WO2022097920A1 - Procédé pour préparer une composition de suspension ophtalmique - Google Patents

Procédé pour préparer une composition de suspension ophtalmique Download PDF

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WO2022097920A1
WO2022097920A1 PCT/KR2021/013358 KR2021013358W WO2022097920A1 WO 2022097920 A1 WO2022097920 A1 WO 2022097920A1 KR 2021013358 W KR2021013358 W KR 2021013358W WO 2022097920 A1 WO2022097920 A1 WO 2022097920A1
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suspension composition
ophthalmic
milling
ophthalmic suspension
active ingredient
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PCT/KR2021/013358
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English (en)
Korean (ko)
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전형균
김준국
권병수
이지혜
강태호
이윤정
황진영
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삼천당제약주식회사
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Publication of WO2022097920A1 publication Critical patent/WO2022097920A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to a method for producing an ophthalmic composition, and more particularly, to a method for producing an ophthalmic composition comprising a step of grinding and dispersing a drug by milling with a bead mill.
  • the ophthalmic compositions are used to provide relief for a variety of ocular conditions and ocular disease conditions.
  • drugs of the ophthalmic composition poorly soluble drugs, specifically poorly soluble steroid-based drugs, are not readily soluble in water, and thus are provided in the form of suspensions.
  • Japanese Patent Laid-Open No. 11-279052 discloses a suspension type eye drop of fluoromethorone having excellent redispersibility and little formation of agglomerates by blending a nonionic surfactant with a cellulosic polymer. .
  • Japanese Patent Laid-Open No. 11-279052 discloses a suspension type eye drop of fluoromethorone having excellent redispersibility and little formation of agglomerates by blending a nonionic surfactant with a cellulosic polymer.
  • 11-029463 discloses dispersed particles of fluoromethorone, a poorly soluble drug, containing a water-soluble cellulose derivative within a concentration range from a concentration at which the surface tension of the liquid agent begins to decrease to a concentration at which the decrease in surface tension stops.
  • the drug in the suspension type eye drop may adhere to the inner surface of the container according to a change in the storage state (storage posture, storage temperature, etc.).
  • the drug in the suspended eye drops settling by stationary storage is exposed to the voids of the container according to a change in the storage posture such as lateral inversion of the container, and is dried to adhere to the inner surface of the container.
  • drug adhesion may occur not only in the void portion of the container but also in the liquid contact portion of the container.
  • a long period of shaking is required to uniformly disperse the drug.
  • the present invention provides a method for preparing an ophthalmic suspension composition comprising a process step of milling an ophthalmic active ingredient with a bead mill.
  • the present invention provides an ophthalmic suspension composition prepared according to the method for preparing the ophthalmic suspension composition.
  • the present invention provides an ophthalmic suspension composition comprising an ophthalmic active ingredient having a D 90 of 1.5 ⁇ m or less.
  • the inventors of the present invention in the preparation of an ophthalmic suspension composition containing a poorly soluble drug, improve the dispersion properties and stability of the drug, and have an optimal particle size distribution with high bioavailability of the drug using a bead milling process. was pulverized and dispersed, and by milling with the bead milling process, the production efficiency of the composition was improved to complete the present invention.
  • a method for preparing an ophthalmic suspension composition comprising the step of milling an ophthalmic active ingredient with a bead mill.
  • the suspension composition prepared according to the preparation method of the present invention may have a D 90 of 1.5 ⁇ m or less, a D 50 of 0.5 ⁇ m or less, and a D 10 of 0.2 ⁇ m or less.
  • D 90 of the ophthalmic active ingredient may be 1.5 ⁇ m or less. Specifically, D 90 may be 1.5 ⁇ m or less, 1.4 ⁇ m or less, 1.3 ⁇ m or less, 1.2 ⁇ m or less, or 1.1 ⁇ m or less.
  • the D 50 of the ophthalmic active ingredient may be 0.5 ⁇ m or less.
  • D 50 may be 0.50 ⁇ m or less, 0.48 ⁇ m or less, 0.46 ⁇ m or less, 0.44 ⁇ m or less, or 0.42 ⁇ m or less.
