WO2022097920A1 - Method for preparing ophthalmic suspension composition - Google Patents

Method for preparing ophthalmic suspension composition Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
suspension composition
ophthalmic
milling
ophthalmic suspension
active ingredient
Prior art date
Application number
PCT/KR2021/013358
Other languages
French (fr)
Korean (ko)
Inventor
전형균
김준국
권병수
이지혜
강태호
이윤정
황진영
Original Assignee
삼천당제약주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 삼천당제약주식회사 filed Critical 삼천당제약주식회사
Publication of WO2022097920A1 publication Critical patent/WO2022097920A1/en

Links

Images

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a method for preparing an ophthalmic suspension composition comprising a step for milling an ophthalmic active ingredient using a bead mill. According to the present invention, by milling and dispersing a drug using a bead mill, the drug can be ground to an optimal particle size that has high dispersion stability, does not adhere to a container, and does not cause agglomeration during sedimentation, and contamination due to abrasion of grinding media (beads) during milling can be minimized. In addition, when the suspension composition prepared according to the preparation method of the present invention is applied to the eye, there is no blurred vision, feeling of irritation, or discomfort, and the suspension composition is excellent in that bioavailability of the drug is high. In addition, by simplifying the process, there is an effect of improving the productivity of suspension composition preparation.

Description

안과용 현탁액 조성물의 제조방법Method for preparing an ophthalmic suspension composition
본 발명은 안과용 조성물의 제조방법에 관한 것으로, 상세하게는 비드밀로 밀링하여 약물을 분쇄 및 분산시키는 공정을 포함하는 안과용 조성물의 제조방법에 관한 것이다.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.
안과용 조성물은 다양한 안구 상태 및 안구 질환 상태의 완화를 제공하는데 사용된다. 안과용 조성물의 약물로서 난용성 약물, 구체적으로는 난용성 스테로이드 계열 약물은 물에 잘 용해되지 않기 때문에 현탁 액제의 형태로 제공되고 있다.The ophthalmic compositions are used to provide relief for a variety of ocular conditions and ocular disease conditions. As 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.
현탁 액제는, 약물이 용해되지 않기 때문에, 사용시에 점안 용기를 흔들어 침강·응집되어 있는 약물을 균일하게 재분산시켜 이용할 필요가 있고, 난용성 약물의 현탁형 점안제에 있어서도 마찬가지인 바, 약물의 재분산성을 향상시키기 위해서 여러 가지 고안이 이루어져 왔다. 예컨대, 일본 특허 공개 평성 제11-279052호 공보에서, 비이온성 계면활성제와 셀룰로오스계 고분자를 배합함으로써, 재분산성이 우수하고, 또한, 응집덩어리 형성이 거의 없는 플루오로메토론 현탁형 점안제가 기재되어 있다. 또한, 일본 특허 공개 평성 제11-029463호 공보에는 액제의 표면 장력이 저하되기 시작하는 농도로부터 표면 장력의 저하가 정지하는 농도 범위 내의 수용성 셀룰로오스 유도체를 함유하는, 난용성 약물인 플루오로메토론 분산 입자의 재분산성을 개선한 수성 현탁 액제가 기재되어 있다.Since the drug does not dissolve in the suspension, it is necessary to uniformly redisperse the sedimented and aggregated drug by shaking the eye drop container during use, and the same is true for the suspension type eye drop of poorly soluble drugs. The redispersibility of the drug Several devises have been made to improve the For example, 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. . In addition, Japanese Patent Laid-Open No. 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. An aqueous suspension formulation with improved redispersibility of
한편, 난용성 약물의 현탁형 점안제에서는, 보존 상태(보존 자세나 보존 온도 등)의 변화에 따라 현탁형 점안제 중의 약물이 용기 내면에 고착되는 경우가 있다. 용기에 약물이 고착되는 일례로서, 정치 보존으로 침강된 현탁형 점안제 중의 약물이, 용기의 횡전(橫轉)과 같은 보존 자세의 변화에 따라 용기의 공극에 노출되고, 건조됨으로써 용기 내면에 고착되는 것을 생각할 수 있다. 이러한 약물의 용기에의 고착은 용기가 정립한 채로의 상태라면 일어나기 어렵지만, 유통 과정 및 사용시의 상황을 고려하면, 약물의 용기에의 고착은 일어날 수 있다고 생각된다. 또한, 용기의 보존 상태에 따라서는, 용기의 공극부 뿐만 아니라, 용기의 액 접촉부에도 약물의 고착이 일어나는 경우도 있다. 이와 같이 약물이 용기에 고착되면, 약물을 균일하게 분산시키는 데 장시간의 진탕이 필요하게 된다.On the other hand, in a suspension type eye drop of a poorly soluble drug, 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.). As an example of drug adhering to the container, 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. can think of Although such adhesion of the drug to the container is unlikely to occur when the container is in an upright state, it is considered that the adhesion of the drug to the container may occur in consideration of the distribution process and the situation at the time of use. In addition, depending on the storage state 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. When the drug is adhered to the container in this way, a long period of shaking is required to uniformly disperse the drug.
이러한 배경 하에서, 최근 약물을 다양한 밀링 방법으로 미분쇄화하여 난용성 약물이 갖는 문제점을 해결하려는 노력이 나타나고 있으나, 분쇄 시 생길 수 있는 오염과 복잡한 공정과정에 따른 비용 및 시간이 많이 소요되어 생산성 및 안정성이 낮은 문제점이 존재하고 있다.Under this background, recent efforts have been made to solve the problems of poorly soluble drugs by pulverizing drugs by various milling methods. There is a problem of low stability.
따라서, 난용성 약물을 포함하는 현탁액 및 이의 제조 공정 중에 발생하는 문제들을 해결하면서 약물의 생체이용률이 높은 현탁액의 개발이 요구되고 있는 실정이다.Accordingly, there is a demand for the development of a suspension containing a poorly soluble drug and a suspension having a high bioavailability of the drug while solving problems occurring during the manufacturing process thereof.
본 발명은 비드밀(bead mill)로 안과용 활성성분을 밀링하는 공정 단계를 포함하는 안과용 현탁액 조성물의 제조방법을 제공한다.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.
본 발명은 상기 안과용 현탁액 조성물의 제조방법에 따라 제조된 안과용 현탁액 조성물을 제공한다.The present invention provides an ophthalmic suspension composition prepared according to the method for preparing the ophthalmic suspension composition.
본 발명의 D90이 1.5 μm 이하인 안과용 활성성분을 포함하는 안과용 현탁액 조성물을 제공한다.The present invention provides an ophthalmic suspension composition comprising an ophthalmic active ingredient having a D 90 of 1.5 μm or less.
본 발명의 발명자들은 난용성 약물을 포함하는 안과용 현탁액 조성물을 제조하는 데 있어서, 약물의 분산특성 및 안정성을 향상시키고, 약물의 생체이용률이 높은 최적의 입도 분포를 갖도록 하기 위해 비드밀링 공정으로 약물을 분쇄 및 분산시켰으며, 상기 비드밀링 공정으로 밀링함으로써 조성물의 생산 효율을 향상시켜 본 발명을 완성시켰다.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.
본 출원에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로서 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 출원에서, “포함하다” 또는 “가지다” 등의 용어는 명에서 상에 기재된 특징, 단계, 구조 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 단계, 구조 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terminology used in the present application is only used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present application, terms such as “comprise” or “have” are intended to designate that a feature, step, structure, or a combination thereof described in the name exists, but one or more other features, steps, structure, or these It should be understood that it does not preclude the possibility of the existence or addition of combinations.
다르게 정의하지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다. Unless defined otherwise, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 측면에 있어서, 비드밀(Bead mill)로 안과용 활성성분을 밀링(milling)하는 단계를 포함하는 안과용 현탁액 조성물의 제조방법을 제공한다.In one aspect of the present invention, there is provided a method for preparing an ophthalmic suspension composition comprising the step of milling an ophthalmic active ingredient with a bead mill.
본 발명의 제조방법에 따라 제조된 현탁액 조성물은 D90이 1.5 μm 이하, D50이 0.5 μm 이하, D10이 0.2 μm 이하일 수 있다. The suspension composition prepared according to the preparation method of the present invention may have a D 90 of 1.5 μm or less, a D 50 of 0.5 μm or less, and a D 10 of 0.2 μm or less.
본 발명의 일 실시예에 있어서, 비드밀(Bead mill)로 안과용 활성성분을 밀링(milling)함에 따라, 안과용 활성성분의 D90이 1.5 μm 이하일 수 있다. 구체적으로, D90이 1.5 μm 이하, 1.4 μm 이하, 1.3 μm 이하, 1.2 μm 이하, 1.1 μm 이하일 수 있다. In one embodiment of the present invention, as the ophthalmic active ingredient is milled with a bead mill, D 90 of the ophthalmic active ingredient may be 1.5 μm or less. Specifically, D 90 may be 1.5 μm or less, 1.4 μm or less, 1.3 μm or less, 1.2 μm or less, or 1.1 μm or less.
또한, 안과용 활성성분의 D50이 0.5 μm 이하일 수 있다. In addition, the D 50 of the ophthalmic active ingredient may be 0.5 μm or less.
