WO2014092596A1 - Substances et compositions pharmaceutiques les contenant pour traiter des affections humaines, y compris les hépatites virales chroniques b et c - Google Patents

Substances et compositions pharmaceutiques les contenant pour traiter des affections humaines, y compris les hépatites virales chroniques b et c Download PDF

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WO2014092596A1
WO2014092596A1 PCT/RU2012/001057 RU2012001057W WO2014092596A1 WO 2014092596 A1 WO2014092596 A1 WO 2014092596A1 RU 2012001057 W RU2012001057 W RU 2012001057W WO 2014092596 A1 WO2014092596 A1 WO 2014092596A1
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Prior art keywords
interferon
particles
interleukin
poloxamer
particles according
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PCT/RU2012/001057
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English (en)
Russian (ru)
Inventor
Тамара Александровна ВИТКАЛОВА
Дмитрий Валерьевич ШПАК
Владимир Александрович ИСАЕВ
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Vitkalova Tamara Aleksandrovna
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Priority to PCT/RU2012/001057 priority Critical patent/WO2014092596A1/fr
Publication of WO2014092596A1 publication Critical patent/WO2014092596A1/fr

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    • 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
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to substances or particles consisting of poloxamer, fatty acid and / or phospholipids, which is a delivery system that increases the transport of any biologically active genetically engineered (recombinant) drugs (interferons, interleukins, cytokines, colony stimulating factors, growth factors, hormones) and peptides.
  • the present invention relates to substances containing, in addition to a special delivery system, interferon, interleukin, colony stimulating factor (G-CSF, M-CSF, GM-CSF) and their pharmaceutical compositions for parenteral and oral administration with improved bioavailability for the treatment of human diseases, in including for the treatment of chronic viral hepatitis B and C.
  • Human interferons for example, interferon-alpha, interferon-beta, and interferon-gamma, as well as interleukins, for example, interleukin 1 alpha, interleukin 1 beta are widely used as therapeutic agents for the treatment of human diseases, including for the treatment of chronic viral hepatitis B and C.
  • the only practical way to deliver interferons and interleukins to the systemic circulation is the parenteral route of administration.
  • parenteral administration provides a rapid onset of action with a rapid decrease in the systemic level of interferon and interleukin.
  • a colony stimulating factor has been added to the treatment of viral hepatitis B and C because it enhances the antiviral signaling of interferon alfa.
  • Encapsulating an active pharmaceutical substance in lipid particles is a promising approach to creating a pharmaceutical composition with improved pharmacokinetic characteristics (see, for example, Wissing SA, Kayser O, Muller RH, Solid lipid nanoparticle for parenteral drug delivery. Advanced Drug Delivery Review, 56. 2004. 1257-1272. Joshi Medha. Muller Rainer, Lipid nanoparticles for parenteral delivery of actives. Euro. J. of Pharm. And Biopharm., 71, 2009, 161-172). Therapeutic agents embedded in lipid-based particles have shown improved bioavailability. However, there are many practical problems limiting the use of lipid-based particles in the manufacture of pharmaceutical compositions.
  • lipid-based particles Some of the problems limiting the production and development of lipid-based particles include problems with stability, reproducibility from batch to batch, difficulty in sterilization, low capture of the substance, control of average particle size, production of large batch size, and short half-life of particles in the bloodstream (Sharma A, Sharma U, Liposomes in drug delivery: progress and limitations. International Journal of Pharmaceutics. 154, 1997, 123-140U.
  • problems with stability, reproducibility from batch to batch difficulty in sterilization, low capture of the substance
  • control of average particle size production of large batch size
  • short half-life of particles in the bloodstream Sharma A, Sharma U, Liposomes in drug delivery: progress and limitations. International Journal of Pharmaceutics. 154, 1997, 123-140U.
  • interferon + interleukin + colony stimulating factor fatty acid, phosphotidylcholine and poloxamer gives stable and reproducible particles with high uptake of the active substance, which are interferons, interleukins and colony stimulating factors and an extended lifetime in the systemic circulation.
  • the critical advantage of such particles formed by fatty acid, phosphotidylcholine and poloxamer compared to other lipid-based particles is the smaller average particle size, which provides increased bioavailability of interferon + interleukin + colony stimulating factor placed in these particles upon parenteral, oral and local administration a mammal in need of it.