  • D 10 of the ophthalmic active ingredient may be 0.2 ⁇ m or less.
  • it may be 0.20 ⁇ m or less, 0.19 ⁇ m or less, or 0.18 ⁇ m or less.
  • milling according to the present invention may be referred to as bead milling or bead milling herein.
  • D 90 value of the active ingredient the higher the D 90 value of the active ingredient, the more active the aggregation between the particles and the faster the sedimentation occurs. A thick ichthyosis is formed.
  • D 90 of the active ingredient is 1.5 ⁇ m or less, preferably close to or smaller than 1.1 ⁇ m, sedimentation occurs at a constant rate without agglomeration between particles, and overall suspension is maintained and the sedimentation layer is thin.
  • an ophthalmic suspension composition may be prepared by bead milling the suspension in the form of a finished product.
  • the finished product may mean that the ophthalmic active ingredient and all excipients are included.
  • the preparation of the ophthalmic suspension composition by bead milling the suspension in the finished form may proceed as follows:
  • the excipients in step (1) include stabilizers, isotonic agents, buffers, suspending agents and preservatives, and in step (1), the slurry can be prepared using a homogenizer.
  • the excipient in step (2) is a viscosity modifier.
  • the suspension prepared in step (3) may be in the form of a finished product.
  • the bead milling in step (4) may be performed in the range of 10 to 30 °C, which can maintain the temperature of the part in which milling is performed using cooling water.
  • a final suspension composition in which the active ingredient has a D 90 of 1.5 ⁇ m or less as particles can be prepared.
  • the slurry may be bead milled to prepare an ophthalmic suspension composition.
  • the slurry contains only a portion of the active ingredient and added excipients, and bead milling the slurry to prepare an ophthalmic suspension composition may proceed as follows:
  • the excipient in step (1) includes a suspending agent and a preservative, and the slurry in step (1) may be prepared using a homogenizer.
  • the bead milling in step (2) may be performed in a temperature range of 10 to 30° C., which may maintain the temperature of the part in which milling is performed using cooling water.
  • a slurry containing the active ingredient present as particles having a D 90 of 1.5 ⁇ m or less can be prepared.
  • the excipient of step (3) may include a viscosity modifier, a stabilizer, an isotonic agent, and a buffer.
  • bead milling the slurry lowers the milling time by 1/4 than that of bead milling the finished product, thereby reducing the processing time in a large-capacity batch of 150 to 300 L to efficiently increase the particle size of the active ingredient. has the advantage of being lowered.
  • dispersion stability was excellent at a similar level to that obtained by bead milling the slurry and bead milling the finished product.
  • the bead mill refers to a facility that uses beads as a grinding medium, and disperses product particles in various fields such as nano-particle materials, colored paints, special chemicals, cosmetics, food and drug materials, and pharmaceutical materials.
  • the vertical type has the advantage of occupying less space than the horizontal type, but the device's uneven wear and bead filling amount is lower than that of the horizontal type.
  • the horizontal type has the advantage of easy maintenance because the amount of bead filling is 80 to 90% of the device, and the uneven wear of the device is small.
  • bead milling was performed using MiniCer manufactured by Netzsch, and the type of bead mill device (or bead mill) for performing bead milling is not particularly limited, and a commercially available bead mill can be used. there is.
  • the bead mill is zirconium oxide, yttrium stabilized zirconium (yttrium stabilized zirconia), magnesia stabilized zirconium oxide (magnesia stabilized zirconia), cerium stabilized zirconium oxide (Cerium stabilized zirconia), zirconium silicate (zirconium silicate) and zirconia stabilized aluminum oxide (zirconia stabilized alumina), aluminum oxide-zirconia composite, etc.
  • zirconium oxide stabilized with yttrium (yttrium stabilized zirconia) may be used, but the scope of the present invention is not limited thereto.
  • zirconium oxide or aluminum oxide is generally used, but zirconium oxide has superior abrasion resistance compared to aluminum oxide, so it is possible to minimize contamination caused by wear of beads as well as impurities caused by impurities such as iron oxide, silica, and manganese oxide.
