KR101151235B1 - Opthalmic composition in form of nanoemulsion - Google Patents

Abstract

PURPOSE: A composition containing a nanoemulsion form prepared by self-emulsification using cyclosporine A together with special oil and surfactant in aqueous medium is provided to enable sterilizing and to ensure stability. CONSTITUTION: An opthalmic composition of a nanoemulsion form with 200nm or less of particles size contains 0.05 w/v% of cyclosporine A, 0.05 v/v% of propylene glycol dicaprylocaprate, 0.37 v/v% of triglyceride, and 1.15 v/v% of polyoxyl 35 hydrogenate castor oil in an aqueous medium. The composition additionally contains sodium phosphate or hydrate thereof, sodium dihydrogenphosphate or hydrate thereof, or mixture thereof.

Description

TECHNICAL FIELD The present invention relates to an ophthalmic composition in the form of a nanoemulsion,

The present invention relates to an ophthalmic composition in the form of a nanoemulsion, and more particularly, to an ophthalmic composition in which a specific oil and a surfactant together with cyclosporin A as an active ingredient are designed in a nanoemulsion form by self-emulsification in an aqueous medium .

Some patients with dry eye, or keratoconjunctivitis sicca, suffer from Sjoegren's syndrome and are particularly prevalent in post-menopausal women due to hormonal changes due to discontinued reproductive capacity. Drying of the eyes can affect individuals with different degrees of severity, usually complaining of dryness, burning, and other discomforts, and in severe cases the eyesight may be impaired. Such ocular dryness is a disease that causes ocular surface problems (such as conjunctiva and corneal damage caused by over-evaporation of tears and lack of tear production), which causes a series of symptoms such as burning sensation and severe deterioration of visual acuity. May be due to a lack of evaporation and leakage (tears from the eye), but in most cases there are two overlapping occurrences.

Ocular drying is defined as an abnormal state of the amount and quality of tears, regardless of the degree of conjunctivitis (Nippon Ganka Kiyo. 1992 43: 1289-1293). According to the definition above, the categories of ocular dryness include diseases such as hypophagitis, tear deficiency, dry eye syndrome, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Jones syndrome, pemphigoid pemphigoid, blindness, eyelid closure deficiency, do. In the case of ocular dryness, in many cases, one of the oily layer, aqueous layer, or mucin layer lacks tears, which causes conjunctivitis.

Among the various approaches to ocular dry treatment, the most common method is to temporarily inject artificial tears into the eyeballs when ocular dryness symptoms appear, and temporarily stabilize the tear film. Such artificial tears are generally applied to the eye as an alternative to mucin, artificial tears containing viscoelastic materials such as methylcellulose, chondroitin sulfate and hyaluronic acid. However, since the substance is physically and physiologically different from mucin, the therapeutic effect is limited.

Cyclosporin A has been used as an agent to increase the amount of tear secretion by inducing stabilization of epithelial cells and increase of goblet cells in drying, unlike a therapeutic drug for relieving temporary dry eye syndrome. Cyclosporine A inhibits the production of interleukin-2, a major cytokine of the immune-mediated inflammatory response, by inhibiting the function of secondary T cells, thereby decreasing lymphocyte deposition in the damaged lacrimal gland and increasing tear production (J Korean Ophthalmol Soc 2009; 50 10): 1489-1494), and is used as a therapeutic agent for dry eye syndrome.

As an ophthalmic composition containing cyclosporin A, International Patent Publication Nos. WO995 / 31211 (Korean Patent Registration Nos. 10-0368181 and 10-0450703) disclose a cosmetic composition comprising castor oil, polysorbate 80 and allyl ether of pentaerythritol and cross-linked acrylic acid polymer is disclosed a non-irritating ophthalmic composition containing a cyclosporin a bar with a mixed state (e.g., Carbomer 1382 (carbomer 1382), such as pepper mulren ^TM (Pemulene ^TM)). The composition I is mixed with a poorly soluble drug, cyclosporine A castor oil and polysorbate, and made of the emulsion, so as to have a stability using a viscoelastic polymer such as Carbomer 1382 (carbomer 1382), page mulren ^TM (Pemulene ^TM) It is designed. The composition is currently used clinically under the trade name Restasis ^TM .