  • the object of the present invention are particles with an average size of from 1 to 350 nanometers, containing interferon, interleukin, colony stimulating factor, poloxamer, phosphotidylcholine and fatty acids, as well as methods for their preparation and pharmaceutical compositions based on them.
  • Fig. 1 shows the distribution of the average size of a substance in particles consisting of interferon, interleukin, oleic acid and poloxamer 470, determined by photon correlation spectroscopy.
  • Fig. 2 represents the distribution of the average size of a substance in particles consisting of interferon, interleukin, oleic acid, lecithin and poloxamer 470 determined by photon correlation spectroscopy.
  • Figure 3 shows the levels of interferon in the systemic circulation after parenteral administration of the pharmaceutical composition of the present invention.
  • the present invention in one embodiment, relates to substances or particles consisting of fatty acids, phospholipids and poloxamers, which are a universal system for the delivery of genetically engineered drugs and peptides.
  • the present invention according to the second of the options relates to particles containing (a) interferon; (b) interleukin; (c) colony stimulating factor; (e) poloxamer; (e) fatty acid for treating human diseases, including the treatment of chronic viral hepatitis B and C.
  • the present invention relates to particles containing in its composition:
  • interferon interferon, interleukin; poloxamer; (d) fatty acid; and (e) phosphotidylcholine or lecithin;
  • particles refers to particles having an average size of from 1 to 350 nanometers.
  • interferon refers to interferon obtained using an interferon expression system, for example, in E. coli or yeast.
  • Non-exclusive examples of interferons include interferon-a1pa2b, interferon-beta and interferon-gamma.
  • interleukin refers to interleukin obtained using an interleukin expression system, for example, in E. coli or yeast.
  • Non-exclusive examples of interleukins include interleukin 1 alpha, interleukin 1 beta, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 18.
  • interferon is selected from the group consisting of recombinant human interferon-a1bb2b, interferon-beta, and interferon-gamma.
  • analogue refers to any interferon that contains one or more amino acid substitutions, deletions, additions or permutations of amino acids compared to natural interferon at such positions that the interferon analogue still retains in vivo biological activity of interferon .
  • derivatives refers to natural interferon and an interferon analog that are chemically or enzymatically modified at one or more amino acid residues, including side chain modifications, backbone modifications, and N- and C-terminal modifications, such as acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and which are retained in vivo biological activity of interferon.
  • interferon derivatives are myristoyl-interferon and HisTag-interferon.
  • the particles comprise from about 0.000001 to 10% by weight of interferon; from about 5 to 70% by weight of poloxamer, and from 3 to 60% by weight of fatty acid.
  • polyxamer refers to any non-ionic copolymer consisting of three blocks, namely a central hydrophobic chain of polyoxypropylene (polypropyleneoxide) located between two hydrophilic chains of polyoxyethylene (polyethylene oxide).
  • Non-exclusive examples of poloxamer include 124 poloxamer, 188, 237, 338 and 407, which have been included in the US National Pharmacopoeia since 1990.
  • Other examples of poloxamer are disclosed in US patent 3740421 and in the Handbook of biodegradable polymers. Domb AJ et al. Harwood Academic Publisher, 1997.
  • fatty acids refers to any saturated or unsaturated aliphatic carboxylic acid consisting of 4-28 carbon atoms. Saturated fatty acids are long chain carboxylic acids, which typically have 12-24 carbon atoms and no double bonds. Non-exclusive examples of saturated fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid and arachidonic acid. Unsaturated fatty acids, unlike saturated fatty acids, have one or more double bonds.
  • Non-exclusive examples of unsaturated fatty acids include myristoleic acid, palmitoleic acid, sapmenic acid, oleic acid, linoleic acid, ⁇ -linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.
  • Particles of the present invention may further comprise other ingredients.
  • Such optional ingredients are typically used individually at a level of from about 0.0005% to 80.0% by weight of the particles.
  • optional suitable ingredients include, but are not limited to, phospholipids such as lecithin, phosphotidylcholine, and polymers such as poly (D, L-lactide) poly (ethylene glycol) -poly (D, L-lactide ) and polyvinylpyrrolidone.
  • phospholipids such as lecithin, phosphotidylcholine
  • polymers such as poly (D, L-lactide) poly (ethylene glycol) -poly (D, L-lactide ) and polyvinylpyrrolidone.