구체적으로, D50이 0.50 μm 이하, 0.48 μm 이하, 0.46 μm 이하, 0.44 μm 이하, 0.42 μm 이하일 수 있다. Specifically, D 50 may be 0.50 µm or less, 0.48 µm or less, 0.46 µm or less, 0.44 µm or less, or 0.42 µm or less.
또한, 안과용 활성성분의 D10이 0.2 μm 이하일 수 있다. In addition, D 10 of the ophthalmic active ingredient may be 0.2 μm or less.
구체적으로, 0.20 μm 이하, 0.19 μm 이하, 0.18 μm 이하일 수 있다.Specifically, it may be 0.20 μm or less, 0.19 μm or less, or 0.18 μm or less.
이하, 본 명세서에서 본 발명에 따른 밀링은 비드밀링 또는 비드밀이라 할 수 있다. Hereinafter, milling according to the present invention may be referred to as bead milling or bead milling herein.
일반적으로, 활성 성분으로서 난용성 화합물을 포함하는 현탁액 조성물에 있어서 활성 성분의 D90 값이 클수록 입자들 간의 응집이 활발히 일어나 침강이 빠른 속도로 일어나며, 분산도가 낮아 조성물이 전반적으로 투명하며 하단에 두꺼운 침천증이 형성된다. 이에 반해 활성 성분의 D90이 1.5 μm이하, 바람직하게는 1.1 μm에 가깝거나 더 작을수록 입자간 응집없이 일정한 속도로 침강이 일어나 전반적으로 현탁도가 유지되며 침전층은 얇게 생긴다. In general, in a suspension composition containing a sparingly soluble compound as an 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. On the other hand, as D 90 of the active ingredient is 1.5 μm or less, preferably close to or smaller than 1.1 μm, sedimentation occurs at a constant rate without agglomeration between particles, and overall suspension is maintained and the sedimentation layer is thin.
따라서, 난용성 약물을 활성 성분으로 포함하는 안과용 치료제의 제조에 있어서, 활성 성분의 입도분포(D90)가 1.5 μm에 가깝거나 더 작아지도록 구현하는 것은 중요한 요소이다.Therefore, in the manufacture of an ophthalmic therapeutic agent comprising a poorly soluble drug as an active ingredient, it is an important factor to implement such that the particle size distribution (D 90 ) of the active ingredient is close to or smaller than 1.5 μm.
본 발명의 일 실시예에 따르면, 완제 형태의 현탁액을 비드밀링하여 안과용 현탁액 조성물을 제조할 수 있다. 상기 완제 형태는 안과용 활성성분 및 모든 부형제들이 포함된 것을 의미할 수 있다. 완제 형태의 현탁액을 비드밀링하여 안과용 현탁액 조성물을 제조하는 것은 다음과 같은 단계로 진행될 수 있다:According to an embodiment of the present invention, 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:
(1) 안과용 활성성분 및 부형제를 포함하는 슬러리(Slurry)를 제조하는 단계;(1) preparing a slurry containing an ophthalmic active ingredient and an excipient;
(2) 상기 슬러리에 부형제를 추가로 첨가하여 혼합물을 제조하는 단계;(2) preparing a mixture by further adding an excipient to the slurry;
(3) 상기 혼합물을 고온 멸균 후 pH를 조절하여 현탁액을 제조하는 단계; 및(3) preparing a suspension by adjusting the pH of the mixture after high-temperature sterilization; and
(4) 상기 현탁액을 비드밀로 밀링하여 안과용 현탁액 조성물을 제조하는 단계.(4) milling the suspension with a bead mill to prepare an ophthalmic suspension composition.
상기 단계 (1) 에서의 부형제는 안정화제, 등장화제, 완충제, 현탁화제 및 보존제를 포함하는 것이며, 단계 (1) 에서 상기 슬러리는 균질기(homogenizer)를 사용하여 제조될 수 있다.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.
또한, 상기 단계 (2)에서의 부형제는 점도조절제이다.In addition, the excipient in step (2) is a viscosity modifier.
상기 단계 (3)에서 제조된 현탁액은 완제 형태일 수 있다.The suspension prepared in step (3) may be in the form of a finished product.
또한, 상기 단계 (4)에서 비드 밀링은 10 내지 30℃의 범위에서 수행될 수 있으며, 이는 밀링이 진행되는 부분의 온도를 냉각수를 이용해 유지할 수 있다. 이와 같은 제조방법을 통해 활성성분의 D90이 1.5 μm 이하인 입자로서 존재하는 최종 현탁액 조성물을 제조할 수 있다.In addition, the bead milling in step (4) may be performed in the range of 10 to 30 ℃, which can maintain the temperature of the part in which milling is performed using cooling water. Through this preparation method, a final suspension composition in which the active ingredient has a D 90 of 1.5 μm or less as particles can be prepared.
또한, 본 발명의 다른 일 실시예에 따르면, 슬러리를 비드밀링하여 안과용 현탁액 조성물을 제조할 수 있다. 상기 슬러리는 활성성분과 첨가되는 부형제들 중 일부만을 포함하는 것으로, 슬러리를 비드밀링하여 안과용 현탁액 조성물을 제조하는 것은 다음과 같은 단계로 진행될 수 있다:In addition, according to another embodiment of the present invention, 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:
(1) 안과용 활성성분 및 부형제를 포함하는 슬러리(Slurry)를 제조하는 단계;(1) preparing a slurry containing an ophthalmic active ingredient and an excipient;
(2) 상기 슬러리를 비드밀로 밀링하는 단계; (2) milling the slurry with a bead mill;
(3) 밀링된 슬러리에 부형제를 첨가하여 혼합용액을 제조하는 단계; 및(3) preparing a mixed solution by adding an excipient to the milled slurry; and
(4) 상기 혼합용액을 제균 여과하여 안과용 현탁액 조성물을 제조하는 단계.(4) preparing an ophthalmic suspension composition by sterilizing and filtering the mixed solution.
상기 단계 (1)에서의 부형제는 현탁화제 및 보존제를 포함하고, 단계 (1) 에서 상기 슬러리는 균질기(homogenizer)를 사용하여 제조될 수 있다.The excipient in step (1) includes a suspending agent and a preservative, and the slurry in step (1) may be prepared using a homogenizer.
또한, 상기 단계 (2)에서 비드 밀링은 10 내지 30℃의 온도 범위에서 수행될 수 있으며, 이는 밀링이 진행되는 부분의 온도를 냉각수를 이용해 유지할 수 있다. 상기 단계 (2)의 밀링 공정을 통해 D90이 1.5 μm 이하인 입자로서 존재하는 활성성분을 포함하는 슬러리를 제조할 수 있다.In addition, 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. Through the milling process of step (2), a slurry containing the active ingredient present as particles having a D 90 of 1.5 μm or less can be prepared.
상기, 단계 (3)의 부형제는 점도조절제, 안정화제, 등장화제 및 완충제를 포함할 수 있다.The excipient of step (3) may include a viscosity modifier, a stabilizer, an isotonic agent, and a buffer.
본 발명에 있어서, 슬러리를 비드밀링하는 것은 완제를 비드밀링하는 것 보다 밀링 시간을 1/4로 낮추어 150 내지 300 L의 대용량의 배치(Batch)에서의 공정 시간을 감소시켜 활성성분의 입도를 효율적으로 낮출 수 있는 이점이 있다. 그러나 분산 안정성은 슬러리를 비드밀링한 것과 완제를 비드밀링한 것이 유사한 수준으로 우수하였다.In the present invention, 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. However, dispersion stability was excellent at a similar level to that obtained by bead milling the slurry and bead milling the finished product.
본 발명에서 비드밀은 그라인딩 매체(grinding medium)로 비드(Bead)를 사용하는 설비를 칭하며, 나노 입자 소재, 착색 도료, 특수 화학제품, 화장품, 식약 재료, 제약 재료 등 다양한 분야의 제품 입자를 분산시켜 입자의 크기를 미세화시킬 수 있는 장치로서, 수평형 및 수직형으로 구분할 수 있다. 수직형은 수평형에 비해 공간을 적게 차지하는 장점이 있으나 기기의 편마모 및 비드의 충전량이 수평형에 비해 낮다. 이에 반해 수평형은 비드의 충전량이 80 내지 90% 정도로 기기의 편마모가 적어 유지관리가 용이한 이점이 있다. 본 발명에서 본 발명의 실시예에서는 Netzsch 사의 MiniCer을 사용하여 비드밀링을 수행하였으며, 비드밀링을 수행하기 위한 비드밀 장치(또는 비드밀기)의 종류는 특별히 제한되는 것은 아니며 시판중인 비드밀기를 사용할 수 있다.In the present invention, 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. As a device that can refine the size of particles by 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. On the other hand, 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. In the present invention, in the embodiment of the present invention, 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.
본 발명에 있어서, 비드밀은 산화 지르코늄, 이트리움으로 안정화한 산화지르코늄(yttrium stabilized zirconia), 마그네시아로 안정화한 산화지르코늄(magnesia stabilized zirconia), 세륨으로 안정화한 산화지르코늄(Cerium stabilized zirconia), 지르코늄 실리케이트(zirconium silicate) 및 지르코니아로 안정화한 산화알루미늄(zirconia stabilized alumina), 산화알루미늄-산화지르코늄 복합체(alumina-zirconia composite) 등을 사용할 수 있으며, 바람직하게는 이트리움으로 안정화한 산화지르코늄(yttrium stabilized zirconia)을 사용할 수 있으나, 본 발명의 범위가 여기에 한정되는 것은 아니다.In the present invention, 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. can be used, preferably zirconium oxide stabilized with yttrium (yttrium stabilized zirconia) may be used, but the scope of the present invention is not limited thereto.
비드밀링 공정에 있어서, 제품의 오염 가능성을 낮추기 위해 적절한 종류의 비드(bead)를 선택하는 것이 중요하다. 비드로서 산화지르코늄 또는 산화알루미늄 등을 일반적으로 사용하는데 산화지르코늄은 산화알루미늄에 비해 내마모성이 우수하여 비드의 마모로 인해 발생하는 오염을 최소화할 수 있을 뿐만 아니라, 산화철, 실리카, 산화망간 등 불순물로 인한 오염 가능성이 적은 이점이 있다. 따라서, 산화지르코늄류의 비드를 사용하는 것이 바람직하다.In the bead milling process, it is important to select an appropriate type of bead to reduce the possibility of product contamination. As beads, 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.
또한, 본 발명의 비드밀의 그라인딩 매체인 비드의 평균 직경은 약 0.03 mm 이상 내지 0.5 mm 미만일 수 있으며, 바람직하게는 약 0.1 내지 0.4 mm일 수 있고, 더욱 바람직하게는 0.2 내지 0.3 mm일 수 있다.In addition, 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.
본 발명의 일 실시예에 있어서, 비드의 평균 직경이 약 0.2 mm인 비드를 사용하여 밀링을 수행할 경우에 비드의 마모에 의한 오염도를 최소화할 수 있다.In one embodiment of the present invention, when milling is performed using beads having an average diameter of about 0.2 mm, the degree of contamination due to wear of the beads can be minimized.
