WO2006056362A2 - Vehicule d'administration fabrique au moyen du procede de miniemulsion - Google Patents

Vehicule d'administration fabrique au moyen du procede de miniemulsion Download PDF

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WO2006056362A2
WO2006056362A2 PCT/EP2005/012339 EP2005012339W WO2006056362A2 WO 2006056362 A2 WO2006056362 A2 WO 2006056362A2 EP 2005012339 W EP2005012339 W EP 2005012339W WO 2006056362 A2 WO2006056362 A2 WO 2006056362A2
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Prior art keywords
nanoparticles
modifying agent
agent
delivery vehicle
agents
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PCT/EP2005/012339
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English (en)
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WO2006056362A3 (fr
Inventor
Kerstin Ringe
Hans-Eckart Radunz
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Nanodel Technologies Gmbh
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Priority claimed from EP04027997A external-priority patent/EP1661559A1/fr
Priority claimed from PCT/EP2005/009894 external-priority patent/WO2006029845A2/fr
Application filed by Nanodel Technologies Gmbh filed Critical Nanodel Technologies Gmbh
Publication of WO2006056362A2 publication Critical patent/WO2006056362A2/fr
Publication of WO2006056362A3 publication Critical patent/WO2006056362A3/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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61K9/5192—Processes

Definitions

  • the present invention is directed to a method of producing a delivery vehicle by the miniemulsion method, said delivery vehicle at least comprising nanoparticles made by the miniemulsion method, optionally a surface modifying agent and a pharmaceutical agent.
  • the present invention is further directed to a delivery vehicle manufactured by this method and its use for the transfection of eucaryotic cells or for the treatment of diseases and conditions, requiring a pharmaceutical agent to cross one or more physiological barriers, in particular the blood-brain barrier.
  • nanoparticles may be prepared by what is genetically te ⁇ ned as an "in ⁇ solvent emulsification-evaporation technique" using single (oil-in-water) or multiple emulsifications (water-in-oil-in-water) depending upon whether the incorporated pharmaceutical agent is hydrophobic or hydrophilic.
  • the solvent is evaporated from the emulsion.
  • the nanoparticles are separated from the remainder by centrifugation, or preferably ultracentrifugation (120,000 to 145,000 g), washed with water, and re-centrifuged and decanted.
  • Miniemulsions are dispersions of, e.g., water, an oil phase, and one or more surfactants which have a droplet size of from about 50 to 500 ran.
  • the miniemulsions were considered metastable (cf. Emulsion Polymerization and Emulsion Polymers, Editors P. A. Lovell and Mohamed S. El- Aasser, John Wiley and Sons, Chichester, New York, Weinheim, 1997, pages 700 et seq.; Mohamed S. El-Aasser, Advances in Emulsion Polymerization and Latex Technology, 30 th Annual Short Course, Volume 3, Jun. 7-11, 1999, Emulsion Polymers Institute, Lehigh University, Bethlehem, Pa., USA). These dispersions find broad application in the art in cleaning products, cosmetics or body care products.
  • aqueous primary dispersions by means of the free-radical miniemulsion polymerization of olefmically unsaturated monomers is known for example from International Patent Application WO 98/02466 or from German Patents DE-A- 196 28 143 and DE-A- 196 28 142.
  • the monomers can be copolymerized in the presence of different low molecular mass, oligomeric or polymeric hydrophobic substances.
  • a preferred method of nanoparticle formation is the miniemulsion technique as developed by K. Landfester et al:
  • miniemulsions are defined as dispersions of critically stabilized oil droplets with a size between 50 and 500 nm prepared by shearing a system containing water, a surfactant (or ,,stabilizer") and a hydrophobe. Polymerizations of monomers in such miniemulsions result in particles which have about the same size as the initial droplets.
  • the principle of miniemulsion polymerization is schematically shown in Figure 1 (K. Landfester, Polyreactions in miniemulsions, Macromol. Rapid Comm. 2001, 896-936. K. Landfester, N. Bechthold, F. Tiarks, and M. Antonietti, Formulation and stability mechanisms of polymerizable miniemulsions. Macromolecules 1999, 32, 5222. K. Landfester, Recent Developments in Miniemulsions - Formation and Stability Mechanisms. Macromol. Symp. 2000, 150, 171).
  • WO0209862 discloses a method for producing polymer capsules, pellets or droplets containing an active ingredient or substance, by means of in-situ encapsulation of said active ingredient or substance using a non-radical miniemulsion polymerisation, preferably polyaddition, of suitable monomers.
  • the polymer vehicle system containing the active ingredient or substance, produced by the above method can be used as a delivery system, in particular, in the field of cosmetics and bodycare, in pharmaceuticals, in adhesive processing and/or in the field of washing and cleaning agents.
  • DEl 9852784 discloses a process for stabilizing oil/water micro- or mini-emulsions with the aid of a surfactant (Sl) and a co-surfactant (S2), in which (S2) consists of water-insoluble compound(s) selected to give an osmotically stabilized emulsion, other than hexadecane, cetyl alcohol, dodecylmercaptan, long-chain alkyl methacrylates and the dyestuff Blue 70. It further discloses osmotically stabilized micro- or mini-emulsions containing an oil phase, an aqueous phase, a surfactant (Sl) and an ultra-hydrophobic co-surfactant (S2) as defined above.