On the other hand, ophthalmic compositions are required to be produced in an aseptic form due to the nature of the preparation. However, the ophthalmic composition according to International Patent Publication No. WO1995 / 31211 call is castor oil, polysorbate 80, and page mulren ^TM (Pemulene ^TM) has a suspended emulsion form prepared from such as an internal particle 0.067 ㎛ ~ 2.489 Mu m, it is not possible to carry out a general sterilization filtration, that is, a sterilization filtration using a 0.22 mu m filter. Therefore, the entire process for preparing the composition must be carried out under sterile conditions in a closed system, which is not only difficult to manufacture in an industrial scale production facility, but also requires a large manufacturing cost.

In order to solve such a problem, it is possible to consider the design in the form of an oily aqueous solution using an organic solvent such as ethanol. However, when an organic solvent such as ethanol is used in an ophthalmic preparation other than the oral administration preparation, The drug compliance of the patient is significantly lowered and the stability over time is also low.

Disclosure of Invention Technical Problem [8] The present invention has been made to solve the above problems of the prior art, and provides an ophthalmic composition which can be subjected to conventional antibacterial filtration using a 0.22 [mu] m filter, and which has excellent stability without using an organic solvent.

In other words, it is an object of the present invention to provide a stable ophthalmic composition containing cyclosporin A, which can be sterilized and filtered to reduce the production cost and which can be easily applied at the production site.

According to one aspect of the present invention, there is provided a pharmaceutical composition comprising cyclosporin A; Propylene glycol dicaprylocarbate, propylene glycol laurate, medium chain triglyceride having 8 to 10 carbon atoms, glyceryl-1,3-diolate, glyceryl monooleate, and glyceryl linoleate One or more oils selected from the group consisting of; And oleoyl macrogol glycerides, linoleoyl macrogol glycerides, caprylocaproyl polyoxyglyceride, polyoxyl 35 hydrogene castor oil, polyoxyl 40 hydrogene castor oil, ethylene oxide and 12-hydroxy There is provided an ophthalmic composition in the form of a nanoemulsion having a particle size of 200 nm or less, which comprises, in an aqueous medium, at least one surfactant selected from the group consisting of a condensation product of stearic acid and polysorbate 80.

In the ophthalmic composition of the present invention, the content of the oil may range from 0.05 v / v% to 1.09 v / v% based on the total composition, and the content of the surfactant may be 0.27 v / v% to 4.05 v / v%. The volume ratio of the oil to the surfactant may preferably be in the range of 1: 0.37 to 19. In addition, the ophthalmic composition according to the present invention may further comprise one or more additives selected from the group consisting of a buffer, an isotonic agent, and a pH adjusting agent.

The ophthalmic composition according to the present invention is a preparation designed in the form of a nano emulsion using a self-emulsifying method (SMEDDS: Self-Emulsion Drug Delivery System), and is thermodynamically stable and has a particle size of 200 nm or less , It is possible to carry out a sterilization filtration using a 0.22 mu m filter. Therefore, the ophthalmic composition according to the present invention has an advantage that it can lower the manufacturing cost and can be easily applied at the production site. In addition, the ophthalmic composition of the present invention can be secured, so thermodynamically stable, Carbomer 1382 (carbomer 1382), without the use of a viscoelastic polymer such as Fe mulren ^TM (Pemulene ^TM), good stability. It is very advantageous in view of the safety that the additives contained in the formulation are minimized as much as possible due to the characteristics of the formulation for eye drops. Therefore, the ophthalmic composition of the present invention can be effectively used in the form of an eye drop for the treatment of dry eye syndrome.

Fig. 1 shows the result of measuring the particle size distribution of an eye drop (eye drop of Example 1) prepared according to the present invention.
Figure 2 shows the result of measuring the particle size distribution of Restasis ^TM (Allergan Corporation).

The present invention relates to an ophthalmic composition in which a specific oil and a surfactant together with cyclosporin A as an active ingredient are designed in the form of a nano-emulsion in a self-emulsifying manner in an aqueous medium, that is, an ophthalmic composition of 200 nm or less (preferably 10 to 200 nm, 10 to 100 nm) particle size of the nanoemulsion.

Since the ophthalmic composition according to the present invention has a particle size of 200 nm or less, it is possible to reduce the manufacturing cost and easily apply it in a production site since the filter can be sterilized by using a 0.22 탆 filter. In addition, the ophthalmic composition of the present invention can be secured, so thermodynamically stable, Carbomer 1382 (carbomer 1382), without the use of a viscoelastic polymer such as Fe mulren ^TM (Pemulene ^TM), good stability. The ophthalmic composition of the present invention has very favorable characteristics in view of the fact that it is well known that the additives contained in the formulation are minimally minimized in view of safety.

