WO2018090112A1 - Procédé d'obtention de composés nanostructurés lipidiques cationiques amphiphiles et polymères cationiques amphiphiles, composés nanostructurés obtenus et leurs utilisations - Google Patents

Procédé d'obtention de composés nanostructurés lipidiques cationiques amphiphiles et polymères cationiques amphiphiles, composés nanostructurés obtenus et leurs utilisations Download PDF

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WO2018090112A1
WO2018090112A1 PCT/BR2017/050297 BR2017050297W WO2018090112A1 WO 2018090112 A1 WO2018090112 A1 WO 2018090112A1 BR 2017050297 W BR2017050297 W BR 2017050297W WO 2018090112 A1 WO2018090112 A1 WO 2018090112A1
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lipid
cationic
ranging
lipids
liquid
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Portuguese (pt)
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Nadia ARACI BOU CHACRA
Milton RUIZ ALVES
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Universidade De São Paulo - Usp
Tecnan Brasil - Pesquisa, Desenvolvimento E Inovação Ltda
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention falls within the field of application of medical science, more specifically in the field of
  • the instilled material may be drained via the nasolacrimal duct and may cause an undesirable systemic effect.
  • Another possibility of undesirable systemic effect is the absorption of the material via conjunctiva, highly vascularized structure.
  • the cornea and tear film also constitute a natural barrier contributing to the reduction of the therapeutic efficacy of eye drops in combating eye disease in the anterior and posterior segment of the eye.
  • the patient must instill the eye drops several times a day, making it difficult to adhere to treatment.
  • the tear film also has a particular feature that can be used to improve the residence time of the eye drops and thereby increase the therapeutic efficacy of this product.
  • this structure presents mucin, protein glycolyzate containing sialic acid, which is negatively charged at neutral pH.
  • the present invention proposes an amphiphilic cationic lipid or polymeric nanoparticulate compound.
  • amphiphilic cationic nanostructured compounds aim to obtain innovative ophthalmic products that present greater efficacy and safety to the patient, since the average particle size, in nanometer scale, and the interaction of these compounds with sialic acid (charged
  • this nanostructure can be used for the development of other pharmaceutical or cosmetic products where the cationic characteristic is desirable.
  • the present compound may be used for the development of medicaments for neglected diseases.
  • the parasite infects macrophages and thus the positively charged nanostructured compound can be internalized into this cell, release the drug and eliminate the parasite.
  • US2015290092 describes nanoparticles containing mono, di or trivalent ions which have a functional core comprising drug containing one or more subsequent polymeric layers of opposite charges for use in dentistry.
  • the present invention proposes amphiphilic cationic lipid or polymeric nanoparticles which do not contain ions of any nature associated with the nanostructure for the development of cationic ophthalmic products.
  • Document BRPI0904083 describes a process for obtaining cationic amphiphilic nanovesicles for application in ophthalmic suspensions in the treatment of eye infections.
  • the polymer and hydrophilic drug are simply mixed and added to the nanostructure. Such procedure results in high variability in the nanostructure zeta potential characteristics revealing low reproducibility of the method.
  • the present invention proposes a process that has additional steps that allow control of the amount of hydrophilic drug associated with
  • nanoparticle as well as the amount of chitosan, so it is possible to cationize the nanoparticle in a controlled manner.
  • at least two drugs to the nanostructure, one hydrophilic and one hydrophobic, and other hydrophilic drugs may be added.
  • the cationic hydrophilic drug class includes a series of cationic peptide substances, cationic peptides with antimicrobial action such as vancomycin.
  • the present invention relates to a process for obtaining amphiphilic cationic lipid and amphiphilic cationic polymeric nanostructured compounds capable of comprising at least two drugs, one hydrophobic and one hydrophilic, associated with an oily and aqueous phase and coated with chitosan .
  • This process comprises four steps, which allow the control of obtaining the nanostructures.
  • it is possible to cationize the nanoparticle in a controlled manner: control of the zeta potential, control of the amount of cationic substance (SC), and control of the amount of drug or active substance.
  • the present invention also relates to the compounds obtained as well as their use for the development of pharmaceutical or
  • Figure 1 graphs the simple linear regression analysis of zeta potential (mV) versus polymyxin B sulfate concentration (IU / mL).