  • the present invention provides a method for producing particles comprising interferon, interleukin, poloxamer, and fatty acid, comprising the steps of: (a) preparing particles of a fatty acid emulsion in water; (b) the embedding of interferon and interleukin in the particles of the emulsion; (c) embedding the poloxamer in the particles of the emulsion; and (d) isolating the particles.
  • the step of producing particles of a • fatty acid emulsion in water with a reproducible average particle size of 1 to 350 nanometers can be implemented using the Microfluidizer Processor MHO EN-30 (USA) device as described in Mayhew E. Lazo R, Vail WJ, King J, Green AM. Characterization of liposomes prepared using a microemulsifier. Biochim Biophys Acta. 1984, 775 (2): 169-74. Briefly, the emulsion is passed through a ceramic chamber of a specific shape at a speed of 500 m / s to obtain the desired particles of the emulsion.
  • the step of incorporating interferon and interleukin into the emulsion particles can be implemented by methods well known in the art. Such methods include extruding an aqueous mixture of interferon and interleukin and lipids through filters with a progressive decrease in pore size from 400 nm to 200 nm, and then 100 nm; ultrasonic disintegration, as described in Martins S, et al., Lipid-based colloidal carriers for peptide and interferon delivery - liposomes versus lipid nanoparticles. Int J Nanomedicine. 2007; 2 (4: 595-607; and conjugation methods of interferons and interleukins with lipids.
  • the solubilized interferon with interleukin can be mixed with a fatty acid emulsion and the mixture is passed at a speed of 500 m / s through a Microfluidizer Processor MHO EN-30 ceramic chamber (USA) to obtain emulsion particles incorporated with interferon and interleukin with a reproducible average particle size of 1 to 350 nanometers.
  • the solubilized interferon with interleukin can be mixed with a fatty acid in water and the mixture is passed at a speed of 500 m / s through a ceramic chamber Microfluidizer Processor MHO EN-30 (USA) to obtain emulsion particles incorporated with interferon and reproducible average particle sizes of 1 to 350 nanometers.
  • the step of embedding the poloxamer in the particles of the emulsion can be implemented by mixing the poloxamer with particles of a fatty acid emulsion with embedded interferon and interleukin and passing the mixture through Micro fluidizer Processor MHO EN-30 (USA) to obtain particles of a fatty acid emulsion with embedded interferon and interleukin and poloxamer with a reproducible average particle size of 1 to 350 nanometers.
  • the solubilized interferon with interleukin can be mixed with fatty acid and poloxamer in a predetermined ratio and the mixture is passed at a speed of 500 m / s through a ceramic chamber Microfluidizer Processor Ml 10 EN-30 (USA) to obtain particles of the invention with a reproducible average size of 1 to 350 nanometers.
  • the present invention provides a pharmaceutical composition for parenteral administration, characterized in that the composition contains (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier.
  • parenteral refers to subcutaneous, intradermal, intravenous, intramuscular injection, as well as various infusion methods.
  • the pharmaceutical compositions of the present invention have increased therapeutic efficacy.
  • the introduction of interferon and interleukin embedded in the particles ensures a longer stay of interferon and interleukin in the systemic circulation in therapeutically effective concentrations, reduces the total number of injections to achieve an effective cure, improves the pharmacoeconomic indicators of treatment and provides convenience for the patient.
  • the pharmaceutical compositions of the present invention do not have the usual practical problems associated with the use of particles containing drugs, such as problems with stability, reproducibility from batch to batch , difficulties with the choice of sterilization methods, low concentration of interferon in the particle, control of the average particle size, difficulty in producing large industrial quantities and is not long enough fractional lifetime of particles in the bloodstream.
  • the pharmaceutical compositions of the present invention are safe and well tolerated by the patient.
  • the pharmaceutical compositions of the present invention can be effective for oral and external administration.
  • the present invention provides a pharmaceutical composition for oral administration, characterized in that the composition comprises (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier.
  • the particles formed by fatty acid and poloxamer are a delivery system that increases the transport of biologically active genetically engineered drugs, for example, active interferon and interleukin through the mucosa into the systemic circulation
  • the pharmaceutical compositions of the present invention can be orally administered in the form of tablets, capsules, dragees, powders, gels, syrups, and other conventional oral forms.
