WO2001037809A1 - Suspension colloidale de particules submicroniques de vectorisation de principes actifs et leur mode de preparation - Google Patents
Suspension colloidale de particules submicroniques de vectorisation de principes actifs et leur mode de preparation Download PDFInfo
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- WO2001037809A1 WO2001037809A1 PCT/FR2000/002831 FR0002831W WO0137809A1 WO 2001037809 A1 WO2001037809 A1 WO 2001037809A1 FR 0002831 W FR0002831 W FR 0002831W WO 0137809 A1 WO0137809 A1 WO 0137809A1
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- Prior art keywords
- particles
- suspension
- aao
- aai
- insulin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/044—Suspensions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/90—Block copolymers
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0004—Preparation of sols
- B01J13/0021—Preparation of sols containing a solid organic phase
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/413—Nanosized, i.e. having sizes below 100 nm
Definitions
- the encapsulation of PA in the PV has in particular, for the purpose of modifying their duration of action and / or of routing them during the treatment and / or increased the biodispombihte of said PA
- Many encapsulation techniques have already been proposed Such techniques aim on the one hand, to allow the transport of the PA to its site of therapeutic action while protecting it against aggressions of the organism (hydrolysis, enzymatic digestion, etc.) and, on the other hand, to control the release of the AP on its site of action, in order to maintain the quantity available for the organism at the desired level.
- PVs It would also be desirable for the PVs to be of sufficiently small size to be able to undergo, in suspension in a liquid, sterilizing filtration by a filter whose pore diameter is less than or equal to 0.2 ⁇ m. 4 It is desirable that PV and PV-PA systems can be obtained by a non-denaturing process for PA.
- US-A-5,286,495 relates to a process of encapsulation by vaporization of proteins in aqueous phase, using materials having opposite charges, namely: alginate (negatively charged) and polylysine (positively charged). This manufacturing process makes it possible to produce particles larger than 35 ⁇ m.
- the hydrodynamic diameter of these objects is less than twice their gyration radius, as explained for example in the works "Dynamic Light Scattering", BJ Berue and R. Pecaran (Wiley, 1976) and "Physicochemical Hydrodynamics", RF Probstein (Wiley 1994).
- the loading rate Ta of the particles is conveniently expressed by the ratio of the mass of insulin to the mass of dry PV.
- WO 96/29991 with an AP consisting of insulin, is at best 0.065 mg / mg, or 6.5% by dry weight of insulin relative to the mass of PAA. Ta is measured according to a procedure Ma described below.
- the particles according to WO 96/29991 are formed spontaneously by bringing PAA into contact with an aqueous solution.
- Another essential objective of the invention is to provide an aqueous colloidal suspension or a pulverulent solid comprising vectoring particles of active principles satisfying the specifications referred to above and which constitutes an appropriate dosage form suitable for administration, for example oral , to humans or animals.
- Another essential objective of the invention is to provide a colloidal suspension comprising particles of vectorization of active principles which can be filtered on 0.2 ⁇ m filters for sterilization purposes.
- Another essential objective of the invention is to propose a process for the preparation of particles (dry or in suspension in a liquid) of PAA useful, in particular, as vectors of active principles, said process having to be simpler to carry out implemented, non-denaturing for the active ingredients and which must also always allow fine control of the average particle size of the particles obtained.
- Another essential objective of the invention is to provide a vaccine vectoring system which is intrinsically non-immunogenic and in combination with one or more antigens.
- the present invention which relates, first of all, to a stable colloidal suspension of structured submicron particles capable of being used, in particular for the vectorization of active principle (s) ( s) PA, these particles being individualized (discrete) supramolecular arrangements: o based on amphiphilic, linear polyamino acids (PAA), with peptide sequences and comprising at least two different types of recurrent amino acids hydrophilic AAI and neutral hydrophobic AAOs, amino acids of each type being identical or different from each other, o and capable of combining in colloidal suspension in the undissolved state, at least one AP and of releasing the latter, in particular in vivo, in a prolonged and / or delayed manner, characterized: • in that the AAI (s) of the polymer chains is (are) chosen from amino acids with an ionizable side chain, natural amino acids Glu and Asp in carboxylic form and / or in the form of salts being particularly preferred,
- AAO (s) of the polymer chains is (are) chosen (s) from the group comprising natural neutral amino acids, preferably those belonging to the subgroup comprising: Leu, Ile, Val, Ala, Gly, Phe;
- the pulverulent PAA powder is suspended in an aqueous 0.15 M sodium chloride solution at pH 7.4, 25 ° C. and at a polymer concentration of between 0.01 and 0.5 g / l and, preferably equal to 0.1 g / 1. This suspension is stirred for 4 hours, then introduced into the diffusion cell of a light diffusion apparatus, of the Brookhaven type, operating with a laser beam of wavelength 488 nm and vertically polarized.
