WO2004000274A1 - Administration par voie orale a l'etre humain d'agents biologiquement actifs sous forme de nano-emulsion - Google Patents

Administration par voie orale a l'etre humain d'agents biologiquement actifs sous forme de nano-emulsion Download PDF

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Publication number
WO2004000274A1
WO2004000274A1 PCT/HU2003/000049 HU0300049W WO2004000274A1 WO 2004000274 A1 WO2004000274 A1 WO 2004000274A1 HU 0300049 W HU0300049 W HU 0300049W WO 2004000274 A1 WO2004000274 A1 WO 2004000274A1
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WO
WIPO (PCT)
Prior art keywords
nanoemulsion
composition
agents
active agents
biologically active
Prior art date
Application number
PCT/HU2003/000049
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English (en)
Inventor
Endre D. Radics
Original Assignee
Radics Endre D
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 Radics Endre D filed Critical Radics Endre D
Priority to AU2003244885A priority Critical patent/AU2003244885A1/en
Publication of WO2004000274A1 publication Critical patent/WO2004000274A1/fr
Priority to GBGB0500594.7A priority patent/GB0500594D0/en

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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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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

  • Present invention relates to the field of compositions of biologically active agents (nutritional supplements, drugs and pharmaceutical agents), their dosage form and new method of administration into the human body.
  • the invention combines the idea of application of nanoemulsions as transport systems for agents and the oral delivery method of said compositions through absorption through the buccal mucosa.
  • Said nanoemulsions contain both water-soluble and fat-soluble biologically active agents, which do not need the conventional emulsifier additives in order to show physical stability.
  • the phase separation of the fat and water soluble particles of the solution is avoided by the addition of pure natural phospholipids.
  • nanoemulsions with mean droplet diameters ranging from 0,00005 to 0,0001 mm are dispersed by a mechanical pump spray into the oral cavity, where they are absorbed through the buccal mucosa and reach the blood stream and benefit the body.
  • the administered agents show their effect sooner ( H-l minutes, against hour to 2 hours in case of delivery through the digestive system) ;
  • the biologically active agents are absorbed in greater percentage (95-98%), than in conventional delivery forms (pills gen. ca. 10%, capsules gen. ca. 15-20%, sublingual liquids gen. ca. 30%, etc.) and 3. the delivery of biologically active agents is executed on a user- friendly and convenient way.
  • the phospholipid enclosure enables an active transport: the agents can access the cells faster and in greater percentage;
  • the invention is a new oral delivery method for administration of biologically active agents, especially vitamins, minerals, amino acids, herbs and plant extracts, as well as pharmaceutical agents, drugs and hormones into the human body.
  • biologically active agents especially vitamins, minerals, amino acids, herbs and plant extracts, as well as pharmaceutical agents, drugs and hormones into the human body.
  • the invention relates to the delivery method, the form of the biologically active solution and the composition of the active ingredients:
  • Method Mechanical pump activated oral spray with a dispenser hole of max. 50 micron diameter. The agents sprayed into the oral cavity are absorbed through the buccal mucosa and reach the blood stream.
  • nanoemulsion The administered agents are transported in a nanoemulsion formulation, which nanoemulsion can contain both fat-soluble and water- soluble components and shows stability without addition of conventional, synthetic emulsifiers.
  • composition can contain, but is not limited to one or more of the following ingredients:
  • Vitamins both water-soluble and fat-soluble, especially the fat soluble vitamins A, E, D, and K,
  • drugs such as glucosar ⁇ ine sulfate, chondroitin sulfate,
  • Nutritional supplements and drugs are typically provided in solid dosage formulations that are taken orally. Examples include coated and compressed pills, compressed capsules or two piece gelatine capsules. These products have the advantage, that they are easy and relatively inexpensive to produce, largely administered and quite stable. However their effectiveness depends on to which amount they can be absorbed and benefit the human body.
  • Solid formulations have the disadvantage that most of the ingredients are degraded by stomach acids. Degradation reduces the efficiency and/or therapeutical effects of the ingredients administered in solid forms.
  • Liquids have proven themselves more effective than solid dosage forms because they do not need to dissolve and therefore bypass the first step of the usual absorption process of solid forms in the digestive system, however they are considerably degraded by digestive acids .
  • the skin patch applied the method of direct absorption through the skin, however it brought up the problem of getting the ingredients into the deeper layers of the skin.