  • the advantage is that there is less possibility of contamination. Therefore, it is preferable to use a bead of zirconium oxide.
  • the average diameter of the beads which is the grinding medium of the bead mill of the present invention, may be about 0.03 mm or more to less than 0.5 mm, preferably about 0.1 to 0.4 mm, and more preferably 0.2 to 0.3 mm.
  • the degree of contamination due to wear of the beads can be minimized.
  • the bead wears out despite the hard material of the bead.
  • the size of the bead and the number of revolutions per minute (milling strength) of the bead mill directly affect the wear of the bead, if the size of the bead is large, wear is more likely to occur, which may cause contamination of the product during milling.
  • the volume of beads contained in the bead mill may be about 70 to 90% by volume based on the volume of the bead mill container.
  • the bead mill container may mean a space in which bead milling is performed.
  • bead milling of the present invention may be performed at a rotor speed of about 2 to 10 m/s, preferably about 4 to 8 m/s, more preferably about 4 m/s. speed, but the scope of the present invention is not limited thereto.
  • the bead milling of the present invention may proceed so that the total passage is about 30 to 200 times, preferably about 40 to 150 times, more preferably about 50 to 80 times, and even more preferably about 60 times. It may proceed to enter the to 70 times, but the scope of the present invention is not limited thereto, and the passage may vary depending on the rotor speed or the bead size.
  • the passages are about 25 to 150 times, about 4 m/s.
  • the milling can be performed so that the passage enters about 50 to 80 times.
  • milling when milling is performed with a bead size of 0.2 mm (or average bead diameter) while performing milling at a rotor speed of 4 m/s, milling may be performed so that the passage enters about 60 times.
  • milling with a bead size of 0.5 mm milling can be performed so that the passage enters about 150 times, so it takes more time for milling.
  • milling with a bead size of 1.0 mm it takes about 600 times. It is difficult to reach the target particle size distribution even if milling is carried out so that
  • the ophthalmic active ingredient may include an ophthalmic active pharmaceutical ingredient (“API: active pharmaceutical ingredient”), and the ophthalmic active ingredient may be a sparingly soluble steroid-based compound or a sparingly-soluble non-steroidal compound.
  • API active pharmaceutical ingredient
  • the sparingly soluble steroidal compound is known in the art as a glucocorticosteroid or corticosteroid, and the sparingly soluble nonsteroidal compound may include a nonsteroidal anti-inflammatory drug (“NSAID”).
  • NSAID nonsteroidal anti-inflammatory drug
  • the ophthalmic active ingredient is fluorometholone, prednisolone acetate, nepafenac, brinzolamide, loteprednol etabonate. ), and difluprednate, and the like, and pharmaceutically acceptable salts thereof may be used.
  • the ophthalmic active ingredient may be preferably fluorometholone or a pharmaceutically acceptable salt thereof, but the scope of the present invention is not limited thereto.
  • the fluorometholone or a pharmaceutically acceptable salt thereof may be used as a therapeutic agent for inflammatory diseases of the external and anterior segments, such as blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, LTDis, ulceris, uveitis, post-operative inflammation, etc.
  • inflammatory diseases of the external and anterior segments such as blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, LTDis, uveitis, post-operative inflammation, etc.
  • the active ingredient may contain the active ingredient in an amount of about 0.05 to 2% by weight, preferably about 0.05 to 1% by weight, more preferably about 0.05 to 0.2% by weight with respect to the entire composition, , most preferably in an amount of about 0.1% by weight.
  • an excipient refers to a compositionally inactive substance formulated in combination with a pharmacologically active ingredient of an ophthalmic suspension composition and serves to improve delivery efficiency and effect of the composition, and a viscosity modifier, stabilizer , isotonic agents, buffers, suspending agents and preservatives, and the like.
  • the stabilizer serves to stabilize the ophthalmic suspension composition.
  • the stabilizer is sodium edetate, sodium perborate, ascorbic acid, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene or their It may be a hydrate or the like, preferably sodium edetate or a hydrate thereof.
