WO2013098841A1 - Nano-dispersion de médicament(s) peu soluble(s) dans l'eau - Google Patents

Nano-dispersion de médicament(s) peu soluble(s) dans l'eau Download PDF

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Publication number
WO2013098841A1
WO2013098841A1 PCT/IN2012/000716 IN2012000716W WO2013098841A1 WO 2013098841 A1 WO2013098841 A1 WO 2013098841A1 IN 2012000716 W IN2012000716 W IN 2012000716W WO 2013098841 A1 WO2013098841 A1 WO 2013098841A1
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WO
WIPO (PCT)
Prior art keywords
nanodispersion
poorly water
drug
drugs
surfactant
Prior art date
Application number
PCT/IN2012/000716
Other languages
English (en)
Inventor
Nandan Mohan Chandavarkar
Kour Chand Jindal
Rajkumar Malayandi
Original Assignee
Fdc Limited
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 Fdc Limited filed Critical Fdc Limited
Publication of WO2013098841A1 publication Critical patent/WO2013098841A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a novel composition of nanodispersion for ocular drug delivery system comprising of poorly water-soluble drug(s).
  • Eye is the most vital and sensitive organ of the body. Eye ailments can cause distress and angst in patients. Many parts of the eye are relatively inaccessible to systemically administered drugs. Thus, topical drug delivery systems remain the preferred route in most of the ocular disorders and hence, a well-accepted route of administration for the treatment of various eye diseases. Drugs may be delivered to treat the precorneal region for diseases namely conjunctivitis and blepharitis, or to provide intraocular treatment via the cornea for diseases such as glaucoma.
  • a major problem with conventional ophthalmic drug delivery systems is poor ocular bioavailability due to ocular anatomical and physiological constraints.
  • the bioavailability of topically administered drug in the anterior chamber of eye is extremely low due to impermeable nature of the cornea.
  • the physiological factors such as rapid clearance of the drug and/or dosage form by the tear-fluid drainage, absorption into the conjunctiva and washout by aqueous humor from the anterior chamber, are responsible for poor precorneal absorption.
  • Topically applied drugs can reach the intraocular tissues by either the corneal and/or the non-corneal pathways.
  • Eye drops are inefficient means of delivering ophthalmic drugs because of limited bioavailability and can cause significant side effects. Under normal conditions, an eye can accommodate very small volume of administered dosage form without overflowing. The drug contained in the eye drops is lost due to absorption through the conjunctiva or through the tear drainage. Attempts to improve ocular bioavailability have been focused on overcoming precorneal constraints through improving corneal penetration, prolonging the precorneal retention, and reducing nasolacrimal drainage.
  • Nanodispersions are promising drug delivery technologies that can be used for enhancing the dissolution of poorly water-soluble drugs.
  • Dispersion associated with pharmaceutical products is a heterogeneous two phase system in which the internal phase (dispersed phase) is distributed or dispersed within external phase (dispersion medium).
  • the dispersed phase and dispersion medium can be solid, liquid or gas.
  • US application no. 2008/0299206 discloses an ophthalmic formulation comprising, a) cyclosporine or a derivative thereof, b) at least one solvent, c) at least one oil selected from medium chain triglycerides, mineral oil, olive oil, peanut oil, wheat germ oil etc. d) surfactant, e) preservatives and (f) water or phosphate buffer.
  • the said application also discloses a composition which comprises cyclosporine, a permeation enhancer and vitamin E TPGS.
  • the said US application does not teach nanodispersion for ocular drug delivery and their potential advantages.
  • US application no. 2008/0102127 discloses a nanoparticulate colloidal delivery vehicle wherein nanoparticles are composed of water insoluble biocompatible polymer, solid lipid material, and outer layer comprising of surfactant, phospholipid, polymer etc.
  • the said solid lipid includes tocopheryl esters such as tocopheryl succinate and tocopheryl palmitate.
  • the said nanoparticle vehicle further contains surfactants, stabilizers, rheological modifiers, antioxidants and preservatives.
  • the said invention describes the formulation of sol id lipid nanoparticles, which consists of lipid material.
  • US 61 14319 discloses ophthalmic emulsion comprising difluprednate, oil such as fatty acid ester of glycerol, water and an emulsifier, for the treatment of ocular inflammation.