  • the wax-like fat tissue of the epidermis prevents the penetration of many agents into the skin.
  • the lipid and keratin containing structure of the horny tissue creates a biological defence system, therefore ingredients can hardly get through dense skin surfaces .
  • the sublingual nitro-glycerine tablet is the most common example for application of the oral absorption method through the buccal mucosa.
  • heart patients can quickly get the active ingredient to the heart with the help of the tablet, because the ingredient is absorbed through the buccal mucosa directly into the blood stream and reaches the heart while the tablet gradually dissolves under the tongue. Otherwise, if the tablet would be swallowed, the active ingredient would face multiple degradation (stomach acids) and delay effects. Passing through the digestive system, it would reach the bloodstream after getting through the liver, therefore the ingredient would not reach the heart in time.
  • Deihl found a more effective method than the sublingual tablet: the oral spray.
  • the significance of the innovation is that the active ingredients compose a solution which is sprayed into the mouth. The fine mist gets on the buccal mucosa and is absorbed into the blood stream.
  • Deihl uses not only the part of the buccal mucosa that is under the tongue, but the entire inner surface of the oral cavity as absorption area, therefore he increases bioavailability.
  • the spray administered ingredients enter the blood stream through diffusion in 95 to 98 percent within 22 to 30 seconds which are very close results to the effectiveness of the above mentioned hospital procedures (intravenular, intramuscular, etc. forms) .
  • the spray administration method which applies the absorption through the buccal mucosa is more effective in both absorption rate and onset rapidity than the conventional solid and liquid forms, moreover it can be used in a more simple and convenient way.
  • Liposomes are microscopic particles with mean diameter of 20 to 100 nanometers that consist one or more lipid layers, enclosing .an aqueous core.
  • the lipid layers are capable to merge into the cell membranes and subsequently allow transmission of the entrapped active ingredients through the membrane .
  • Liposomes were described first by A. D. Bangham and colleagues in 1965. They observed that liposomes tend to enclose part of their environment. The small liposome spheres are encircled by membrane bi-layers, just like the biological membranes surround the body cells. This remarkable resemblance lead to Bangham' s discovery. Today, we know what causes this similarity. The basic structure of biological membranes is made up by approximately the same ratio of lipids and proteins, in addition to them, there are 2 to 7 percent carbohydrates. Liposomes can be also regarded as models for biological membranes, however their structure is far more simple, they usually do not contain proteins, lipids are predominant.
  • the most important lipids are phosphoglycerides in which the first and second carbon atoms of the glycerine are esterified with long carbon chain saturated and unsaturated fatty acids, the third carbon atom is bonded to an alcohol (ethanolamine, choline, glycerine or serine) through a phosphoric acid.
  • the most important phosphoglycerides are phosphotidylcholine (lecithin) , phophotidylserine and phosphotidylinositol.
  • Liposomes are formed when the concentration of phospholipids is further increased. During this process, the bi-layer splits and the smaller parts that break down close themselves into it selves and form globes, so that bi-layer membrane enclosed particles, that is liposomes are created.
  • liposomes as delivery systems for biologically active agents has become the subject of extensive research over the last ten years. Their nature and application in clinical practice are presented in numerous scientific publications, such as Barenholz, Amselem, Liposome Technology, 2. Edition, G. Gregoriadis, ed. , CRC press, 1992.
  • Liposomes may hold both hydrophilic and lipophilic substances, the technology of production has to be adjusted to the agents.
  • One possibility is that the appropriate lipid mixture is dissolved with the help of an organic solvent and the solvent is eliminated by distillation.
  • a thin lipid film remains on the wall of the test-tube, out of which the liposomes incorporating the lipophilic agents can be formed by dispersion in distilled water - by shaking or ultrasound irradiation.
  • the lipophilic agents are added to the lipid components at the beginning of the preparation of the film, before the dissolution with the organic solvent, so that the agents can be incorporated into the liposome membrane.
  • a further advantage of the liposomes is that they are harmless to the skin and the human body, because the elements of this "delivery system" are identical to the basics that compose the biological membranes.
  • This varied lipids are non-toxic, they don't initiate immune reaction and they decay biologically. Liposomes act as dosage systems as well, because their firm structure resolves gradually and the agents encapsulated are released slowly. Through the encapsulation, the agents in the liposomes are better protected against decomposition.