  • Figure 2 graphs the simple linear regression analysis of mean hydrodynamic diameter versus polymyxin B sulfate concentration (IU / mL) for CLN-Dexa + Poli-Prot.
  • FIG. 3 graphs the linear regression of mean hydrodynamic diameter (DHM) versus (a) polymyxin B sulfate concentration (SP IU / mL); and (B-E) DHM residues, where (B) is the normal probability plot, (C) versus adjusted, (D) histogram, and (E) versus order.
  • DHM mean hydrodynamic diameter
  • Figure 4 graphs the linear regression of zeta potential (PZ) versus (a) polymyxin B sulfate concentration (SP IU / mL); and (B-E) DHM residues, where (B) is the normal probability plot, (C) versus adjusted, (D) histogram, and (E) versus order.
  • FIG. 5 AF graphs analysis of variance (ANOVA): mean hydrodynamic diameter (DHM) of VP-Dexa + Poly (polymyxin sulfate concentrations: 2,500, 5,000, 7,500 and 10,000 IU / mL) after coating employing 0.15% (w / v) Protasan®, which (a) is the means and confidence interval; (b) the Tukey test and, (C-F) are the residuals, where (C) is the normal probability plot, (D) versus adjusted, (E) histogram, and (F) versus order.
  • DDM mean hydrodynamic diameter
  • Poly polymyxin sulfate concentrations: 2,500, 5,000, 7,500 and 10,000 IU / mL
  • Protasan® which (a) is the means and confidence interval; (b) the Tukey test and, (C-F) are the residuals, where (C) is the normal probability plot, (D) versus adjusted, (E) histogram, and (F)
  • Figure 6 A-F graphically analyzes the variance (ANOVA) of the zeta potential (PZ) of VP-Dexa + Poly
  • the present invention relates to a process for obtaining amphiphilic cationic lipid and amphiphilic cationic polymeric nanostructured compounds.
  • lipid carriers comprising one liquid lipid or two or more liquid lipids, or comprising one solid lipid or two or more solid lipids, or mixture of liquid lipid and one solid lipid or mixture of two or more liquid lipids and solid lipids, comprising at least one hydrophobic or lipophilic drug or active substance;
  • step "c) Incorporating SC into the formulation obtained in step “a”; and d) Coat the formulation obtained in step “c” with low molecular weight (50000-400000 g / mol) and high grade chitosan.
  • Said drug or active substance is selected from the groups consisting of hydrophobic or lipophilic active substances, such as immunosuppressants (cyclosporine); prostaglandins such as latanoprost, bimatoprost and travoprost; antioxidants such as carotenoids, ⁇ -, ⁇ -, ⁇ -, ⁇ -tocopherol and a-, ⁇ -, ⁇ -, ⁇ -tocotrienol, retinoic acid, retinol and their esters, ubiquinol, ubiquinone, glutathione in their reduced form, flavonoids, lipoic acid and active components of biotechnological origin such as etanercept, pegaptanib, ranibizumab and bevacizumab; and cholinergic drugs such as pilocarpine, ezerin and neostigmine; and non-spheroidal and spheroidal anti-inflammatory, preferably dexamethasone acetate.
  • Said cationic substance is selected from the group consisting of hydrophilic drugs, cationic peptides such as polymyxin B sulfate, vancomycin, gramicidine, bacitracin and others. cationic antimicrobial peptides; and benzalkonium chloride and other quaternary ammoniums, preferably polymyxin B sulfate.
  • step "a" the preparation of lipid carriers is obtained by heating the oil phase and the aqueous phase separately at a temperature ranging from 55 to 90 ° C,
  • the oil phase comprises from 0.0001 to 10%
  • the lipids are selected from the groups consisting of liquid lipid (oil) at a concentration of 1 to 20% or a mixture of liquid lipids in the proportion ranging from 0.01: 1 to 1: 10; and solid lipid at a concentration of 1 to 20% or a mixture of solid lipids in a ratio ranging from 0.01: 1 to 1: 100; or a mixture of liquid and solid lipids ranging from 0.01: 1 to 1: 100 of the total lipid carrier formulation.
