WO2024136219A1 - Formulation pour inhalation comprenant des nanoparticules et son procédé de préparation - Google Patents
Formulation pour inhalation comprenant des nanoparticules et son procédé de préparation Download PDFInfo
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- WO2024136219A1 WO2024136219A1 PCT/KR2023/019824 KR2023019824W WO2024136219A1 WO 2024136219 A1 WO2024136219 A1 WO 2024136219A1 KR 2023019824 W KR2023019824 W KR 2023019824W WO 2024136219 A1 WO2024136219 A1 WO 2024136219A1
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- WO
- WIPO (PCT)
- Prior art keywords
- nanoparticles
- oil
- pharmacologically active
- inhalation
- lipids
- Prior art date
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Images
Definitions
- the present invention relates to inhalation formulations containing nanoparticles and methods for their preparation.
- BACKGROUND Delivery of pharmaceutical formulations containing drugs suspended or dissolved in a carrier to the lungs by inhalation is an important means of treating a variety of diseases, including common diseases such as bronchial asthma and chronic obstructive pulmonary disease.
- diseases including common diseases such as bronchial asthma and chronic obstructive pulmonary disease.
- drugs administered pulmonaryly are steroids, ⁇ 2-adrenergic receptor agonists, and anti-cholinergics.
- These drugs are typically administered in aerosol formulations containing the drug, one or more propellants, and co-solvents such as surfactants and/or ethanol.
- the above formulation is an inhalation formulation, and while the inhalation formulation has the advantage of achieving the desired therapeutic effect with a small amount of the pharmacologically active ingredient, only a portion of the administered pharmacologically active ingredient reaches the target site, and the pharmacologically active ingredient This treatment has the disadvantage of reaching other organs that do not require treatment and causing side effects.
- the transport carrier (Lactose, etc.) and additives were pulverized by selecting from jet fusion, hammer grinding, knife grinding, ultracentrifugation grinding, and high pressure homogenization, thereby lowering the surface energy of the transport carrier and making it effective. Methods of increasing the particle amount were often used.
- the object of the present invention is to provide an inhalation formulation containing nanoparticles and a method for preparing the same.
- nanoparticles contain a pharmacologically active ingredient, have a uniform particle size, and have excellent biocompatibility, so that the remaining time in the lung is increased and the pharmacologically active ingredient can be continuously released.
- Another object of the present invention is to optimally control the particle size, encapsulation ratio, and zeta potential difference by including biocompatible polymers and/or lipids and surfactants in an appropriate ratio to form nanoparticles, so as to have a uniform particle size distribution. , to provide a method for manufacturing a novel inhalation formulation that can prevent agglomeration between particles.
- the present invention is an inhalation formulation containing nanoparticles, which are nanoparticles containing biocompatible polymers and/or two or more types of lipids and surfactants, and contain a pharmacologically active ingredient inside the nanoparticles.
- the nanoparticles have a diameter of 50 nm to 1,000 nm, and may be a lung-targeting formulation.
- the nanoparticles may have a mass median aerodynamic diameter (MMAD) of 1 ⁇ m to 5 ⁇ m.
- MMAD mass median aerodynamic diameter
- the nanoparticles may have a zeta potential difference (mV) within the following range:
- the nanoparticles may have an encapsulation rate of 75% or more for the pharmacologically active ingredient.
- the inhalation formulation containing the nanoparticles can continuously release the pharmacologically active ingredient for 24 hours.
- the pharmacologically active ingredient may be selected from the group consisting of antibiotics, antifungal agents, and antiviral agents.
- biocompatible polymers include polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), and polycaprolactone, which can be degraded in vivo. (Polycarprolactone), copolymers thereof, and combinations thereof.
- the lipids include cetyl palmitate, Precirol ATO 5, Compritol 888 ATO, trimyristin, tripalmitin, tristearin, and glyceryl.
- the surfactant is a natural surfactant obtained from lecithin, saponin, sugar ester, polyglycerin ester, sorbitan, glucose, etc.
- the hydrophobic parts include long-chain fatty acid, hydroxy fatty acid, and ⁇ -alkyl- ⁇ -hydroxy fatty acid
- the hydrophilic parts include carbohydrates, amino acids, cyclic peptides, phosphate, carboxylic acid, and alcohol, and glycolipids, lipopeptides, lipoproteins, etc.