  • WO2004017945 discloses the use of nanoparticles for a transfection of DNA into eucaryotic cells. It further discloses the DNA administration to a target organ in the human or animal body. In particular, WO2004017945 teaches the use of nanoparticles for the administration of cancer treatment-related DNA to a tumor-affected target organ in the human or animal body as, for example, the brain in the case of brain tumors. WO2004017945 also discloses to use substances (,,stabilizers”) which act as enhancers of the bond between the DNA and the nanoparticles. Among others, Diethylaminoethyl-(DEAE)- dextran and dextran 70.000 are listed as stabilizers.
  • nanoparticles according to WO2004017945 are by conventional emulsion polymerization, i.e. forming nanoparticles directly from a solution of the monomers in a solvent. Furthermore, a surface modifying agent is not being used for specifically attaching the pharmaceutical agent to the nanoparticles. Furthermore, the stabilizers used in WO2004017945 are described as being incorporated in the nanoparticles and it is not suggested to coat the nanoparticles with said stabilizers.
  • WO 02/076441 nanoparticles are di closed on which Chol-mannan is absorbed onto the surface of the nanoparticles.
  • the use of the miniemulsion method is not described. Instead, WO 02/076441 is using wax nanoparticles.
  • nanoparticles are known having chitosan on their surface being capable of binding negatively charged macromolecules (oligonucleotides). Chitosan is incorporated into the nanoparticles. Further, the nanoparticles are formed by emulsion polymerisation, a preparation method by the miniemulsion method is not disclosed.
  • WO 95/22963 and WO 98/56361 disclose methods for preparing nanoparticles. Said nanoparticles are manufactured by way of emulsion polymersation, interfacial polymerisation, solvent deposition, solvent evaporation etc. The miniemulsion method and its use in such a method of preparing nanoparticles is not disclosed.
  • the nanoparticles of the present invention are formed by a "miniemulsion method", which is per se well known and is, for example, disclosed in K. Landfester, ,,Polyreactions in miniemulsions", Macromol. Rapid Comm. 2001, 896-936. K. Landfester, N. Bechthold, F. Tiarks, and M. Antonietti, ,,Formulation and stability mechanisms of polymerizable miniemulsions".
  • This technology basically differs from the well known conventional methods (as, for example, used in WO2004017945) by involving a different order of manufacturing steps: in this approach, a miniemulsion, containing dispersed hydrophobic, monomer containing droplets in a hydrophilic continous phase, are formed to polymeric particles. In the conventional approach, the polymers are directly formed from the solution containing monomers.
  • the term ,miniemulsion as used herein generally means a technology, by which a dispersion is made containing a continuous W (hydrophilic) and an O (hydrophobic) phase, dispersed in the continuous phase. Further, this term is directed to emulsion droplets formed of 1 to 1.000 nm, usually approximately between 50 and 500 nm (the size of the particles following polymerization is identical or almost identical).
  • a further difference between the conventional process and the miniemulsion process is that in the latter, two liquid phases are brought into contact in the beginning of the method, and an emulsion is formed subsequently. In the conventional emulsion method, only droplets of the one phase are dropped into the other phase in the beginning.
  • the mean diameter of the generated nanoparticles is 200-300 nm (range ⁇ 1 ⁇ m) (see Figure 2).
  • the O phase is consisting of 6 g monomer + 250 mg hydrophobe
  • the W phase is 24 g 0.01 N HCl + stabilizer
  • the maximum content of solids will be 25% w/w (6/24 x 100) corresponding to a yield of 100%.
  • a content of 20% w/w then corresponds to a yield of 80%.
  • the remaining 20% are represented by monomers, which were lost during polymerization, for example by polymerizing at the vessel surface or at the homogenizer or the like.
  • the present invention is furthermore partially based on the surprising finding that polysaccharides as chitosan, dextran and the like are deleterious or at least disadvantageous for manufacturing nanoparticles by the miniemulsion method, if introduced in the reaction system in an early stage, i.e. before emulsif ⁇ cation and polymerisation starts.
  • this approach of the present invention does not involve the incorporation of polysaccharide stabilizers, such as chitosan, into the nanoparticles.
  • polysaccharide stabilizers such as chitosan
  • negative influences of said materials on the physical properties of the nanoparticles as described in the prior art may be avoided.
  • the present invention in an embodiment provides a coating of said polysaccharides (or of compounds derived therefrom) following the miniemulsion droplets polymerisation. Therefore, an important step of the present method may be seen in the fact that those polysaccharides are not added to the reaction system before the preparation of the miniemulsion is completed.
  • this approach of the present invention i.e. adding a coating of polysaccharide based surface modifying agents to the nanoparticles formed, may be used to precisely set the amount of a pharmaceutical agent bound thereon.
  • the chemical group of polysaccharides is in particular suitable to reach this object, since those substances are capable of binding pharmaceutical agents due to their polarity or charge (pH dependent) and are therefore providing an excellent means for reversibly binding pharmaceutical agents to nanoparticles in a precise amount.