  • the lipids are selected from the groups consisting of liquid lipid (oil) at a concentration of 1 to 20% or a mixture of liquid lipids in the proportion ranging from 0.01: 1 to 1: 10; and solid lipid at a concentration of 1 to 20% or a mixture of solid lipids in a ratio ranging from 0.01: 1 to 1: 100; or a mixture of liquid and solid lipids ranging from 0.01: 1 to 1: 100 of the total lipid carrier formulation.
  • Liquid lipids are selected from the group consisting of unsaturated fatty acids, such as caprylic and caprylic acid glycerol triesters. And solid lipids are selected from the group consisting of saturated fatty acids, such as cetyl palmitate.
  • the aqueous phase comprises at least one nonionic surfactant such as polysorbate 80, soy or egg phospholipids, poloxamer 188, poloxamer 407 and TPGS (d-alpha tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - oil). polyoxyl 35 castor), Kolliphor HS 15 (polyoxyl hydroxystearate 15) diluted in ultrapure water. Alternatively, it may contain an anionic surfactant such as sodium dodecyl sulfate.
  • nonionic surfactant such as polysorbate 80, soy or egg phospholipids, poloxamer 188, poloxamer 407 and TPGS (d-alpha tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - oil). polyoxyl 35 castor), Kolliphor HS 15 (polyoxyl hydroxystearate 15) diluted
  • the aqueous phase comprises from 0.05 to 10%, more preferably 2.5% of poloxamer 188 and poloxamer 407; from 0.05 to 10%, more preferably 1.5% polysorbate 80; from 0.001 at 10%, more preferably 0.5% sodium dodecyl sulfate; and qsp 100% ultrapure water from the total formulation of lipid carriers.
  • the aqueous phase is dispersed in the oil phase under mechanical agitation ranging from 1000 to 25000 rpm, preferably 8000 rpm for a period of time ranging from 1 to 10 min.
  • preemulsion which is homogenised using 1 to 6 successive cycles, preferably 3 cycles, at a pressure ranging from 200 to 1000 bar, preferably 600 bar.
  • the cationic solution containing the hydrophilic drugs (SC) is diluted or not in a suitable container with ultrapure water in a ratio ranging from 1: 1 to 1: 5. preferably 1: 2 such that a concentration ranging from 50,000 to 1,000,000 IU / mL of the cationic substance is obtained.
  • Step "c” incorporates the cationic peptide substance at a concentration of 5 to 25,000 IU / mL
  • Incorporation is performed slowly, preferably by dripping, and under agitation ranging from 50 to 300 rpm, preferably 100 rpm, for a period of time ranging from 0.5 to 6 hours, preferably 2 hours.
  • step “c” a lipid nanoparticulate compound comprising a hydrophobic or lipophilic active substance or drug incorporated with at least one cationic substance.
  • the coating is controlled to produce smaller but still negative modulus zeta potential particles ranging from -30 to -1 mV, depending on the concentration of the cationic substance (s).
  • s examples: polymyxin B sulfate and vancomycin
  • This control is performed by concentrating the cationic substance used. (example: 1 to 1,000,000 IU / mL).
  • step "d" 0.001% to 10%, preferably 0.2% dispersion of 2.0% (w / w) chitosan in ultrapure water is
  • step "d" the coating is controlled to produce particles with zeta potential between +5 and +65 mV.
  • the preparations obtained in step "d” comprise from 0.001 to 10%, preferably 0.2% (w / v%) chitosan, thus obtaining an amphiphilic cationic lipid nanostructured compound with particles of medium hydrodynamic diameter in the sub-micron range, with an average diameter between 100 and 600 nm,
  • the present process relates to obtaining an amphiphilic cationic polymeric nanostructured compound, wherein to this end, step "a” is to prepare polymeric vesicles comprising one liquid lipid or two or more liquid lipids, or liquid mixture of liquid lipid and a solid lipid, or liquid mixture of two or more liquid lipids and solid lipids, comprising at least one hydrophobic or lipophilic active substance or drug.
  • the preformed polymer precipitation method consisting of the addition of the organic phase comprising the polymer, one or more lipids, the organic solvent, the nonionic surfactant and the lipophilic drug is used.
  • temperature below 60 ° C, preferably 45 ° C under stirring at 50 to 300 rpm, preferably at 100 rpm, for the time required for complete polymer solubilization, between 15 and 45 minutes, over the aqueous phase.
  • the solvent and part of the water are eliminated using a rotary evaporator and the volume of the suspension is adjusted with the addition of purified water.