  • US 5556848 discloses an ophthalmic suspension comprising difluprednate, water soluble polymer selected from a group consisting of hydroxypropylmethyl cellulose and polyvinyl alcohol, and buffer selected from a group consisting of sodium acetate and ⁇ - aminocaproic acid, for the treatment of inflammation.
  • Nanosuspensions were formulated using 0. 1 % Pluronic as a surfactant.
  • nanodispersion for ocular drug delivery comprising mineral oil.
  • the mineral oil has the advantage of being inert and physic- chemical ly stable as compared to vegetable oils and other fatty esters of glycerol, which are prone to oxidation and rancidity on storage.
  • the present invention discloses a cost effective and technically simple alternative for preparation of nanodispersion for ocular drug delivery of poorly water-soluble drugs(s).
  • the nanodispersion of present invention exhibits improved corneal penetration, prolonged precorneal retention, reduced nasolacrimal drainage and enhanced magnitude of drug action.
  • the present invention relates to nanodispersion formulation for ocular drug delivery comprising, poorly water-soluble drugs(s), mineral oil, surfactant(s), optionally permeation enhancer and other pharmaceutically acceptable excipients, with improved patient compliance, reduced dosing frequency, safety and better therapeutic efficacy.
  • the invention further discloses a process for preparation of the nanodispersion.
  • Figure 1 relates to the size distribution of nanodispersion in Example 1 , wherein the extrapolated line indicates the average particle radius.
  • Figure 2 relates to the size distribution of nanodispersion in Example 2, wherein the extrapolated line indicates the average particle radius.
  • Figure 3 relates to the size distribution of nanodispersion in Example 3, wherein the extrapolated line indicates the average particle radius.
  • Figure 4 relates to the size distribution of nanodispersion in Example 4, wherein the extrapolated line indicates the average particle radius.
  • Figure 5 relates to the size distribution of nanodispersion in Example 5, wherein the extrapolated line indicates the average particle radius.
  • the present invention provides nanodispersion for ocular drug delivery system comprising, poorly water-soluble drugs(s), mineral oil, surfactant(s), optionally permeation enhancer; and other pharmaceutically acceptable excipients.
  • Nanodispersion of present invention offers improved drug surface area and increased intraocular drug permeation. Moreover, nanosized dispersion of drug provides less mechanical irritation to the ocular tissue, when compared to microcrystals and coarse particles. The ocular irritation induces lachrymal fluid secretion, and hence results in drainage of the drug from the eye. The increased lachrymal secretion not only leads to precorneal elimination of the drug by draining out from the ocular cavity, but also causes dilution of the drug. The dilution of the drug in precorneal area, reduces the concentration gradient and hence reduces the rate of absorption of drug(s), which follows passive diffusion.
  • Ophthalmic solutions have been considered as the ideal choice of dosage form for ocular drug delivery because of their clarity, better biopharmaceutical properties and patient compliance.
  • it is very difficult to formulate ophthalmic solutions for poorly soluble drugs because of limited availability of non-toxic solubilizers for ophthalmic use.
  • the present inventors have developed nanodispersion, as conventional ophthalmic formulations has problems associated with it, which include blurred vision, mechanical irritation of the eye caused by coarser particles, sedimentation of particles, agglomeration of the particles during storage and poor content uniformity. Such factors hinder the clinical performance of the ophthalmic formulations.
  • the present invention develops nanodispersion for ocular drug delivery of poorly water- soluble drug(s) to combat the problems associated with the conventional ophthalmic formulations and offer better biopharmaceutical and clinical outcomes.
  • the present invention has used, mineral oil, surfactant(s), optionally permeation enhancer and other pharmaceutically acceptable excipients which are further processed through high pressure homogenizer to produce homogenous nanodispersion.
  • Such nanodispersion enhances the magnitude of drug action along with drug absorption in ocular cavity with limited volume of lachrymal fluid.
  • increased saturation solubility of the drug has been achieved due to high surface area of drug particles which is offered by nanosizing process in combination with the surfactant. Further increased saturation solubility increases the concentration gradient of the drug across the ocular surface and hence improves the rate of absorption.