  • the ophthalmic suspension composition of the present invention may include an isotonic agent, and the isotonic agent serves to adjust the isotonicity of the physiological electrolyte of the ophthalmic therapeutic agent.
  • the isotonic agent sodium chloride, potassium chloride, calcium chloride, glycerin, mannitol, etc. may be used, and sodium chloride is preferably used among them.
  • the composition of the present invention may include a buffer, which is necessary to adjust the acidity or alkalinity of the composition, and in order for the ophthalmic suspension composition to be accepted by the eye without causing irritation, a pH similar to or similar to tears in mammals It is important to be isotonic with Therefore, the suspension composition of the present invention may be used by mixing a buffer to maintain the pH in a predetermined range.
  • the buffer may be a phosphate buffer, a phosphate citrate buffer, a lactate buffer, a borate buffer, a borate citrate buffer, aminocaproic acid, an acetate buffer, etc., preferably a phosphate buffer, more preferably sodium dihydrogen phosphate. hydrate and anhydrous sodium hydrogen phosphate.
  • the suspending agent (also referred to as a surfactant) is glycerol ester, glycol ester, polyethylene glycol, polyethylene glycol (15)-hydroxystearate, polyoxyethylene-polyoxypropylene block copolymer Coalesced, polyoxyethylene 40 stearate (POE40 stearate), polysorbate 20, polysorbate 80 or polyoxyethylene (80) sorbitan monooleate, sorbitan monostearate, polyoxyethyleneglycerol trilish It may be nolate 35, polysorbate, sorbitan, polyoxyethylene, glycerol triricinolate 35, cyclodextrin, hydroxypropyl cyclodextrin, etc., and polysorbate 20 and polysorbate 80 are preferably used. and, more preferably, polysorbate 80 may be used.
  • the ophthalmic suspension composition of the present invention may contain a preservative to prevent microbial contamination and the like.
  • the preservative includes a cationic preservative including benzalkonium chloride; quaternary ammonium compounds including polyquaternium-1 and the like; guanidine-based preservatives including polyhexanide (PHMB) and chlorhexidine; chlorobutanol; mercury preservatives including thimerosal, phenylmercury acetate, phenylmercury nitrate, and the like; oxidative preservatives including stable oxychloro complexes such as PURITE; and the like may be used, preferably a cationic preservative, more preferably benzalkonium chloride.
  • the viscosity-increasing agent controls the viscosity of the ophthalmic suspension composition, and serves to temporarily relieve symptoms and conditions of dry holding when administered to the eye, polyvinyl alcohol, polyvinylpyrrolidone ( povidone), hyaluronic acid, sodium hyaluronate, gelatin, colddroitin sulfate, polysaccharide (TSP, TS polysaccharide), carbomer (Polyacrylic acid), methylcellulose, ethylcellulose, methylhydroxyethylcellulose, hydroxyethyl Cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (Hypromellose, HPMC), polyethylene glycol, polyethylene glycol 400 (PEG 400), sodium carboxymethylcellulose (CMC), floxamer, hydroxypropyl guar (HP Guar), guar It may be gum (Guar Gum), xanthan gum (Xanthan Gum), gum arabic (Arabic Gum), etc
  • the pH of the ophthalmic suspension composition of the present invention may be about 4 to 8, preferably about 5 to 8, more preferably about 6.2 to 7.5, but in the range generally used for ophthalmic suspension compositions If the pH is, the scope of the present invention is not particularly limited.
  • an ophthalmic suspension composition prepared according to the method for preparing the ophthalmic suspension composition.
  • an ophthalmic suspension composition comprising an ophthalmic active ingredient having a D 90 of about 1.5 ⁇ m or less.
  • the ophthalmic suspension composition may include excipients such as stabilizers, isotonic agents, buffers, suspending agents, preservatives, and viscosity modifiers, and the description of the excipients is as described above.
  • the ophthalmic suspension composition comprises about 0.05 to 2% by weight of an ophthalmic active ingredient, 0.5 to 2.0% by weight of a stabilizer, 0.1 to 0.5% by weight of an isotonic agent, 4.0 to 6.0% by weight of a buffer, 0.1 to 0.1% by weight of a suspending agent 0.5% by weight, 0.01 to 0.2% by weight of a preservative, 10 to 20% by weight of a viscosity modifier, and the remaining amount of water.