- TPGS D- ⁇ -Tocopherol polyethylene glycol 1000 succinate
- poly(oxyethylene)sorbitan fatty acid ester poly( It may be selected from the group consisting of oxyethylene)stearate, poly(oxyethylene)alkyl ether, polyglycolated glyceride, poly(oxyethylene)castor oil, sorbitan fatty acid ester, and mixtures thereof.
- a method for producing an inhalation formulation containing nanoparticles includes preparing an oily solution containing a biocompatible polymer containing a pharmacologically active ingredient and/or two or more types of lipids; Preparing an aqueous solution containing a surfactant; Preparing nanoparticles using the oil phase solution and the aqueous phase solution; and mixing a freeze-drying agent into the nanoparticles and freeze-drying them, wherein the nanoparticles have a diameter of 50 nm to 1,000 nm and may be a lung-targeting formulation.
- the oil phase solution is prepared by mixing biocompatible polymers and/or lipids, dissolving them, and then mixing the pharmacologically active ingredients, and the lipids may be solid lipids or liquid lipids.
- the oil phase solution and the aqueous phase solution are mixed and stirred at a speed of 5,000 rpm to 20,000 rpm using a homogenizer under temperature conditions of 70°C to 90°C. .
- the oil phase solution may dissolve a biocompatible polymer and/or two or more types of lipids in an organic solvent, and mix the pharmacologically active ingredient with the organic solvent in which the biocompatible polymers and/or lipids are dissolved.
- the solution may be injected through the dispersed phase inlet of the membrane contactor, and the aqueous solution may be injected through the continuous phase inlet of the membrane contactor.
- the injection rate of the oil phase solution injected through the dispersed phase injection port may be 0.06 L/hr to 200 L/hr, and the injection rate of the aqueous solution may be 0.06 L/hr to 1,500 L/hr.
- the present invention contains a pharmacologically active ingredient in nanoparticles, has a uniform particle size, and has excellent biocompatibility, so that the remaining time in the lung is increased and the pharmacologically active ingredient can be continuously released.
- the particle size, encapsulation ratio, and zeta potential difference are optimally controlled, resulting in uniform particle size distribution and agglomeration phenomenon between particles. can be prevented.
- Figure 1 shows the experimental design results for particle size according to excipients and surfactants when manufacturing nanoparticles through response surface design generation (Box-Behnken) design according to an embodiment of the present invention.
- Figure 2 is an experimental design result for the encapsulation ratio according to excipients and surfactants when manufacturing nanoparticles through response surface design generation (Box-Behnken) design according to an embodiment of the present invention.
- Figure 3 is an experimental design result for zeta potential difference according to excipients and surfactants when manufacturing nanoparticles through response surface design generation (Box-Behnken) design according to an embodiment of the present invention.
- Figure 4 is a photograph of analysis using a transmission electron microscope for nanoparticles according to an embodiment of the present invention.
- Figure 5 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 6 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 7 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 8 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 9 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 10 shows the MMAD measurement results of nanoparticles according to an embodiment of the present invention.
- Figure 11 shows the results of a drug dissolution test of nanoparticles according to an embodiment of the present invention.
- Figure 12 shows the results of a test to confirm the minimum inhibitory concentration of microorganisms in nanoparticles according to an embodiment of the present invention.
- Figure 13 shows the results of a single-dose survival test of nanoparticles according to an embodiment of the present invention.
- Figure 14 shows the change in concentration of pharmacologically active ingredients in plasma according to the route of administration of nanoparticles according to an embodiment of the invention.
- Figure 15 shows the change in concentration of the pharmacologically active ingredient in the tissue according to the route of administration of nanoparticles according to an embodiment of the present invention.
- Figure 16 shows the content change under long-term stability test conditions of nanoparticles according to an embodiment of the present invention.
- Figure 17 shows the change in content of nanoparticles under accelerated stability test conditions according to an embodiment of the present invention.
- the present invention is a nanoparticle containing a biocompatible polymer and/or two or more types of lipids and a surfactant, and contains a pharmacologically active ingredient inside the nanoparticle.
- the nanoparticle has a diameter of 50 nm to 1,000 nm, and targets the lungs. It relates to an inhalable formulation comprising nanoparticles as a formulation.
- Inhalation therapy is an important therapeutic method of drug delivery primarily used to treat lung diseases.
- Inhalation treatment has several advantages compared to oral treatment, namely, it can achieve the same therapeutic effect even if a smaller amount of drug is used than oral administration, and systemic side effects that may occur due to oral administration can be reduced. It has the advantage of having a faster action time than oral administration.