일반적으로, 비드밀의 특성상 강한 힘으로 지속적인 충격이 비드와 비드밀 내부에 가해지므로, 비드의 재질이 단단함에도 불구하고 비드가 마모하게 된다. 특히, 비드의 사이즈와 비드밀의 분당 회전수(밀링 강도)가 비드의 마모에 직접적인 영향을 미치므로, 비드의 사이즈가 크면 마모가 더 잘 일어나 밀링시 제품의 오염을 일으킬 수 있다.In general, since a continuous impact is applied to the bead and the inside of the bead mill with a strong force due to the characteristics of the bead mill, the bead wears out despite the hard material of the bead. In particular, since 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.
따라서 비드밀링을 통해 목표로 하는 크기로 입자를 분쇄하면서 밀링에 의해 발생할 수 있는 오염을 최소화시키는 동시에 효율적인 생산을 위해서 적절한 크기의 비드를 선택하는 것이 중요하다.Therefore, it is important to select beads of an appropriate size for efficient production while minimizing contamination that may occur by milling while grinding particles to a target size through bead milling.
본 발명에서, 비드밀에 포함된 비드의 부피는 비드밀 용기의 부피 기준으로 약 70 내지 90 부피%일 수 있다. 상기 비드밀 용기는 비드 밀링이 수행되는 공간을 의미할 수 있다.In the present invention, 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.
또한, 본 발명의 비드밀링은 약 2 내지 10 m/s의 로터 속도(Rotor speed)로 수행될 수 있으며, 바람직하게는 약 4 내지 8 m/s, 더욱 바람직하게는 약 4 m/s의 로터 속도로 수행될 수 있으나, 본 발명의 범위가 여기에 한정되는 것은 아니다.In addition, the 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.
또한, 본 발명의 비드밀링은 총 패시지(passage)가 대략 30 내지 200 회, 바람직하게 대략 40 내지 150회, 보다 바람직하게 대략 50 내지 80회에 들어오도록 진행할 수 있으며, 보다 더 바람직하게는 대략 60 내지 70회에 들어오도록 진행할 수 있으나, 본 발명의 범위가 여기에 한정되는 것은 아니며, 로터 속도 또는 비드 사이즈에 따라 패시지(passage)가 달라질 수 있다. In addition, 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.
예를 들어, 비드 사이즈(또는 비드 평균 직경) 0.1 내지 0.4 mm의 비드를 사용하여 2 m/s 내지 8 m/g 로터 속도로 밀링을 진행할 경우, 패시지가 약 25 내지 150회, 약 4 m/s 로 밀링을 진행할 경우 패시지가 약 50 내지 80회에 들어오도록 밀링을 진행할 수 있다.For example, when milling is performed at a rotor speed of 2 m/s to 8 m/g using beads with a bead size (or average bead diameter) of 0.1 to 0.4 mm, the passages are about 25 to 150 times, about 4 m/s. When milling in s, the milling can be performed so that the passage enters about 50 to 80 times.
또한, 예를 들어, 4 m/s 로터 속도로 밀링을 수행하면서 0.2 mm 비드 사이즈(또는 비드 평균 직경)로 밀링을 진행할 경우 패시지가 약 60회에 들어오도록 밀링을 진행할 수 있다. 반면, 비드 사이즈가 0.5 mm 비드 사이즈로 밀링을 진행할 경우 패시지가 약 150 회 정도에 들어오도록 밀링을 진행할 수 있어 밀링 시간이 더 소요되며, 1.0 mm 비드 사이즈로 밀링을 진행할 경우 약 600회 정도에 들어오도록 밀링을 진행해도 타겟으로 하는 입도 분포에 도달하기 어렵다.In addition, for example, 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. On the other hand, when 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. When 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
본 발명에 있어서, 상기 안과용 활성성분은 안과용 활성 제약 성분 ("API: active pharmaceutical ingredient")을 포함할 수 있으며, 상기 안과용 활성성분은 난용성 스테로이드계 화합물 또는 난용성 비스테로이드계 화합물일 수 있다. 상기 난용성 스테로이드계 화합물은 글루코코르티코스테로이드 또는 또는 코르티코스테로이드로서 관련 기술분야에 공지된 것이며, 난용성 비스테로이드계 화합물은 비스테로이드성 항염증 약물 ("NSAID: nonsteroidal anti-inflammatory drug")을 포함할 수 있다.In the present invention, 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. can 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”). can
또한, 본 발명에 있어서, 상기 안과용 활성성분은 플루오로메톨론(Fluorometholone), 프레드니솔론 아세테이트(prednisolone acetate), 네파페낙(Nepafenac), 브린졸라마이드 (Brinzolamide), 로테프로드놀 에타보네이트(loteprednol etabonate), 및 디플루프레드네이트(difluprednate) 등일 수 있으며 이들의 약학적으로 허용가능한 염을 사용할 수 있다. 안과용 활성성분으로 바람직하게는 플루오로메톨론 또는 그의 약학적으로 허용가능한 염일 수 있으나, 본 발명의 범위에 이에 한정되는 것은 아니다. In addition, in the present invention, 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.
상기 플루오로메톨론 또는 그의 약학적으로 허용가능한 염은 외안부 및 전안부의 염증성 질환, 예컨대, 안검염, 결막염, 각막염, 공막염, 상공막염, 홍채염, 홍채모양염, 포도막염, 수술 후 염증 등의 치료제로서 사용될 수 있다.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, iritis, iritis, uveitis, post-operative inflammation, etc. can
또한, 상기 전체 조성물에 대하여 활성성분을 약 0.05 내지 2 중량%의 함량으로 포함할 수 있으며, 바람직하게는 약 0.05 내지 1 중량%, 더욱 바람직하게는 약 0.05 내지 0.2 중량% 함량으로 포함할 수 있으며, 가장 바람직하게는 약 0.1 중량% 함량으로 포함할 수 있다.In addition, it 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.
본 발명에 있어서, 부형제는 안과용 현탁액 조성물의 약리학적 활성 성분과의 조합으로 제형화되고 상기 조성물의 전달 효율 및 효과를 개선시키는 역할을 하는 조성 약리학적 불활성 물질을 지칭하고, 점도조절제, 안정화제, 등장화제, 완충제, 현탁화제 및 보존제 등을 포함한다.In the present invention, 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.
본 발명에 있어서, 상기 안정화제는 안과용 현탁액 조성물의 안정화를 도모하는 역할을 한다. 상기 안정화제는 에데트산나트륨, 과붕산나트륨, 아스코르브산, 메타중아황산나트륨, 티오황산나트륨, 아세틸시스테인, 부틸화된 하이드록시아니솔(Butylated Hydroxyanisole), 부틸화된 하이드록시톨루엔(Butylated Hydroxytoluene) 또는 이들의 수화물 등일 수 있으며, 바람직하게는 에데트산나트륨 또는 이의 수화물일 수 있다.In the present invention, 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.
또한 본 발명의 안과용 현탁액 조성물은 등장화제를 포함할 수 있으며, 등장화제는 안과용 치료제의 생리적 전해질의 등장성을 조절하는 역할을 한다. 상기 등장화제로는 염화나트륨, 염화칼륨, 염화칼슘, 글리세린, 만니톨 등을 사용할 수 있으며, 이중에서 염화나트륨을 사용하는 것이 바람직하다.In addition, 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. As the isotonic agent, sodium chloride, potassium chloride, calcium chloride, glycerin, mannitol, etc. may be used, and sodium chloride is preferably used among them.
또한, 본 발명의 조성물은 완충제를 포함할 수 있으며 상기 완충제는 조성물의 산도 또는 알칼리도를 조정하는데 필요한 것으로 안과용 현탁액 조성물이 자극을 일으키지 않고 눈에 의해 수용되기 위해서는 포유동물이 눈물과 같거나 비슷한 pH를 가진 등장액인 것이 중요하다. 따라서 본 발명의 현탁액 조성물은 pH를 소정의 범위로 유지하기 위해 완충제를 배합하여 사용할 수 있다. 상기 완충제는 포스페이트 완충제, 포스페이트 시트레이트 완충제, 락테이트 완충제, 보레이트 완충제, 보레이트 시트레이트 완충제, 아미노카프론산, 아세테이트 완충제 등일 수 있으며, 바람직하게는 포스페이트 완충제일 수 있으며, 더욱 바람직하게는 인산이수소나트륨수화물 및 무수인산수소나트륨일 수 있다.In addition, 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.
또한, 상기 현탁화제(또는 계면활성제라고도 칭함)는 글라이세롤 에스터, 글라이콜 에스터, 폴리에틸렌 글라이콜, 폴리에틸렌 글라이콜 (15)-하이드록시스테아레이트, 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체, 폴리옥시에틸렌 40 스테아레이트 (POE40 스테아레이트), 폴리솔베이트 20, 폴리솔베이트 80 또는 폴리옥시에틸렌 (80) 솔비탄 모노올레이트, 솔비탄 모노스테아레이트, 폴리옥시에틸렌글라이세롤 트라이리시놀레이트 35, 폴리솔베이트, 솔비탄, 폴리옥시에틸렌, 글라이세롤트라이리시놀레이트 35, 사이클로덱스트린, 히드록시프로필 사이클로덱스트린 등 일수 있으며, 바람직하게는 폴리솔베이트 20 및 폴리솔베이트 80을 사용할 수 있으며, 더욱 바람직하게는 폴리소르베이트 80을 사용할 수 있다.In addition, 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.
또한, 본 발명의 안과용 현탁액 조성물은 미생물 오염 등을 방지하기 위해 보존제를 포함할 수 있다. 상기 보존제로는 염화벤즈알코늄 등을 포함하는 양이온성 보존제; 폴리쿼터늄-1 등을 포함하는 4급 암모늄 화합물; 폴리헥사나이드 (PHMB), 클로르헥시딘 등을 포함하는 구아니딘계 보존제; 클로로부탄올; 티메로살, 페닐수은 아세테이트, 페닐수은 나이트레이트 등을 포함하는 수은 보존제; 퓨라이트 (PURITE)와 같은 안정된 옥시클로로 복합체 등을 포함하는 산화 보존제; 등을 사용할 수 있으며, 바람직하게는 양이온성 보존제, 더욱 바람직하게는 염화벤즈알코늄일 수 있다.In addition, 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.
또한, 점도조절제 (Viscosity-increasing Agent)는 안과용 현탁액 조성물의 점도를 조절하고, 안구에 투여 시 안고 건조 증상 및 상태의 일시적 경감을 위한 역할을 하는 것으로, 폴리비닐알코올, 폴리비닐피롤리돈(포비돈), 히알루론산, 히알루론산 나트륨, 젤라틴, 콜드로이틴 술페이트, 폴리사카라이드 (TSP, TS polysaccharide), 카보머 (Polyacrylic acid), 메틸셀룰로오스, 에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스 (Hypromellose, HPMC), 폴리에틸렌글리콜, 폴리에틸렌글리콜 400 (PEG 400), 카르복시메틸셀룰로오스나트륨 (CMC), 플록사머, 히드록시프로필 구아 (HP Guar), 구아검 (Guar Gum), 산탄검 (Xanthan Gum), 아라비아검 (Arabic Gum) 등일 수 있으며, 바람직하게는 폴리비닐알코올일 수 있다.In addition, 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., preferably polyvinyl alcohol.
또한, 본 발명의 안과용 현탁액 조성물의 pH는 약 4 내지 8이 될 수 있으며, 바람직하게는 약 5 내지 8, 더욱 바람직하게는 약 6.2 내지 7.5일 수 있으나, 안과용 현탁액 조성물에 범용되고 있는 범위의 pH라면 본 발명의 범위가 특별히 제한되는 것은 아니다.In addition, 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.
본 발명의 다른 일 측면에 있어서, 상기 안과용 현탁액 조성물의 제조방법에 따라 제조된 안과용 현탁액 조성물을 제공한다.In another aspect of the present invention, there is provided an ophthalmic suspension composition prepared according to the method for preparing the ophthalmic suspension composition.
본 발명의 또 다른 일 측면에 있어서, D90이 약 1.5 μm 이하로 존재하는 안과용 활성성분을 포함하는 안과용 현탁액 조성물을 제공한다.In another aspect of the present invention, there is provided an ophthalmic suspension composition comprising an ophthalmic active ingredient having a D 90 of about 1.5 μm or less.
상기 안과용 현탁액 조성물은 안정화제, 등장화제, 완충제, 현탁화제, 보존제, 점도조절제와 같은 부형제를 포함할 수 있으며, 상기 부형제에 대한 설명은 상술한 바와 같다.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.
또한, 상기 안과용 활성성분과 상기 안과용 현탁액 조성물에 대한 설명은 상술한 바와 같다.In addition, the description of the ophthalmic active ingredient and the ophthalmic suspension composition is the same as described above.