- the hydrodynamic diameter is calculated from the autocorrelation function of the electric field by the cumulants method, as described in the book “Surfactant Science Series” volume 22, Surfactant
- the suspension according to the invention is characterized in that the submicron particles do not draw their cohesion from the presence of the following three compounds:
- the particles form a stable colloidal suspension in water and in a physiological medium
- the PVs associate with proteins or other PAs in an aqueous medium, by a spontaneous and non-denaturing mechanism for the protein, “the PVs release the PAs in physiological medium and, more precisely, in vivo; the release kinetics are a function of the nature of the PAA precursor polymer of PV.
- the constituent PAAs are of the “block” type and are characterized by a AAO / (AAI + AAO) molar ratio such that
- the absolute length of each block of AAO, expressed in number of AAO is such that
- the constituent PAAs are of the “statistical” type, that is to say prepared by simultaneous copolymerization of monomers of AAI and AAO, and the molar ratio AAO / (AAO + AAI ) is such that
- the molar mass Mw of these statistical PAAs is such that *
- the PAA blocks or statistics constituting particles have degrees of polymerization DP comp ⁇ s between 30 and 600, preferably between 50 and 200 and, more preferably still, between 60 and 150.
- the PAA constituting the PV particles are PAA "diblocks"
- the present invention relates not only to suspensions of bare particles, as defined above, but also to particles comprising at least one active principle PA.
- the suspension according to the invention is aqueous and stable. These particles, loaded or not with PA, are advantageously in the form dispersed in a liquid (suspension), preferably aqueous, but can also be in the form of a pulverulent solid, obtained from the PV suspension as defined above.
- the invention relates, in addition to a colloidal (preferably aqueous) suspension of PV, a pulverulent solid comprising PV and obtained from the suspension according to the invention.
- Another essential object of the invention relates to the preparation of the selected particles (as described above), both in the form of a colloidal suspension and in the form of a pulverulent solid.
- the preparation process considered consists, essentially, in synthesizing precursor PAAs and transform them into structured particles.
- submicron structured particles capable of being used, in particular for the vectorization of active principle (s), these particles being discrete supramolecular arrangements : “Based on linear amphiphilic polyamino acids (PAA), with sequences (hydrophilic -AAI and hydrophobic AAO, the amino acids of each type being identical or different from each other;
- PAA linear amphiphilic polyamino acids
- NCA-pAAI designating an AAI precursor
- NCA-AAO N-MethylPyrrolidone
- DiMethylAcetamide (DMAc), pyrrolidone, NMP being more particularly preferred, o and, optionally at least one protic co-solvent preferably chosen from the group comprising pyrrolidone, water, alcohols; methanol being particularly preferred;
- the recurring units pAAI of the precursor copolymer PAA of the particles are transformed into recurring units AAI, by implementing a hydrolysis, preferably acid, for which an acidic aqueous phase is added to the abovementioned organic medium;
- reaction medium is purified by dialysis to obtain an aqueous suspension of structured particles
- the liquid medium is removed to collect the pulverulent solid comprising the particles.
- the first stage of the process is inspired by known techniques for the polymerization of N-carboxy anhydrides - (- amino acids (NCA), described, for example, in the article “Biopolymers, 15, 1869 (1976)” and in work by HR KRICHELDORF "(- Aminoacid-N-carboxy Anhydride and Related Heterocycles” Springer Verlag (1987).