- the advantage and therapeutic effect of inhalation treatment is that a high concentration of drug can be administered directly locally while minimizing systemic absorption, so it can reduce various side effects caused by the administration of oral antibiotics and is better than existing oral or intravenous antibiotics. It can be used as a new additional treatment method in patients who do not listen or have difficulty using it.
- DPI immediate-release dry powder inhalation
- the present invention relates to nanoparticles containing a pharmacologically active ingredient inside, which can be used as an inhalation formulation to deliver the pharmacologically active ingredient directly to the lungs, as well as prolonging the residence of the pharmacologically active ingredient in the lungs. It relates to an inhalable formulation capable of sustained release.
- the inhalation formulation containing nanoparticles is a nanoparticle containing a biocompatible polymer and/or two or more lipids and a surfactant, and contains a pharmacologically active ingredient inside the nanoparticle.
- the nanoparticles have a diameter of 50 nm to 1,000 nm, and may be a lung-targeted inhalation formulation.
- the nanoparticle contains a biocompatible polymer and/or two or more types of lipid and a surfactant.
- the biocompatible polymer can be located inside the nanoparticle to form a core, and the lipid is a core formed of a polymer. It may be in a core-shell form by forming a shell surrounding the outside of the.
- the nanoparticles of the present invention may contain pharmacologically active ingredients in the form of liposomes composed of two types of lipids that do not contain biocompatible polymers.
- the nanoparticles of the present invention may contain a pharmacologically active ingredient in a matrix containing a biocompatible polymer and/or two or more lipids and a surfactant.
- the nanoparticles may have an average diameter of 50 nm to 1,000 nm, 100 nm to 800 nm, and 200 nm to 500 nm. As it has an average diameter within the above range, the mass median aerodynamic diameter (MMAD) may be 1 ⁇ m to 5 ⁇ m, 2 ⁇ m to 4 ⁇ m, or 2 ⁇ m to 3 ⁇ m. As the nanoparticles have a range of average diameter and mass median aerogravity diameter, they may be used as an inhalation formulation.
- MMAD mass median aerodynamic diameter
- the nanoparticles may have a zeta potential difference (mV) in the following range:
- the zeta potential difference (mV) of the nanoparticles may be -50mV to -5mV, -40mV to -10mV, and -35mV to -20mV. Alternatively, it may be 5mV to 50mV, 10mV to 40mV, or 20mV to 35mV.
- the zeta potential difference of nanoparticles can be adjusted to show a negative or positive potential, and by showing a zeta potential difference within the above range, agglomeration between nanoparticles can be prevented.
- the nanoparticles have an encapsulation ratio of the pharmacologically active ingredient of 75% or more, which means that the pharmacologically active ingredient encapsulated in the nanoparticle is 75% or more compared to the total weight of the pharmacologically active ingredient used to prepare the initial nanoparticle.
- This means that the nanoparticles are encapsulated inside the nanoparticles, and this means that the nanoparticles of the present invention and the nanoparticle production method described later can produce nanoparticles with a pharmacologically active ingredient encapsulated in high yield.
- An inhalation formulation containing the nanoparticles can continuously release bioactive ingredients for 24 hours.
- the nanoparticles of the present invention can increase the residence time in the lung and continuously release pharmacologically active ingredients, thereby solving the problem of repeated use in large numbers for inhalation treatment.
- the physiologically active ingredient may be selected from the group consisting of antibiotics, antifungal agents, and antiviral agents.
- the antibiotic may be colistin or vancomycin.
- the antifungal agent may be itraconazole, and the antiviral agent may be oseltamivir.
- the above-mentioned antibiotics, antifungal agents, or antiviral agents are not limited to these examples, and any drug that can be used as a lung-targeted inhalation formulation can be used.
- Polymyxin is an antibiotic produced by Bacillus polymyxa and was discovered in 1947. Polymyxins are antibiotic decapeptides containing a heptapeptide ring and an N-terminal amide-linked fatty acid. Today, two commercial polymyxin mixtures, polymyxin B and polymyxin E (Colistin), are used clinically.
- colistin must contain more than 77% polymyxins E1, E2, E3, E1-i and E1-7MOA, but the non-critical components polymyxins E3, E1-i and E1. -7MOA should contain less than 10% of each.
- CMS colistimethate sodium
- CMS still protects against multidrug-resistant organisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klemsiella pneumonia, and others. It is used clinically as a last-line treatment option for negative pathogens.