The cyclosporin A contained as an active ingredient may be contained in a therapeutically effective amount and may be suitably selected by those skilled in the art. For example, the cyclosporin A may be contained in an amount of 0.05 to 0.20 w / v%, preferably about 0.05 w / v%, based on the total composition. The cyclosporine A is preferably desirable to have an average particle size of 1 ~ 100 ㎛, and the average particle size of D ₅₀ preferably has a 10 ~ 20 ㎛.

Wherein the oil is propylene glycol caprylate (propylene glycol monocaprylate) [for example, Capri come ^TM PGMC (Capryol ^TM PGMC), Capri come ^TM 90 (Capryol ^TM 90), etc.], propylene glycol dicarboxylic ruffle Rocca freight (proylene glycol dicaprylocaprate) [for instance, in case of bras Pak ^TM PG (Labrafac ^TM PG), etc.], propylene glycol laurate (propylene glycol laurate) [e.g., lauroyl glycol ^TM FCC (Laurogrycol ^TM FCC), lauroyl glycol ^TM 90 (Laurogrycol ^TM 90), etc.], medium-chain triglycerides with a carbon number of 8 to _{10 (medium chain (C 8 ~} C 10) triglycerides) [ for instance, in case of bras Park lipoic peel ^{TM WL 1349 (Labrafac Lipophile TM WL} 1349) , etc. ], glyceryl-1,3-diol rate (glyceryl-1,3-dioleate) [e.g., flu ol ol Lake ^TM cc497 (Plurol oleique cc497 ^TM), etc.], glyceryl monooleate (glyceryl monooleate) [ for example, the buffer seol ^TM (Peceol ^TM), etc.], and glyceryl linoleate (glyceryl linoleate) [for example, G., May be at least one selected from the group consisting of azithromycin ^TM 35-1 ^(TM Maisine 35-1) and so on]. The oil content may range from 0.05 v / v% to 1.09 v / v%, preferably from 0.05 v / v% to 0.68 v / v%, based on the total composition.

The surfactant may be selected from the group consisting of oleoyl macrogolglycerides (e.g., Labrafil ^TM M 1944CS (Labrafil ^TM M 1944CS, Gattefosse, France), linoleoyl macrogolglycerides, [for example, LabrafilTM ^TM M 2125CS (Labrafil ^TM M 2125CS, Gattefosse Co., France), etc.], CAP reel caproyl polyoxyethylene glycerides (caprylocaproyl polyoxylglycerides) [for instance, in case of bras Sol ^TM (Labrasol ^TM, Gattefosse Co., France), etc.], polyoxyl 35 dihydro claim carbonate castor oil (polyoxyl 35 hydrogenated caster oil) [for example, crushers mode pore ^TM EL (Cremophor ^TM EL, BASF, Germany), Crescent mode pore ^TM ELP ( Cremophor ^TM ELP, BASF, Germany), etc.], polyoxyl 40 dihydro claim carbonate castor oil (polyoxyl 40 hydrogenated caster oil) [for example, crushers mode pore ^TM RH40 (Cremophor ^TM RH40, BASF, Germany), etc.], Condensation formation of ethylene oxide and 12-hydroxystearic acid Water (condensation product of ethylene oxide with 12 -hydroxystearic acid) [ for example, solution toll ^TM HP15 (Solutol ^TM HP15, BASF, Germany), etc.], and polysorbate 80 (polysorbate 80, Croda Ltd., United Kingdom) with One or more kinds selected from the group consisting of The content of the surfactant may range from 0.27 v / v% to 4.05 v / v%, preferably from 0.27 v / v% to 0.96 v / v%, based on the total composition.

The volume ratio of the oil to the surfactant may preferably be in the range of 1: 0.37 to 19, and preferably in the range of 1: 0.67 to 5.

The ophthalmic composition according to the present invention may contain additives commonly used in ophthalmic preparations such as buffers, isotonic agents, pH adjusting agents and the like.

As the buffer, sodium hydrogen phosphate (or a hydrate thereof), sodium dihydrogen phosphate (or a hydrate thereof) and the like may be used, but the present invention is not limited thereto. The amount of the buffer to be used may be appropriately selected by those skilled in the art, for example, from 0.80 w / v% to 3.00 w / v% of sodium hydrogen phosphate (or its hydrate), sodium dihydrogenphosphate .