본 발명에 있어서, 상기 안과용 현탁액 조성물은, 안과용 활성성분 약 0.05 내지 2 중량%, 안정화제 0.5 내지 2.0 중량%, 등장화제 0.1 내지 0.5 중량%, 완충제 4.0 내지 6.0 중량%, 현탁화제 0.1 내지 0.5 중량%, 보존제 0.01 내지 0.2 중량%, 점도조절제 10 내지 20 중량% 및 잔량의 물을 포함할 수 있다.In the present invention, 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.
바람직하게는, 상기 안과용 현탁액 조성물은 플루오로메톨론 0.05 내지 0.2 중량%, 에데트산나트륨 또는 이의 수화물 0.5 내지 2.0 중량%, 염화나트륨 0.1 내지 0.5 중량%, 인산이수소나트륨수화물 및 무수인산수소나트륨 4.0 내지 6.0 중량%, 폴리소르베이트 80 0.1 내지 0.5 중량%, 염화벤즈알코늄 0.01 내지 0.2 중량%, 폴리비닐알코올 10 내지 20 중량% 및 잔량의 물을 포함할 수 있으며,Preferably, 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,
더욱 바람직하게는, 상기 안과용 현탁액 조성물은 플루오로메톨론 0.1 중량%, 에데트산나트륨 또는 이의 수화물 1.0 내지 1.5 중량%, 염화나트륨 0.2 내지 0.4 중량%, 인산이수소나트륨수화물 4.0 내지 5.0 중량%, 무수인산수소나트륨 0.4 내지 0.8 중량%, 폴리소르베이트 80 0.2 내지 0.4 중량%, 염화벤즈알코늄 0.01 내지 0.1 중량%, 폴리비닐알코올 12 내지 15 중량% 및 잔량의 물을 포함할 수 있다.More preferably, 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.
본 발명에 있어서, 상기 안과용 현탁액 조성물을 개체에 투여하여 염증을 억제하는 방법을 제공한다.In the present invention, there is provided a method for inhibiting inflammation by administering the ophthalmic suspension composition to a subject.
본 발명에 있어서, 상기 “개체”는 안과 염증성 질환을 갖는 인간을 포함한 모든 동물을 의미할 수 있다. 상기 동물은 인간뿐만 아니라 이와 유사한 증상의 치료를 필요로 하는 소, 말, 양, 돼지, 염소, 낙타, 영양, 개, 고양이 등의 포유동물일 수 있으나, 이에 제한되지는 않는다.In the present invention, 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.
본 발명에 있어서, 상기 "투여"는 어떠한 적절한 방법으로 개체에게 본 발명의 안과용 현탁액 조성물을 도입하는 것을 의미하며, 본 발명의 투여 경로는 조성물이 점안제인 특성상 안구에 국소적으로 투여하는 것이다. In the present invention, 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.
본 발명의 염증 억제 방법은 본 발명의 안과용 현탁액 조성물을 치료학적 유효량으로 투여하는 것을 포함한다. 본 발명의 조성물은 약학적으로 유효한 양으로 투여할 수 있다. 상기 약학적으로 유효한 양은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 구체적으로 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수 있고, 1회 투여 당 0.01ml 내지 0.1 ml 투여할 수 있으나, 이에 제한되지 않는다.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.
본 발명에 따른 안과용 현탁액 조성물은 멸균용기 내 충진하여 제공할 수 있으며, 이의 사용에 관한 지시문을 포함하여 제공될 수 있으며, 상기 지시문은 상기 점안제가 충진된 용기 또는 상기 용기를 포장한 제2의 용기에 물리적으로 부착하거나 또는 제2의 용기 내부에 함께 포장될 수 있다.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.
본 발명의 제조방법에 따라 제조된 현탁액 조성물은 제조 공정 중에 비드밀을 이용하여 약물을 밀링 및 분산시킴으로써, 분산 안정도가 높고 용기에 고착되지 않으며 침강시 응집이 일어나지 않는 최적의 입자 크기로 약물을 분쇄할 수 있으며, 밀링 시 그라인딩 매체 (비드)의 마모에 의한 오염을 최소화할 수 있다.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.
또한, 본 발명의 제조방법에 따라 제조된 현탁액 조성물을 눈에 적용시 시야 혼탁, 이물감 및 불쾌감이 없으며, 약물의 생체 이용률이 높은 점에서 우수하다.In addition, when the suspension composition prepared according to the preparation method of the present invention is 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.
또한, 공정 과정을 단순화함에 따라 제조 시간을 단축시켜 현탁액 조성물 제조의 생산성을 향상시킬 수 있는 효과가 있다.In addition, there is an effect that can improve the productivity of the suspension composition preparation by shortening the manufacturing time by simplifying the process.
도 1은 밀링 방법에 따른 활성성분의 입도분포를 나타낸 도면이다.1 is a view showing the particle size distribution of the active ingredient according to the milling method.
도 2는 밀링 공정을 수행하지 않은 현탁액의 터비스캔 분석 결과는 나타낸 것이다.Figure 2 shows the results of the analysis of Turbiscan of the suspension not subjected to the milling process.
도 3은 기존 고압 균질기 (High pressure homogenizer, HPH)로 분산된 현탁액 조성물의 터비스캔 분석 결과를 나타낸 것이다.3 shows the results of Turbiscan analysis of a suspension composition dispersed using a conventional high pressure homogenizer (HPH).
도 4는 비드밀링으로 밀링하는 실시예 1-1에 따라 제조된 현탁액 조성물의 터비스캔 분석 결과를 나타낸 것이다.4 shows the results of Turbiscan analysis of the suspension composition prepared according to Example 1-1 milled by bead milling.
도 5는 비드밀링으로 밀링하는 실시예 1-2에 따라 제조된 현탁액 조성물의 터비스캔 분석 결과를 나타낸 것이다.5 shows the results of Turbiscan analysis of the suspension composition prepared according to Example 1-2 milled by bead milling.
도 6은 입자도를 조절하는 어떠한 공정도 수행하지 않은 현탁액 원액(Before milling) 및 본 발명의 비드밀링 공정을 포함하는 제조방법에 따라 제조된 현탁액 조성물 (비드 평균 직경=0.2 mm)의 침전 양상 결과를 확인한 사진이다.6 shows the results of the precipitation pattern of the suspension stock solution (Before milling) without any process of controlling the particle size and the suspension composition (average bead diameter = 0.2 mm) prepared according to the manufacturing method including the bead milling process of the present invention. This is a verified photo.
도 7은 본 발명의 안과용 현탁액 조성물의 제조시 패시지 횟수에 따른 입자 분포 결과를 나타낸 것이다.7 shows the particle distribution results according to the number of passages during the preparation of the ophthalmic suspension composition of the present invention.
도 8은 1.0 mm 크기의 비드로 비드밀링한 슬러리의 입도분포를 나타낸 도면이다.8 is a view showing the particle size distribution of the slurry bead milled with beads having a size of 1.0 mm.
도 9는 0.5 mm 크기의 비드로 비드밀링한 슬러리의 입도분포를 나타낸 도면이다.9 is a view showing the particle size distribution of the slurry bead milled with 0.5 mm size beads.
도 10은 0.2 mm 크기의 비드로 비드밀링한 슬러리의 입도분포를 나타낸 도면이다.10 is a view showing the particle size distribution of the slurry bead milled with beads having a size of 0.2 mm.
도 11은 동일한 패시지 조건에서 비드 크기에 따른 입도분포를 나타낸 도면이다. 11 is a view showing the particle size distribution according to the bead size under the same passage conditions.
본 발명의 이해를 돕기 위하여 실시예를 제시한다. 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Examples are provided to help the understanding of the present invention. The following examples are only provided for easier understanding of the present invention, and the content of the present invention is not limited by the examples.
<제조예> 안과용 현탁액 조성물<Preparation Example> Ophthalmic suspension composition
본 발명의 안과용 현탁액 조성물은 하기의 성분들을 포함하거나, 하기의 성분들로 이루어져 있다:The ophthalmic suspension composition of the present invention comprises or consists of the following ingredients:
기능function 성분ingredient 전체 조성의 중량%% by weight of total composition
활성성분(API)Active ingredient (API) 플루오로메톨론Fluorometholone 0.10.1
부형제excipient 안정화제stabilizer 에데트산나트륨수화물Sodium Edetate Hydrate 1.0~1.5 1.0~1.5
등장화제isotonic agent 염화나트륨sodium chloride 0.2~0.40.2~0.4
완충제buffer 인산이수소나트륨수화물, 무수인산수소나트륨Sodium dihydrogen phosphate hydrate, anhydrous sodium hydrogen phosphate 4.0~5.0
0.4~0.84.0~5.0
0.4~0.8
현탁화제suspending agent 폴리솔베이트 80Polysorbate 80 0.2~0.40.2~0.4
보존제preservative 염화벤즈알코늄benzalkonium chloride 0.01~0.1 0.01~0.1
점도조절제viscosity modifier 폴리비닐알코올polyvinyl alcohol 12~15 12-15
용매menstruum 물water 잔량remaining amount
<실시예 1> 비드밀링을 이용한 안과용 현탁액 조성물 제조<Example 1> Preparation of ophthalmic suspension composition using bead milling
실시예 1-1: 완제를 비드밀링하여 안과용 현탁액 조성물 제조Example 1-1: Preparation of ophthalmic suspension composition by bead milling the finished product
전체 부피의 70% 정도의 물에 점도조절제를 넣고 80℃의 온도에서 약 2시간 정도 교반하여 용해시킨 용액을 제조하였다.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.
한편, 전체 부피의 10 내지 20% 가량의 물에 안정화제, 등장화제, 완충제, 현탁화제 및 보존제를 넣고 완전히 용해시킨 후, 활성성분인 플루오로메톨론을 첨가하여 빠른 속도로 교반하여 분산시켰다. On the other hand, 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.
이후, 균질기(homogenizer)를 사용하여 약 1 내지 2시간 정도 플루오로메톨론 입자의 wetting을 수행하여 슬러리를 제조하고 여기에 점도조절제를 포함하는 용액을 섞은 후 고온 멸균을 진행하였다.Thereafter, using a homogenizer, wetting of the fluorometholone particles was performed for about 1 to 2 hours to prepare a slurry, a solution containing a viscosity modifier was mixed therewith, and then high-temperature sterilization was performed.
멸균 완료 후 pH를 6.2 내지 7.5로 맞추고 최종적으로 부피를 맞추어 현탁액(완제)을 제조하였다. 상기 현탁액에 포함된 성분의 함량은 제조예와 같다.After completion of sterilization, the pH was adjusted to 6.2 to 7.5 and finally the volume was adjusted to prepare a suspension (finished product). The content of the components included in the suspension is the same as in Preparation Example.
이후, 상기 현탁액을 비드밀 장비를 이용하여 다음의 조건으로 밀링을 수행하여 활성성분인 플루오로메톨론이 D90 ≤ 1.5 μm를 갖는 입자로서 존재하는 최종 현탁액 조성물을 제조하였다.Thereafter, 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 μm.