- Vancomycin is a glycopeptide antibiotic used for the prevention and treatment of infections caused by Gram-positive bacteria. It has been proposed that vancomycin functions to inhibit cell wall synthesis in certain Gram-positive bacteria. More specifically, vancomycin is thought to inhibit the binding of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) glycan subunits to the peptidoglycan matrix, which forms the main structural component of the Gram-positive cell wall. Binding of vancomycin to the terminal D-alanyl-D-alanine moiety of the NAM/NAG-peptide inhibits their binding to the peptidoglycan matrix.
- NAM N-acetylmuramic acid
- NAG N-acetylglucosamine
- Vancomycin is administered not only orally for the treatment of pseudomembranous colitis, but also intravenously for systemic treatment. Vancomycin is used off-label in spray aerosol form for the treatment of various infections of the upper and lower respiratory tract.
- use of drugs approved off-label may place patients at risk because safety and efficacy studies and/or appropriate dosages are not available. Additionally, delivery by nebulization can take up to 20 minutes, which is significantly burdensome for the patient.
- Itraconazole is a triazole fungicide that can be used in the treatment of fungal infections, e.g. mild infections, e.g. onychomycosis, as well as systemic fungal infections, e.g. pneumonoblastoma or extrathoracic blastoma, histoplasmosis and asteriomycosis. It is a compound.
- a solid oral dosage form of itraconazole is commercially available under the brand name SPORANOX ® . Since the bioavailability of itraconazole in the Sporanox ® formulation increases when Sporanox ® is taken on an empty stomach, Sporanox ® should be taken with food. In addition, the bioavailability of itraconazole among Sporanoks® is highly variable depending on the dose between subjects (inter-subject) and even within one subject (intra-subject).
- Oseltamivir (international generic name) or Tamiflu, the brand name, is a neuraminidase inhibitor developed by Gilead Sciences in the United States in 1996 under the leadership of Kim Jong-un, a Korean chemist, and administered in Switzerland. It is an antiviral drug against influenza virus sold globally by Hoffmann-La Roche.
- the lipids include cetyl palmitate, Precirol ATO 5, Compritol 888 ATO, trimyristin, tripalmitin, tristearin, and glyceryl monoester.
- the surfactant is selected from the group consisting of anionic surfactants, nonionic surfactants, zwitterionic surfactants, and mixtures thereof.
- the surfactant is D- ⁇ -Tocopherol polyethylene glycol 1000 succinate (TPGS), poly(oxyethylene)sorbitan fatty acid ester, poly(oxyethylene)stearate, poly( It is selected from the group consisting of oxyethylene)alkyl ethers, polyglycolated glycerides, poly(oxyethylene)castor oil, sorbitan fatty acid esters, and mixtures thereof.
- TPGS D- ⁇ -Tocopherol polyethylene glycol 1000 succinate
- poly(oxyethylene)sorbitan fatty acid ester poly(oxyethylene)stearate
- poly( It is selected from the group consisting of oxyethylene)alkyl ethers, polyglycolated glycerides, poly(oxyethylene)castor oil, sorbitan fatty acid esters, and mixtures thereof.
- poly(oxyethylene)sorbitan fatty acid ester is commercially available and is a mono-, di- or tri-ester of a fatty acid (8 to 18 carbon atoms) and sorbitan, such as POE(20) sorbitan.
- polyoxyethylene stearate refers to stearic acid and polyoxyethylene glycol esters, such as PEG 22 stearate, PEG 32 stearate and PEG 40 stearate. This compound is well known in the art and is commercially available, for example in the Myrj variety.
- poly(oxyethylene) alkyl ether refers to an ether composed of polyoxyethylene and an alkyl group, such as POE (7) alkyl ether with 12 to 14 carbon atoms, POE (9) alkyl ether with 12 to 14 carbon atoms, POE (3) Refers to alkyl ethers having 12 to 14 carbon atoms and POE(9) alkyl ethers having 12 to 14 carbon atoms, such as the Brij type.
- polyglycolated glycerides are surfactants, such as the Gelucire type, prepared by a) saponification of oil, and b) re-esterification of fatty acids with polyethylene glycol (PEG), or a mixture of poly(oxyethylene) fatty acid ester and glyceride.
- PEG polyethylene glycol
- poly(oxyethylene) castor oil refers to castor oil reacted with polyethylene glycol, such as polyoxyl 35 castor oil (Cremophor EL), PEG-30 castor oil, PEG- Refers to 40 castor oil, PEG-25 hydrogenated castor oil and PEG-40 hydrogenated castor oil (chromophore RH).