As the isotonic agent, sodium chloride, potassium chloride, boric acid, borax, etc. may be used, but the present invention is not limited thereto. The amount of isotonic agent to be used can be suitably selected by those skilled in the art. For example, when sodium chloride is used, it can be used in the range of 0.75 w / v% to 0.95 w / v%. When sodium chloride, boric acid, and borax are used, they may be used in the range of 0.05 w / v% to 1.00 w / v%, respectively.

The pH adjusting agent may be added to adjust the pH of the resultant ophthalmic solution composition to an appropriate range, for example, pH 5.0 to 8.0, preferably about pH 7.0, and hydrochloric acid or sodium hydroxide may be usually used. The pH adjusting agent may be used in an amount required for obtaining a suitable range of pH, and is not particularly limited.

In the ophthalmic composition of the present invention, as the aqueous medium, sterilized purified water, injection water and the like suitable for preparation of ophthalmic preparations can be used. The ophthalmic composition according to the present invention can be used in the form of an ordinary eye drop.

The present invention also provides the provision of an ophthalmic composition in the form of a nanoemulsion in which the anti-irritation is minimized. According to one embodiment of the present invention, cyclosporin; Propylene glycol dicaprylroccaprate as an oil and medium chain triglycerides having 8 to 10 carbon atoms; And a polyoxyl 35 hydrogelate castor oil as a surfactant in an aqueous medium. The ophthalmic composition is in the form of a nanoemulsion having a particle size of 200 nm or less. In this embodiment, the oil content may be from 0.05 v / v% to 0.80 v / v%, more preferably from 0.05 v / v% to 0.37 v / v%, based on the total composition; The content of the surfactant may be 0.63 v / v% to 1.32 v / v%, more preferably 1.00 v / v% to 1.15 v / v% based on the total composition. Also, in a preferred embodiment, 0.05 w / v% cyclosporine; 0.05 v / v% propylene glycol dicaprylroccaprate; 0.37 v / v% of a medium chain triglyceride having 8 to 10 carbon atoms; There is provided an ophthalmic composition in the form of a nanoemulsion having a particle size of 200 nm or less, comprising 1.15 v / v% of polyoxyxyl 35 hydrogene castor oil in an aqueous medium. In the above embodiments and preferred embodiments, the ophthalmic composition may further include sodium hydrogen phosphate or a hydrate thereof, sodium dihydrogenphosphate or a hydrate thereof, or a mixture thereof as a buffer, more preferably sodium hydrogenphosphate Or 2.72 w / v% of its hydrate and 0.84 w / v% of sodium dihydrogenphosphate or its hydrate. In a particularly preferred embodiment, 0.05 w / v% cyclosporin; 0.05 v / v% propylene glycol dicaprylroccaprate; 0.37 v / v% of a medium chain triglyceride having 8 to 10 carbon atoms; Polyoxyl 35 Hydrogenate castor oil 1.15 v / v%; 2.72 w / v% sodium hydrogen phosphate (or hydrate thereof); And 0.84 w / v% of sodium dihydrogenphosphate (or hydrate thereof) in an aqueous medium. The ophthalmic composition is in the form of a nanoemulsion having a particle size of 200 nm or less.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example .

According to the ingredients and contents of Tables 1 to 8 below, a liquid composition for a point-of-care liquid in the form of a nano-emulsion was prepared. After thoroughly mixing the surfactant and oil with a stirrer, cyclosporin A was added to completely dissolve it, and then 90 ml of sterilized purified water was added and sufficiently mixed. The osmotic pressure was adjusted to 0.9 by adding a buffer and / or an isotonic agent, and a pH adjuster was added to adjust the pH to about 7.0. Sterile purified water was added to the solution, the total volume was adjusted to 100 ml, and the solution was filtered through a 0.22 탆 filter and filled in an eyedrops container.

Test Example 1. Particle size distribution and average particle size measurement

Cyclosporine A-containing eyedrops of reseutasiseu ^TM (Allergan between the copper federated) and particle size distribution and average particle diameter of the eye drops (Example 1, 5, eye drops prepared in 7, 12, 31, and 39) produced in accordance with the present invention Were measured. The particle size was measured using a Zetasizer (Malvern Instruments, UK), and the particle size was measured by optical scattering after injecting 2 mL of each sample solution (eye drops) without dilution. The results of measuring the particle size distribution of the eye drop and Restasis ^TM of Example 1 are shown in FIGS. 1 and 2. FIG. The average particle sizes of the eye drops prepared in Examples 1, 5, 7, 12, 31, and 39 are shown in Table 9 below.