  • This effect is in particular important for pharmaceutical agents having a narrow therapeutic index in order to avoid delivery of said pharmaceutical agent in a too small (i.e. uneffective) or too large (i.e. toxic) amount to the tissue in question.
  • a further advantage of the present method of manufacturing pharmaceutical agents containing delivery vehicles is that pharmaceutical agents may be used, which usually would undergo destruction due to the high shear forces in the miniemulsion method.
  • pharmaceutical agents may be used, which usually would undergo destruction due to the high shear forces in the miniemulsion method.
  • DNA as a pharmaceutical agent is mostly desintegrated during shearing the reaction system used for the preparation of miniemulsions.
  • the present invention offers for the first time the possibility of providing nanoparticles carrying highly unstable pharmaceutical agents, which nanoparticles being produced by the mini emulsion method.
  • the present invention is directed to a method of producing a delivery vehicle containing one or more pharmaceutical agents comprising the steps of:
  • reaction system as used herein is defined as any environment, which fulfills the requirements of forming a miniemulsion according to the above definition.
  • the already known miniemulsion technique as, for example, disclosed in Landfester et al. (supra), may be used to prepare the miniemulsion. This may, for example be done by at first combining monomers, an O and a W phase and a stabilizer (defined below). It is noted that the W phase may contain further ingredients, for example HCl for setting a suitable pH value. Second, the reaction system may be mixed by, for example, a homogenizer or the like, in order to mix all ingredients.
  • the preparation of the miniemulsion itself is performed by applying high shear forces to the reaction system, for example by ultrasound and high pressure homogenizers. Furthermore, the shear forces may be applied for a time range of from 2-5 min. depending on the size of the reaction system and the homogenizer used. Basically, a time range of between 3 and 4 min. is regarded as being sufficient.
  • the ultrasound homogenizer may have an amplitude of about 60-100%, preferably about 70- 90%.
  • the nanoparticles prepared by the above miniemulsion method have unexpected characteristics and advantages.
  • the yield of the manufacturing method is much higher than that of the conventional ones.
  • the nanoparticles produced by the method of the present invention have an improved capability to bind pharmaceutical agents to their surface (see Examples 8 and 9 and Comparative Examples 2 and 3). Surprisingly, this effect could be shown independently from the pharmaceutical agent's (or drug's) characteristics involved.
  • the three-dimensional structure of the nanoparticles of the present invention allows a more stable attachment of the drug particles to the nanoparticle.
  • Microscopic evaluation showed not a smooth, uniform surface of the nanoparticles, but a clew-like structure of the surface. It is our theory that this clew-like structure facilitates binding of drug molecules to the nanoparticles independently of their physical oi ⁇ chemical behaviour.
  • a further step is provided following step c) or between step b) and c), by adding a polysaccharide based surface modifying agent to said nanoparticles and wherein the one or more pharmaceutical agents are capable of being bound via that surface modifying agent to said nanoparticles.
  • the amount of polysaccharide based surface modifying agent introduced into the reaction system may be set to between 0,1-50% w/w regarding the amount of monomeric substances used.
  • the amount of 100% polysaccharide w/w regarding the amount of monomeric substances corresponds to those amounts, which are required in the conventional process of producing nanoparticles (other than miniemulsion). Therefore, by the method of the present invention, the high amounts of polysaccharides used in the prior art may be avoided, thus circumventing the problems, which are associated with their use (see above).
  • the temperatures used in this process are preferably from -1 to 5 °C, preferably O 0 C.
  • the weight ratio of O to W phase is from 15-40 % w/w, preferably 20-30 % w/w and more preferably about 25 % w/w.
  • the polymerisation process is started, for example by simply increasing the pH to a value of pH 7,0 or the like. This may be done, whenever PBCA monomers are used in the reaction system and the pH increase is performed, for example, by adding a sufficient amount OfK 2 CO 3 to the reaction system.
  • the nanoparticles of the invention preferably have a diameter in the range of between 50 and 500 nm, more preferably between 200 and 300 nm (see Fig. 2 for an example).
  • a stabilizer coating is applied to said nanoparticles.
  • the nanoparticles are coated with polysorbate 80 that allows the passage through the blood brain barrier.
  • a novel method of delivering drugs and diagnostics across the blood-brain barrier or blood-nerve barrier is disclosed.
  • Drugs or diagnostic agents are incorporated into nanoparticles which have been fabricated in conventional ways. These nanoparticles are then coated with additional surfactant and given to the body of animals or humans.
  • This allows drugs or diagnostic agents to cross the blood-brain barrier (bbb) to achieve one or more of the following benefits: (1) reducing the dose of a therapeutic drug or diagnostic agent which, when given peripherally, maintains the biological or diagnostic potency in the nervous system, (2) allowing drugs that normally do not cross the bbb to penetrate into the nervous system, and (3) reducing the peripheral side effects by increasing the relative amount of the drug reaching the brain.