- NCA N-carboxy anhydrides - (- amino acids
- This variant corresponds to a discontinuous mode of preparation of particles, in which the poly (AAO) (pAAI) copolymer is isolated in the form of a precipitate forming a stable intermediate product.
- This precipitate can be, for example, filtered, washed and dried.
- the copolymerization takes place at a temperature between 20 and 120 ° C, at atmospheric pressure and in the presence of an amino initiator, eg: NH 3 .
- Acid hydrolysis (step 2) is carried out using water and at least one mineral acid, such as phosphoric or hydrochloric aid - the latter being preferred - and / or an organic acid, such as acid.
- TriFluoroAcetic (TFA), acetic acid, dichloroacetic acid, or organosulfonic acids.
- the water / acid proportions - expressed in parts by weight - in an acidic aqueous hydrolysis phase are, advantageously:
- aqueous hydrolysis / NMP aqueous phase proportions - expressed in parts by weight - are advantageously:
- step 3 takes place, in practice, for example using sodium hydroxide.
- step 4 the salt formed after neutralization is then eliminated, as well as the solvent, by any appropriate physical separation treatment, for example by diafiltration (dialysis) (step 4), filtration, pH modification, chromatography, etc.
- step 6 the particles from their liquid suspension medium, the aqueous phase is possibly eliminated, for example by drying (eg in an oven), by lyophilization or any other suitable physical means: ultrafiltration, centrifugation. Is recovered, at the end of this step 6, a powdery solid, white in color.
- the concentration step can be carried out by a chemical treatment, such as a lowering of the pH, which transforms the hydrophilic part of the glutamate monomers into acid, which makes them insoluble in water.
- a chemical treatment such as a lowering of the pH, which transforms the hydrophilic part of the glutamate monomers into acid, which makes them insoluble in water.
- These acid PAA intermediates can be filtered, washed and dried. Said acid intermediates can be neutralized with a chemical base in a subsequent step in order to obtain a suspension of particles.
- steps 1, 2, 3, 4 and possibly 5 of the above method corresponding to a preparation of a colloidal suspension of submicronic particles and with a high loading rate with the PAs.
- the poly (AAO) (AAI) amphiphilic PAAs of step 2 are placed in an aqueous medium in which at least part of the AAI is soluble and at least part of the AAO is insoluble.
- PAAs exist in the form of nanoparticles in this aqueous medium.
- An alternative for preparing the PV suspension according to the invention consists in bringing the pulverulent solid into contact, as described above and as a product and by its process for obtaining, with an aqueous, non-solvent medium for AAO.
- the association of PA with the particles is carried out by bringing a liquid phase (aqueous or not) containing the PA into contact with the colloidal suspension of particles.
- the association of the PA with the particles is carried out by bringing a PA in the solid state into contact with the colloidal suspension of particles.
- the PA solid can be, for example, in the form of lyophilisate, precipitate, powder or the like.
- the pulverulent solid (PAA) is brought into contact, as described above as a product and by its production characteristics, with a liquid phase (aqueous or not) containing the PA.
- the pulverulent solid is brought into contact, as described above as a product and by its production characteristics, with the PA in solid form.
- This mixture of solids is then dispersed in a liquid phase, preferably an aqueous solution.
- the PA used can be in pure or preformulated form.
- the suspension can be filtered through sterilization filters, which makes it possible to obtain sterile injectable medicated liquids easily and at low cost.
- the present invention also relates to new intermediate products of the process described above, characterized in that they consist of PAA copolymers which are precursors of particles.
- the invention relates to a suspension and / or a pulverulent solid, as defined above and / or as obtained by the process presented above, this suspension and this solid comprising at least one active principle , preferably chosen from:
- proteins and / or peptides among which the most preferred are: hemoglobins, cytochromes, albumin, interferons, antigens, antibodies, erythropoietin, insulin, growth hormones, factors VIII and LX, interleukins or their mixtures, the stimulating factors of hematopoiesis,
- the invention also relates to a suspension and / or the pulverulent solid loaded with nutritional, phytosanitary or cosmetic AP.
- the invention relates to a pharmaceutical, nutritional, phytosanitary or cosmetic specialty, characterized in that it comprises a suspension and / or powdery solid loaded with PA and as defined above.