- the surfactant of the present invention is preferably D- ⁇ -Tocopherol polyethylene glycol 1000 succinate (TPGS) and polyoxyethylene stearate (Polyoxyethylene 40 stearate, PEG40-SA). .
- TPGS D- ⁇ -Tocopherol polyethylene glycol 1000 succinate
- PEG40-SA polyoxyethylene stearate
- the polyoxyethylene 40 stearate can exhibit hydrophilic characteristics and is located on the outside of the nanoparticles, thereby increasing biocompatibility and increasing the remaining time in the body.
- the surfactant of the present invention is not limited to the above examples, but can be used in the production of nanoparticles containing a pharmacologically active ingredient, increases biocompatibility, increases the remaining time in the body, and can continuously release the pharmacologically active ingredient. Anything that can exhibit sustained release can be used without limitation.
- a method for producing an inhalation formulation containing nanoparticles includes preparing an oily solution containing a biologically active ingredient; Preparing an aqueous solution containing a surfactant; Preparing nanoparticles using the oil phase solution and the aqueous phase solution; And mixing the nanoparticles with a freeze-drying agent and freeze-drying the nanoparticles, wherein the nanoparticles have a diameter of 50 nm to 1,000 nm and may be a lung-targeted inhalation formulation.
- Methods for producing inhalation formulations containing the above-described nanoparticles can be broadly divided into two types.
- the first method may be a hot melt method
- the second method may be a membrane method
- an oily solution can be prepared by mixing biocompatible polymers and/or solid lipids and liquid lipids, dissolving them, and then mixing the physiologically active ingredients.
- the biocompatible polymers include, for example, polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), and polylactic acid, which can be degraded in vivo. It may be selected from the group consisting of polycarprolactone, copolymers thereof, and combinations thereof.
- the biocompatible polymer is poly(lactic-co-glycolic acid), and is not limited to the above examples, but polymers that can form nanoparticles and sustainably release pharmacologically active ingredients are without limitation. All are available.
- the solid lipids include, for example, cetyl palmitate, Precirol ATO 5, Compritol 888 ATO, trimyristin, tripalmitin, and tristearin. , glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, shea butter, cocoa butter, stearic acid. ), palmitic acid, decanoic acid, stearyl alcohol, palmityl alcohol, and myristyl alcohol.
- the liquid lipids include, for example, Miglyol, Kernel Oil, Seed Oil, Flower Oil, Fruit Oil, Capmul MCM, Olive Oil (olive oil), eutanol G, cetiol CC, medium-chain triglyceride, squalane, coconut oil, jojoba oil, almond oil, olive oil, argan oil, bobobe oil and It may be one or more selected from the group consisting of camelina oil.
- the solid lipid may be Precirol ATO 5, and the liquid lipid may be Miglyol, but is not limited to the above example, and is a lipid that can form nanoparticles and sustainably release a pharmacologically active ingredient. can be used without any restrictions.
- an oily solution by the hot melt method biocompatible polymers and/or two or more types of lipids are mixed without using a separate organic solvent, and heat is provided in a water bath at 60°C to 90°C to form an oily solution.
- An oily solution can be prepared by mixing the pharmacologically active ingredient in the oily solution.
- the two or more lipids may be solid lipids and liquid lipids.
- the biocompatible polymer and two or more lipids included in the oil phase solution may be included in a weight ratio of 0:10 to 7:3, and the two types of lipids included in the lipid solution, Precirol ATO 5 and Mi.
- Miglyol may be included in a weight ratio of 1:1 to 15:1, and may be included in a weight ratio of 7:1 to 12:1.
- the pharmacologically active ingredient is uniformly contained therein, and the pharmacologically active ingredient can be continuously released within the lungs.
- biocompatible polymers and/or lipids and pharmacologically active ingredients contained in the oil phase solution are included in a weight ratio of 1:0.3 to 1:1, 1:0.4 to 1:0.9, and 1 It may be included in a weight ratio of :0.5 to 1:0.8. If the amount of the pharmacologically active ingredient is contained below the above range, the amount of the pharmacologically active ingredient encapsulated in the nanoparticle is small, and a large amount of nanoparticles must be used in an inhalation formulation, or the release effect of the pharmacologically active ingredient may not be observed for 24 hours. You can. In addition, if the pharmacologically active ingredient is included in excess of the above range, the encapsulation rate may be lowered and the problem of not being easily formed into nanoparticles may occur.
- the aqueous solution can be prepared by dissolving a surfactant in purified water.
- the surfactant may be D- ⁇ -Tocopherol polyethylene glycol 1000 succinate (TPGS) and polyoxyethylene stearate (Polyoxyethylene 40 stearate, PEG40-SA).