  • the stabilizer comprises one or more of the following substances: fatty acid esters of glycerols, sorbitol and other multifunctional alcohols, preferably, glycerol monostearate, sorbitan monolaurate, or sorbitan monoleate; poloxamines, preferably poloxamine 904 or 1508; polyoxyethylene ethers and polyoxy ethylene esters; ethoxylated triglycerides; ethoxylated phenols and ethoxylated diphenols; surfactants of the Genapol TM and Bauki series; metal salts of fatty acids, metal salts of fatty alcohol sulfates, sodium lauryl sulfate; sodium dodecylsulfate; and metal salts of sulfosuccinates; preferably polysorbates, more preferably polysorbate 20, 40, 60 and most preferably polysorbate 80; preferably poloxamers, more preferably poloxamer 188, 338 or
  • the method of the present invention contains an additional step, wherein the stabilizer is at least partially removed from the obtained nanoparticles.
  • This can preferably be done by dialysis or centrifugation.
  • the stabilizers may be at least partially removed after the final nanoparticles were formed.
  • an ,,excess" of stabilizers can be removed which is not required for maintaining the stability of the nanoparticles, but can cause potential risks for in vivo applications. It is assumed that the lowest possible amount of stabilizers in the nanoparticles should be regarded as having the lowest in vivo risk.
  • the O phase is containing a hydrophobe, preferably selected from olive oil, miglyol and/or hexadecane.
  • the amount of hydrophobe is usually relatively small and should be sufficient to prevent Ostwald ripening (about 2-10% w/w based on the overall weight of the O-phase (further containing the monomer)).
  • the polymeric materials used in the present method are selected from the group consisting of polyacrylates, polymethacrylates, polyalkylcyanoacrylates, polyalkylcyanacrylates, polyarylamides, polylactates, polyglycolates, polyanhydrates, polyorthoesters, gelatin, polysaccharides, albumin, polystyrenes, polyvinyls, polyacrolein, polyglutaraldehydes and derivatives, copolymers and mixtures thereof.
  • Preferred synthetic biodegradable polymeric materials comprise solid or film forming polymers, preferably polyalkylcyanoacrylates, more preferably polybutylcyanoacrylates, polylactic acid and polybutyric acid and mixtures and derivatives thereof.
  • the terms ,biodegradable polymer denotes any synthetic or naturally-derived polymeric material which is known as being suitable for uses in the body of a living being, i.e., is biologically inert and physiologically acceptable, non-toxic, and, in the delivery systems of the present invention, is biodegradable in the environment of use, i.e., can be resorbed by the body.
  • biodegradable polymers which may be also used to formulate nanoparticles include, but are not limited to, polyesters, such as polyglycolides and polylactic polyglycolic copolymers (PLGA); polyethers, such as such as hydroxy-terminated poly( ⁇ -caprolactone)-polyether or polycaprolactone (PCL); polyanhydrides; polyacrylamides; poly(orthoesters); polyamino acids; and biodegradable polyurethanes. It is to be understood that the term polymer is to be construed as to include copolymers and oligomers.
  • pharmaceutical agents as used herein, thus, comprises both, therapeutic agents and diagnostic agents. It is noted that the terms ,,drug” and ,,therapeutic agent” are used interchangeably herein.
  • the therapeutic agent is preferably selected from substances which are incapable of crossing physiological barrieres without a delivery vehicle or carrier.
  • This physiological barrier is preferably selected from, although not restricted to, the group consisting of blood-brain barrier (bbb), blood-air barrier, blood-cerebrospinal fluid barrier and buccal mucosa.
  • the one or more therapeutic agents may have central nervous system activity but cannot cross the blood brain barrier without a delivery vehicle.
  • the delivery vehicle of the invention comprises one or more therapeutic agents selected from the group consisting of drugs acting at synaptic sites and neuroeffector junctional sites; general and local analgetics; hypnotics and sedatives; drags for the treatment of psychiatric disorders such as depression and schizophrenia; anti-epileptics and anticonvulsants; drags for the treatment of Parkinson's and Huntington's disease, aging and Alzheimer's disease; excitatory amino acid antagonists, neurotrophic factors and neuroregenerative agents; trophic factors; drags aimed at the treatment of CNS trauma or stroke; drags for the treatment of addiction and drag abuse; antacoids and anti-inflammatory drags; chemotherapeutic agents for parasitic infections and diseases caused by microbes; immunosuppressive agents and anti-cancer drags; hormones and hormone antagonists; heavy metals and heavy metal antagonists; antagonists for non-metallic toxic agents; cytostatic agents for the treatment of cancer; diagnostic substances for use in nuclear medicine; immunoactive and immuno
  • DNA as used in the present specification basically refers to any DNA conceivable in the present field of the art.
  • the term “DNA” is meant to comprise two types of DNA, i. e. plasmid DNA, more preferably plasmid DNA comprising the information of tumor suppressor genes, even more preferably plasmid DNA comprising the information of the tumor suppressor genes p53 and pRB, on the one hand, and antisense oligonucleotides, more preferably antisense oligonucleotides against oncogenes, even more preferably antisense oligonucleotides against oncogenes like Bcl2, on the other hand.
  • plasmid DNA more preferably plasmid DNA comprising the information of tumor suppressor genes, even more preferably plasmid DNA comprising the information of the tumor suppressor genes p53 and pRB, on the one hand
  • antisense oligonucleotides more preferably antisense oligonucleotides against oncogen
  • DNA there may be used one type of DNA (and, consequently, one type of DNA-loaded nanoparticles) in the present invention.