- the invention also relates to the use of these PVs (in suspension or in solid form) loaded with PA, for the manufacture of medicaments of the PA release type systems.
- medicaments they may be, for example those which can be administered, preferably by the oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral or parenteral route.
- compositions comprising a PA associated with the PVs according to the invention and applicable transdermally.
- the phytosanitary products concerned can be, for example, herbicides, pesticides, insecticides, fungicides, etc.
- Fig. 1 Nanoparticles corresponding to a block copolymer la: leucine 50 / Glutamate
- Fig. 2 Nanoparticles obtained with the block copolymer according to the present invention (Example 2). Note that the bar here only represents 50 nm.
- Fig 3 Evolution of the glucose concentration (average in% basal on 4 dogs) after injection of a PV formulation loaded with insulin at the rate of 2 IU / kg.
- Fig. 4 Evolution of the serum insulin concentration (average in 4 dogs) after injection of a PV formulation loaded with insulin at a rate of 2 IU / kg.
- EXAMPLE 1 Obtaining, in stable colloidal aqueous suspension and in pulverulent solid form, vectoring particles, from a block polyamino acid, poly (Leu / Glu) 40/80 diblock
- a 1 liter reactor thermostatically controlled at 20 ° C, 112.4 g of NCA-GluOMe (0.60 mole) and 449 g of N-Methyl Pyrrolidine-one-2 (NMP) are introduced with stirring. After dissolution, 21.38 g of a 0.34 M ammonia solution in 1,4-dioxane (1.25% molar / NCA) are added.
- the polymerization is followed by measurement of the carbon dioxide released in a gas bell and verified by disappearance of the vibration bands characteristic of the NCA at 1860 and 1790 cm-1. After 30 min, a solution of 47.17 g of NCA Leucine (0.30 mole) in 631 g of NMP is introduced. After 10 min of reaction, the temperature is increased to 60 ° C. The polymerization is followed as above and is complete after 2 hours. The temperature of the reaction mixture obtained is increased to 80 ° C. To 350 g of the reaction mixture obtained at the end of step 1 are added 31.5 g of concentrated aqueous hydrochloric acid (35%, 12M) with mechanical stirring over 30 min. The reactor is then placed under reduced pressure regulated at 600 mBar for 6 hours.
- a mixture of 31.5 g of 35% hydrochloric acid and 126 g of water is then added over 60 min, followed by a second vacuum phase at 250 mBar for 18 hours.
- the overall ratio Water / pure hydrochloric acid is 7.6 / 1 by mass and the ratio aqueous acid / NMP phase of 60/100 by mass.
- the reaction mixture is then cooled to 50 ° C, then neutralized with aqueous sodium hydroxide (35% by mass).
- aqueous sodium hydroxide 35% by mass
- the NMP and the sodium chloride formed during neutralization are removed by diafiltration against 20 volumes of Milli Q water, on an MWCO membrane of 1000 Daltons (Pellicon II system, Millipore).
- a stable aqueous colloidal suspension of vectoring nanoparticles is thus obtained.
- the nanoparticle suspension is finally lyophilized.
- leucine units are determined by nuclear magnetic resonance of the proton (signals at 2.10, 2.22 and 2.58 ppm for 4H of Glu and at 0.85 ppm for 6H of Leu).
- the average hydrodynamic diameter (Dh) is 70 nm (according to Md).
- the Ma procedure is used.
- the concentration of free insulin, determined by HPLC chromatography, is equal to 0.59 mg / ml and the associated insulin concentration equal to 1.51 mg / ml is deduced therefrom.
- the loading capacity of a 10 mg / ml colloidal solution reaches 1.51 mg / ml of insulin.
- the ratio of the mass of insulin associated with the mass bLE (Ta) is 15.1%.
- EXAMPLE 3 Obtaining, in stable colloidal aqueous suspension and in pulverulent solid form, vectorization particles from a PAA block poly (Leu / g! U) 25/70 diblock.
- NCA GluOMe 146.4 g of NCA GluOMe are dissolved in 586g of NMP to which are added 18.43 g of a 0.48 M ammonia solution in methanol.