- TPGS D- ⁇ -Tocopherol polyethylene glycol 1000 succinate
- PEG40-SA polyoxyethylene stearate
- the TPGS and PEG40-SA may be included in a weight ratio of 1:1 to 2:1, 1.2:1 to 1.8:1, and 1.3:1 to 1.7:1. Within the above range, uniform nanoparticles can be formed, and nanoparticles with excellent hydrophilicity and biocompatibility that can increase residence time in the lung can be formed.
- the oil phase solution and the aqueous phase solution can be prepared and used to produce nanoparticles.
- the oil phase solution and the aqueous phase solution are mixed and homogenized by stirring at a speed of 5,000 rpm to 20,000 rpm using a homogenizer under temperature conditions of 70°C to 90°C. .
- recrystallization is performed by cooling in a cold bath at 2°C to 6°C. Thereafter, pharmacologically active ingredients not encapsulated in the nanoparticles can be removed using a molecular weight cutoff dialysis membrane.
- sugars such as D-mannitol, sucrose, and trehalose, amino acids such as arginine, and proteins such as albumin can be added as freeze-drying inhibitors and freeze-dried.
- the freeze drying is carried out firstly by changing the temperature and time conditions in the order of -40°C(6hr)/-20°C(6hr)/0°C(24hr), and then secondarily at 10°C(24hr)/20°C. Temperature and time conditions may be changed in the order of °C (2hr).
- the oil phase solution is prepared by dissolving a biocompatible polymer and/or two or more lipids in an organic solvent, and adding a physiologically active ingredient to the organic solvent in which the biocompatible polymer and/or lipids are dissolved. Can be mixed.
- the organic solvent may be selected from the group consisting of ethyl acetate, ether, n-hexane, cyclohexane, tetrahydrofuran, methylene chloride, and mixtures thereof, preferably methylene chloride, but is not limited to the above examples and is biocompatible. Any organic solvent in which the polymer and/or lipid and pharmacologically active ingredient can be completely dissolved can be used without limitation.
- the biocompatible polymer may be poly(lactic-co-glycolic acid), but is not limited to the above examples, and may form nanoparticles and continuously release pharmacologically active ingredients. All biocompatible polymers can be used without restrictions.
- the lipid may be Precirol ATO 5 and Miglyol, but is not limited to the above examples, and any lipid that can form nanoparticles and sustainably release pharmacologically active ingredients can be used without limitation. do.
- the aqueous solution can be prepared in the same manner as the hot melt method described above.
- the lipid solution is injected into the dispersed phase inlet of the membrane contactor, and the aqueous solution is injected through the continuous phase inlet of the membrane contactor to form nanoparticles.
- the injection rate of the oil phase solution injected through the dispersed phase injection port is 0.06 L/hr to 200 L/hr
- the injection rate of the aqueous solution is 0.06 L/hr to 1,500 L/hr
- the pores of the membrane contactor are 1 ⁇ m to 20 ⁇ m. It may be ⁇ m.
- Nanoparticles formed through the membrane contactor contain organic solvents on the outside and inside. To remove this, the organic solvent remaining on the outside and inside can be removed by stirring at a speed of 100 rpm to 1,000 rpm.
- pharmacologically active ingredients not encapsulated in the nanoparticles can be removed using a molecular weight cutoff dialysis membrane.
- sugars such as D-mannitol, sucrose, and trehalose, amino acids such as arginine, and proteins such as albumin can be added as freeze-drying inhibitors and freeze-dried.
- the freeze drying may be carried out in the first and second stages under the conditions described above.
- D-mannitol was added as a freeze-drying inhibitor and freeze-dried.
- freeze-drying conditions were -40°C (6hr)/-20°C(6hr)/0°C(24hr) for the first condition and 10°C(24hr)/20°C(2hr) for the second condition.
- the injection rate of the dispersed phase may be in the range of 0.06 to 200 L/hr
- the injection rate of the continuous phase may be in the range of 0.06 to 1500 L/hr
- the pores of the membrane contactor may be in the range of 1 to 20 ⁇ m.
- D-mannitol was added as a freeze-drying inhibitor and freeze-dried.
- freeze-drying conditions were -40°C (6hr)/-20°C(6hr)/0°C(24hr) for the first condition and 10°C(24hr)/20°C(2hr) for the second condition.