  • liposomes have the disadvantage of being able to encapsulate only a very small quantity of agents because of their small size, further it is difficult to produce them with the preferred stability, which has key importance in case of medications.
  • the instability is both in vitro and in vivo significant: instability in vitro can manifest itself in different ways: often, the size and structure of the liposome particles show a discrepancy, the particles can accumulate, break up and release the biologically active hydrophilic agents.
  • the contact of liposomes with biological liquids often leads to an increased permeability of the liposome membrane.
  • the hydrophilic agents encapsulated into the aqueous core can escape through diffusion.
  • particles inside the liposomes strive for balance with the environment that surrounds the lipid layer of the liposome. In other words, only the quantity of hydrophilic agents can be hold in the liposome that is in equilibrium with the environment outside the liposome. If the substance outside becomes thinner - and this can happen because of contact with biological liquids, such as enzymes in the saliva, stomach acid or simple PH inconsistency,- the appropriate amount of the agents inside the ' liposome can leave by diffusion.
  • the level of in vivo degradation of the liposomes varies by delivery method. Liposomes are ineligible for numerous delivery methods, such as water-based systems (drinks), because depending on its concentration, the solution can become turbid.
  • Emulsions Emulsions , emulsifiers
  • Emulsions are mixtures of solutions that are naturally not miscible in each other, whereas the particles of one solution are dispersed in the other solution, for example water-in-oil or oil-in-water emulsions.
  • emulsifiers are needed, that is materials that reduce the surface tension in the liquid.
  • Conventional emulsifiers are artificial additives, generally tensides, but also foamers and detergents that administered to the human body in higher dosage over a long time period can cause serious harm to the blood and blood-vessels.
  • Object of the present invention is to elaborate a composition for the delivery method of oral absorption, so that said composition incorporates a greater quantity of fat soluble agents than liposomes can do, and that said composition enables active delivery of the agents, just like liposomes do, but that said composition solves the problem of instability as seen at the liposomes, however without addition of synthetic emulsifiers.
  • Aim of the inventor is to solve the problem in a way that is industrially applicable and economically executable.
  • nanoemulsions do not contain synthetic emulsifiers. They deal with particles which surpass the particle size of the liposomes, they have diameters of 50-1000 nanometers, and in order to achieve stability they contain only naturally pure phosphotidylcholine.
  • phosphotidylcholine is made from lecithin which is the essential element of every single natural cell membrane. By means of high pressure technology phosphotidylcholine forms membranes which enclose the oil/fat droplets that are insoluble in water.
  • a nanoemulsion is a dispersion of nanoparticles with a lipid core in an aqueous surrounding, wherein said lipid core can be in both liquid or solid state.
  • Phospholipid content 0.5-2% 5-10% 0.1-5%
  • Non-natural emulsifier present none none
  • Nanoemulsions can deliver biologically active agents, both fat and water soluble: they can incorporate great amounts of fat soluble agents in their solid or liquid lipid core as well as and they can contain water soluble agents in the aqueous surrounding of their lipid core separated by phospholipids.
  • nanoemulsions are more stable than liposomes.
  • Nanoemulsions can be prepared by high-pressure homogenisation which can follow in a cold or hot process :
  • the resulting lipid film is hydrated and dispersed by covering and shaking or ultrasound irradiation.
  • High-pressure homogenisation is applied (up to 800 bar), for example with a Gaulin-type homogeniser (AVP Gaulin International, Holland) .
  • High-pressure homogenisation is described in detail in Brandl, Liposome Technology, 2. Edition, G. Gregoriadis, Volume 1, Ch. 3, CRC Press, Boca Ranton, FI (1992) .
  • the particle size distribution of the formulation can be determined using an electronical microscope.
  • Example 1 Multivitamin nanoemulsion spray formulation, 10 ml Additives %/ weight
  • Lecithin and the fat soluble biologically active agents were dissolved in dichloromethane and the organic solvent was eliminated by distillation.
  • the water mixture was added to the lipid mixture and mixed in a high speed homogenizing mixer at app. 15.000 rp for 5 minutes.
  • the particle size of the nanoemulsion was controlled with the help of a N4MD Coulter particle-determination instrument (Coulter Electronics, Yale) .
  • the mean particle size was 90 +- 40 nanometer.
  • flavouring agent The flavouring agent, the rose hip extract and potassium sorbate was added and the solution was filled into the spray container.
  • Example 2 Nanoemulsion spray formulation for strengthening the immune system, 10 ml
  • Example 3 Melatonin nanoemulsion spray formulation, 10 ml
  • Vitamin E 0.4% /weight