- a solution of 43.9 g of NCA Leu in 708 g of NMP is introduced and the polymerization of NCA Leu is continued until the monomers disappear.
- the medium is then brought to 80 ° C. and 129.4 g of 35% HCl are added to it dropwise over 30 min to 1 hour.
- a vacuum of 600 mBar is applied for 6 hours, then an additional 129.4 g of 35% HCl is added in a mixture with 517.5 g of water.
- a vacuum of 250 mBar is then applied for 18 hours. After this step, the temperature is reduced to 50 ° C, 1 liter of water is introduced, followed by 280 ml of 35% NaOH to bring the pH to 7.4. The suspension is then filtered (5 ⁇ m), dialyzed (cut-off threshold 1000 Da) in water, to remove the solvent and the salts, and finally filtered (0.22 ⁇ m). This suspension can be used directly or undergo subsequent treatments, such as the distillation of water (step 5) or freeze-drying (step 6). The average hydrodynamic diameter Dh (according to Md) is 14.8%.
- the loading rate Ta of insulin determined according to the procedure Ma, is 35 nm.
- EXAMPLE 4 Obtaining vectorization nanoparticles in stable aqueous colloidal suspension from a block polyamino acid, poly (Leu / Glu) 50/70 diblock and characteristics of the nanoparticles
- NCA-GluOMe (0.208 mole) and 156 g N-Methyl Pyrrolidine-one-2 (NMP) are introduced into a 0.5 liter reactor thermostatically controlled at 30 ° C. After dissolution, 5.79 g of a 0.407 M ammonia solution in methanol (1.25 mol% / NCA) is added. The polymerization is followed by measurement of the carbon dioxide released in a gas bell and verified by disappearance of the vibration bands characteristic of the NCA at 1860 and 1790 cm-1. After 30 min, a solution is introduced 23.3 g of NCA Leucine (0.148 mole) in 263 g of NMP. After 10 min of reaction, the temperature is increased to 60 ° C.
- the polymerization is followed as above and is complete after 1-2 hours.
- the temperature of the reaction mixture obtained above is increased to 80 ° C.
- 41.9 g of aqueous hydrochloric acid (35% by mass) are added to the reaction medium with mechanical stirring over 30 min.
- the reactor is then placed under reduced pressure regulated at 600 mBar for 6 hours.
- a mixture of 41.9 g of 35% hydrochloric acid and 167.5 g of water is then added over 60 min, followed by a second vacuum phase at 250 mBar for 18 hours.
- the reaction mixture is then cooled to 50 ° C. then neutralized with aqueous sodium hydroxide (35% of the mass).
- the NMP and the sodium chloride formed during neutralization are removed by diafiltration against 20 volumes of Milli Q water, on an MWCO membrane of 1,000 Daltons (Pellicon II system. Millipore). A stable aqueous colloidal suspension of vectoring nanoparticles is thus obtained. The nanoparticle suspension is finally lyophilized. The mean hydrodynamic diameter Dh is measured according to Md on aqueous suspensions of the lyophilisates. The loading rate Ta of the insulin is determined according to the procedure Ma.
- EXAMPLE 5 Obtaining, in stable aqueous colloidal suspension of vectoring nanoparticles, from a block polyamino acid, the poly (Leu / Glu) 25/35 diblock and characteristics of the nanoparticles
- NCA-GluOMe (0.208 mole) and 156 g of N-Methyl Pyrrolidine-one-2 (NMP) are introduced into a 0.5 liter reactor thermostatically controlled at 30 ° C. After dissolution, 5.78 g of a 0.452 M ammonia solution in methanol (1.25 mol% / NCA) is added. The polymerization is followed by measurement of carbon dioxide released in a gas bell and verified by disappearance of the vibration bands characteristic of the NCA at 1860 and 1790 cm-1. After 30 min, a solution of 23.3 g of NCA Leucine (0.149 mole) in 5,219 g of NMP is introduced. After 10 min of reaction, the temperature is increased to 60 ° C.
- the polymerization is followed as above. It is complete after 1-2 hours.
- the temperature of the reaction mixture obtained above is increased to 80 ° C.
- 42.0 g of aqueous hydrochloric acid (35% by mass) are added to the reaction medium with mechanical stirring over 30 min.
