WO2015063510A1 - Delivery of drugs - Google Patents

Delivery of drugs Download PDF

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Publication number
WO2015063510A1
WO2015063510A1 PCT/GB2014/053254 GB2014053254W WO2015063510A1 WO 2015063510 A1 WO2015063510 A1 WO 2015063510A1 GB 2014053254 W GB2014053254 W GB 2014053254W WO 2015063510 A1 WO2015063510 A1 WO 2015063510A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
substituted
group
unsubstituted
drug
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/GB2014/053254
Other languages
English (en)
French (fr)
Inventor
Ijeoma Uchegbu
Andreas Schatzlein
Lisa GODFREY
Katerina LALATSA
Antonio IANNITELLI
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.)
Nanomerics Ltd
Original Assignee
Nanomerics 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 Nanomerics Ltd filed Critical Nanomerics Ltd
Priority to CA2928697A priority Critical patent/CA2928697C/en
Priority to EP14802477.1A priority patent/EP3065779B1/en
Priority to US15/034,321 priority patent/US10213474B2/en
Priority to JP2016526933A priority patent/JP6486349B2/ja
Publication of WO2015063510A1 publication Critical patent/WO2015063510A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides

Definitions

  • Rats intranasally administered with these chitosan modified nanoparticles had an increased concentration of neurotoxin in the periaqueductal gray in comparison to polylactic acid alone loaded nanoparticles (Zhang et al; Drug Development and Industrial Pharmacy 2013, 39, (1 1 ), 1618-24).
  • LENK Leucine5-enkephalin
  • MENK Methionine5- enkephalin
  • Chitosan formulations can also reduce the degradation of peptides.
  • a chitosan-EDTA conjugate has been shown to reduce the degradation of LENK (Bernkop-Schnurch et al; 1997, Pharm Res 14, 917-22).
  • LENK has also been nasally administered with trimethyl chitosan nanoparticles and shown enhanced antinociception in two mouse pain models in comparison to LENK alone (Kumar et al; Int J Biol Macromol 2013, 61 C, 189-195).
  • WO2004/026912 describes polysaccharides which are used to solubilise hydrophobic drugs.
  • WO2008/017839 describes micellar clusters formed from amphiphilic carbohydrate polymers and their use in formulating hydrophobic drugs.
  • GCPQ is specifically exemplified as an amphiphilic carbohydrate polymer.
  • chitosan and its derivatives are well documented for the delivery of drugs via the nasal route, nasal delivery with self-assembling amphiphilic carbohydrates such as GCPQ has not been reported.
  • GCPQ is capable of self-assembly at neutral pH, and this confers an advantage over its parent compound for nasal delivery.
  • palmitoyi chain to chitosan enables this chitosan derivative to self-assemble and confers greater association with drug compounds and therefore enhanced delivery.
  • GCPQ is not thought to function in the same manner as the documented chitosan derivatives.
  • Chitosan Artusson, P., et al; 1994. 11 1358- 1361
  • trimethyl chitosan (Thanou, M.M., et al; Journal of Controlled Release, 2000, 64, 15-25) open intercellular tight junctions and are believed to promote membrane permeabilisation and hydrophilic drug absorption through this mechanism even when administered intranasally (Kumar, M., et al; International Journal of Biological Macromolecules, 2013, 61 , 189-95).
  • Endogenous opioid neuropeptides preferably neuropentapeptides are particularly preferred drugs for use in this invention.
  • Examples include MENK and LENK.
  • a is between 0.00 and 0.970
  • the molar proportion of the c unit is between 0.0200 and 0.850, and more preferably between 0.05 and 0.550.
  • R 2 and R 3 are preferably independently selected from a substituted or unsubstituted alkyl group such as a d-i 0 alkyl group.
  • R 2 and/ or R 3 may be linear or branched.
  • R ⁇ R 2 and R 3 are independently selected from methyl, ethyl or propyl groups.
  • the amphiphilic carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ).
  • TEM transmission electron microscopy
  • a drop of unfiltered solution was placed on Formvar/Carbon Coated Grid (F1961 100 3.05 mm, Mesh 300, Tab Labs Ltd, UK). Excess sample was filtered off with No. 1 Whatman Filter paper and negatively stained with 1 % aqueous Uranyl Acetate. Imaging was carried out using an FEI CM120 BioTwin Transmission Electron Microscope (FEI, USA). Digital Images were captured using an AMT digital camera. Polymer nanoparticles (unfiltered) presented a spherical morphology.
  • Sprague Dawley rats 200 - 250 g were housed four per cage in an air conditioned unit maintained at 20 - 22°C and 50 - 60% humidity and were allowed free access to standard rodent chow and water. Lighting was controlled on a twelve-hour cycle, lights on at 07.00 h. Animals were habituated for 7 days prior to experimentation and acclimatised to the procedure room for 1 hr prior to testing. All protocols were conducted under a UK Home office licence and approved by a local ethics committee. Formulations
  • rats were evaluated for thresholds 24 hr after CFA injection; they were then randomised according to their threshold values and dosed with formulations. Rats were evaluated by an observer blinded to the treatments.
  • Pre-CFA baseline paw withdrawal force was 24.4 ⁇ 4 g.
  • Post- CFA (24 hr) baseline was 3.3 ⁇ 1.3 g.
  • No statistical difference was observed between LENK solution (30 mg mL "1 ) and the vehicle control at any of the time points measured (20, 40 min, 1 , 1.5, 2, 3 and 4 hr).
  • the LENK-GCPQ (30 mg mL "1 LENK) formulation significantly reversed the nociception for up to 4 hr, in comparison to the vehicle control and the LENK solution.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Optics & Photonics (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Psychology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/GB2014/053254 2013-11-04 2014-11-03 Delivery of drugs Ceased WO2015063510A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA2928697A CA2928697C (en) 2013-11-04 2014-11-03 Delivery of drugs
EP14802477.1A EP3065779B1 (en) 2013-11-04 2014-11-03 Delivery of drugs
US15/034,321 US10213474B2 (en) 2013-11-04 2014-11-03 Delivery of drugs
JP2016526933A JP6486349B2 (ja) 2013-11-04 2014-11-03 薬物の送達