  • two or more types of DNA may be used, resulting into a plurality of types of nano ⁇ particles loaded with different types of DNA and useable in accordance with the present invention.
  • DNA and particularly DNA of the above two types could be adsorbed onto nanoparticles, and the resulting DNA-nanoparticle complexes could be inoculated into the organism, particularly into the organism suffering from cancer (specifically, but not limited to, brain cancer). Thereafter, a suppression of the tumor proliferation could be observed, and even a tumor necrosis and apoptosis could be induced.
  • plasmid DNA comprising a promoter can be loaded onto the nanoparticles.
  • an inducible promoter, and thereby an external control of the expression of the relevant gene may be achieved, and the gene may be "switched" on and off at will.
  • the timing of the gene/DNA expression can be controlled. Such a control may reduce toxic side effects of a continuous gene expression and/or may lower the probability that cells become resistant to the gene products, producing a negative selection.
  • the human papilloma vims upstream regulatory region (HPV-URR) was used as the inducible promoter.
  • the expression of the tumor suppressor is induced after the administration of Dexamethasone or other inducers or compounds. In that way, an apoptosis of the tumor cells as well as a regression of the tumor could be achieved.
  • Other exemplary promoters useable in accordance with the present invention are the cytomegalia virus (CMV) promoter or the simian virus 40 (SV 40) promoter.
  • tumor suppressor DNA even more preferred behind an inducible promoter, may be injected prior to inoculation of a nanoparticle complex containing a cytostatically effective compound.
  • the cytostatically effective compound is Doxorubicine.
  • the first step comprises the preparation of nanoparticles in a way defined above.
  • active ingredients can be any substance affecting the nervous system or used for diagnostic tests of the nervous system.
  • active ingredients e.g., drugs
  • these are described by Gilman et al. (1990), "Goodman and Gilman's - The Pharmacological Basis of Therapeutics", Pergamon Press, New York, and include the following agents: acetylcholine and synthetic choline esters, naturally occurring cholinomimetic alkaloids and their synthetic congeners, anticholinesterase agents, ganglionic stimulants, atropine, scopolamine and related antimuscarinic drugs, catecholamines and sympathomimetic drugs, such as epinephrine, norepinephrine and dopamine, adrenergic agonists, adrenergic receptor antagonists, transmitters such as GABA, glycine, glutamate, acetylcholine, dopamine, 5-hydroxytryptamine, and histamine, neuroactive peptides; analgesics and ane
  • Anti-Parkinson drugs such as L-DOPA/ CARBIDOPA, apomorphine, amatadine, ergolines, selegeline, ropinorole, bromocriptine mesylate and anticholinergic agents; antispasticity agents such as baclofen, diazepam and dantrolene; neuroprotective agents, such as excitatory amino acid antagonists, neurotrophic factors and brain derived neurotrophic factor, ciliary neurotrophic factor, or nerve growth factor; neurotrophine (NT) 3 (NT3); NT4 and NT5; gangliosides; neuroregenerative agents; drugs for the treatment of addiction and drug abuse include opioid antagonists and anti-depressants; autocoids and anti-inflammatory drugs such as histamine, bradykinin, kailidin and their respective agonists and antagonists; chemotherapeutic agents for parasitic infections and microbial diseases; anti-cancer drugs including alkylating agents (e.g., nitrosourea
  • a apolar substance may be present in its salt form in order to bind to the surface modifying agent. If, for example, alginate is used as such a modifying agent (carrying negatively charged groups), an drug like morphine might be converted to morphine-HCl and then be bound to said alginate.
  • the diagnostic agent is selected from the group consisting of diagnostics useful in the diagnosis in nuclear medicine and in radiation therapy.
  • the polysaccharide based surface modifying agents are preferably selected from dextrans, alginates, chitosan, or derivatives thereof.
  • the group of dextrans comprises in particular: Dextran 12.000, Dextran 70.000 and Diethylaminoethyl-Dextran (DEAE-Dextran).
  • Chitosan is a natural polymer obtained by the hydrolysis of chitin, a native polymer present in shellfish. Together with chitin, chitosan is considered the second most abundant polysaccharide after cellulose. However, unlike cellulose, the use of chitosan as an excipient in pharmaceutical formulations is a relatively new development.
  • Chitosan (poly[-(l,4)-2-amino-2-deoxy-D- glucopyranose]) has the following structure: Cteiti tat 3! ⁇ «fa ⁇ rt Di mitimn, The psljner is airtst ⁇ rf by tJs ⁇ pitital deatefirttMw >s MtMf 1 IiI 1 J e-itu'tsii? pntymw, elift ⁇ n.
  • the amino groups are carrying a positive charge.
  • the polymer differs from chitin in that a majority of the N-acetyl groups in chitosan are hydrolyzed (deacetylated).
  • the degree of deacetylation has a significant effect on the solubility and rheological properties of the polymer.
  • the amine group on the polymer has a pKa in the range of 5.5 to 6.5, depending on the source of the polymer.
  • the polymer is soluble, with the sol-gel transition occurring at approximate pH 7.