  • Said aqueous phase comprises from 0.1 to 10% of at least one nonionic surfactant such as span 20, span 40, span 60, span 80 (sorbitan esters) polysorbate 80, poloxamer 188 and TPGS (d alpha-tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - polyoxyl 35 castor oil), Kolliphor HS 15
  • nonionic surfactant such as span 20, span 40, span 60, span 80 (sorbitan esters) polysorbate 80, poloxamer 188 and TPGS (d alpha-tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - polyoxyl 35 castor oil), Kolliphor HS 15
  • the organic phase comprises 0.0001 to 10%, preferably 0.10% of the lipid-associated hydrophobic or lipophilic active substance or drug, wherein lipids are selected from the groups consisting of liquid lipid (oil) in the concentration of 1 to 20% or mixture of liquid lipids in the ratio ranging from 0.01: 1 to 1: 10, or a liquid mixture of liquid and solid lipids in the ratio ranging from 0.01: 1 to 1: 100; from 0.01 to 20% of polymers selected from the group consisting of lactic polyacid, copolymers derived from lactic and glycolic acids, aliphatic polyanhydrides, polymer derived from lactones, preferably poly (s-caprolactone); from 5 to 50% organic solvent selected from the group consisting of acetone, ethanol and methanol, preferably acetone; from 0.0001 to 10% hydrophobic or lipophilic drug or substance; and from 0.5 to 10% of unsaturated fatty acids such as capric and caprylic acid glycerol triesters and from
  • Liquid lipids are selected from the group consisting of unsaturated fatty acids, such as caprylic and caprylic acid glycerol triesters. And solid lipids are selected from the group consisting of saturated fatty acids, such as cetyl palmitate. Surfactants are selected from nonionics such as span 20, span 40, span 60 and span 80 (sorbitan esters).
  • step “c” a polymeric nanoparticulate compound comprising a hydrophobic or lipophilic active substance or drug incorporated with at least one cationic substance.
  • step “d” an amphiphilic cationic polymeric nanostructured compound having particles of medium hydrodynamic diameter in the sub-micron range with positive zeta potential is obtained.
  • the present invention relates to the amphiphilic cationic lipid nanostructured compound obtained according to the process described herein, which comprises at least two drugs, one hydrophobic and one hydrophilic, associated with:
  • Said hydrophobic drug is selected from the group consisting of hydrophobic or lipophilic active substances such as immunosuppressants (cyclosporine), prostaglandins (latanoprost, bimatoprost and travoprost), non-spheroidal and spheroidal anti-inflammatory agents, preferably dexamethasone acetate; and antioxidants such as carotenoids, ⁇ -, ⁇ -, ⁇ -, ⁇ -tocopherol and a-, ⁇ -, ⁇ -, ⁇ -tocotrienol, retinoic acid, retinol and their esters, ubiquinol, ubiquinone, glutathione in their reduced form, flavonoids, lipoic acid and active components of biotechnological origin such as etanercept, pegaptanib, ranibizumab and bevacizumab; and cholinergic drugs such as pilocarpine, ezerin and neostigmine.
  • Said hydrophilic drug is selected from the group consisting of hydrophilic cationic substances, cationic peptides, antimicrobial cationic peptides such as polymyxin B sulfate, vancomycin, gramicidine, bacitracin; other cationic antimicrobial peptides; and benzalkonium chloride, preferably polymyxin B sulfate.
  • the oil phase comprises from 0.0001 to 10%,
  • the lipids are selected from the groups consisting of a liquid lipid at a concentration of 0.1 to 20% or a mixture of liquid lipids ranging from 0.001: 1 to 1: 10; and solid lipid at a concentration of 1 to 20% or a mixture of solid lipids in a ratio ranging from 0.01: 1 to 1: 100; or a mixture of liquid and solid lipids ranging from 0.01: 1 to 1: 100 of the total lipid carrier formulation.
  • Liquid lipids are selected from the group consisting of unsaturated fatty acids, such as caprylic and caprylic acid glycerol triesters. And solid lipids are selected from the group consisting of saturated fatty acids, such as cetyl palmitate.