  • the present invention provides a pharmaceutical composition for external administration, characterized in that the composition comprises (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention can be administered externally in the form of gels, solutions, drops and other conventional external forms.
  • compositions of the present invention can be obtained using procedures well known in the art. Such procedures include, but are not limited to, mixing particles with other ingredients of the composition in the usual way.
  • Guidance on the preparation of the pharmaceutical compositions of the invention can be found in "Remington: The science and practice of pharmacy” 20th ed. Mack Publishing, Easton PA. 2000 ISBN 0-912734-04-3 and "Encyclopedia of Pharmaceutical Technology", edited bv Swarbrick. J . & JC Boylan. Marcel Dekker. Inc .. New York. 1988 ISBN 0-8247-2800-9 "or a newer version of this book.
  • pharmaceutically acceptable carrier refers to a carrier that is compatible with active interferon, active interleukin, and is not harmful to the subject to be treated.
  • Non-exclusive examples of such carriers include, but are not limited to, water for injection, mannitol, lactose, starch, talc, magnesium stearate, etc.
  • Emulsions were obtained from a mixture of oleic acid and water in a mass ratio of 1: 4, pH 4.9 and using a Microfluidizer Processor MHO EN-30 device (USA). Lyophilized recombinant human interferon alpha2b was added to the emulsion and the mixture was subjected to a second particle preparation procedure using the Microfluidizer Processor Ml 10 EN-30 (USA). Emulsions underwent ultrafiltration. Pre-ultrafiltered poloxamer gel 470 was embedded in the particles of the emulsion. The particles thus obtained were lyophilized.
  • Figure 1 shows the particle size distribution determined by photon correlation spectroscopy.
  • the average particle size was about 50 nm and about 80% of the particles had an average particle size of 10 to 100 nm for particles derived from oleic acid and poloxamer 470 taken in a mass ratio of 1: 5.
  • lecithin may be added during the preparation of the emulsion.
  • Fig.1b shows the distribution of the average particle size prepared using lecithin in a mass ratio of 5: 1: 5 for lecithin, oleic acid, and poloxamer 470, respectively.
  • the average particle size was about 75 nm.
  • Tables 1 and 2 show the content of lyophilized particles in a dosage form.
  • Poloxamer 470 about 80%
  • Tables 3 and 4 show the lyophilized particles obtained by the method as described in example 1 in a dosage form.
  • Poloxamer 470 about 80%
  • Poloxamer 470 about 80%
  • Poloxamer 470 about 80%
  • a pharmaceutical composition containing particles in accordance with example 1 was prepared by dissolving a single dose of lyophilized particles containing 3 million Units. HR-interferon-alpha2b in 2 ml of water for injection (Table 6).
  • Plasma interferon levels were measured over 7 days.
  • the administration of a control solution of interferon-a1ppa2b showed a significant increase in its plasma level on the first day, there was no difference in blood plasma on day 2 between the group receiving physiological saline and a solution of interferon-a1pa2b.
  • Fig. 3 shows that a single administration of interferon-a! Pn2b embedded in the particles maintains a therapeutically effective level of interferon-alp2b in the blood for at least 5 days, which is comparable to the duration of action of pegylated interferon.
  • an interferon pharmaceutical composition containing particles in accordance with the present invention has improved pharmacokinetic properties compared to a conventional interferon composition, maintains the desired therapeutic levels of interferon in the bloodstream for a long time, and can reduce the total number of injections, while maintaining the effectiveness of the treatment and pharmacoeconomic indicators.
  • Example 4 Demonstrates the oral pharmaceutical compositions of the present invention containing particles in accordance with examples 1 and 2.
  • Table 6 shows an example of sublingual tablets containing particles with a therapeutically effective amount of interferon and interleukin.
  • the gel is prepared by mixing the ingredients in water and gradually adding sodium carboxymethyl cellulose with constant stirring.
  • a control solution containing the same amount of rh-interferon-a1bba2b was administered to control mice.
  • Plasma concentrations of interferon- ⁇ lp2b were measured 1 hour after administration.
  • the plasma levels of interferon in the group receiving the particles turned out to be 47 ⁇ 17% (the levels achieved by subcutaneous injection were taken as 100%), while the levels in the control group were below the detection limit of the method.