완제를 비드밀링하여 안과용 현탁액 조성물 제조하는 경우 비드밀링기로 Netzsch사의 MiniCer 또는 Netzsch사의 Labstar를 사용하였으며, 각 기기의 사용에 따른 비드밀링 조건은 아래와 같다.In the case of preparing an ophthalmic suspension composition by bead milling the finished product, Netzsch's MiniCer or Netzsch's Labstar was used as a bead milling machine, and the bead milling conditions according to the use of each device are as follows.
<비드밀링 조건><Bead milling conditions>
(1) Netzsch사의 MiniCer 비드밀링기를 사용하는 경우(1) When using Netzsch's MiniCer bead milling machine
- 비드 종류: 이트리움으로 안정화한 산화지르코늄- Bead type: zirconium oxide stabilized with yttrium
- 비드 사이즈: 0.2~0.3 mm- Bead size: 0.2~0.3 mm
- 로터 속도(Rotor speed): 4 m/s- Rotor speed: 4 m/s
- Flow rate: 880 mL/min- Flow rate: 880 mL/min
- Total 패시지(passage): 60~70회(Fluorometholone 기준, 4 m/s rotor speed, Passage=현탁액 용량 전체가 Bead mill을 통과하는 횟수; Flow rate*시간/전체용량)- Total passage: 60~70 times (Fluorometholone standard, 4 m/s rotor speed, Passage = the number of times the entire suspension volume passes through the bead mill; Flow rate*time/total volume)
- 밀링이 진행되는 부분 온도: 냉각수를 이용해 10~30℃ 범위의 온도 유지- Temperature of the part where milling is performed: Maintain the temperature in the range of 10~30℃ using cooling water
(2) Netzsch사의 Labstar 비드밀링기를 사용하는 경우(2) When using Netzsch's Labstar bead milling machine
- 비드 종류: 이트리움으로 안정화한 산화지르코늄- Bead type: zirconium oxide stabilized with yttrium
- 비드 사이즈: 0.2~0.3 mm- Bead size: 0.2~0.3 mm
- 로터 속도(Rotor speed): 4 m/s- Rotor speed: 4 m/s
- Flow rate: 1000 mL/min- Flow rate: 1000 mL/min
- Total 패시지(passage): 60~70회(Fluorometholone 기준, 4 m/s rotor speed, Passage=현탁액 용량 전체가 Bead mill을 통과하는 횟수; Flow rate*시간/전체용량)- Total passage: 60~70 times (Fluorometholone standard, 4 m/s rotor speed, Passage = the number of times the entire suspension volume passes through the bead mill; Flow rate*time/total volume)
- 밀링이 진행되는 부분 온도: 냉각수를 이용해 10~30℃ 범위의 온도 유지- Temperature of the part where milling is performed: Maintain the temperature in the range of 10~30℃ using cooling water
실시예 1-2: 슬러리를 비드밀링하여 안과용 현탁액 조성물 제조Example 1-2: Preparation of Ophthalmic Suspension Composition by Bead Milling Slurry
전체 부피의 5~50% 가량의 물에 현탁화제 및 보존제를 넣고 용해시킨 후 활성성분인 플루오로메톨론을 첨가하고 빠른 속도로 교반하여 분산시켰다. 이후, homogenizer를 사용하여 약 1 내지 2시간 정도 플루오로메톨론 입자의 wetting을 수행하여 슬러리를 제조하고 고온 멸균을 진행하였다.After dissolving the suspending agent and preservative in 5-50% of the total volume of water, fluorometholone, an active ingredient, was added and dispersed by stirring at high speed. Thereafter, 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.
고온 멸균된 슬러리를 비드밀 장비를 이용하여 다음의 조건으로 밀링을 수행하였다.The high temperature sterilized slurry was milled using a bead mill equipment under the following conditions.
<비드밀링 조건><Bead milling conditions>
- 비드밀링기: Netzsch사의 MiniCer - Bead milling machine: Netzsch's MiniCer
- 비드 종류: 이트리움으로 안정화한 산화지르코늄- Bead type: zirconium oxide stabilized with yttrium
- 비드 사이즈: 0.2~0.3 mm- Bead size: 0.2~0.3 mm
- 로터 속도(Rotor speed): 4 m/s- Rotor speed: 4 m/s
- Total 패시지(passage): 60~70회 (Fluorometholone 기준, 4 m/s rotor speed, Passage=현탁액 용량 전체가 Bead mill을 통과하는 횟수; Flow rate*시간/전체용량)- Total passage: 60~70 times (Fluorometholone standard, 4 m/s rotor speed, Passage=number of times the entire suspension volume passes through the bead mill; Flow rate*time/total volume)
- 밀링이 진행되는 부분 온도: 냉각수를 이용해 10~30℃ 범위의 온도 유지- Temperature of the part where milling is performed: Maintain the temperature in the range of 10~30℃ using cooling water
밀링된 슬러리에 전체 부피의 50~70% 가량의 물에 점도조절제를 넣고 80℃의 온도에서 약 2시간 교반시켜 제조한 용액을 첨가하여 혼합액을 제조하였다. 제조된 혼합액에 안정화제, 등장화제 및 완충제를 첨가한 후 완전히 용해시킨 후 제균 여과를 수행하여 활성성분인 플루오로메톨론이 D90 ≤ 1.5 μm를 갖는 입자로서 존재하는 최종 현탁액 조성물을 제조하였다.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 μm by adding a stabilizer, a tonicity agent, and a buffer to the prepared mixture, followed by complete dissolution, followed by sterilization filtration.
상기 최종 현탁액 조성물에 포함된 각 성분의 함량은 상기 제조예와 같다.The content of each component included in the final suspension composition is the same as in Preparation Example.
<실험예 1> 비드밀링 공정으로 제조된 현탁액 조성물의 활성성분의 입자분포 분석<Experimental Example 1> Particle distribution analysis of the active ingredient of the suspension composition prepared by the bead milling process
실시예 1-2에 따라 제조된 현탁액 조성물에 포함된 플루오로메톨론의 입자 분포와 기존 고압 균질기(High pressure homogenizer, HPH)를 사용하여 제조된 현탁액 조성물에 포함된 플루오로메톨론의 입자 분포를 비교 분석하였으며, 그 결과는 하기 표 2 및 도 1과 같다.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.
ConditionCondition InitialInitial Bead mill
(실시예 1)bead mill
(Example 1) 		HPHHPH
D10(μm)D 10 (μm) 4.284.28 0.1450.145 1.081.08
D50(μm)D 50 (μm) 10.310.3 0.3540.354 1.891.89
D90(μm)D 90 (μm) 19.919.9 0.9980.998 3.473.47
* SPAN=(D90 - D10)/D50(여기서 D90, D10 및 D50은 각각 고형분 입도의 누적분포에서 최대값에 대하여 90%, 10% 및 50%에 해당하는 입도를 말함)* SPAN=(D 90 - D 10 )/D 50 (where D 90 , D 10 and D 50 refer to particle sizes corresponding to 90%, 10% and 50% of the maximum value in the cumulative distribution of solid particle size, respectively)
표 2 및 도 1에서 확인할 수 있는 바와 같이, 비드밀링 공정을 포함하는 본 발명의 제조방법으로 제조된 현탁액 조성물은 플루오로메톨론의 D90이 0.998 μm로, 기존 HPH 공정으로 제조된 조성물의 플루오로메톨론의 입도(D90=3.47)에 대비하여 입도가 현저히 작아졌다.As can be seen in Table 2 and FIG. 1, 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 μm, and the fluorometholone of the composition prepared by the conventional HPH process. The particle size was significantly smaller compared to that of Tolon (D 90 =3.47).
<실험예 2> 터비스캔 분석을 이용한 분산 특성 및 안정성 분석<Experimental Example 2> Analysis of dispersion characteristics and stability using Turbiscan analysis
본 발명의 비드밀링 공정을 포함하는 실시예 1-1 및 실시예 1-2에 따라 제조된 현탁액 조성물, 기존 HPH를 사용하여 제조된 현탁액 조성물, 입자도를 조절하는 공정을 진행하지 않은 현탁액 원액에 대하여 터비스캔 분석을 수행하여 분산 특성 및 안정성을 비교 분석하였으며, 침전 양상을 육안으로 확인하였다. 이에 대한 결과는 도 2 내지 6과 같다.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 .
도 2에서 확인할 수 있는 바와 같이, 입자도를 조절하는 어떠한 공정도 수행하지 않은 현탁액 원액의 경우, 입도(D90)가 10 μm 이상으로 큰 입자를 가지고 있으므로 빠른 속도로 침강(flocculation)이 일어나는 것으로 나타났다. 또한, 입자들 사이에서 응집(aggregation)이 지속적으로 침강이 진행되는 것으로 나타났다. 도 6에서 확인할 수 있는 바와 같이 1일 후, 현탁액 원액은 투명하고 하단에 침전층이 두껍게 생기는 것으로 나타났다(before milling).As can be seen in FIG. 2 , in the case of the suspension stock solution in which no process of controlling the particle size was performed, since the particle size (D 90 ) has large particles of 10 μm or more, flocculation occurs at a rapid rate. . In addition, it was found that aggregation between the particles continued to proceed with sedimentation. As can be seen in FIG. 6 , after 1 day, the suspension stock solution was transparent and a thick precipitation layer was formed at the bottom (before milling).
또한, 도 3에서 확인할 수 있는 바와 같이, 기존 HPH 공정으로 분산된 현탁액 조성물의 경우, 입도분포(D90)가 5 μm 보다 작아져 현탁액 원액과 대비하여서는 침강 속도가 느려졌으나 현탁액 원액과 마찬가지로 입자 간 응집이 지속적으로 일어나며 침강이 진행되는 것으로 나타났다.In addition, as can be seen in FIG. 3 , in the case of the suspension composition dispersed by the conventional HPH process, the particle size distribution (D 90 ) was smaller than 5 μm, 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.
이에 반해, 도 4에서 확인할 수 있는 바와 같이, 본 발명의 실시예 1-1(Netzsch사의 Labstar 비드밀링기를 사용)에 따라 제조된 현탁액 조성물에 포함된 활성성분의 입도(D90)가 1 μm 정도로 작아져 침강이 현저히 느리게 일어나며, 입자 간 응집이 적게 일어나 침강이 천천히 진행되는 것으로 나타났다. 도 6에서 확인할 수 있는 바와 같이, 1일 후, 본 발명의 제조방법에 따라 제조된 현탁액 조성물은 전반적으로 현탁도가 유지되며 하단부에 침전층은 얇게 생긴 것으로 나타났다(0.2 mm).In contrast, as can be seen in FIG. 4 , the particle size (D 90 ) of the active ingredient contained in the suspension composition prepared according to Example 1-1 of the present invention (using Netzsch's Labstar bead milling machine) is about 1 μm. 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).
또한, 도 5에서 확인할 수 있는 바와 같이, 본 발명의 실시예 1-2에 따라 제조된 현탁액 조성물은 실시예 1-1에 따라 제조된 현탁액 조성물과 유사한 결과를 보이는 것을 확인하였다. 이에, 현탁액의 농도가 분산 안정성에 큰 영향을 미치지 않은 것으로 보이는 바, 슬러리 형태를 비드밀링하여 현탁액 조성물 제조가 가능한 것을 확인하였다.In addition, as can be seen in FIG. 5 , it was confirmed that the suspension composition prepared according to 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.