- the reactor is then placed under reduced pressure regulated at 600 mBar for 6 hours.
- a mixture of 42.0 g of 35% hydrochloric acid and 167.9 g of water is then added over 60 min, followed by a second vacuum phase at 250 Mbar for 18 hours.
- the reaction mixture is then cooled to 50 ° C., then neutralized by the aqueous soda (35% by mass).
- the NMP and the sodium chloride formed during neutralization are removed by diafiltration against 20 volumes of Milli Q water, on an MWCO membrane of 1000 Daltons (Pellicon II system, Millipore). A stable aqueous colloidal suspension of vectoring nanoparticles is obtained. The suspension of nanoparticles is finally lyophilized.
- the contents of leucine units are determined by nuclear magnetic resonance of the proton (signals at 2.10, 2.22 and 2.58 ppm for 4H of Glu and at 0.85 ppm for 6H of Leu).
- the mean hydrodynamic diameter Dh is measured according to Md on aqueous suspensions of the lyophilisates.
- the insulin loading rate is determined according to Ma.
- EXAMPLE 6 Obtaining, in stable aqueous colloidal suspension of vectoring nanoparticles, a block polyamino acid, poly (Leu / glu) 50/150 diblock and characteristics of the nanophases
- a block polyamino acid poly (Leu / glu) 50/150 diblock and characteristics of the nanophases
- NMP N-Methyl Pyrrolidine-one-2
- the polymerization is followed by measurement of the carbon dioxide released in a gas bell and verified by disappearance of the vibration bands characteristic of the NCAs of 1860 and 1790 cm-1. After 30 min, a solution of 12.97 g of NCA Leucine (0.083 mole) in 218 g of NMP is introduced. After 10 min of reaction, the temperature is increased to 60 ° C. The polymerization is followed as above. It is complete after 1-2 hours. The temperature of the reaction mixture obtained above is increased to 80 ° C. 40.3 g of aqueous hydrochloric acid (35% by mass) are added to the reaction medium with mechanical stirring over 30 min. The reactor is then placed under reduced pressure regulated at 600 mBar for 6 hours.
- a mixture of 40.3 g of 35% hydrochloric acid and 161.3 g of water is then added over 60 min, followed by a second vacuum phase at 250 mBar for 18 hours.
- the reaction mixture is then cooled to 50 ° C, then neutralized with aqueous sodium hydroxide (35% by mass).
- the NMP and the sodium chloride formed during neutralization are removed by diafiltration against 20 volumes of Milli Q water, on a NWCO membrane of 1000 Daltons (Pellicon II system, Millipore). A stable aqueous colloidal suspension of vectoring nanoparticles is obtained. The nanophase suspension is finally lyophilized.
- the contents of leucine units are determined by nuclear magnetic resonance of the proton (signals at 2.10; 2.22 and 2.58 ppm for 4H of Glu and at 0.85 ppm for 6H of Leu).
- the mean hydrodynamic diameter Dh is measured according to Md.
- the loading rate of inulin is determined according to Ma.
- the particles obtained by the teaching of patent WO 96/29991 are those appearing in FIG. 1.
- the particles according to the invention are those appearing in FIG. 2 attached corresponding to a photograph taken with a transmission electron microscope.
- FIG. 1 which represents PV according to the prior art, on the one hand
- FIG. 2 showing PVs according to the invention, on the other hand.
- the minutes of FIG. 2 are such that the majority of the larger particles have an elongated shape.
- the powdery powder of Example 2 is dissolved in an amount of 60 mg / ml of powder in a phosphate buffer.
- the pH was adjusted to 7.3 and the osmolality of the suspension was adjusted to 300 mOsm / kg using a 5M NaCl solution.
- the solution was filtered (0.22 ⁇ m) before being distributed at the rate of 5 ml in sterile 10 ml bottles.
- the stability of the samples was evaluated over a period of 4 months.
- Verification of the homogeneity of the colloidal solution Without stirring the suspension, three samples of 100 ⁇ l are taken so as to represent the state of the solution at the top, in the middle and at the bottom of the bottle. The refractive index of each sample is measured at 25 ° C on an Abbe refractometer calibrated against pure water. Three readings are taken for each sample and the three means are compared. all variation in concentration of the solution would result in a difference in the refractive index.