- nanoparticles encapsulated with pharmacologically active ingredients were analyzed using a transmission electron microscope (Field Emission Transmission Electron Microscopy, JEM-2100F, JEOL, Japan). A sample pretreated with a 1.0% (w/v) phosphotungstic acid hydrate solution was loaded onto a carbon grid and dried at room temperature for 24 hours. The particle shape of the nanoparticles prepared in Preparation Example 1 is shown in Figure 4. Same as
- Scale bar in FIG. 4 200 nm, and according to FIG. 4, it can be confirmed that uniform, spherical nanoparticles are formed.
- the particle size of nanoparticles containing pharmacologically active ingredients was analyzed using dynamic light scattering (DLS, Zetasizer, Malvern panalytical) in Stokes-Einstein Equation Mode for the speed of Brownian motion that varies depending on the particle size.
- the ⁇ -potential difference is dependent on the composition of lipid nanoparticles, and a high ⁇ -potential difference can prevent particles from agglomerating due to electrical repulsion with highly charged particles. If the ⁇ -potential difference is low, the repulsion force is overcome and the particles are more likely to aggregate, which may reduce physical stability.
- ⁇ -potential difference values within the range of -5mV to -50mV were confirmed depending on the composition of excipients and main ingredients. Nanoparticles with ⁇ -potential difference within the range of -20mV to -35mV were confirmed to have excellent dispersion and storage stability. there was.
- the nanoparticles of Preparation Examples 1 to 6 all exhibit the same negative zeta potential difference (mV), and the
- the Mass Median Aerodynamic Diameter (MMAD) of the nanoparticles was measured using a Malvern Spray Particle Size Analyzer (Malvern Panalytical, Spraytec), which can analyze the particle size of sprays and aerosols with a laser diffraction system.
- MMAD Mass Median Aerodynamic Diameter
- the sample was suspended in physiological saline and the particle size distribution of the sprayed sample was sprayed at a constant speed in the laser diffraction measurement area to analyze the size of the spray droplets.
- MMAD mass median aerogravity diameter
- Production example 1 Production example 2
- Production example 3 Production example 4
- Production example 5 Production example 6
- EE encapsulation efficiency
- HPLC conditions are as follows:
- the dilution was made with triple distilled water.
- sample solution 40 mg of sample was placed in a 20 mL volumetric flask, 10 mL of diluent was added, and the sample was completely dissolved in an 80°C water bath. Afterwards, it was sonicated for 30 minutes. After cooling this solution to room temperature, the mark was adjusted with a diluent, filtered using a 0.45 ⁇ m PVDF filter, and this solution was used as the sample solution.
- the drug encapsulation rate can be calculated using the following calculation formula.
- the dissolution rate of the pharmacologically active ingredients encapsulated in nanoparticles was analyzed using High Performance Liquid Chromatography (HPLC, Agilent).
- the dilution solution was PBS buffer 7.4.
- eluted sample 80 mg of sample was placed in a microtube, 0.4 mL of diluent was added, and the sample was evenly dispersed using a vortex.
- the elution method 100 ⁇ l of sample is placed into an insert cell with a 0.4um pore. After this, 1.5 mL of diluent was added to the outside of the insert cell. At a given time, the entire 1.5 mL of diluent from the outside of the insert cell was recovered, and then 1.5 mL of new diluent was added back to the outside of the insert cell. At this time, the recovered diluted solution was used as the test solution.
- the nanoparticles of the present invention continuously release the pharmacologically active ingredient encapsulated therein for more than 24 hours.
- MIC Minimum Inhibitory Concentration
- the Minimum Inhibitory Concentration (MIC) of an antibiotic that inhibits the growth of microorganisms was measured against Gram-negative bacteria. It was measured using Escherichia coli.
- a 96-well plate containing strains cultured at a certain concentration was treated with the same drug concentrations of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 ⁇ g/mL for the test group (Preparation Example 1) and the control group (Collins Co., Samcheongdang). did.
- the test was repeated three times, and a positive control (Growth control, Broth with bacterial inoculum, no sample) and negative control (Sterility control, broth only) were also conducted.
- the plate treated with bacteria and samples was placed in an incubator at 37°C and incubated for a certain period of time (24 hours) to confirm the concentration at which bacteria did not grow.
- a survival test was conducted using Sprague-Dawley rats at Notus, a specialized testing institute, upon single administration of nanoparticles.
- the test group composition and dose settings are shown in Table 3.
- a single dose of 300 ⁇ L/head of the test substance was administered to all test groups, and the anesthetized animal was placed in the dorsal recumbent position and administered intrabronchially using a syringe equipped with a 20-gauge catheter.