<실험예 3> 밀링 수행시 패시지 횟수에 따른 입자 분포 분석<Experimental Example 3> Particle distribution analysis according to the number of passages during milling
비드밀링을 수행시 패시지 횟수에 따른 입자 분포도를 분석하기 위해 실시예 1-2와 동일한 방법으로 밀링을 수행하는 대신에 패시지 횟수를 10~60으로 달리하면서 밀링 패시지에 따른 입자 분포를 분석하였으며, 그 결과는 도 7과 같다.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 .
HPH 공정을 진행 시 현탁액 원액(Initial) 대비 원료(API)수준으로 입자도가 낮아지긴 하지만 그 이하로는 낮아지지 않으므로, 기존 HPH 공정은 분산은 가능하나 분쇄에 용이하지 않는 문제점이 있었다.When the HPH process is carried out, 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.
그러나, 도 7에서 확인할 수 있는 바와 같이, 비드밀(Bead mill) 공정은 밀링 패시지의 횟수 증가에 비례하여 입자가 지속적으로 작아지는 것으로 나타났으며, 약 60 패시지로 밀링을 수행할 경우 목표로 하는 입도분포(D90이 1.5 μm 이하)가 되는 것으로 나타났다.However, as can be seen in FIG. 7, in the bead mill process, it was found that the particles were continuously reduced in proportion to the increase in the number of milling passages, and when milling was performed in about 60 passages, the target It was found that the particle size distribution (D 90 is 1.5 μm or less).
<실험예 4> 그라인딩 매체인 비드(bead) 크기에 따른 밀링 특성 분석<Experimental Example 4> Milling characteristics analysis according to the grinding medium bead size
비드밀링을 통한 분산 및 분쇄 공정에 있어서 그라인딩 매체인 비드의 크기에 따른 밀링 특성을 분석하기 위해 실시예 1-2와 동일한 방법으로 수행하는 대신에 비드 평균 직경(비드 사이즈)이 1.0 mm, 0.5 mm 및 0.2 mm인 것 각각을 사용하여 비드밀링을 수행하여 현탁액 조성물을 제조하여 입도분포를 분석하였으며, 그 결과는 하기 표 3 내지 5 및 도 8 내지 10과 같다.In the dispersion and grinding process through bead milling, in order to analyze the milling characteristics according to the size of the bead, which is the grinding medium, instead of performing in the same manner as in Example 1-2, 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.
Condition Condition 50
passage50
passage 		100 passage100 passage 150 passage150 passage 200 passage200 passage 250 passage 250 passage 300 passage300 passage
D10(μm)D 10 (μm) 0.6190.619 0.5370.537 0.4540.454 0.3480.348 0.3260.326 0.3100.310
D50(μm)D 50 (μm) 2.122.12 1.951.95 1.701.70 1.281.28 1.081.08 0.9550.955
D90(μm)D 90 (μm) 4.524.52 4.344.34 4.084.08 3.773.77 3.603.60 3.553.55
SPANSPAN 1.8381.838 1.9471.947 2.1412.141 2.6752.675 3.0223.022 3.3903.390
Bead size: 1.0 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 250 mLBead size: 1.0 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 250 mL
Condition Condition 50 passage 50 passage 100 passage 100 passage 150 passage 150 passage
D10(μm)D 10 (μm) 0.2480.248 0.1950.195 0.1630.163
D50(μm)D 50 (μm) 0.7460.746 0.4760.476 0.3760.376
D90(μm)D 90 (μm) 2.472.47 1.711.71 1.181.18
SPANSPAN 2.9802.980 3.1803.180 2.6982.698
Bead size: 0.5 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 250 mLBead size: 0.5 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 250 mL
Condition Condition 60 passage60 passage 100 passage100 passage
D10(μm)D 10 (μm) 0.1800.180 0.148 0.148
D50(μm)D 50 (μm) 0.4020.402 0.323 0.323
D90(μm)D 90 (μm) 1.061.06 0.774 0.774
SPANSPAN 2.2032.203 1.938 1.938
Bead size: 0.2 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 500 mLBead size: 0.2 mm, Rotor speed: 4 m/s, Flow rate: 880 mL/min, Slurry 500 mL
위 결과로부터 확인할 수 있는 바와 같이, 0.5 mm 비드를 사용하여 비드밀링 공정을 수행할 경우, D90이 1.5 μm 이하에 이르는 입도분포(Particle size distribution)를 얻기까지 passage가 약 150회 정도가 되도록 밀링을 수행해야하므로 밀링 시간이 더 걸리며, 1.0 mm 비드의 경우 passage를 약 300회로 밀링을 수행하여도 D90이 3.55 μm 정도로 나타났다.As can be seen from the above results, when the bead milling process is performed using 0.5 mm beads, milling so that the passage becomes about 150 times until a particle size distribution with a D 90 of 1.5 μm or less is obtained. It takes more time for milling because it has to be performed, and in the case of 1.0 mm beads, D 90 was found to be about 3.55 μm even when the passage was milled about 300 times.
이에 반해, 0.2 mm 비드를 사용하여 비드밀링을 수행할 경우, passage를 약 60회 정도로 수행하여도 D90이 1.06 μm에 도달하는 것으로 나타났으며, 100회로 수행할 경우 1.0 μm 이하가 되는 것으로 나타났다.In contrast, when bead milling was performed using 0.2 mm beads, it was found that D 90 reached 1.06 μm even when passage was performed about 60 times, and it was found to be 1.0 μm or less when performed 100 times. .
또한, 50~60 패시지의 동일한 조건에서 1.0 mm, 0.5 mm 및 0.2 mm의 비드 각각을 사용하여 비드밀링을 수행하여 현탁액 조성물을 제조하여 입도분포를 분석하였으며, 그 결과는 하기 도 11과 같다.In addition, 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.
도 11에서 확인할 수 있는 바와 같이, 패시지 조건이 동일한 경우 비드 사이즈가 0.2 mm인 비드를 사용하여 밀링을 수행할 때 입도 분포가 가장 작은 것으로 나타났다.As can be seen in FIG. 11 , when the passage conditions were the same, when milling was performed using beads having a bead size of 0.2 mm, the particle size distribution was the smallest.
<실험예 5> 그라인딩 매체인 비드(bead) 크기에 따른 밀링시의 오염도 분석<Experimental Example 5> Analysis of contamination level during milling according to the size of the bead, which is the grinding medium
비드밀링 수행 시 그라인딩 매체인 비드의 크기에 따른 오염도를 분석하기 위해 실시예 1-2와 동일한 방법으로 수행하는 대신에 비드 평균 직경(비드 사이즈)이 0.5 mm 및 0.2 mm인 것을 각각 사용하여 비드밀링을 수행하고, ICP-MS 분석을 통해 오염도를 분석하였으며, 그 결과는 하기 표 6과 같다.In order to analyze the degree of contamination according to the size of the bead, which is the grinding medium, when performing bead milling, instead of performing in the same manner as in Example 1-2, bead milling using those having an average bead diameter (bead size) of 0.5 mm and 0.2 mm, respectively , and the degree of contamination was analyzed through ICP-MS analysis, and the results are shown in Table 6 below.
ConditionCondition ppmppm
비드 직경(mm)Bead diameter (mm) 패시지(passage) 횟수number of passes
No millingNo milling 0.0280.028
0.2 mm0.2 mm 60 passage60 passage 0.0350.035
100 passage100 passage 0.0440.044
0.5 mm0.5 mm 50 passage50 passage 0.6160.616
100 passage100 passage 0.7460.746
표 6에서 확인할 수 있는 바와 같이, 밀링을 진행하지 않은 샘플(No milling)에서는 Zr가 0.028 ppm로 나타났으며, 오차범위 수준으로 Zr이 거의 검출되지 않은 것으로 확인되었다. As can be seen in Table 6, in the sample without milling (No milling), Zr was found to be 0.028 ppm, and it was confirmed that Zr was hardly detected at the level of the error range.
또한, 0.2 mm 크기의 비드를 사용하여 밀링을 수행할 경우는 Zr이 약 0.05 ppm 이하로 검출된 반면, 0.5 mm 크기의 비드를 사용하여 밀링을 수행하는 경우 Zr이 0.6 ppm 이상으로 약 10배 이상 높은 것으로 나타났다.In addition, 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.
이러한 결과로부터 0.2 mm 크기의 비드를 사용하여 밀링을 수행하는 것이 비드의 마모가 적어 비드 마모에 따른 오염을 줄이면서 약물의 입도분포를 목표로 하는 수준으로 구현할 수 있는 것을 확인할 수 있었다. 또한, 패시지 횟수가 많아질수록 Zr이 증가하는 것으로 나타나는 바, 비드의 마모로 인한 오염을 줄이면서 목표의 입도분포를 가지도록 하기 위한 최적의 패시지 횟수를 확인할 수 있었다.From these results, it was confirmed that milling using beads having a size of 0.2 mm can achieve a target level of particle size distribution of drugs while reducing contamination due to bead abrasion due to low bead abrasion. In addition, as the number of passages increases, Zr appears to increase, and the optimal number of passages to have a target particle size distribution while reducing contamination due to wear of the beads was confirmed.
명세서는 본 발명의 기술 분야에서 통상의 지식을 가진 자이면 충분히 인식하고 유추할 수 있는 내용은 그 상세한 기재를 생략하였으며, 본 명세서에 기재된 구체적인 예시들 이외에 본 발명의 기술적 사상이나 필수적 구성을 변경하지 않는 범위 내에서 보다 다양한 변형이 가능하다. 따라서 본 발명은 본 명세서에서 구체적으로 설명하고 예시한 것과 다른 방식으로도 실시될 수 있으며, 이는 본 발명의 기술 분야에 통상의 지식을 가진 자이면 이해할 수 있는 사항이다.In the specification, the detailed description of the content that can be sufficiently recognized and inferred by those of ordinary skill in the art of the present invention is omitted, and the technical spirit or essential configuration of the present invention is not changed other than the specific examples described in the present specification. More various modifications are possible within this range. Therefore, the present invention may be practiced in a manner different from that specifically described and illustrated in this specification, which will be understood by those of ordinary skill in the art of the present invention.