  • the ophthalmic suspension composition comprises 0.05 to 0.2 wt% of fluorometholone, 0.5 to 2.0 wt% of sodium edetate or a hydrate thereof, 0.1 to 0.5 wt% of sodium chloride, sodium dihydrogen phosphate hydrate and 4.0 to anhydrous sodium hydrogenphosphate 6.0% by weight, polysorbate 80 0.1 to 0.5% by weight, benzalkonium chloride 0.01 to 0.2% by weight, polyvinyl alcohol 10 to 20% by weight, and the balance of water,
  • the ophthalmic suspension composition comprises 0.1 wt% of fluorometholone, 1.0 to 1.5 wt% of sodium edetate or a hydrate thereof, 0.2 to 0.4 wt% of sodium chloride, 4.0 to 5.0 wt% of sodium dihydrogen phosphate hydrate, phosphoric anhydride 0.4 to 0.8 wt% of sodium hydrogen, 0.2 to 0.4 wt% of polysorbate 80, 0.01 to 0.1 wt% of benzalkonium chloride, 12 to 15 wt% of polyvinyl alcohol, and the balance of water.
  • a method for inhibiting inflammation by administering the ophthalmic suspension composition to a subject.
  • the "individual” may refer to all animals, including humans, having an ophthalmic inflammatory disease.
  • the animal may be a mammal, such as a cow, a horse, a sheep, a pig, a goat, a camel, an antelope, a dog, or a cat, in need of treatment for symptoms similar to those of a human as well as humans, but is not limited thereto.
  • the "administration” means introducing the ophthalmic suspension composition of the present invention to an individual by any suitable method, and the administration route of the present invention is to be administered locally to the eye due to the nature of the composition as an eye drop.
  • the method of inhibiting inflammation of the present invention comprises administering the ophthalmic suspension composition of the present invention in a therapeutically effective amount.
  • the composition of the present invention can be administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's health condition, disease type, severity,
  • the activity of the drug, the sensitivity to the drug, the administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well known in the medical field may be determined according to factors. Specifically, according to the judgment of the doctor or pharmacist, it may be administered in divided doses from once to several times a day at regular time intervals, and 0.01 ml to 0.1 ml may be administered per one administration, but is not limited thereto.
  • the ophthalmic suspension composition according to the present invention may be provided by filling in a sterile container, and may be provided including instructions on its use, wherein the instructions include a container filled with the eye drop or a second container packaged with the container. It may be physically attached to the container or packaged together inside a second container.
  • the suspension composition prepared according to the preparation method of the present invention mills and disperses the drug using a bead mill during the manufacturing process, so that the drug is pulverized to an optimal particle size that has high dispersion stability, does not stick to the container, and does not cause agglomeration during sedimentation and it can minimize contamination due to wear of grinding media (beads) during milling.
  • suspension composition prepared according to the preparation method of the present invention when applied to the eye, there is no blurred vision, foreign body feeling and discomfort, and it is excellent in that the bioavailability of the drug is high.
  • 1 is a view showing the particle size distribution of the active ingredient according to the milling method.
  • Figure 2 shows the results of the analysis of Turbiscan of the suspension not subjected to the milling process.
  • Example 5 shows the results of Turbiscan analysis of the suspension composition prepared according to Example 1-2 milled by bead milling.
  • FIG. 8 is a view showing the particle size distribution of the slurry bead milled with beads having a size of 1.0 mm.
  • FIG. 9 is a view showing the particle size distribution of the slurry bead milled with 0.5 mm size beads.
  • FIG. 10 is a view showing the particle size distribution of the slurry bead milled with beads having a size of 0.2 mm.
  • 11 is a view showing the particle size distribution according to the bead size under the same passage conditions.