  • the pH sensitivity coupled with the reactivity of the primary amine groups, make chitosan a unique polymer for oral drug delivery applications.
  • chitosan Many derivatives of chitosan are available. The following are presented as examples: N- Trimethylene Chloride Chitosan (TMC), chitosan esters and chitosan conjugates.
  • TMC Trimethylene Chloride Chitosan
  • chitosan esters and chitosan conjugates.
  • Alginates are cell-wall constituents of brown algae (Phaeophycota). They are chain-forming heteropolysaccharides made up of blocks of mannuronic acid and guluronic acid. The composition of the blocks depends on the species being used for extraction and the part of the thallus from which extraction is made. Extraction procedures also affect alginate quality. Alginates usually are usually employed in this invention at a pH of 6-7. Then, a negatively charged surface (Alginat) of nanoparticles leads to the binding of, preferential cationic drugs, that possess positively charged groups, such as dopamine.
  • a positively charged surface (Chitosan, DEAE-Dextran, Cetylammonium bromide) of nanoparticles leads to the binding of, preferential DNA or oligonucleotides, because it possesses negatively charged phosphate groups.
  • drugs which may be bound to alginates (apart from dopamine) are drugs, which are carrying amino function (-NH2, -NHR oder -NR2).
  • Alkaloids as morphine or naxolone; tricyclic antidepressants, as doxepine or trimipramine are very suitable, as well as drugs as diazepam, noradrenaline, phentolamine or phenylethylamine.
  • the therapeutic agent and the surface modifying agent are selected from a) a polysaccharide based modifying agent providing a positive or negative charge to the surface of the nanoparticles and a therapeutic agent which is negatively or positively charged, in order to provide a ionic binding between the modifying agent and the therapeutic agent, and wherein the modifying agent preferably is chitosan and the therapeutic agent preferably is genetic material suitable for the DNA or anti-sense treatment of diseases, or wherein the modifying agent preferably is alginate and the therapeutic agent preferably is dopamine; or b) a polysaccharide based modifying agent providing a polar surface to the nanoparticles and the therapeutic agent being polar in order to provide a dipole-dipole binding between the modifying agent and the therapeutic agent, wherein the modifying agent preferably is dextran and the therapeutic agent preferably is a polar agent.
  • alginates - dopamine chitosan and/or dextrans — nucleic acids.
  • PBCA is used as substance to generate nanoparticles.
  • a delivery vehicle for pharmaceutical agents for administration to a mammal or a eucaryotic cell comprising:
  • nanoparticles made of a polymeric material ; b) one or more pharmaceutical agents, which are coated on and bind to the surface of the nanoparticles; and optionally c) a stabilizer coating deposited thereon,
  • nanoparticles made of a polymeric material; b) a polysaccharide based surface modifying agent, which is coated on said nanoparticles; and c) one or more pharmaceutical agents, which are coated on and bind to the surface modifying agent; and optionally d) a stabilizer coating deposited thereon,
  • the invention is directed to a pharmaceutical composition containing a delivery vehicle as defined above and a pharmaceutically acceptable carrier.
  • the nanoparticles in a practical embodiment in vivo, they may be reconstituted into a suspension with normal saline or phosphate buffered aqueous solution at physiological pH and osmolality.
  • the nanoparticles are present in the injectable suspension at a concentration ranging from 0.1 mg nanoparticles per ml suspending fluid to 100 mg nanoparticles per ml suspending fluid. 10 mg nanoparticles per ml is preferred.
  • the amount of nanoparticles used will strongly depend on the amount of pharmaceutical agent contained in an individual nanoparticle and the skilled artisan or the physician in charge will be readily able to adapt the dosage of the nanoparticles to the specific circumstances.
  • the pharmaceutical composition may take other forms required to transfer the delivery vehicle of the invention to and across other physiological barriers, for example to and across the blood-air barrier. Then it may, for example have the form of an aerosol or the like in order to deliver the composition by inhalation to the barrier in question.
  • the invention provides the use of a drug delivery vehicle or a pharmaceutical composition as defined herein for the transfection of eucaryotic cells or (for the manufacture of a medicament) for the treatment of diseases and conditions, requiring a pharmaceutical agent to cross one or more physiological barriers, in particular the blood-brain barrier.
  • the delivery vehicle will find application in the treatment of diseases related to the CNS. Furthermore, this includes the treatment of AIDS, since in many people with advanced AIDS - possibly a third of adults and half of all children - HIV also infiltrates and harms the brain, triggering HIV-associated dementia.
  • the disorder is marked by poor concentration, decreased memory and slow thinking and movements. However, it is particularly hard to target the virus in the brain.
  • the present invention may open up new therapeutic successes by delivering anti-HIV agents to the brain.
  • Fig. 1 is an illustration showing the miniemulsion polymerzation technique
  • Fig. 2 is a photograph of nanoparticles manufactured in accordance with the present invention
  • Fig. 3 is a representation of the particle size distribution of nanoparticles manufactured in Example 1. Examples:
  • Comparative Example 1 The Conventional Method of Emulsion Polymerisation (prior art)
  • PBCA-Nanoparticles A solution of 10 mg of a mixture of dextran 70.000 in 1 ml 0.01 N HCl is prepared. After this, 0.01 ml butylcyanoacrylate is added carefully, and sti ⁇ ing is continued for 4 h at 25°C to assure complete polymerisation of the monomer. After neutralization by addition of 1 ml 0.01 M sodium hydroxide solution, larger polymer aggregates are separated from nanoparticles by filtration. For purification the prepared nanoparticle suspension is then centrifuged and resuspended in Millipore filtered water (3 times).
