WO2020166820A1 - Composition pour injection sous-cutanée contenant des microparticules comprenant du finastéride - Google Patents

Composition pour injection sous-cutanée contenant des microparticules comprenant du finastéride Download PDF

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WO2020166820A1
WO2020166820A1 PCT/KR2020/000008 KR2020000008W WO2020166820A1 WO 2020166820 A1 WO2020166820 A1 WO 2020166820A1 KR 2020000008 W KR2020000008 W KR 2020000008W WO 2020166820 A1 WO2020166820 A1 WO 2020166820A1
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microparticles
finasteride
subcutaneous injection
composition
biodegradable polymer
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PCT/KR2020/000008
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English (en)
Korean (ko)
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김주희
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(주)인벤티지랩
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K9/14—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
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the present invention relates to a composition for subcutaneous injection containing microparticles containing finasteride, and more particularly, to a composition for subcutaneous injection capable of long-term sustaining the effect through finasteride through subcutaneous injection.
  • DHT dihydrotestosterone
  • 5- ⁇ -reductase inhibitors can be classified into Type 1 and Type 2.
  • Type 1 is distributed in the scalp and sebaceous glands
  • Type 2 is distributed in the scalp and prostate. Finasteride blocks only Type 2 of the 5- ⁇ -reductase inhibitor, but Dutasteride blocks both Type 1 and Type 2. It is known that dutasteride has a stronger DHT inhibitory effect than finasteride by this mechanism. However, on the basis of the first year of administration, the incidence of side effects of Dutasteride was higher, and finasteride is currently the most widely used as a hair loss treatment, and has advantages over Dutasteride in terms of safety in that it is the only approved by the FDA.
  • Hair loss treatments such as dutasteride and finasteride have been designated as contraindicated drugs for women of childbearing age or pregnant women because they are associated with male hormones, and exposing hair loss treatments to women of childbearing age or pregnant women can cause abnormalities in the external genitalia of the male fetus, giving birth to malformed babies. As there is a risk of hair loss, it should be taken with care in storage or handling. In addition, since the drug is absorbed through the skin and may affect the fetus, it should not be touched, and there existed a problem that should be handled with special care for those who live with women of childbearing age or pregnant women.
  • This use has a problem that makes it uncomfortable to use a hair loss treatment for women of childbearing age or pregnant women, when exposure is contraindicated.
  • Patent Document 1 KR 10-2016-0002411 A1
  • Another object of the present invention is that it is provided in a dosage form capable of subcutaneous injection, not an oral dosage form, so that the user does not need to store it, and through a method administered directly at a hospital, the effect of treating hair loss by finasteride can be exhibited. It is to provide a composition for subcutaneous injection excellent in ease.
  • Another object of the present invention is to provide a composition for subcutaneous injection containing sustained-release microparticles capable of maintaining a hair loss treatment effect continuously for 1 to 3 months when microparticles containing finasteride are administered.
  • Another object of the present invention is a sustained-release particle containing finasteride, while maintaining a long-term drug administration effect for a period of 1 month to 3 months, and at the same time maintaining the average diameter of the particles in a size of a constant micro size, from microparticles
  • the effective drug concentration can be kept constant, and it is applied to an injection made of particles of uniform size to reduce the feeling of foreign body and pain when administered as an injection to a patient.
  • a composition for subcutaneous injection containing microparticles comprising finasteride includes microparticles comprising finasteride and a biodegradable polymer; And a suspension solvent, wherein the microparticles have a shape in which finasteride drugs are evenly distributed in a spherical biodegradable polymer, and the microparticles have a particle diameter of 20 to 150 ⁇ m.
  • composition for subcutaneous injection may be injected subcutaneously with microparticles to continuously release finasteride for 1 to 3 months.
  • the suspending solvent may include an isotonic agent, a suspending agent, and a solvent.
  • the tonicity agent may be selected from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride, and mixtures thereof. .
  • the suspending agent is sodium carboxymethylcellulose (Soduim Carboxymethylcellulose), polysorbate 80 (Polysorbate 80), starch (starch), starch derivatives, polyhydric alcohols, chitosan (chitosan), chitosan derivatives, cellulose (cellulose), cellulose derivatives, Collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate ), dextran, dextran sulfate, polylysine, titin, fibrin, agares, fluran, xanthan gum ) And mixtures thereof.