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions d'agents biologiquement actifs (compléments alimentaires, médicaments et agents pharmaceutiques), leur forme posologique et un nouveau procédé d'administration de celles-ci à l'être humain. L'invention combine l'utilisation de nano-émulsions comme vecteurs d'agents et un procédé d'administration des compositions par voie orale en vue de l'absorption de celles-ci par la muqueuse buccale. Les nano-émulsions contiennent des agents biologiques hydrosolubles et liposolubles ne nécessitant aucun additif émulsifiant classique pour leur stabilité physique. Une séparation de phases des particules liposolubles et hydrosolubles de la solution est évitée par l'ajout de phospholipides naturels purs. Ces nano-émulsions, qui présentent des diamètres moyens de gouttelettes compris entre 0,00005 et 0,0001 mm, sont dispersées par un atomiseur mécanique dans la cavité buccale, où elles sont absorbées par la muqueuse buccale, atteignent le flux sanguin et ont une action bénéfique pour le corps.
PCT/HU2003/000049 2002-06-19 2003-06-18 Administration par voie orale a l'etre humain d'agents biologiquement actifs sous forme de nano-emulsion WO2004000274A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003244885A AU2003244885A1 (en) 2002-06-19 2003-06-18 Oral delivery of biological active agents in a nanoemulsion formulation to the human body
GBGB0500594.7A GB0500594D0 (en) 2002-06-19 2005-01-12 Oral delivery of biological active agents in a nanoemulsion formulation to the human body