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.0 mg of Daunorubizin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20.000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Daunorubizin at a known concentration. The loading rate could be determined as 23% (0.46 mg of Daunorubizin was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1% (w/w) Tween ® 80 solution containing 0.9% NaCl.
  • Example 2 Preparation of PBCA-dextran-nanoparticIes loaded with Mithramyzin and coated with Tween 80
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.0 mg of Mithramyzin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Mithramyzin at a known concentration. The loading rate could be determined as 31,6% (0.632 mg of Mithramyzin was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1% (w/w) Tween ® 80 solution containing 0.9% NaCl.
  • Example 3 Preparation of PBCA-dextran-nanoparticles loaded with Mithramyzin and coated with Tween 80
  • This example is illustrating on an embodiment, in which the surface modifying agent is added following the polymerzation step.
  • 6 g of butyl cyanacrylate and 250 ml mygliol were added to a 30 ml beaker.
  • 500 mg Lutensol AT 50 are dissolved in 24 g 0.1 N HCl in another 30 ml beaker. Both solutions are combined and homogenized for 2 min. using a dispersion stirrer. Then the miniemulsion was formed using ultrasound for 4 min. at an amplitude of 70% at 0 0 C. After the preparation of the miniemulsion the pH was slowly (1 h) raised to 7 using a saturated K 2 C ⁇ 3 -solution. Then 960 mg of Dextran were added. The resulting nanoparticles were obtained as a suspension with a solid content of 24% (w/w) (240 mg/ml) and a particle size of 242 nm.
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.0 mg of Mithramyzin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20.000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Mithramyzin at a known concentration. The loading rate could be determined as 25,6% (0.513 mg of Mithramyzin was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1% (w/w) Tween® 80 solution containing 0.9% NaCl.
  • Example 4 Preparation of PBCA-dextran-nanoparticles loaded with Mitomyzin and coated with Tween 80
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.5 mg of Mitomyzin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20.000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Mitomyzin at a known concentration. The loading rate could be determined as 70,6% (1.764 mg of Mitomyzin was bound to 10 mg of nanoparticles). The pellet was then resuspended in a 1% (w/w) Tween ® 80 solution containing 0.9% NaCl.
  • Example 5 Preparation of PBCA-dextran-nanoparticles loaded with Mitomyzin and coated with Tween 80
  • This example is illustrating on an embodiment, in which the surface modifying agent is added following the polymerzation step.
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.5 mg of Mitomyzin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Mitomyzin at a known concentration. The loading rate could be determined as 70,8% (1.77 mg of Mitomyzin was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1 % (w/w) Tween ® 80 solution containing 0.9% NaCl.
  • Example 6 Preparation of PBCA-alginat-nanoparticles loaded with Dopamine and coated with Tween 80 6 g of butyl cyanacrylate and 250 ml mygliol were added to a 30 ml beaker. 500 mg Lutensol AT 80 were dissolved in 24 g 0.1 N HCl in another 30 ml beaker. Both solutions were combined and homogenized for 2 min. using a dispersion stirrer. Then the miniemulsion was formed using ultrasound for 4 min. at an amplitude of 70% at 0°C. After the preparation of the miniemulsion 120 mg of Alginat were added and the pH was slowly (1 h) raised to 7 using a saturated K 2 CO 3 - solution. The resulting nanoparticles were obtained as a suspension with a solid content of 17,2% (w/w) (172 mg/ml) and a particle size of 140 nm.
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 2.5 mg of Dopamine was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20.000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Dopamine at a known concentration. The loading rate could be determined as 32,1% (0.802 mg of Dopamine was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1% (w/w) Tween ® 80 solution containing 0.9% NaCl.
  • Example 8 Binding of Doxorubicin to PBCA-nanoparticles prepared using the miniemulsion method of the invention
  • Solution 1 36,0 ml of hydrochloric acid (0,1 moll "1 ) are added into a 100 ml flask (PP). Then 0,900 g sodium dodecylsulfate (SDS) are added to this solution. The resulting solution is stirred until the SDS is completely solved.
  • SDS sodium dodecylsulfate
  • Solution 1 is added to solution 2 and the miniemulsion is immediately formed by ultrasoni cation (amplitude 90%, 0°C) of the resulting suspension for 2 min. Then the polymerisation of the monomer droplets is initiated by rapidly changing the pH value from 1 to 7 by adding the miniemulsion into 38,0 ml of 0,1 mol I "1 aqueous NaOH solution (100 ml flask). The obtained suspension is then stirred for 5 min. The nanoparticle suspension possesses a solid content of 110 mg/ml and a mean particle size (photon correlation spectroscopy) of 150 ⁇ 1,3 nm.