Claims (25)

  1. 비드밀(Bead mill)로 안과용 활성성분을 밀링(milling)하는 단계를 포함하는 안과용 현탁액 조성물의 제조방법.A method for preparing an ophthalmic suspension composition comprising the step of milling an ophthalmic active ingredient with a bead mill.
  2. 제1항에 있어서, According to claim 1,
    상기 밀링은 안과용 활성 성분을 포함하는 슬러리 형태일 때 수행되거나, 안과용 활성 성분을 포함하는 현탁액 형태일 때 수행되는 것인, 안과용 현탁액 조성물의 제조방법.The method for preparing an ophthalmic suspension composition, wherein the milling is carried out in the form of a slurry comprising the ophthalmic active ingredient or in the form of a suspension comprising the ophthalmic active ingredient.
  3. 제1항에 있어서, According to claim 1,
    안과용 활성성분의 D90이 1.5 μm 이하가 되도록 비드밀(Bead mill)로 밀링(milling)하는 것인 안과용 현탁액 조성물의 제조방법.A method for producing an ophthalmic suspension composition by milling with a bead mill so that the D 90 of the ophthalmic active ingredient is 1.5 μm or less.
  4. 제1항에 있어서, According to claim 1,
    상기 안과용 활성성분의 D50이 0.5 μm 이하 및 D10이 0.2 μm 이하가 되도록 밀링하는 것인, 안과용 현탁액 조성물의 제조방법.D 50 of the ophthalmic active ingredient is 0.5 μm or less and D 10 of the ophthalmic active ingredient is milled to 0.2 μm or less, the method for producing an ophthalmic suspension composition.
  5. 제1항에 있어서, According to claim 1,
    (1) 안과용 활성성분 및 부형제를 포함하는 슬러리(Slurry)를 제조하는 단계;(1) preparing a slurry containing an ophthalmic active ingredient and an excipient;
    (2) 상기 슬러리에 부형제를 추가로 첨가하여 혼합물을 제조하는 단계;(2) preparing a mixture by further adding an excipient to the slurry;
    (3) 상기 혼합물을 고온 멸균 후 pH를 조절하여 현탁액을 제조하는 단계; 및(3) preparing a suspension by adjusting the pH of the mixture after high-temperature sterilization; and
    (4) 상기 현탁액을 비드밀로 밀링하여 안과용 현탁액 조성물을 제조하는 단계; 를 포함하는 것인, 안과용 현탁액 조성물의 제조방법.(4) milling the suspension with a bead mill to prepare an ophthalmic suspension composition; A method for preparing an ophthalmic suspension composition comprising a.
  6. 제5항에 있어서, 6. The method of claim 5,
    단계 (1)의 부형제는 안정화제, 등장화제, 완충제, 현탁화제 및 보존제를 포함하고,The excipients of step (1) include stabilizers, isotonic agents, buffers, suspending agents and preservatives,
    단계 (2)의 부형제는 점도조절제를 포함하는 것인, 안과용 현탁액 조성물의 제조방법.The method for preparing an ophthalmic suspension composition, wherein the excipient of step (2) includes a viscosity modifier.
  7. 제1항에 있어서, According to claim 1,
    (1) 안과용 활성성분 및 부형제를 포함하는 슬러리(Slurry)를 제조하는 단계;(1) preparing a slurry containing an ophthalmic active ingredient and an excipient;
    (2) 상기 슬러리를 비드밀로 밀링하는 단계; (2) milling the slurry with a bead mill;
    (3) 밀링된 슬러리에 부형제를 첨가하여 혼합용액을 제조하는 단계; 및(3) preparing a mixed solution by adding an excipient to the milled slurry; and
    (4) 상기 혼합용액을 제균 여과하여 안과용 현탁액 조성물을 제조하는 단계; 를 포함하는 것인, 안과용 현탁액 조성물의 제조방법.(4) preparing an ophthalmic suspension composition by sterilizing and filtering the mixed solution; A method for preparing an ophthalmic suspension composition comprising a.
  8. 제7항에 있어서, 8. The method of claim 7,
    단계 (1)의 부형제는 현탁화제 및 보존제를 포함하고,The excipients of step (1) include suspending agents and preservatives,
    단계 (3)의 부형제는 점도조절제, 안정화제, 등장화제 및 완충제를 포함하는 것인, 안과용 현탁액 조성물의 제조방법.The excipient of step (3) comprises a viscosity modifier, a stabilizer, an isotonic agent and a buffering agent, the method for producing an ophthalmic suspension composition.
  9. 제1항에 있어서, According to claim 1,
    상기 비드밀은 평균 직경 0.03 mm 이상 내지 0.5 mm 미만의 비드(bead)를 포함하는 것인, 안과용 현탁액 조성물의 제조방법.The bead mill is a method for producing an ophthalmic suspension composition comprising a bead (bead) having an average diameter of 0.03 mm or more to less than 0.5 mm.
  10. 제1항에 있어서, According to claim 1,
    상기 비드밀은 산화 지르코늄, 이트리움으로 안정화한 산화지르코늄(yttrium stabilized zirconia), 마그네시아로 안정화한 산화지르코늄(magnesia stabilized zirconia), 세륨으로 안정화한 산화지르코늄(Cerium stabilized zirconia), 지르코늄 실리케이트(zirconium silicate), 지르코니아로 안정화한 산화알루미늄(zirconia stabilized alumina) 및 산화알루미늄-산화지르코늄 복합체(alumina-zirconia composite)로 이루어진 군으로부터 선택된 1종 이상인 것인 안과용 현탁액 조성물의 제조방법.The bead mill includes zirconium oxide, yttrium-stabilized zirconia, magnesia-stabilized zirconia, cerium-stabilized zirconium, and zirconium silicate. , zirconia-stabilized aluminum oxide (zirconia stabilized alumina) and aluminum oxide-zirconium composite (alumina-zirconia composite) is at least one selected from the group consisting of a method for producing an ophthalmic suspension composition.
  11. 제1항에 있어서, According to claim 1,
    비드밀에 포함된 비드의 부피는 비드밀 용기의 부피 기준으로 70 내지 90 부피%인 안과용 현탁액 조성물의 제조방법.A method for producing an ophthalmic suspension composition wherein the volume of beads contained in the bead mill is 70 to 90 vol% based on the volume of the bead mill container.
  12. 제1항에 있어서, According to claim 1,
    밀링은 2 내지 10 m/s의 로터 속도(Rotor speed)로 수행되는 것인, 안과용 현탁액 조성물의 제조방법.Milling is performed at a rotor speed of 2 to 10 m/s (Rotor speed), the method for producing an ophthalmic suspension composition.
  13. 제1항에 있어서, According to claim 1,
    밀링은 총 패시지(passage)가 30 내지 200회로 수행되는 것인, 안과용 현탁액 조성물의 제조방법.Milling is a method for producing an ophthalmic suspension composition, wherein the total passage (passage) is performed 30 to 200 times.
  14. 제1항에 있어서, According to claim 1,
    안과용 활성성분은 난용성 스테로이드계 화합물 또는 난용성 비스테로이드계 화합물인, 안과용 현탁액 조성물의 제조방법.A method for producing an ophthalmic suspension composition, wherein the ophthalmic active ingredient is a sparingly soluble steroid-based compound or a sparingly soluble non-steroidal compound.
  15. 제1항에 있어서, According to claim 1,
    안과용 활성성분은 플루오로메톨론(Fluorometholone), 프레드니솔론 아세테이트(prednisolone acetate), 네파페낙(Nepafenac), 브린졸라마이드 (Brinzolamide), 로테프로드놀 에타보네이트(loteprednol etabonate), 및 디플루프레드네이트(difluprednate)로 이루어진 군으로부터 선택된 1종 이상인, 안과용 현탁액 조성물의 제조방법.Ophthalmic active ingredients include fluorometholone, prednisolone acetate, nepafenac, brinzolamide, loteprednol etabonate, and difluprednate ( difluprednate) at least one selected from the group consisting of, a method for producing an ophthalmic suspension composition.
  16. 제6항 또는 제8항에 있어서, 9. The method according to claim 6 or 8,
    상기 안정화제는 에데트산나트륨, 과붕산나트륨, 아스코르브산, 메타중아황산나트륨, 티오황산나트륨, 아세틸시스테인, 부틸화된 하이드록시아니솔(Butylated Hydroxyanisole) 및 부틸화된 하이드록시톨루엔(Butylated Hydroxytoluene) 으로 이루어진 군에서 선택된 1종 이상인, 안과용 현탁액 조성물의 제조방법.The stabilizer is sodium edetate, sodium perborate, ascorbic acid, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole (Butylated Hydroxyanisole) and the group consisting of butylated hydroxytoluene (Butylated Hydroxytoluene) At least one selected from, a method for producing an ophthalmic suspension composition.
  17. 제6항 또는 제8항에 있어서, 9. The method according to claim 6 or 8,
    상기 등장화제는 염화나트륨, 염화칼륨, 염화칼슘, 글리세린 및 만니톨로 이루어진 군에서 선택된 1종 이상인, 안과용 현탁액 조성물의 제조방법.The isotonic agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, glycerin and mannitol, a method for producing an ophthalmic suspension composition.
  18. 제6항 또는 제8항에 있어서, 9. The method of claim 6 or 8,
    상기 완충제는 포스페이트 완충제, 포스페이트 시트레이트 완충제, 락테이트 완충제, 보레이트 완충제, 보레이트 시트레이트 완충제, 아미노카프론산 및 아세테이트 완충제로 이루어진 군에서 선택된 1종 이상인, 안과용 현탁액 조성물의 제조방법.The buffer is at least one selected from the group consisting of a phosphate buffer, a phosphate citrate buffer, a lactate buffer, a borate buffer, a borate citrate buffer, an aminocaproic acid and an acetate buffer.
  19. 제6항 또는 제8항에 있어서,9. The method according to claim 6 or 8,
    상기 현탁화제는 글라이세롤 에스터, 글라이콜 에스터, 폴리에틸렌 글라이콜, 폴리에틸렌 글라이콜 (15)-하이드록시스테아레이트, 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체, 폴리옥시에틸렌 40 스테아레이트(POE40 스테아레이트), 폴리솔베이트 20, 폴리솔베이트 80 또는 폴리옥시에틸렌 (80) 솔비탄 모노올레이트, 솔비탄 모노스테아레이트, 폴리옥시에틸렌글라이세롤 트라이리시놀레이트 35, 폴리솔베이트, 솔비탄, 폴리옥시에틸렌, 글라이세롤트라이리시놀레이트 35, 사이클로덱스트린 및 히드록시프로필 사이클로덱스트린로 이루어진 군에서 선택된 1종 이상인 안과용 현탁액 조성물의 제조방법.The suspending agent is glycerol ester, glycol ester, polyethylene glycol, polyethylene glycol (15)-hydroxystearate, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene 40 stearate ( POE40 Stearate), Polysorbate 20, Polysorbate 80 or Polyoxyethylene (80) Sorbitan Monooleate, Sorbitan Monostearate, Polyoxyethyleneglycerol Triricinolate 35, Polysorbate, Sorbi A method for preparing an ophthalmic suspension composition of at least one selected from the group consisting of tan, polyoxyethylene, glycerol triricinolate 35, cyclodextrin and hydroxypropyl cyclodextrin.
  20. 제6항 또는 제8항에 있어서, 9. The method according to claim 6 or 8,
    상기 보존제는 양이온성 보존제, 4급 암모늄 화합물, 구아니딘계 보존제, 클로로부탄올, 수은 보존제 및 산화 보존제로 이루어진 군으로부터 선택된 1종 이상인 것인, 안과용 현탁액 조성물의 제조방법.The method for preparing an ophthalmic suspension composition, wherein the preservative is at least one selected from the group consisting of cationic preservatives, quaternary ammonium compounds, guanidine-based preservatives, chlorobutanol, mercury preservatives and oxidation preservatives.
  21. 제6항 또는 제8항에 있어서,9. The method of claim 6 or 8,
    상기 점도조절제는 폴리비닐알코올, 폴리비닐피롤리돈(포비돈), 히알루론산, 히알루론산 나트륨, 젤라틴, 콜드로이틴 술페이트, 폴리사카라이드(TSP, TS polysaccharide), 카보머 (Polyacrylic acid), 메틸셀룰로오스, 에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스(Hypromellose, HPMC), 폴리에틸렌글리콜, 폴리에틸렌글리콜 400(PEG 400), 카르복시메틸셀룰로오스나트륨(CMC), 플록사머, 히드록시프로필 구아(HP Guar), 구아검(Guar Gum), 산탄검(Xanthan Gum) 및 아라비아검(Arabic Gum)으로 이루어진 군으로부터 선택된 1종 이상인, 안과용 현탁액 조성물의 제조방법.The viscosity modifier is polyvinyl alcohol, polyvinylpyrrolidone (povidone), hyaluronic acid, sodium hyaluronate, gelatin, colddroitin sulfate, polysaccharide (TSP, TS polysaccharide), carbomer (Polyacrylic acid), methyl Cellulose, ethyl cellulose, methyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (Hypromellose, HPMC), polyethylene glycol, polyethylene glycol 400 (PEG 400), sodium carboxymethyl cellulose (CMC) , floxamer, hydroxypropyl guar (HP Guar), guar gum (Guar Gum), xanthan gum (Xanthan Gum) and at least one selected from the group consisting of gum arabic (Arabic Gum), a method for producing an ophthalmic suspension composition.
  22. 제1항에 있어서, According to claim 1,
    상기 전체 조성물에 대하여 활성성분을 0.05 내지 2 중량%의 함량으로 포함하는 것인, 안과용 현탁액 조성물의 제조방법.The method for producing an ophthalmic suspension composition comprising the active ingredient in an amount of 0.05 to 2% by weight based on the total composition.
  23. 제1항의 제조방법에 따라 제조된 안과용 현탁액 조성물.An ophthalmic suspension composition prepared according to the method of claim 1.
  24. D90이 1.5 μm 이하로 존재하는 안과용 활성성분을 포함하는 안과용 현탁액 조성물.An ophthalmic suspension composition comprising an ophthalmic active ingredient having a D 90 of 1.5 μm or less.
  25. 제24항에 있어서, 25. The method of claim 24,
    상기 안과용 활성성분은 D50이 0.5 μm 이하 및 D10이 0.2 μm 이하로 존재하는 것인, 안과용 현탁액 조성물.The ophthalmic active ingredient is an ophthalmic suspension composition, wherein D 50 is 0.5 μm or less and D 10 is 0.2 μm or less.
PCT/KR2021/013358 2020-11-04 2021-09-29 Method for preparing ophthalmic suspension composition WO2022097920A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020200145961A KR102271247B1 (en) 2020-11-04 2020-11-04 Method for preparing ophthalmic suspension composition
KR10-2020-0145961 2020-11-04