  • Soduim Carboxymethylcellulose polysorbate 80
  • starch starch
  • starch derivatives polyhydric alcohols
  • chitosan chitosan
  • chitosan derivatives cellulose
  • Collagen gelatin
  • hyaluronic acid HA
  • alginic acid alg
  • the microparticles may contain a biodegradable polymer and finasteride in a weight ratio of 2:1 to 15:1.
  • the biodegradable polymer is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, It may be selected from the group consisting of polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and combinations thereof.
  • the biodegradable polymer is polylactide-co-glycolide (PLGA).
  • microparticles are manufactured using microchannels, and the width (w) of the cross section of the channel is in the range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles.
  • microparticles are prepared using microchannels, and the height (d) of the cross section of the channel is in the range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles.
  • the term "injection” refers to injecting a chemical solution intradermally, subcutaneously, intramuscularly, intravenous, or intraarterial using a syringe.
  • the injection may be a subcutaneous injection, but is not limited thereto because the pharmaceutical composition of the present invention exhibits an effect of preventing hair loss or promoting hair growth.
  • the syringe may be used without limitation as long as it is a syringe used to administer the composition of the present invention subcutaneously as well as a general syringe capable of administering a drug solution through a needle.
  • the subcutaneous tissue is a part between the muscle and bone under the dermis layer, and has fat cells including a large amount of fat, which gives the human body softness, gives the body a contour, and can be used as energy. It also means that the arteries and lymph fluid are circulating.
  • an isotonicity agent is a compound that is physiologically resistant and imparts appropriate tonicity to the formulation in order to prevent the net flow of water across cell membranes in contact with the formulation.
  • administration means introducing a predetermined substance into an individual by an appropriate method.
  • the composition may be administered to a subcutaneous tissue due to the nature of preventing hair loss or promoting hair growth by injection into an individual.
  • composition for subcutaneous injection containing microparticles containing finasteride includes microparticles and a suspension solvent containing finasteride and a biodegradable polymer.
  • composition for subcutaneous injection in which microparticles having a particle diameter of 20 to 150 ⁇ m are put in a suspension solvent and suspended so as to be uniformly mixed.
  • the microparticles have a shape in which finasteride drugs are evenly distributed in a spherical biodegradable polymer.
  • microparticles according to the present invention are manufactured using biodegradable polymers and finasteride, and when spherical microparticles are manufactured using biodegradable polymers, they are uniform in biodegradable polymers rather than particles containing finasteride inside. It is configured to be included, characterized in that the finasteride is uniformly distributed in the particles themselves.
  • the composition for subcutaneous injection of the present invention when the composition for subcutaneous injection of the present invention is injected into the body, the microparticles themselves are administered into the body, and as the biodegradable polymer constituting the microparticles decomposes over time, finasteride which was evenly distributed. Is released into the body.
  • the finasteride released into the body may prevent hair loss or promote hair growth.
  • finasteride is composed of a solid oral dosage form for oral administration, so the user has to take the finasteride dosage form at a certain time every day, and there is a problem in that the drug has to be stored at home to take it.
  • finasteride is associated with male hormones and is therefore designated as a contraindication to women of childbearing age or pregnant women, and exposure of hair loss treatments to women of childbearing age or pregnant women may cause abnormalities in the external genitalia of the male fetus. Therefore, there were inconveniences that should be taken with care in storage or handling of the hair loss treatment.
  • finasteride is provided in an injection formulation to solve the storage and handling problems when provided in a solid oral formulation.
  • finasteride is continuously released from the body for 1 to 3 months through a single injection administration, it is possible to improve user convenience by solving a problem that must be taken every day.
  • composition for subcutaneous injection containing microparticles containing finasteride of the present invention is that microparticles are uniformly suspended in a suspension solvent, and the microparticles are composed of a spherical biodegradable polymer, and the spherical biodegradable polymer contains finasteride. Is evenly distributed.
  • the suspending solvent includes an isotonic agent, a suspending agent, and a solvent.
  • the tonicity agent is from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride, and a mixture thereof. It may be selected, preferably D-mannitol, but is not limited to the above examples.