  • a control gel containing the same amount of gp-interferon-a1ppa2b was applied to mice of the control group.
  • Concentrations of interferon-a1bba2b in plasma were measured 1 hour after topical application.
  • the plasma levels of interferon in the group receiving the particles turned out to be 21 ⁇ 10% (the levels achieved by subcutaneous injection were taken as 100%), while the levels in the control group were below the detection limit of the method.

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Abstract

L'invention concerne des particules consistant en un système universel d'administration de protéines issues du génie génétique. Les particules comprennent des interférons, des interleukynes, un facteur de stimulation de colonies, des poloxamères et des acides gras, et ont une taille moyenne de 1 à 350 nm, l'interféron étant choisi dans le groupe comprenant des interférons humains alpha, béta et gamma, tandis que l'interleukine est choisie dans le groupe comprenant l'interleukine humaine 1 alpha et l'interleukine humaine 1 béta, et que le facteur de stimulation de colonies est choisi dans le groupe comprenant un facteur de stimulation de colonies granulocytaire, un facteur de stimulation de colonies macrophage, et un facteur de stimulation de colonies granulocytaire-macrophage. L'invention concerne en outre des compositions pharmaceutiques pour administration parentérale externe ou orale, se caractérisant en ce qu'elles comprennent des particules contenant des particules propres et un excipient pharmaceutiquement acceptable. L'invention concerne également des particules contenant de l'interféron alpha, de l'interleukine 1 béta, et un facteur de stimulation de colonies afin de traiter des maladies humaines, y compris les hépatites virales chroniques B et C.
PCT/RU2012/001057 2012-12-12 2012-12-12 Substances et compositions pharmaceutiques les contenant pour traiter des affections humaines, y compris les hépatites virales chroniques b et c WO2014092596A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740421A (en) 1966-09-19 1973-06-19 Basf Wyandotte Corp Polyoxyethylene-polyoxypropylene aqueous gels
WO2002051390A2 (fr) * 2000-12-27 2002-07-04 Ares Trading S.A. Nanoparticules lipidiques amphiphiles destinees a l'incorporation de peptides et/ou proteines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740421A (en) 1966-09-19 1973-06-19 Basf Wyandotte Corp Polyoxyethylene-polyoxypropylene aqueous gels
WO2002051390A2 (fr) * 2000-12-27 2002-07-04 Ares Trading S.A. Nanoparticules lipidiques amphiphiles destinees a l'incorporation de peptides et/ou proteines

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Encyclopedia of Pharmaceutical Technology", 1988, MARCEL DEKKER, INC.
"Remington: The science and practice of pharmacy", 2000, MACK PUBLISHING
DOMB AJ ET AL.: "Handbook of biodegradable polymers", 1997, HARWOOD ACADEMIC PUBLISHER
JOSHI MEDHA; MULLER RAINER: "Lipid nanoparticles for parenteral delivery of actives", EURO. J. OF PHARM. AND BIOPHARM., vol. 71, 2009, pages 161 - 172, XP025941747, DOI: doi:10.1016/j.ejpb.2008.09.003
MARTINS S ET AL.: "Lipid-based colloidal carriers for peptide and interferon delivery - liposomes versus lipid nanoparticles", INT J NANOMEDICINE, vol. 2, no. 4, 2007, pages 595 - 607
MAYHEW E; LAZO R,; VAIL WJ; KING J; GREEN AM.: "Characterization of liposomes prepared using a microemulsifier", BIOCHIM BIOPHYS ACTA, vol. 775, no. 2, 1984, pages 169 - 74, XP023509461, DOI: doi:10.1016/0005-2736(84)90167-6
SHARMA A; SHARMA U: "Liposomes in drug delivery: progress and limitations", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 154, 1997, pages 123 - 140, XP008047948, DOI: doi:10.1016/S0378-5173(97)00135-X
WISSING SA; KAYSER O; MULLER RH: "Solid lipid nanoparticle for parenteral drug delivery", ADVANCED DRUG DELIVERY REVIEW, vol. 56, 2004, pages 1257 - 1272, XP055076604, DOI: doi:10.1016/j.addr.2003.12.002
ZHANG N ET AL: "Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 327, no. 1-2, 11 December 2006 (2006-12-11), pages 153 - 159, XP027972490, ISSN: 0378-5173, [retrieved on 20061211] *

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