  • the poorly water soluble drugs used in the nanodispersion of the present invention are selected from a group consisting of steroid anti-inflammatory agents, non-steroidal antiinflammatory agents, antimicrobial, anti-viral, anti-glaucoma, and drugs used in the treatment of cataract and dry eye syndrome preferably difluprednate, dexamethasone; ciprofloxacin, levofloxacin and chloramphenicol.
  • the poorly water soluble drugs used in the nanodispersion of the present invention are in the range of 0.005% to 2.0% of the total weight of the composition.
  • the mineral oil is used as an oil phase, and further increases the partition of drug in lipoidal biological membrane with the help of surfactant.
  • the mineral oil used in the present invention is selected from a group consisting liquid paraffin such as light liquid paraffin, heavy liquid paraffin and mixtures thereof, and is in the range of 0.5% to 10% w/w of the total weight of the composition.
  • the surfactants are wetting agents that lower the surface tension of a liquid, thus allowing easier spreading of the formulation on the ocular surface. They also lower the interfacial tension between two liquids and facilitate drug partitioning, thereby enhancing its absorption. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface.
  • the surfactant(s) used in the present invention are preferably non-ionic surfactants selected from Polysorbate 80, Polysorbate 20, Polysorbate 60, Polyvinyl alcohol, Polyoxy 35 castor oil, polyoxy 40 stearate, polypropylene glycol or sorbitan esters of fatty acids such as monooleate, monolaurate, monopalmitate, monostearate and tristearate, and ranges from 0.0005% to 5.0% w/v of total weight of the composition.
  • the permeability enhancer(s) are used in the present invention to improve the transcorneal permeability of the drug, and hence increase the intraocular drug concentration.
  • the permeation enhancer is preferably selected from tocophersolan (Vitamin E Tocopheryl Polyethylene Glycol 1000 Succinate (Vitamin ETPGS)) or polyethylene glycol glycerides.
  • the other pharmaceutically acceptable excipients used in the present invention include but are not limited to tonicity modifiers, pH adjusting agents, buffers, preservatives, antioxidants, viscosity modifiers, stabilizers and chelating agents.
  • the tonicity modifier used in the present invention is selected from but not limited to sodium chloride, glycerol, glucose, mannitol or sorbitol.
  • the buffer used in the present invention is selected from but not limited to borate, acetate, phosphate, citrate, citrophosphate or TRIS buffer.
  • the preservatives used in the system are selected from but not limited to quaternary ammonium salts such as benzalkonium chloride; benzethonium chloride; benzdodecanium bromide; polyquaternium; cationic compound such as chlorhexidine gluconate; parahydroxy benzoates such as methyl paraben, propyl paraben; alcoholic compounds such as chlorobutanol, benzyl alcohol; sodium dehydroacetate; sorbic acid; thiomersol; sodium perborate or stabilized oxychloro complex.
  • quaternary ammonium salts such as benzalkonium chloride; benzethonium chloride; benzdodecanium bromide; polyquaternium; cationic compound such as chlorhexidine gluconate; parahydroxy benzoates such as methyl paraben, propyl paraben; alcoholic compounds such as chlorobutanol, benzyl alcohol; sodium dehydroacetate; sorbic
  • the antioxidant is a molecule capable of inhibiting the oxidation of drug substances in the formulations.
  • the antioxidants used in the present invention are selected from the group consisting of but not limited to sodium bisulphite, sodium metabisulphite, thiourea, tocophersolan and ethylenediamine tetraacetic acid.
  • the size of the nanodispersion of the present invention is less than l OOOnm, preferably less than 200nm, more preferably less than 20nm.
  • the osmolarity of the nanodispersion of present invention is 250-400 mosm/s, and the viscosity of the nanodispersion of present invention is 1 - 1000 cps preferably 1 -200 cps.
  • the following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Examples:
  • step ( 1 ) phase Adding liquid paraffin phase to step ( 1 ) phase under high speed homogenizer to get a dispersion.
  • step ( 1 ) phase Adding liquid paraffin phase to step ( 1 ) phase under high speed homogenizer to get a dispersion.
  • step ( 1 ) phase Adding liquid paraffin phase to step ( 1 ) phase under high speed homogenizer to get a dispersion.
  • step 2 Adding and dissolving vitamin E TPGS in one tenth volume of purified water (80°C). Cooling to room temperature and adding to the solution of step 1.
  • Table 1 includes evaluation parameters of nanodispersion
  • Polydispersity index is a measurement of distribution of particle sizes in the formulation (measured using Malvern zetasizer)
  • Peak 2 Average PDI % % (cps) (mosm) particle size Peak l Peak 2