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1319437.8 2013-11-04
GBGB1319437.8A GB201319437D0 (en) 2013-11-04 2013-11-04 Delivery of drugs

Publications (1)

Publication Number Publication Date
WO2015063510A1 true WO2015063510A1 (en) 2015-05-07

Family

ID=49767616

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2014/053254 Ceased WO2015063510A1 (en) 2013-11-04 2014-11-03 Delivery of drugs

Country Status (6)

Country Link
US (1) US10213474B2 (enExample)
EP (1) EP3065779B1 (enExample)
JP (1) JP6486349B2 (enExample)
CA (1) CA2928697C (enExample)
GB (1) GB201319437D0 (enExample)
WO (1) WO2015063510A1 (enExample)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB202007703D0 (en) * 2020-05-22 2020-07-08 Nanomerics Ltd Amphiphilic carbohydrate compounds
MX2023002109A (es) * 2020-08-24 2023-07-13 Nanomerics Ltd Inhibidores virales.
WO2023059716A1 (en) * 2021-10-06 2023-04-13 Purdue Pharma L.P. Compositions and methods for levodopa delivery

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026912A1 (en) 2002-09-20 2004-04-01 The University Of Strathclyde Solubilising polysaccharides substituted with hydrophilic and hydrophobic groups
WO2008017839A1 (en) 2006-08-09 2008-02-14 The School Of Pharmacy, University Of London Polymeric micellar clusters and their uses in formulating drugs
US20100222281A1 (en) * 2009-03-02 2010-09-02 School Of Pharmacy, University Of London Delivery of hydrophilic drugs