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0202032 2002-06-19
HU0202032A HUP0202032A2 (hu) 2002-06-19 2002-06-19 Nanoemulziós formulációban található bioaktív anyagok emberi szervezetbe való bevitele a szájüreg nyálkahártyáján keresztül, mechanikus pumpájú spray által.

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WO2004000274A1 true WO2004000274A1 (fr) 2003-12-31

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GB (1) GB0500594D0 (fr)
HU (1) HUP0202032A2 (fr)
WO (1) WO2004000274A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1864578A1 (fr) * 2006-06-09 2007-12-12 FUJIFILM Corporation Composition d'émulsion à base de caroténoïde, son procédé de fabrication et produit alimentaire et cosmétique le contenant
US8105637B2 (en) * 2006-04-07 2012-01-31 Shinji Shimada Composition comprising nanoparticle Ginkgo biloba extract with the effect of brain function activation
CN101759727B (zh) * 2009-09-30 2013-03-27 钱娟 一种纳米级松树皮提取物及其制备方法
US9468626B2 (en) 2014-03-13 2016-10-18 Chiesi Farmaceutici S.P.A. Melatonin-based formulations for parenteral administration
EP2512648B1 (fr) * 2009-12-15 2018-01-24 Emultec S.r.L. Nanoémulsion, son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
US4525341A (en) * 1984-04-09 1985-06-25 Mayor Pharmaceutical Laboratories, Inc. Method of administering vitamins
US5576016A (en) * 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
US5891465A (en) * 1996-05-14 1999-04-06 Biozone Laboratories, Inc. Delivery of biologically active material in a liposomal formulation for administration into the mouth
US20010028887A1 (en) * 2000-01-21 2001-10-11 Veronique Douin Nanoemulsions comprising at least one amphiphilic lipid, at least one oil, and at least one cationic polymer, and uses thereof
US20010036450A1 (en) * 2000-01-21 2001-11-01 Claude Verite Nanoemulsions comprising at least one amphiphilic lipid, at least one oil, and at least one poly ethylene glycol (PEG) ester, and uses thereof
US20020015721A1 (en) * 1999-01-05 2002-02-07 Jean-Thierry Simonnet Nanoemulsion based on ethylene oxide and propylene oxide block copolymers and its uses in the cosmetics, dermatological and/or ophthalmological fields
EP1327434A1 (fr) * 2002-01-05 2003-07-16 Pacific Corporation Nanoemulsion comprenant des derives de ginseng saponines et composition pour le traitement des signes cutanes du vieillissement comprenant cette nanoemulsion

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4525341A (en) * 1984-04-09 1985-06-25 Mayor Pharmaceutical Laboratories, Inc. Method of administering vitamins
US5576016A (en) * 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
US5891465A (en) * 1996-05-14 1999-04-06 Biozone Laboratories, Inc. Delivery of biologically active material in a liposomal formulation for administration into the mouth
US20020015721A1 (en) * 1999-01-05 2002-02-07 Jean-Thierry Simonnet Nanoemulsion based on ethylene oxide and propylene oxide block copolymers and its uses in the cosmetics, dermatological and/or ophthalmological fields
US20010028887A1 (en) * 2000-01-21 2001-10-11 Veronique Douin Nanoemulsions comprising at least one amphiphilic lipid, at least one oil, and at least one cationic polymer, and uses thereof
US20010036450A1 (en) * 2000-01-21 2001-11-01 Claude Verite Nanoemulsions comprising at least one amphiphilic lipid, at least one oil, and at least one poly ethylene glycol (PEG) ester, and uses thereof
EP1327434A1 (fr) * 2002-01-05 2003-07-16 Pacific Corporation Nanoemulsion comprenant des derives de ginseng saponines et composition pour le traitement des signes cutanes du vieillissement comprenant cette nanoemulsion

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* Cited by examiner, † Cited by third party
Title
BURCZYK F ET AL: "LIPOHYPARTS", SOFW-JOURNAL SEIFEN, OELE, FETTE, WACHSE, VERLAG FUR CHEMISCHE INDUSTRIE, H. ZIOLKOWSKY K.G. AUGSBURG, DE, vol. 118, no. 18, 12 November 1992 (1992-11-12), pages 1150 - 1151, XP000323748, ISSN: 0942-7694 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8105637B2 (en) * 2006-04-07 2012-01-31 Shinji Shimada Composition comprising nanoparticle Ginkgo biloba extract with the effect of brain function activation
EP1864578A1 (fr) * 2006-06-09 2007-12-12 FUJIFILM Corporation Composition d'émulsion à base de caroténoïde, son procédé de fabrication et produit alimentaire et cosmétique le contenant
CN101759727B (zh) * 2009-09-30 2013-03-27 钱娟 一种纳米级松树皮提取物及其制备方法
EP2512648B1 (fr) * 2009-12-15 2018-01-24 Emultec S.r.L. Nanoémulsion, son procédé de préparation et son utilisation
US9468626B2 (en) 2014-03-13 2016-10-18 Chiesi Farmaceutici S.P.A. Melatonin-based formulations for parenteral administration

Also Published As

Publication number Publication date
GB0500594D0 (en) 2005-02-16
HU0202032D0 (fr) 2002-08-28
HUP0202032A2 (hu) 2004-10-28
AU2003244885A1 (en) 2004-01-06

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