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation de nano-dispersion pour l'administration de médicament oculaire comportant un/des médicament(s) peu soluble(s) dans l'eau, de l'huile minérale, un/des tensioactif(s), éventuellement un activateur de perméation et d'autres excipients pharmaceutiquement acceptables, avec une observance améliorée de patient, une fréquence de dosage réduite, une efficacité thérapeutique sure et meilleure. L'invention concerne également un procédé pour la préparation de la nano-dispersion.
PCT/IN2012/000716 2011-10-31 2012-10-30 Nano-dispersion de médicament(s) peu soluble(s) dans l'eau WO2013098841A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN3064/MUM/2011 2011-10-31
IN3064MU2011 2011-10-31
IN2021MU2012 2012-07-12
IN2021/MUM72012 2012-07-12

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WO2013098841A1 true WO2013098841A1 (fr) 2013-07-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081593A1 (fr) * 2014-11-19 2016-05-26 Fmc Corporation Formulation de nanosuspension
JP2019214525A (ja) * 2018-06-12 2019-12-19 ライオン株式会社 水性眼科用組成物

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005298A1 (fr) * 1992-08-28 1994-03-17 Pharmos Corporation Emulsion sous-micronique comme vehicule pour l'administration oculaire d'un medicament
WO1995005163A1 (fr) * 1993-08-13 1995-02-23 Pharmos Corporation Preparations d'emulsion bioadhesive pour la liberation amelioree de medicament
US5556848A (en) 1993-12-27 1996-09-17 Senju Pharmaceutical Co., Ltd. Ophthalmic suspension containing diflupredonate
US6114319A (en) 1997-05-14 2000-09-05 Senju Pharmaceutical Co., Ltd. Compositions containing difluprednate
US20070264349A1 (en) * 2006-03-07 2007-11-15 Novavax, Inc. Nano-structured compositions and methods of making and using the same
WO2008012367A2 (fr) * 2006-07-28 2008-01-31 Novagali Pharma Sa Compositions contenant des composés ammonium quaternaire
US20080102127A1 (en) 2006-10-26 2008-05-01 Gao Hai Y Hybrid lipid-polymer nanoparticulate delivery composition
US20080299206A1 (en) 2006-03-07 2008-12-04 Novavax, Inc. Ophthalmic preparations
US20100003330A1 (en) * 1999-04-28 2010-01-07 The Regents Of The University Of Michigan Antimicrobial nanoemulsion compositions and methods

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005298A1 (fr) * 1992-08-28 1994-03-17 Pharmos Corporation Emulsion sous-micronique comme vehicule pour l'administration oculaire d'un medicament
WO1995005163A1 (fr) * 1993-08-13 1995-02-23 Pharmos Corporation Preparations d'emulsion bioadhesive pour la liberation amelioree de medicament
US5556848A (en) 1993-12-27 1996-09-17 Senju Pharmaceutical Co., Ltd. Ophthalmic suspension containing diflupredonate
US6114319A (en) 1997-05-14 2000-09-05 Senju Pharmaceutical Co., Ltd. Compositions containing difluprednate
US20100003330A1 (en) * 1999-04-28 2010-01-07 The Regents Of The University Of Michigan Antimicrobial nanoemulsion compositions and methods
US20070264349A1 (en) * 2006-03-07 2007-11-15 Novavax, Inc. Nano-structured compositions and methods of making and using the same
US20080299206A1 (en) 2006-03-07 2008-12-04 Novavax, Inc. Ophthalmic preparations
WO2008012367A2 (fr) * 2006-07-28 2008-01-31 Novagali Pharma Sa Compositions contenant des composés ammonium quaternaire
US20080102127A1 (en) 2006-10-26 2008-05-01 Gao Hai Y Hybrid lipid-polymer nanoparticulate delivery composition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 301, 2005, pages 121 - 128
INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 340, no. 1-2, 2007, pages 126 - 33

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081593A1 (fr) * 2014-11-19 2016-05-26 Fmc Corporation Formulation de nanosuspension
US11504324B2 (en) 2014-11-19 2022-11-22 DuPont Nutrition USA, Inc. Nanosuspension formulation
JP2019214525A (ja) * 2018-06-12 2019-12-19 ライオン株式会社 水性眼科用組成物
JP7139703B2 (ja) 2018-06-12 2022-09-21 ライオン株式会社 水性眼科用組成物

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