (c) weighting granule 2, comprising magnesium aluminometasilicate, polyvinyl alcohol, neotame, cherry flavoring agent and titanium dioxide; and passing through a #30 sieve; (d) mixing granule 2 for at least 5 minutes, pouring the labrasol on the mixing granule 2 and waiting for overnight; (e) coating mixing granule 2 by fluid bed granulation; and (f) forming the dosage form by final mixing granule 1 and granule 2.
  • the formulation is a solid dosage form and does not contain any antacid, it is very stable when stored in vitro.
  • the formulation of this invention is automatically emulsified to form colloid micelle with insulin loading inside under the participation of gastric juice. Thereby completing the mission of lowering blood sugar. This way is more similar to the normal human metabolism.
  • formulation was prepared as follows:
  • Granule 2 was prepared by a wet granulation method,in which all the granule 2 compounds were weighed and passed through a #30 sieve. After mixing for at least 5 minutes, pouring the labrasol on the mixing granule 2 and waiting for overnight. And then coating mixing granule 2 by fluid bed granulation.
  • Formulation was prepared by combining granule 1 and granule 2 and then finally filled into capsules or compressed into tablets.
  • the formulation is a solid form with FDA approved polymeric excipients.
  • the solidified dosage form improves the stability of peptide/protein/hormone drug especially insulin.
  • the preparing steps is much easier than before and leads to the low-cost for production.
  • it can be orally administered to a subject,which greatly decreases the inconvenience of patients compared to the injection.
  • the hydrophobic insulin along with some polymeric excipients or lipid component is delivered into the duodenum, the micelle solubilization process takes place.
  • the liquidcrystal liked W/W nano-emulsion especially colloidal micelle is formed with insulin entrapped in the core.
  • the micelle is formed in the gastrointestinal tract, some of the insulin may go through the first-pass effect, which can minimize the insulin-induced weight gain. And then some of the micelle with insulin inside will then get into the blood vessel, the others can be absorbed via the lymphatic system, bypassing the hepatic first -pass metabolism. Since the stearic acid we used is a long-chain fatty acid which can convert to triglyceride by re-esterification in the small intestine and incorporated into chylomicron, a large lipoprotein like insulin can be secreted into the lymph vessel by exocytosis. Therefore, this kind of delivery of insulin is mimic to physiologic situation, and it can minimize insulin-induced weight gain.
  • in vivo hypoglycemic study with SMEDDS containing insulin after oral administration in diabetic mice to study the pharmacokinetic (PK) / pharmacodynamics (PD) profile.
  • PK pharmacokinetic
  • PD pharmacodynamics
  • the formulation containing 200IU/kg of human insulin was administered by oral gavage to each of five STZ-induced DB mice (around 30g body weight).
  • Four STZ-induced DB mice was orally administrated with same amount of water as the control group.
  • the formulation containing 200IU/kg of human insulin was administered by oral gavage to each of five genetic-deficient DB mice (BKS.Cg-Dock7m +/+ Leprdb/Jnarl, around 30g body weight).
  • Four genetic-deficient DB mice was orally administrated with same amount of water as the control group.
  • FIG. 3 Blood samples were drawn from each mouse following gavage, and blood glucose levels in those samples were determined. The results of these blood glucose determinations are shown in FIG. 3. The formula for calculating is the same with FIG.1.To avoid the influence of other parameters like the initial glucose level, a percent of control blood glucose values was calculated and shown in FIG.4. The formula for calculating is the same with FIG.2.
  • mice Due to first introducing dose by oral route, the initial raise of blood glucose on mice can be expected (i.e. no experience) which is widely seen in previous animal studies with oral administration. But compared to the about 230% increase of the control group in the early 30 minutes, about 50% increase of the tested group means that the mice still exert a exhibited a substantial drop in blood glucose level. And then the glucose level slowly decrease over the remaining study period for abound 4 hours.
  • the formulation is useful for diabetes type 2.
  • the insulin resistance is a core feature of diabetes type 2.
  • the insulin resistance contributes to the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis that accompany it. As a result, it is easy to draw a conclusion that the formulation is useful for the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis.
  • Alzheimer disease model has been widely studied. Especially since 2006, clinical trials have been conducted to evaluate the clinical benefit of insulin in Alzheimer patients. It was found that moderate doses of intranasal insulin improved some memory symptoms in older adults with Alzheimer disease or mild cognitive impairment. Insulin exerts its actions in the body also mediate its roles in synaptic neurotransmission, neuronal and glial metabolism, and the neuroinflammatory response in the brain. The actions of insulin in the brains include central modulation of body metabolism and enhancement or regulation of memory and other cognitive and emotional functions. Thus the formulation is effective for Alzheimer patients.

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

Abstract

La présente invention concerne un type de forme posologique solide de formulation pour l'administration orale et le procédé de préparation de la formulation, qui est stable aussi bien in vivo qu'in vitro. Elle contient le système d'administration de médicament auto-nanoémulsifié, de telle sorte que la solubilisation des micelles a lieu après administration de la formulation dans le duodénum. La formulation subit l'effet de premier passage et puis transporte non seulement jusqu'au vaisseau sanguin, mais également au vaisseau lymphatique. Ainsi, cette formulation peut réduire au minimum le gain de poids induit par l'insuline et éviter l'hypoglycémie réactionnelle.
PCT/KR2019/010364 2019-08-14 2019-08-14 Forme posologique solide pour administration orale Ceased WO2021029467A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2019/010364 WO2021029467A1 (fr) 2019-08-14 2019-08-14 Forme posologique solide pour administration orale

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2019/010364 WO2021029467A1 (fr) 2019-08-14 2019-08-14 Forme posologique solide pour administration orale

Publications (1)

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WO2021029467A1 true WO2021029467A1 (fr) 2021-02-18

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103657A2 (fr) * 2005-03-31 2006-10-05 Dexcel Pharma Technologies Ltd. Composition solide de distribution intra-buccale d'insuline
US8323689B2 (en) * 1999-02-22 2012-12-04 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
WO2015010927A1 (fr) * 2013-07-24 2015-01-29 Novo Nordisk A/S Composition pharmaceutique pour administration orale d'insuline comprenant un cœur de comprimé et un enrobage de copolymère anionique
US20160045503A1 (en) * 2012-06-18 2016-02-18 Principia Biopharma Inc. Formulations containing reversible covalent compounds
US20180000742A1 (en) * 2015-01-29 2018-01-04 Novo Nordisk A/S Pharmaceutical Composition for Oral Insulin Administration Comprising a Tablet Core and a Polyvinyl Alcohol Coating

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8323689B2 (en) * 1999-02-22 2012-12-04 Merrion Research Iii Limited Solid oral dosage form containing an enhancer
WO2006103657A2 (fr) * 2005-03-31 2006-10-05 Dexcel Pharma Technologies Ltd. Composition solide de distribution intra-buccale d'insuline
US20160045503A1 (en) * 2012-06-18 2016-02-18 Principia Biopharma Inc. Formulations containing reversible covalent compounds
WO2015010927A1 (fr) * 2013-07-24 2015-01-29 Novo Nordisk A/S Composition pharmaceutique pour administration orale d'insuline comprenant un cœur de comprimé et un enrobage de copolymère anionique
US20180000742A1 (en) * 2015-01-29 2018-01-04 Novo Nordisk A/S Pharmaceutical Composition for Oral Insulin Administration Comprising a Tablet Core and a Polyvinyl Alcohol Coating

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