  • the aqueous phase comprises 0.05 to 10% of at least one nonionic surfactant such as polysorbate 80, soy or egg phospholipids, poloxamer 188, poloxamer 407, TPGS (d-alpha tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - polyoxyl 35 castor oil) and Kolliphor HS 15 (polyoxyl hydroxystearate 15) diluted in ultrapure water.
  • TPGS d-alpha tocopheryl polyethylene glycol 1000
  • Kolliphor ELP microgolglyceryl ricinoleate - polyoxyl 35 castor oil
  • Kolliphor HS 15 polyoxyl hydroxystearate 15
  • it may contain from 0.001 to 10% anionic surfactant such as sodium dodecyl sulfate.
  • the aqueous phase comprises 2.5% poloxamer 188 and poloxamer 407, 1.5% polysorbate 80, 0.5% sodium dodecyl sulfate, and 100% ultrapure water of the total lipid carrier formulation.
  • amphiphilic cationic lipid nanostructured compound has zeta potential ranging from +5 to +65 mV
  • HVM average hydrodynamic diameter
  • the present invention also relates to the amphiphilic cationic polymeric nanostructured compound obtained as an alternative embodiment of the present process, which comprises at least two drugs, one hydrophobic and one hydrophilic, associated with: 0.5 to 20% organic phase (without the organic solvent to be evaporated);
  • Said hydrophobic drug is selected from the group consisting of hydrophobic or lipophilic active substances such as immunosuppressants (cyclosporine), prostaglandins (latanoprost, bimatoprost and travoprost), non-spheroidal and spheroidal anti-inflammatory agents, preferably dexamethasone acetate; antioxidants such as carotenoids, ⁇ -, ⁇ -, ⁇ -, ⁇ -tocopherol and a-, ⁇ -, ⁇ -, ⁇ -tocotrienol, retinoic acid, retinol and its esters, ubiquinol, ubiquinone, glutathione in their reduced form, flavonoids lipoic acid and active components of biotechnological origin such as etanercept, pegaptanib, ranibizumab and bevacizumab; and cholinergic drugs such as pilocarpine, ezerin and neostigmine.
  • active substances such
  • Said hydrophilic drug is selected from the group consisting of hydrophilic cationic substances, cationic peptides, cationic antimicrobial peptides such as polymyxin B sulfate, vancomycin, gramicidine, bacitracin; other cationic antimicrobial peptides; and benzalkonium chloride, preferably polymyxin B sulfate.
  • the organic phase comprises from 0.0001 to 10%
  • lipid-associated hydrophobic or lipophilic active substance or drug wherein the lipids are selected from the groups consisting of liquid lipid (oil) at a concentration of 1 to 20% or a mixture of liquid lipids in the proportion ranging from 0.01: 1 to 1: 10, or a liquid mixture of liquid and solid lipids in a ratio ranging from 0.01: 1 to 1: 100; from 0.01 to 20% polymer selected from the group consisting of lactic polyacid, copolymers derived from lactic and glycolic acids, aliphatic polyanhydrides, polymer derived from lactones, preferably poly (s-caprolactone; from 0.01 to 10% nonionic surfactants such as sorbitan monostearate; from 0.5 to 10% unsaturated fatty acids such as caprylic and caprylic acid glycerol triesters; 0.0001 to 5% hydrophilic drug, and 5 to 30% organic solvent selected from the group consisting of acetone, ethanol and methanol, preferably
  • Liquid lipids are selected from the group consisting of unsaturated fatty acids, such as caprylic and caprylic acid glycerol triesters. And solid lipids are selected from the group consisting of saturated fatty acids, such as cetyl palmitate.
  • the aqueous phase comprises from 0.1 to 10% of at least one nonionic surfactant such as polysorbate 80, poloxamer 188 and TPGS (d-alpha tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - polyoxyl castor 35), Kolliphor HS 15
  • nonionic surfactant such as polysorbate 80, poloxamer 188 and TPGS (d-alpha tocopheryl polyethylene glycol 1000), Kolliphor ELP (macrogolglyceryl ricinoleate - polyoxyl castor 35), Kolliphor HS 15
  • amphiphilic cationic polymeric nanostructured compound has zeta potential ranging from +15 to +55 mV
  • HVM hydrodynamic diameter
  • the present invention relates to the use of said amphiphilic cationic lipid and amphiphilic cationic polymeric nanostructured compounds as a carrier of at least two drugs, one hydrophilic and the other hydrophobic, for the development of pharmaceutical or cosmetic products in which they are present.