  • the suspending agent is sodium carboxymethylcellulose (Soduim Carboxymethylcellulose), polysorbate 80 (Polysorbate 80), starch (starch), starch derivatives, polyhydric alcohols, chitosan (chitosan), chitosan derivatives, cellulose (cellulose), cellulose derivatives, Collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate ), dextran, dextran sulfate, polylysine, titin, fibrin, agares, fluran, xanthan gum ) And a mixture thereof, and preferably sodium carboxymethylcellulose and polysorbate 80, but is not limited to the above examples.
  • the solvent may be injection water, and any solvent that can be used as injection water may be used without limitation.
  • Preparation of microparticles containing finasteride of the present invention is 1) preparing a first mixture (S100); 2) preparing a second mixture (S200); 3) Injecting the first mixture into a microchannel in a linear direction (S300); 4) injecting the second mixture into microchannels on both sides or one side (S40O); 5) collecting microparticles (S500); 6) stirring the collected microparticles (S600); And 7) washing and drying the microparticles (S700).
  • Step (S100) is a step of preparing a first mixture, a step of preparing a first mixture by dissolving a biodegradable polymer and finasteride in an organic solvent, wherein the biodegradable polymer is polylactic acid, polylactide, polylactic acid.
  • the biodegradable polymer is polylactic acid, polylactide, polylactic acid.
  • the organic solvent is not mixed with water, for example, any one or more selected from the group consisting of chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof, preferably dichloromethane, but for example It is not limited to, and is an organic solvent capable of dissolving a biodegradable polymer and finasteride, and is not limited to the above example, and any organic solvent that can be easily selected by a person skilled in the art can be used.
  • Step 1) is to prepare a first mixture in which the biodegradable polymer and finasteride are dissolved, and the solvent is an organic solvent, as described above. It is completely dissolved using an organic solvent, utilizing the dissolution properties of finasteride and biodegradable polymer. After complete dissolution, the first mixture contains the biodegradable polymer and finasteride in a weight ratio of 2:1 to 15:1.
  • the weight ratio of the biodegradable polymer and finasteride is less than 2:1, that is, when the biodegradable polymer is included in less than the above weight ratio, the weight ratio of the biodegradable polymer is small compared to the weight of finasteride, and thus spherical biodegradable polymer particles It is difficult to manufacture microparticles in a form in which finasteride is evenly distributed and contained, and when the weight ratio of the biodegradable polymer and finasteride exceeds 15:1, that is, the biodegradable polymer is included in excess of the weight ratio. In this case, the content of finasteride in the microparticles is small, and thus a problem in that a large amount of microparticles must be administered to administer a drug at a desired concentration may occur.
  • the biodegradable polymer in the first mixture contains 10 to 20% by weight, preferably 15% by weight, but is not limited to the above example.
  • Step 2) is a step of preparing a second mixture, and a second mixture is prepared by dissolving a surfactant in water.
  • the surfactant can be used without limitation as long as the biodegradable polymer solution can help form a stable emulsion.
  • Steps 3) (S300) and 4) (S400) are steps of injecting and flowing the first mixture and the second mixture into microchannels formed on the wafer.
  • ⁇ is deposited on a silicon wafer using an e-beam evaporator, and a photoresist is patterned on the aluminum using a photolithography technique. Thereafter, aluminum is etched using a photoresist as a mask, and after removing the photoresist, silicon is etched with deep ion reactive etching (DRIE) using aluminum as a mask, and after removing the aluminum, anodic bonding of glass to the wafer is used for sealing.
  • DRIE deep ion reactive etching
  • the microchannels have an average diameter of 40 to 100 ⁇ m, preferably 40 to 60 ⁇ m, more preferably 50 ⁇ m, but are not limited to examples. If the average diameter of the microchannel is 40 ⁇ m or less, there is a possibility that small microparticles with a diameter of 20 ⁇ m or less produced are likely to be produced.Therefore, the possibility of being engulfed by macrophages after injection into the human body is increased, through which effective drug release and in vivo May affect absorption. In addition, if the average diameter of the channel is 100 ⁇ m or more, there is a possibility that microparticles with a size of 150 ⁇ m or more manufactured microparticles may be produced, which may increase foreign body sensation and pain when administering injections. It is difficult to produce particles.
  • the cross-sectional width (w) and the cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the microparticles to be produced.
  • the width (w) of the microchannel cross-section is in the range of 0.7 to 1.3 with respect to the average diameter (d') of the micro-channel cross-section
  • the height (d) of the micro-channel cross-section is the average diameter (d) of the microparticles ') in the range of 0.7 to 1.3.