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763393A (en) * 1996-05-17 1998-06-09 Neurotherapeutics L.P. Neuroactive peptides
GB0315632D0 (en) * 2003-07-04 2003-08-13 West Pharm Serv Drug Res Ltd Pharmaceutical formulations
US8187570B1 (en) * 2005-01-04 2012-05-29 Gp Medical, Inc. Nanoparticles for protein drug delivery
JP2009252275A (ja) * 2008-04-03 2009-10-29 Nec Electronics Corp 半導体記憶装置
TWI437007B (zh) 2008-07-24 2014-05-11 Food Industry Res & Dev Inst 於水相中製備幾丁聚醣奈米顆粒之方法
US10307372B2 (en) * 2010-09-10 2019-06-04 The Johns Hopkins University Rapid diffusion of large polymeric nanoparticles in the mammalian brain
WO2013110077A1 (en) * 2012-01-19 2013-07-25 Hybrid Medical, Llc Topical therapeutic formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026912A1 (en) 2002-09-20 2004-04-01 The University Of Strathclyde Solubilising polysaccharides substituted with hydrophilic and hydrophobic groups
WO2008017839A1 (en) 2006-08-09 2008-02-14 The School Of Pharmacy, University Of London Polymeric micellar clusters and their uses in formulating drugs
US20100222281A1 (en) * 2009-03-02 2010-09-02 School Of Pharmacy, University Of London Delivery of hydrophilic drugs
US8278277B2 (en) 2009-03-02 2012-10-02 University College London Delivery of hydrophilic drugs

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
ABDEL MOUEZ ET AL., EUR J PHARM SCI, vol. 30, 2013, pages 59 - 66
BERNKOP-SCHNURCH ET AL., PHARM RES, vol. 14, 1997, pages 917 - 22
KUMAR ET AL., INT J BIOL MACROMOL, vol. 61 C, 2013, pages 189 - 195
KUMAR ET AL.: "Evaluation of neuropeptide loaded trimethyl chitosan nanopatticles for nose to brain delivery", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 61C, 2013, pages 189 - 195
KUMAR MANOJ ET AL: "Evaluation of neuropeptide loaded trimethyl chitosan nanoparticles for nose to brain delivery", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 61, 2 July 2013 (2013-07-02), pages 189 - 195, XP028729244, ISSN: 0141-8130, DOI: 10.1016/J.IJBIOMAC.2013.06.041 *
KUMAR, M. ET AL., INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 61, 2013, pages 189 - 95
KUMAR, M. ET AL.: "Evaluation of neuropeptide loaded trimethyl chitosan nanopatticles for nose to brain delivery", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 61C, 2013, pages 189 - 195
POLNOK, A. ET AL.: "Influence of methylation process on the degree of quaternization of N-trimethyl chitosan chloride", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS : OFFICIAL JOURNAL OF ARBEITSGEMEINSCHAFT FUR PHARMAZEUTISCHE VERFAHRENSTECHNIK E.V, vol. 57, no. 1, 2004, pages 77 - 83, XP004518753, DOI: doi:10.1016/S0939-6411(03)00151-6
SIEVAL, A.B. ET AL.: "Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride", CARBOHYDRATE POLYMERS, vol. 36, no. 2-3, 1998, pages 157 - 165, XP004134492, DOI: doi:10.1016/S0144-8617(98)00009-5
SIEW, A. ET AL., MOLECULAR PHARMACEUTICS, vol. 9, 2012, pages 14 - 28
THANOU, M.M. ET AL., JOURNAL OF CONTROLLED RELEASE, vol. 64, 2000, pages 15 - 25
UCHEGBU I F ET AL: "POLYMERIC CHITOSAN-BASED VESICLES FOR DRUG DELIVERY", JOURNAL OF PHARMACY AND PHARMACOLOGY, JOHN WILEY & SONS LTD, LONDON; GB, vol. 50, no. 5, 1 May 1998 (1998-05-01), pages 453 - 458, XP000863265, ISSN: 0022-3573 *
ZHANG ET AL., DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 39, no. 11, 2013, pages 1618 - 24

Also Published As

Publication number Publication date
JP6486349B2 (ja) 2019-03-20
GB201319437D0 (en) 2013-12-18
JP2016539100A (ja) 2016-12-15
CA2928697A1 (en) 2015-05-07
EP3065779A1 (en) 2016-09-14
US10213474B2 (en) 2019-02-26
CA2928697C (en) 2022-01-25
EP3065779B1 (en) 2019-06-26
US20160279189A1 (en) 2016-09-29

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