  • cationic characteristic is desirable, preferably ophthalmic products.
  • the present invention may be used for the development of medicaments for neglected diseases.
  • Nanostructured lipid carriers comprising dexamethasone acetate, polymyxin B and guitosan chloride coated (CLN-Dexa-Poly-Prot):
  • Amount equal to 100.0g of nanostructured lipid carriers (CLN) was first obtained by transferring exact 6.0g of cetyl palmitate (saturated fatty acid); 4.0 g caprylic and caprylic acid glycerol triesters (fatty acid
  • the aqueous phase was dispersed in the lipid phase under mechanical agitation (8000 rpm) using a stirrer for 5 minutes to form a pre-emulsion which was subjected to high pressure homogenization using four successive cycles at 600 bar.
  • polymyxin B sulfate potency 8106 Ul / mg
  • Solution A was also used for preparation 4, but a volume of 1.1 mL in 8.9 mL of CLN-Dexa was used.
  • preparation 12 was obtained by adding 0.8 mL of Solution C to 9.2 mL of CLN-Dexa.
  • lipid nanostructured compound containing dexamethasone acetate and polymyxin B at concentrations 25, 50, 75 and 100 lipid nanostructured compound containing dexamethasone acetate and polymyxin B at concentrations 25, 50, 75 and 100 (2,500 IU / mL; 5,000 IU / mL; 7,500 IU / mL and 10,000 IU / mL)
  • CLN-Dexa + Poli was negatively charged in the concentration range of the antimicrobial agent used (2,500 to 10,000 IU / mL). Such behavior allowed the coating of the carrier (CLN-Dexa + Poly) using cationic polymer (0.15% w / w).
  • Table 4 presents the results of dexamethasone acetate-containing nanostructured lipid carriers (CLN-Dexa) prepared after incorporation of polymyxin B sulfate employing concentrations of 2,500, 5,000, 7,500 and 10,000 IU / mL (Table 4). .
  • Polymyxin which has a surfactant characteristic (cationic surfactant), was confirmed by simple regression analysis ( Figure 1). Like polymyxin B sulfate, other cationic surfactants can be used such as benzalkonium chloride. After incorporation of polymyxin B sulfate into the CLN-Dexa, the zeta potential was changed from -18.6 mV (CLN-Dexa) to -2.00 mV (10,000 IU / mL) (Table 4). This result demonstrated the incorporation of cationic surfactant (polymyxin B sulfate) in the carrier.
  • cationic surfactant polymyxin B sulfate
  • LP lipid nanostructured compound containing dexamethasone acetate and polymyxin B at concentrations 25, 50, 75 and 100 (2,500 IU / mL; 5,000 IU / mL; 7,500 IU / mL and 10,000 IU / mL) and 0, 15% (p / p) of
  • DHM was dependent on the concentration of polymyxin sulfate as shown in Table 9 and Figure 2.
  • Table 8 Average hydrodynamic diameter (nm) of CLN-Dexa and CLN-Dexa + Poly employing 1,000, 2,000, 3,000,
  • Antibiotic culture medium No. 10 was used, which was sterilized using pressurized saturated water vapor at 121 ° C for 15 minutes in a vertical autoclave.
  • Negative control was performed by adding 200 ⁇ _ of uninoculated culture medium in a row of the microplate; Positive media control was obtained by transferring 100 ⁇ _ from the uninoculated culture medium and 100 ⁇ from the inoculated medium to the well. Incubation was incubated at 37 ⁇ 0.5 ° C for 24 hours. After reading this result, 50 ⁇ 50_ of the triphenyl tetrazolium chloride solution was added and incubated for 2 hours in an oven at 37 ⁇ 0,5 ° C. The plates were read visually, observing the appearance of reddish color indicating microbial growth.
  • Nanostructured polymeric vesicles comprising dexamethasone acetate, polymyxin B and guitosan chloride-coated (VP-Dexa-Poli-Prot):
  • the preformed polymer precipitation method which consists, under stirring, of the organic phase containing the poly- ⁇ ( ⁇ -caprolactone) acid (PCL), acetone, dexamethasone and the capric / caprylic acid triglyceride mixture over an aqueous phase containing polysorbate 80 (Table 12). Solvent and part of the water were removed using a rotary evaporator and the volume of the suspension was adjusted in a volumetric flask.