  • the ophthalmic suspension composition of the present invention comprises or consists of the following ingredients:
  • Active ingredient Fluorometholone 0.1 excipient stabilizer Sodium Edetate Hydrate 1.0 ⁇ 1.5 isotonic agent sodium chloride 0.2 ⁇ 0.4 buffer Sodium dihydrogen phosphate hydrate, anhydrous sodium hydrogen phosphate 4.0 ⁇ 5.0 0.4 ⁇ 0.8 suspending agent Polysorbate 80 0.2 ⁇ 0.4 preservative benzalkonium chloride 0.01 ⁇ 0.1 viscosity modifier polyvinyl alcohol 12-15 menstruum water remaining amount
  • Example 1-1 Preparation of ophthalmic suspension composition by bead milling the finished product
  • a solution was prepared by adding a viscosity modifier to 70% of the total volume of water and stirring at a temperature of 80° C. for about 2 hours.
  • stabilizers, isotonic agents, buffers, suspending agents and preservatives were added to about 10 to 20% of the total volume of water and completely dissolved, and then fluorometholone, an active ingredient, was added and dispersed by stirring at a high speed.
  • the suspension was milled using a bead mill equipment under the following conditions to prepare a final suspension composition in which the active ingredient, fluorometholone, was present as particles having a D 90 ⁇ 1.5 ⁇ m.
  • Example 1-2 Preparation of Ophthalmic Suspension Composition by Bead Milling Slurry
  • fluorometholone an active ingredient
  • wetting of the fluorometholone particles was performed for about 1 to 2 hours using a homogenizer to prepare a slurry and high-temperature sterilization was performed.
  • the high temperature sterilized slurry was milled using a bead mill equipment under the following conditions.
  • a mixed solution was prepared by adding a solution prepared by adding a viscosity modifier to 50 to 70% of the total volume of water in the milled slurry and stirring at a temperature of 80° C. for about 2 hours.
  • a final suspension composition was prepared in which the active ingredient, fluorometholone, was present as particles having a D 90 ⁇ 1.5 ⁇ m by adding a stabilizer, a tonicity agent, and a buffer to the prepared mixture, followed by complete dissolution, followed by sterilization filtration.
  • the content of each component included in the final suspension composition is the same as in Preparation Example.
  • the particle distribution of fluorometholone contained in the suspension composition prepared according to Example 1-2 was compared with the particle distribution of fluorometholone contained in the suspension composition prepared using a conventional high pressure homogenizer (HPH). analysis, and the results are shown in Table 2 and FIG. 1 below.
  • HPH high pressure homogenizer
  • the suspension composition prepared by the preparation method of the present invention including the bead milling process has a D 90 of fluorometholone of 0.998 ⁇ m, and the fluorometholone of the composition prepared by the conventional HPH process.
  • the suspension composition prepared according to Examples 1-1 and 1-2 including the bead milling process of the present invention With respect to the suspension composition prepared according to Examples 1-1 and 1-2 including the bead milling process of the present invention, the suspension composition prepared using the conventional HPH, and the suspension stock solution without the process of controlling the particle size The dispersion characteristics and stability were comparatively analyzed by performing Terviscan analysis, and the sedimentation pattern was visually confirmed. The results for this are shown in FIGS. 2 to 6 .
  • the particle size distribution (D 90 ) was smaller than 5 ⁇ m, so the sedimentation rate was slow compared to the suspension stock solution, but between the particles as in the suspension stock solution. It was found that agglomeration occurred continuously and sedimentation proceeded.
  • the particle size (D 90 ) of the active ingredient contained in the suspension composition prepared according to Example 1-1 of the present invention is about 1 ⁇ m. It was found that sedimentation proceeds slowly due to small agglomeration and less agglomeration between particles. As can be seen in FIG. 6 , after 1 day, the suspension composition prepared according to the preparation method of the present invention maintained overall suspendability and it was found that a thin sedimentation layer was formed at the lower end (0.2 mm).
  • Example 1-2 of the present invention showed similar results to the suspension composition prepared according to Example 1-1. Accordingly, it was confirmed that the suspension composition could be prepared by bead milling the slurry form as the concentration of the suspension did not appear to have a significant effect on the dispersion stability.