- Viscosity measurement The measurements are taken on samples of 0.75 ml using an AR1000 rheometer (TA instruments) equipped with a Cone / Plan geometry (4 cm / 2 ° C cone) at a temperature from 20.0 ° C +/- 0.1 ° C (regulation by Pelletier effect). The viscosity curve as a function of the shear gradient is recorded for gradients varying from 1 to 100 s ⁇ 1 . At these concentrations the solutions are slightly shear-thinning and the viscosity value adopted is taken for a gradient of 10 s ⁇ 1 .
Abstract
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002391986A CA2391986A1 (fr) | 1999-11-23 | 2000-10-11 | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et leur mode de preparation |
EP00968011A EP1239836B1 (fr) | 1999-11-23 | 2000-10-11 | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et leur mode de preparation |
NZ518875A NZ518875A (en) | 1999-11-23 | 2000-10-11 | Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same |
BR0015690-6A BR0015690A (pt) | 1999-11-23 | 2000-10-11 | Suspensão coloidal de partìculas submicrÈnicas, sólido pulverulento, processo de preparação do sólido pulverulento, processo de preparação da suspensão, produtos intermediários do processo e produto especial farmacêutico, nutricional, fitossanitário ou cosmético |
AU77986/00A AU781539B2 (en) | 1999-11-23 | 2000-10-11 | Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same |
JP2001539424A JP5095896B2 (ja) | 1999-11-23 | 2000-10-11 | 有効成分のための担体としてのサブミクロンの大きさの粒子のコロイド懸濁液およびそれを調製するための方法 |
AT00968011T ATE247460T1 (de) | 1999-11-23 | 2000-10-11 | Kolloidale suspension von submikronischen teilchen als vektoren von aktiven prinzipien sowie deren herstellung |
MXPA02005191A MXPA02005191A (es) | 1999-11-23 | 2000-10-11 | Suspension coloidal de particulas submicronicas de vectorizacion de principios activos y metodo para preparar las mismas. |
DK00968011T DK1239836T3 (da) | 1999-11-23 | 2000-10-11 | Kolloid suspension af submikronpartikler som bærere for aktive principper samt fremstilling deraf |
DE60004704T DE60004704T2 (de) | 1999-11-23 | 2000-10-11 | Kolloidale suspension von submikronischen teilchen als vektoren von aktiven prinzipien sowie deren herstellung |
US10/130,783 US7226618B1 (en) | 1999-11-23 | 2000-10-11 | Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same |
HK03104605.6A HK1052642A1 (zh) | 1999-11-23 | 2003-06-27 | 作為用於活性成分的載體的亞微粒子的膠體懸浮液及其製備方法 |
US11/783,801 US20070248686A1 (en) | 1999-11-23 | 2007-04-12 | Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR99/14751 | 1999-11-23 | ||
FR9914751A FR2801226B1 (fr) | 1999-11-23 | 1999-11-23 | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et son mode de preparation |
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US11/783,801 Division US20070248686A1 (en) | 1999-11-23 | 2007-04-12 | Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same |
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WO2001037809A1 true WO2001037809A1 (fr) | 2001-05-31 |
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PCT/FR2000/002831 WO2001037809A1 (fr) | 1999-11-23 | 2000-10-11 | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et leur mode de preparation |
Country Status (19)
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US (2) | US7226618B1 (fr) |
EP (1) | EP1239836B1 (fr) |
JP (1) | JP5095896B2 (fr) |
KR (1) | KR100583929B1 (fr) |
CN (2) | CN1823744A (fr) |
AT (1) | ATE247460T1 (fr) |
AU (1) | AU781539B2 (fr) |
BR (1) | BR0015690A (fr) |
CA (1) | CA2391986A1 (fr) |
DE (1) | DE60004704T2 (fr) |
DK (1) | DK1239836T3 (fr) |
ES (1) | ES2206311T3 (fr) |
FR (1) | FR2801226B1 (fr) |
HK (1) | HK1052642A1 (fr) |
MX (1) | MXPA02005191A (fr) |
NZ (1) | NZ518875A (fr) |