  • the length of the width (w) and the height (d) of the microchannel cross-section must be set to a ratio of 0.7 to 1.3 of d', It is possible to manufacture microparticles of a desired size.
  • the step 3) (S300) is to inject and flow the first mixture into the microchannel in the linear direction
  • the step 4) (S400) is to form the crossing point of the second mixture with the microchannel in the linear direction. Or, it flows by injecting it into the microchannel on one side.
  • the first mixture flows along the microchannel in a linear direction
  • the second mixture flows along the microchannel forming an intersection with the microchannel in the linear direction on both sides or one side with respect to the microchannel in the linear direction, It encounters the flow of the first mixture.
  • the first mixture when the first mixture is injected into a microchannel in a linear direction, it is injected under a constant pressure condition to flow at a constant flow rate, and the pressure condition at this time is 500 to 1500 mbar, preferably 1100 mbar, but is not limited to an example.
  • the second mixture when the second mixture is injected into the microchannels on both sides or one side, it is injected under a constant pressure condition to flow at a constant flow rate, and the pressure condition at this time is 1500 to 2500 mbar, preferably 2200 mbar, but is not limited to examples. Does not.
  • the second mixture flows under a higher pressure condition.
  • the flow rate of the first mixture and the second mixture are relatively more
  • a second mixture having a fast flow rate compresses the first mixture, and in this case, due to the repulsive force of the first mixture and the second mixture, the biodegradable polymer and finasteride in the first mixture generate spherical microparticles.
  • microparticles in a form in which finasteride is evenly distributed in a spherical biodegradable polymer are formed.
  • the step 5) is a step of collecting microparticles, and by collecting microparticles in a tank containing the second mixture, aggregation between initially generated microparticles is prevented.
  • Step 5) is to use the second mixture prepared in step 2), that is, a mixed solution of a surfactant and water, after the second mixture is prepared in step 2) (S200), some Is injected into the microchannel, and the other part is moved to the water tank in step 5) (S500), and is used to prevent agglomeration between the collected microparticles.
  • Step 6) is a step of agitating the microparticles collected in a water tank, and the microparticles are stirred at a constant temperature condition and agitation speed to evaporate and remove the organic solvent present on the surface of the microparticles.
  • the stirring conditions are the steps of first stirring at a speed of 100 to 500 rpm for 0.5 to 1.5 hours at 15 to 20 °C; And after the first stirring step, second stirring at a speed of 200 to 800 rpm for 0.5 to 1.5 hours at 20 to 30°C. And after the second stirring step, it proceeds in the order of the third stirring at a speed of 300 to 1200 rpm for 2.0 to 6.0 hours at 35 to 45 °C.
  • the stirring speed is agitation at different rates in the first and second stirring steps, and the stirring process is performed using a faster speed in the second stirring process than in the first stirring process.
  • the temperature conditions are characterized by raising the temperature in the second stirring process compared to the first stirring process and stirring.
  • the organic solvent present on the surface of the microparticles The evaporation rate can be adjusted. That is, by gradually evaporating the organic solvent present on the surface of the microparticles, microparticles having a smooth surface can be manufactured.
  • the temperature when the first mixture and the second mixture flow through the microchannel is also 15 to 20°C, preferably 17°C. That is, after flowing through the microchannel and forming the crossing point to generate microparticles, the collected microparticles are kept at a constant low temperature of 15 to 20°C until the first stirring. It is possible to manufacture and maintain spherical particles only by maintaining a low temperature during the manufacturing process of microparticles. That is, in the case of non-low temperature conditions, it is difficult to produce particles having a certain spherical shape.
  • step 7) is a step of washing and drying the microparticles.
  • the microparticles from which all the organic solvents on the surface are removed by stirring are washed several times with purified water that has been filtered to remove the surfactant remaining in the microparticles. Remove and then freeze-dry.
  • the finally produced microparticles have a form in which finasteride drugs are evenly distributed in spherical biodegradable polymer microparticles, the particle diameter of the microparticles is 20 to 150 ⁇ m, and the biodegradable polymer and finasteride are 2:1 to 15:1 Included in a weight ratio of.