  • Three stock solutions of polymyxin B sulfate were prepared by transferring 123.37 mg, 92.52 mg and 61.68 mg (potency of polymyxin B sulfate: 8106 Ul / mg) to volumetric flasks. 10.0 mL, the volume being supplemented with Milli-Q® ultrapure water. In this way, final concentrations were obtained,
  • the average hydrodynamic particle diameter (DHM) and polydispersity index (IP) of dexamethasone acetate-containing polymeric vesicles (VP-Dexa) were determined by
  • Table 13 shows the VP-Dexa + Poly DHM, IP and PZ using different concentrations of polymyxin B sulfate (2,500, 5,000, 7,500 and 10,000 IU / mL) after coating employing 0, 15% (w / v ) from Protasan® (VP-Dexa + Poly + Prot).
  • Figures 3 and 4 show the linear regression between DHM and polymyxin B sulphate concentration and between zeta potential and polymyxin B sulphate concentration of VP-Dexa + Poly
  • DHM 339.8 nm for the lowest concentration (2,500 IU / mL polymyxin B sulfate) and 445,8nm (10,000 IU / mL polymyxin B sulfate). DHM values are stable for 4 weeks under refrigeration.
  • dexamethasone (VP-Dexa) employing the highest concentration of polymyxin B sulfate (10,000 IU / mL).
  • PZ values were changed from -37 mV (without addition of polymyxin B sulfate) to -19 mV (after addition of 10,000 IU / mL polymyxin B sulfate).
  • Figures 4 and 5 show the analysis of variance for DHM and PZ of VP-Dexa + Poli + Prot, respectively employing 0.15% (w / v) Protasan®.
  • polymyxin B sulfate concentrations (2,500, 5,000, 7,500 and 10,000 IU / mL) ( Figures 5 and 6).
  • these characteristics are dependent on the concentration of chitosan used in the coating of VP-Dexa + Poly.
  • the VP-Dexa + Poli DHM values which ranged from 339.8 to 445.8 nm, for the different concentrations of polymyxin B sulfate (Table 13), after coating using Protasan ® , presented DHM values. between 623.9 and 740.7 nm (not significantly different DHM).
  • pH analysis revealed a value between 4.5 and 6.5 for formulations before and after coating using polymyxin B sulfate and Protasan ® .
  • the encapsulation efficiency of dexamethasone acetate was 97.2% (w / v).
  • the present invention provides lipid or polymeric nanostructured compounds comprising hydrophilic and hydrophobic drugs, therefore with amphiphilic characteristic, and cationic due to chitosan chloride.

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Abstract

La présente invention concerne un procédé d'obtention de composés nanostructurés lipidiques cationiques amphiphiles et polymères cationiques amphiphiles pouvant comprendre au moins deux substance pharmaceutiques, l'une hydrophobe et l'autre hydrophile, associées à une phase huileuse et aqueuse, et enrobées de chitosane. Ledit procédé comprend quatre étapes, lesquelles permettent le contrôle d'obtention des nanostructures. Ainsi, il est possible de cationiser la nanoparticule de manière contrôlée. La présente invention concerne également les composés obtenus ainsi que leur utilisation pour l'élaboration de produits pharmaceutiques ou cosmétiques dans lesquels la caractéristique cationique est souhaitable, de préférence des produits ophtalmiques.
PCT/BR2017/050297 2016-11-18 2017-09-29 Procédé d'obtention de composés nanostructurés lipidiques cationiques amphiphiles et polymères cationiques amphiphiles, composés nanostructurés obtenus et leurs utilisations WO2018090112A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220023450A1 (en) * 2018-09-11 2022-01-27 Memorial Sloan Kettering Cancer Center Bone marrow-, reticuloendothelial system-, and/or lymph node-targeted radiolabeled liposomes and methods of their diagnostic and therapeutic use
JP2021031412A (ja) * 2019-08-20 2021-03-01 クラレトレーディング株式会社 抗ウイルス性樹脂組成物及びこれを用いた成形体
JP7295531B2 (ja) 2019-08-20 2023-06-21 クラレトレーディング株式会社 抗ウイルス性樹脂組成物及びこれを用いた成形体

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