PT (1) | PT1239836E (fr) |
WO (1) | WO2001037809A1 (fr) |
ZA (1) | ZA200203618B (fr) |
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US20200179489A1 (en) | 2018-12-07 | 2020-06-11 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin which pi is from 5.8 to 8.5 and a co-polyamino-acid bearing carboxylate charges and hydrophobic radicals and a limited amount of m-cresol |
WO2020115334A1 (fr) | 2018-12-07 | 2020-06-11 | Adocia | Procede de preparation d'une composition stable sous forme d'une solution aqueuse injectable |
WO2020245470A1 (fr) | 2019-06-07 | 2020-12-10 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5, du liraglutide et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
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US7270832B2 (en) | 2000-10-06 | 2007-09-18 | Flamel Technologies, Inc. | Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation |
US10004693B2 (en) | 2002-04-09 | 2018-06-26 | Flamel Ireland Limited | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
US9814684B2 (en) | 2002-04-09 | 2017-11-14 | Flamel Ireland Limited | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
US7683024B2 (en) | 2002-06-07 | 2010-03-23 | Flamel Technologies | Polyaminoacids functionalized by alpha tocopherol and uses thereof, particular for therapeutic applications |
US8017156B2 (en) | 2004-07-19 | 2011-09-13 | Flamel Technologies | Long-acting colloidal insulin formulation and its preparation |
WO2006016078A1 (fr) | 2004-07-19 | 2006-02-16 | Flamel Technologies | Formulation colloïdale d'insuline longue action et sa preparation |
FR2896164A1 (fr) * | 2006-01-18 | 2007-07-20 | Flamel Technologies Sa | Formulation colloidale d'insuline longue action et sa preparation |
WO2007082712A1 (fr) * | 2006-01-18 | 2007-07-26 | Flamel Technologies | Formulation colloïdale d'insuline longue action et sa préparation |
WO2013054298A2 (fr) | 2011-10-13 | 2013-04-18 | Bio-Ker S.r.l | Polyéthylène glycols modifiés et leurs complexes supramoléculaires à macromolécules biologiquement actives |
US10383918B2 (en) | 2016-06-07 | 2019-08-20 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a statistical co-polyamino acid |
US10383920B2 (en) | 2016-06-07 | 2019-08-20 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the pI of which is from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals |
US10485851B2 (en) | 2016-06-07 | 2019-11-26 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid |
US10548952B2 (en) | 2016-06-07 | 2020-02-04 | Adocia | Injectable solution at pH7 comprising at least one basal insulin the pI of which is from 5.8 to 8.5, a prandial insulin and/or a gastrointestinal hormone, and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals |
Also Published As
Publication number | Publication date |
---|---|
BR0015690A (pt) | 2002-07-09 |
ZA200203618B (en) | 2003-07-30 |
EP1239836A1 (fr) | 2002-09-18 |
DE60004704D1 (de) | 2003-09-25 |
US20070248686A1 (en) | 2007-10-25 |
CN1823744A (zh) | 2006-08-30 |
ES2206311T3 (es) | 2004-05-16 |
JP5095896B2 (ja) | 2012-12-12 |
HK1052642A1 (zh) | 2003-09-26 |
EP1239836B1 (fr) | 2003-08-20 |
DK1239836T3 (da) | 2003-11-24 |
ATE247460T1 (de) | 2003-09-15 |
MXPA02005191A (es) | 2003-09-22 |
PT1239836E (pt) | 2004-01-30 |
NZ518875A (en) | 2006-01-27 |
AU781539B2 (en) | 2005-05-26 |
AU7798600A (en) | 2001-06-04 |
CN1399541A (zh) | 2003-02-26 |
FR2801226A1 (fr) | 2001-05-25 |
KR100583929B1 (ko) | 2006-05-26 |
JP2003514844A (ja) | 2003-04-22 |
KR20020067040A (ko) | 2002-08-21 |
CA2391986A1 (fr) | 2001-05-31 |
US7226618B1 (en) | 2007-06-05 |
FR2801226B1 (fr) | 2002-01-25 |
DE60004704T2 (de) | 2004-07-08 |
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