- Sprague-Dawley rats were used to analyze blood and tissue distribution following intrabronchial and intravenous administration of the test substance.
- Preparation Example 1 was used as the test drug
- Samchundang Pharmaceutical's Colis Inj. was used as the control drug.
- Test groups and doses are shown in Table 6.
- IT means intratracheal instillation
- IV means intravenous instillation.
- Test method> The method of administration is to place an animal in a compensator and then use a syringe equipped with a 26 gauge needle. After anesthetizing the animal and laying it down in the dorsal recumbent position, the trachea was checked through the oral cavity, and then administered intrabronchially using a syringe equipped with a 20 gauge catheter.
- Whole blood of 0.5 mL was collected six times through the jugular vein before (0) administration of the test substance and at 0.083, 0.5, 1.5, 4, and 24 hours after administration.
- the collected blood was placed in a 1.5 mL micro tube treated with heparin (5 IU/mL) and centrifuged at 12,000 rpm for 2 minutes at 4°C. 100 ⁇ L of separated plasma was obtained and 1.5 mL labeled with the animal number and blood collection time. It was placed in a micro tube and stored at approximately 70°C in an ultra-low temperature freezer.
- the animal For necropsy, the animal is anesthetized, and when anesthesia is confirmed, the abdominal aorta and posterior vena cava are cut and killed by exsanguination. Then, the lower body organs of all animals are opened, the organs are removed, and the extracted tissues are kept below 70°C until analysis. Store in an ultra-low temperature freezer.
- the present invention relates to inhalation formulations containing nanoparticles and methods for their preparation.
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Abstract
La présente invention concerne une formulation pour inhalation comprenant des nanoparticules et son procédé de préparation, dans laquelle des principes pharmacologiquement actifs sont inclus dans les nanoparticules, les tailles de particule sont uniformes, et la biocompatibilité est excellente de telle sorte que le temps de séjour dans les poumons est augmenté, ce qui permet d'utiliser la formulation en tant que formulation pour inhalation ciblée sur les poumons qui peut libérer en continu des principes pharmacologiquement actifs. De plus, pour former des nanoparticules, en incluant un polymère biocompatible et/ou un lipide et un tensioactif à un rapport approprié, la taille de particule, le rapport d'encapsulation et la différence de potentiel zêta sont régulés de manière optimale, de telle sorte qu'une distribution granulométrique uniforme peut être obtenue et l'agglomération entre les particules peut être évitée.
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KR1020230169962A KR20240096358A (ko) | 2022-12-19 | 2023-11-29 | 나노 입자를 포함하는 흡입 제형 및 이의 제조 방법 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5804212A (en) * | 1989-11-04 | 1998-09-08 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
KR100949539B1 (ko) * | 2000-06-27 | 2010-03-25 | 벡투라 리미티드 | 약학 조성물용 입자의 제조 방법 |
KR20140138639A (ko) * | 2012-01-19 | 2014-12-04 | 더 존스 홉킨스 유니버시티 | 점막 침투 강화를 나타내는 나노 입자 제형 |
KR20150032944A (ko) * | 2012-05-23 | 2015-03-31 | 더 오하이오 스테이트 유니버시티 | 지질 나노입자 조성물 및 이를 제조하는 방법 및 사용하는 방법 |
KR20200060424A (ko) * | 2017-09-20 | 2020-05-29 | 아토픽 메디컬, 엘엘씨. | 호흡기 질환 및 점막 염증의 치료 및 개선을 위한 조성물 및 방법 |
-
2023
- 2023-12-04 WO PCT/KR2023/019824 patent/WO2024136219A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5804212A (en) * | 1989-11-04 | 1998-09-08 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
KR100949539B1 (ko) * | 2000-06-27 | 2010-03-25 | 벡투라 리미티드 | 약학 조성물용 입자의 제조 방법 |
KR20140138639A (ko) * | 2012-01-19 | 2014-12-04 | 더 존스 홉킨스 유니버시티 | 점막 침투 강화를 나타내는 나노 입자 제형 |
KR20150032944A (ko) * | 2012-05-23 | 2015-03-31 | 더 오하이오 스테이트 유니버시티 | 지질 나노입자 조성물 및 이를 제조하는 방법 및 사용하는 방법 |
KR20200060424A (ko) * | 2017-09-20 | 2020-05-29 | 아토픽 메디컬, 엘엘씨. | 호흡기 질환 및 점막 염증의 치료 및 개선을 위한 조성물 및 방법 |
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