  • the average diameter of the microparticles is less than 20 ⁇ m, the possibility of being predated by macrophages after injection into the human body increases, and thus, the release from the particles of the drug and absorption in the living body may be affected, and the average diameter of the particles is If it exceeds 150 ⁇ m, pain may increase when the drug is administered by using a thick gauge syringe needle to a patient receiving administration included in the injection.
  • the weight ratio of the biodegradable polymer and finasteride contained in the microparticles is the same as the weight ratio in the first mixture, which is the weight ratio in the first mixture as the microparticles are prepared and all organic solvents are evaporated and removed.
  • Microparticles containing a biodegradable polymer and finasteride can be prepared in the same ratio as.
  • composition for subcutaneous injection containing microparticles containing finasteride of the present invention it is provided in a dosage form capable of subcutaneous injection rather than an oral dosage form, so that there is no need for storage by the user, and finasteride is administered directly at a hospital. It is excellent in storage and handling as it can exhibit the effect of treating hair loss.
  • microparticles containing finasteride are administered using the composition for subcutaneous injection of the present invention, the effect of long-term drug administration can be maintained for a period of 1 to 3 months.
  • the present invention controls the release of the drug from the microparticles to maintain a constant effective drug concentration, as the diameter of the particles is manufactured to a size of a constant micro size, and is applied to an injection formulation composed of particles of a uniform size.
  • it can be provided as an injectable composition that reduces foreign body sensation and pain when administered as an injection to a patient.
  • 1 is a mechanism of action of a hair loss treatment agent.
  • Figure 2 is a flow chart for a method for producing microparticles containing finasteride of the present invention.
  • Figure 3 is a graph of the results of the drug release period according to the weight ratio of the biodegradable polymer and finasteride of the present invention.
  • FIG. 5 is a SEM photograph of microparticles according to the manufacturing method according to an embodiment of the present invention.
  • FIG. 6 is a SEM photograph of microparticles according to the manufacturing method according to an embodiment of the present invention.
  • FIG. 7 is a SEM photograph of microparticles according to the manufacturing method according to an embodiment of the present invention.
  • FIG. 8 is a diagram of the relationship between the average diameter of microparticles and the microchannel cross section.
  • the present invention is microparticles containing finasteride and a biodegradable polymer; And a suspension solvent, wherein the microparticles have a shape in which the finasteride drug is evenly distributed in a spherical biodegradable polymer, and the microparticles have a particle diameter of 20 to 150 ⁇ m, a subcutaneous note containing microparticles containing finasteride. It relates to the composition used.
  • a first mixture was prepared by dissolving polylactide-co-glycolide (PLGA) and finasteride in dichloromethane. At this time, the polylactide-co-glycolide in the first mixture is included in a ratio of 15% by weight, and the weight ratio of polylactide-co-glycolide and finasteride is 2:1.
  • Polyvinyl alcohol as a surfactant was mixed with water to prepare a second mixture containing 0.25% by weight of polyvinyl alcohol.
  • the first mixture and the second mixture were injected into microchannels formed on a silicon wafer to flow.
  • the first mixture was flowed under a pressure condition of 1,100 mbar
  • the second mixture was flowed under a pressure condition of 2,200 mbar.
  • the temperature condition was maintained at 17°C.
  • the microparticles generated at the intersection of the flow of the first mixture and the flow of the second mixture were collected in a water tank containing the second mixture.
  • the microparticles collected in the water tank were first stirred at 17° C. for 1 hour at a speed of 200 to 400 rpm, and the temperature was raised to 25° C., and then stirred for a second time at a rate of 300 to 600 rpm for 1 hour, and then at 43° C. The temperature was raised and the mixture was stirred for 4 hours at a speed of 300 to 800 rpm.
  • microparticles were washed several times with sterile filtered purified water, and freeze-dried to prepare microparticles.
  • the weight ratio of polylactide-co-glycolide and finasteride was prepared in the same manner as in Example 1, except that the weight ratio was 9:1.
  • the weight ratio of polylactide-co-glycolide and finasteride was prepared in the same manner as in Example 1, except that the weight ratio was 1:1.
  • the weight ratio of polylactide-co-glycolide and finasteride was prepared in the same manner as in Example 1, except that the weight ratio was 12:1.
  • the weight ratio of polylactide-co-glycolide and finasteride was prepared in the same manner as in Example 1, except that the weight ratio was 15:1.