Publications (1)

Publication Number Publication Date
WO2022097920A1 true WO2022097920A1 (en) 2022-05-12

Family

ID=76601884

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/013358 WO2022097920A1 (en) 2020-11-04 2021-09-29 Method for preparing ophthalmic suspension composition

Country Status (2)

Country Link
KR (1) KR102271247B1 (en)
WO (1) WO2022097920A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1129463A (en) * 1997-05-14 1999-02-02 Senju Pharmaceut Co Ltd Aqueous suspension agent having good re-dispersibility
KR100786927B1 (en) * 2000-06-28 2007-12-17 스미스클라인비이참피이엘시이 Wet milling process
JP2013512894A (en) * 2009-12-03 2013-04-18 ルピン・リミテッド Method for preparing ophthalmic pharmaceutical composition
KR20150139501A (en) * 2013-03-15 2015-12-11 이노텍 파마슈티컬스 코포레이션 Ophthalmic formulations
KR20170105610A (en) * 2015-01-26 2017-09-19 보오슈 앤드 롬 인코포레이팃드 Ophthalmic suspension composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3418751B2 (en) 1998-01-22 2003-06-23 参天製薬株式会社 Fluorometholone suspension ophthalmic solution

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1129463A (en) * 1997-05-14 1999-02-02 Senju Pharmaceut Co Ltd Aqueous suspension agent having good re-dispersibility
KR100786927B1 (en) * 2000-06-28 2007-12-17 스미스클라인비이참피이엘시이 Wet milling process
JP2013512894A (en) * 2009-12-03 2013-04-18 ルピン・リミテッド Method for preparing ophthalmic pharmaceutical composition
KR20150139501A (en) * 2013-03-15 2015-12-11 이노텍 파마슈티컬스 코포레이션 Ophthalmic formulations
KR20170105610A (en) * 2015-01-26 2017-09-19 보오슈 앤드 롬 인코포레이팃드 Ophthalmic suspension composition

Also Published As

Publication number Publication date
KR102271247B1 (en) 2021-06-30

Similar Documents

Publication Publication Date Title
US20180296487A1 (en) Sustained release injectable neurosteroid formulations
EP3209331B1 (en) Ophthalmic solution
US20120283252A1 (en) Process for preparing pharmaceutical ophthalmic compositions
JP2001522890A (en) Aqueous suspension of submicron 9-hydroxyrisperidone fatty acid ester
WO2018084627A2 (en) Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone
WO2014171748A1 (en) Orally administrable pharmaceutical composition for prevention or treatment of dry eye syndrome, comprising rebamipide or prodrug thereof
EP3096740B1 (en) Pharmaceutical composition comprising brinzolamide
WO2015016667A1 (en) Orally disintegrating film preparation containing donepezil or pharmaceutically acceptable salt thereof, and preparation method therefor
US9522160B2 (en) Ophthalmic formulations
WO2022097920A1 (en) Method for preparing ophthalmic suspension composition
WO2012148181A2 (en) Composition for the controlled-release of drugs
WO2021261837A1 (en) Oral pharmaceutical composition comprising nafamostat mesylate as active ingredient
US20060211662A1 (en) Combination therapy for topical application in the treatment of age-related macular degeneration and ocular hypertension
WO2019151744A1 (en) Adult stem cell-derived nanovesicles and use thereof for targeted therapy
WO2019059479A1 (en) Novel eye drop composition for treating dry eye syndrome containing rebamipide and method for solubilizing and stabilizing same
WO2018124700A1 (en) Novel preparation containing benzimidazole derivative
WO2018066963A1 (en) Pharmaceutical composition for treating corneal injury containing 8-oxo-deoxyguanosine or pharmaceutically acceptable salt thereof as active ingredient
WO2022146007A1 (en) Efinaconazole oral composition
WO2022071768A1 (en) A pharmaceutical composition comprising fenofibrate particles with improved bioavailability
WO2021101344A1 (en) Eye drop composition for preventing or treating eye disease
WO2011031100A2 (en) Aripiprazole-bentonite-aea hybrid, pharmaceutical composition containing the same and method for preparing the same
WO2019031902A2 (en) Pharmaceutical composition containing (r)-n-[1-(3,5-difluoro-4-methansulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide
WO2018088663A1 (en) Eye-drop composition for lowering intraocular pressure
WO2023171989A1 (en) Pharmaceutical composition for preventing or treating eye diseases
WO2023106447A1 (en) Nanosuspension containing progerinin, and preparation method therefor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21889385

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21889385

Country of ref document: EP

Kind code of ref document: A1