  • Example 1-2 In order to analyze the particle distribution according to the number of passages when performing bead milling, instead of performing milling in the same manner as in Example 1-2, the particle distribution according to the milling passage was analyzed while the number of passages was varied from 10 to 60, and the The result is shown in FIG. 7 .
  • the particle size is lowered to the level of the raw material (API) compared to the suspension undiluted solution (Initial), but it does not decrease below that level.
  • the average bead diameter (bead size) is 1.0 mm, 0.5 mm and 0.2 mm, respectively, to prepare a suspension composition by performing bead milling to analyze the particle size distribution, and the results are shown in Tables 3 to 5 and FIGS. 8 to 10 below.
  • passage 100 passage 150 passage D 10 ( ⁇ m) 0.248 0.195 0.163 D 50 ( ⁇ m) 0.746 0.476 0.376 D 90 ( ⁇ m) 2.47 1.71 1.18 SPAN 2.980 3.180 2.698 Bead size: 0.5 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 250 mL
  • the particle size distribution was analyzed by preparing a suspension composition by performing bead milling using each of 1.0 mm, 0.5 mm and 0.2 mm beads under the same conditions of 50 to 60 passages, and the results are shown in FIG. 11 below.
  • Zr when milling was performed using beads having a size of 0.2 mm, Zr was detected to be about 0.05 ppm or less, whereas when milling was performed using beads having a size of 0.5 mm, Zr was 0.6 ppm or more, about 10 times or more. appeared to be high.

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Abstract

La présente invention concerne un procédé pour préparer une composition de suspension ophtalmique comprenant une étape pour broyer un principe actif ophtalmique à l'aide d'un broyeur à billes. Selon la présente invention, en broyant et en dispersant un médicament à l'aide d'un broyeur à billes, le médicament peut être broyé à une taille de particule optimale qui présente une stabilité de dispersion élevée, n'adhère pas à un récipient, et ne provoque pas d'agglomération pendant la sédimentation, et la contamination due à l'abrasion des corps broyants (billes) pendant le broyage peut être réduite au minimum. De plus, lorsque la composition de suspension préparée selon le procédé de préparation de la présente invention est appliquée à l'œil, il n'y a pas de vision floue, de sensation d'irritation ou de gêne, et la composition de suspension est excellente dans la mesure où la biodisponibilité du médicament est élevée. En outre, la simplification du processus a pour effet d'améliorer la productivité de la préparation de composition de suspension.
PCT/KR2021/013358 2020-11-04 2021-09-29 Procédé pour préparer une composition de suspension ophtalmique WO2022097920A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1129463A (ja) * 1997-05-14 1999-02-02 Senju Pharmaceut Co Ltd 再分散性の良い水性懸濁液剤
KR100786927B1 (ko) * 2000-06-28 2007-12-17 스미스클라인비이참피이엘시이 습식 분쇄방법
JP2013512894A (ja) * 2009-12-03 2013-04-18 ルピン・リミテッド 眼科用医薬組成物の調製方法
KR20150139501A (ko) * 2013-03-15 2015-12-11 이노텍 파마슈티컬스 코포레이션 안과용 제형
KR20170105610A (ko) * 2015-01-26 2017-09-19 보오슈 앤드 롬 인코포레이팃드 안과용 현탁액 조성물

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3418751B2 (ja) 1998-01-22 2003-06-23 参天製薬株式会社 フルオロメトロン懸濁型点眼剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1129463A (ja) * 1997-05-14 1999-02-02 Senju Pharmaceut Co Ltd 再分散性の良い水性懸濁液剤
KR100786927B1 (ko) * 2000-06-28 2007-12-17 스미스클라인비이참피이엘시이 습식 분쇄방법
JP2013512894A (ja) * 2009-12-03 2013-04-18 ルピン・リミテッド 眼科用医薬組成物の調製方法
KR20150139501A (ko) * 2013-03-15 2015-12-11 이노텍 파마슈티컬스 코포레이션 안과용 제형
KR20170105610A (ko) * 2015-01-26 2017-09-19 보오슈 앤드 롬 인코포레이팃드 안과용 현탁액 조성물

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