  • the weight ratio of polylactide-co-glycolide and finasteride was prepared in the same manner as in Example 1, except that the weight ratio was 20:1.
  • microparticles prepared in Examples 1 to 12 were added to 2.0 ml of a suspension solvent based on 1 vial (84.0 mg), and then uniformly suspended to prepare a composition for subcutaneous injection.
  • the suspension solvent was composed of the composition shown in Table 2 below.
  • Example 1 to 6 About 100 mg of the microparticles of Examples 1 to 6 were put in a glass test container having an inner volume of 120 mL, and 100 mL of the release test solution was filled. As an accelerated experiment condition for drug release, it was placed in a water bath at 45°C, and an amplitude of 4 cm and a shaking frequency of 120 times/min were reciprocated to conduct a drug release test. When collecting a sample, shake the bottle well, mix, and take 1 mL. After centrifugation at 13,000 rpm for 3 minutes, the supernatant was taken and analyzed by high performance liquid chromatography.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6 0 0 0 0 0 0 0 0 0 0.02 32.60 27.85 35.00 16.40 15.30 5.49 0.04 38.83 30.73 40.3 18.6 17.32 6.53 0.06 44.97 39.6 47.1 20.4 20.6 7.49 0.08 42.47 23.4 50.3 21.6 21.7 8.51 0.10 46.80 28.80 50.40 22.00 21.90 8.70 0.13 50.53 32.53 53.70 24.50 23.70 9.42 0.17 47.03 33.67 65.80 22.80 22.75 10.42 0.25 62.60 29.53 70.60 25.00 24.64 12.24 0.33 50.93 29.03 76.30 21.60 25.86 12.12 0.50 35.67 17.27 65.20 20.70 26.75 13.24 1.00 23.40 12.38 51.80 18.40 23.46 11.05 7 33.27 9.13 35.70 16.70 22.45 15.64 14 20.50 25.73 25.73 14.
  • Example 3 the amount of drug release is too large at the beginning, and release is almost complete after 14 days, so that it is difficult to exhibit a long-term drug release effect.
  • Example 6 there is a problem that the initial drug release amount is too insufficient, and the therapeutic effect of the finasteride drug is insufficient.
  • Example 1 it was confirmed that the finasteride drug was continuously released for one month, and in the case of Examples 2, 4 and 5, it was confirmed that the finasteride drug was continuously released for up to 3 months.
  • Example 1 As shown in the SEM photographs of FIGS. 6 and 7, it was confirmed that the properties of the microparticles were formed evenly and no aggregation phenomenon occurred.
  • the present invention relates to a composition for subcutaneous injection containing microparticles containing finasteride, and more particularly, to a composition for subcutaneous injection capable of long-term sustaining the effect through finasteride through subcutaneous injection.

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Abstract

La présente invention concerne une composition pour injection sous-cutanée contenant des microparticules comprenant du finastéride, la composition comprenant : des microparticules comprenant du finastéride et un polymère biodégradable; et un solvant pour suspension. La composition pour injection sous-cutanée de la présente invention est fournie sous une forme injectable par voie sous-cutanée, non sous une forme d'administration par voie orale, et un utilisateur n'a donc pas besoin de ranger la composition, et un effet de traitement de perte de cheveux par finastéride peut être présenté par l'intermédiaire d'un procédé d'administration directe à l'hôpital, et ainsi la facilité de stockage et de manipulation est excellente. Lorsque des microparticules comprenant du finastéride sont administrées à l'aide de la composition pour injection sous-cutanée de la présente invention, un effet d'administration de médicament à long terme sur une période de 1 à 3 mois peut être maintenu. De plus, dans la présente invention, étant donné que le diamètre des particules représente une micro-taille uniforme, la libération d'un médicament à partir de microparticules est contrôlée, ce qui permet de maintenir constamment une concentration de médicament efficace, et la présente invention peut être fournie sous la forme d'une composition pour injection, dans laquelle, lorsqu'elle est appliquée à une injection consistant en une taille uniforme de particules et administrée sous la forme d'une injection à un patient, la sensation de matière étrangère et la douleur sont réduites.
PCT/KR2020/000008 2019-02-15 2020-01-02 Composition pour injection sous-cutanée contenant des microparticules comprenant du finastéride WO2020166820A1 (fr)

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