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 1,5 mg of Doxorubizin was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drug/nanoparticle suspension was centrifuged for 30 min. at 20000 ipm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Doxorubizin at a known concentration. The loading rate could be determined as 100 % (1,5 mg of Doxorubizin was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1 % (w/w) Tween ® 80 solution containing 0,9% NaCl.
  • Example 9 Binding of Mitoxantron to PBCA-nanoparticles prepared using the miniemulsion method
  • Solution 1 36,0 ml of hydrochloric acid (0,1 mol l "1 ) are added into a 100 ml flask (PP). Then 0,900 g sodium dodecylsulfate (SDS) are added to this solution. The resulting solution is stirred until the SDS is completely solved.
  • SDS sodium dodecylsulfate
  • Solution 1 is added to solution 2 and the miniemulsion is immediately formed by ultrasonication (amplitude 90%, 0°C) of the resulting suspension for 2 min. Then the polymerisation of the monomer droplets is initiated by rapidly changing the pH value from 1 to 7 by adding the miniemulsion into 38,0 ml of 0,1 mol 1 "! aqueous NaOH solution (100 ml flask). The obtained suspension is then stirred for 5 min.
  • the nanoparticle suspension possesses a solid content of 110 mg/ml and a mean particle size (photon correlation spectroscopy) of 150 ⁇ 1,3 nm.
  • the obtained nanoparticle suspension was diluted to 1% (w/w) (10 mg/ml). 1,0 mg of Mitoxantron was added to 10 mg of the prepared nanoparticles. The resulting suspension was stirred for 4 h. To determine the loading rate the drag/nanoparticle suspension was centrifuged for 30 min. at 20000 rpm. The supernatant was analyzed using a UV-spectrometer that was previously calibrated using different solutions of Mitoxantron at a known concentration. The loading rate could be determined as 100 % (1,0 mg of Mitoxantron was bound to 10 mg of nanoparticles).
  • the pellet was then resuspended in a 1% (w/w) Tween ⁇ 80 solution containing 0,9% NaCl.
  • Comparative Example 2 Binding of Doxorubizin to PBCA-nanoparticles prepared by the emulsion polymerisation method (prior art)
  • PBCA-Nanoparticles A solution of 10 mg of a mixture of dextran 70.000 in 1 ml 0.01 N HCl is prepared. Then 0.01 ml butylcyanoacrylate is added carefully, and sti ⁇ ing is continued for 4 h at 25 0 C to assure complete polymerisation of the monomer. For bigger scales the time of polymerisation has to be extended to 24 or 48 hrs. After neutralization by addition of 1 ml 0.01 M sodium hydroxide solution, larger polymer aggregates are are separated from nanoparticles by filtration. For purification the prepared nanoparticle suspension is then centrifuged and resuspended in Millipore filtered water (3 times).
  • Comparative example 3 Binding of Mitoxantron to PBCA-nanoparticles prepared by the emulsion polymerisation method (prior art)
  • PBCA-Nanoparticles A solution of 10 mg of a mixture of dextran 70.000 in 1 ml 0.01 N HCl is prepared. Then 0.01 ml butylcyanoacrylate is added carefully, and stirring is continued for 4 h at 25°C to assure complete polymerisation of the monomer. For bigger scales the time of polymerisation has to be extended to 24 or 48 hrs. After neutralization by addition of 1 ml 0.01 M sodium hydroxide solution, larger polymer aggregates are are separated from nanoparticles by filtration. For purification the prepared nanoparticle suspension is then centrifuged and resuspended in Millipore filtered water (3 times).

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Abstract

L'invention concerne un procédé de fabrication d'un véhicule d'administration au moyen du procédé de miniémulsion, ce véhicule d'administration comprenant au moins des nanoparticules fabriquées au moyen du procédé de miniémulsion, éventuellement un agent de modification de surface et un agent pharmaceutique. L'invention concerne également un véhicule d'administration fabriqué au moyen de ce procédé et son utilisation pour la transfection de cellules eucaryotes ou pour le traitement de maladies et d'états pathologiques, dans lequel un agent pharmaceutique doit traverser un ou plusieurs barrières physiologiques, notamment la barrière sang-cerveau.
PCT/EP2005/012339 2004-11-25 2005-11-17 Vehicule d'administration fabrique au moyen du procede de miniemulsion WO2006056362A2 (fr)

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EP04027997.8 2004-11-25
EP04027997A EP1661559A1 (fr) 2004-11-25 2004-11-25 Systéme de délivrance produit par un procédé de miniémulsion
EPPCT/EP2005/009894 2005-09-14
PCT/EP2005/009894 WO2006029845A2 (fr) 2004-09-14 2005-09-14 Vehicule d'administration de medicaments contenant des nanoparticules

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EP1815851A1 (fr) * 2006-02-03 2007-08-08 NanoDel Technologies GmbH Nanoparticules pour l'administration de médicaments
EP1876188A1 (fr) * 2006-07-04 2008-01-09 NanoDel Technologies GmbH Polymerisation en miniemulsion en deux étapes
CN102706856A (zh) * 2012-06-28 2012-10-03 福州大学 一种增强拉曼纳米粒子及其制备方法

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CN102706856A (zh) * 2012-06-28 2012-10-03 福州大学 一种增强拉曼纳米粒子及其制备方法

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