Example 1 Example 5 Example 7 Example 12 Example 31 Example 39 Average particle diameter (nm) 11.20 40.22 11.20 61.22 44.71 69.58

From the results of Figs. 1 and 2, Resistis ^TM showed a broad particle size distribution of 0.067 mu m to 2.489 mu m, while the eye drops prepared according to the present invention showed a particle size distribution of 11.2 to 69.58 nm. In addition, since the eye drops prepared according to the present invention have a very small particle size, it is possible to perform the sterilization filtration using a 0.22 μm filter.

Test example 2. Measurement of permeability and property

The permeability and properties of Resistis ^TM (manufactured by Allergan Inc.) and the eye drops prepared in accordance with the present invention (eye drops prepared in Examples 1, 5, 7, 12, 31, and 39) were measured. Transmittance was measured using a Uv-vis spectrophotometer (Shimazdu, Japan), and 2 mL of each sample solution (eye drop) was injected into the apparatus without dilution. After scanning at 700 to 200 nm, the transmittance at 650 nm was measured . Appearance was visually observed. The results are shown in Table 10 below.

Restasis ^™ Example One  5  7  12  31  39 UV 650nm transmittance 0.3% 99.0% 99.0% 98.2% 85.2% 90.6% 95.3% Appearance opacity Transparency Transparency Transparency Translucent Translucent Transparency

From the results shown in Table 10, the eye drops prepared according to the present invention exhibit excellent transparency and show transparency / translucency, thereby minimizing visual blurring in patients and exhibiting excellent drug compliance .

Test Example 3. Stability test

(1) Measurement of transmittance change

The eye drops prepared in accordance with the present invention (eye drops prepared in Examples 1, 5, 7, 12, 31, and 39) were stored at 50 ° C for 4 months, and then the transmittance and properties were measured in the same manner as in Test Example 2 Respectively. The results are shown in Table 11 below.

Example One 5 7 12 31  39 UV 650nm transmittance (initial) 99.0% 99.0% 98.2% 85.2% 90.6% 95.3% UV 650nm transmittance (4 months) 98.9% 99.2% 97.9% 83.7% 90.4% 94.5% Appearance (4 months) Transparency Transparency Transparency Translucent Translucent Transparency

(2) Measurement of content change

The ophthalmic solution (eye drops prepared in Examples 1, 5, 7, 12, 31, and 39) prepared according to the present invention was stored at 40 2 캜 and 25% relative humidity for 6 months, Respectively. Content changes were analyzed using HPLC (High Performance Liquid Chromatography) at the following analysis conditions. The results are shown in Table 12 below.

<HPLC analysis conditions>

- Wavelength: 210 nm

- Column: C8 column

- mobile phase: tetrahydrofuran: 0.03 M phosphoric acid solution = 4: 6 (v / v)

- Flow rate: 1.0 mL / min

Example 1 Example 5 Example 7 Example 12 Example 31 Example 39 Content (Initial) 100.9% 100.7% 99.8% 101.5% 99.7% 102.3% Content (6 months old) 98.4% 97.5% 97.1% 99.7% 96.6% 99.8%

The results of Table 11 and Table 12 show that the nanoemulsion type eye drops according to the present invention are thermodynamically stable systems and have excellent physical and chemical stability.

(3) Long term stability test

The compositions of Examples 1, 5, 7 and 39 were stored for 15 months at 25 占 2 占 폚 and 40 占 占 폚, and the properties and precipitation were measured. The compositions of Examples 43, 44, 45, 46, 47 and 48 were stored at 25 占 2 占 폚 and 40 占 占 폚 for 10 months, and the properties and precipitation were measured. The results are shown in Tables 13 and 14 below.

Storage conditions (15 months) Example One 5 7 39 25 ± 2 ° C Appearance Transparency Transparency Transparency Transparency Presence or absence of precipitation radish radish radish radish 40 ± 2 ° C Appearance Transparency Transparency Transparency Transparency Presence or absence of precipitation radish radish radish radish

Storage conditions (10 months) Example 43 44 45 46 47 48 25 ± 2 ° C Appearance Transparency Transparency Transparency Transparency Transparency Transparency Presence or absence of precipitation radish radish radish radish radish radish 40 ± 2 ° C Appearance Transparency Transparency Transparency Transparency Transparency Transparency Presence or absence of precipitation radish radish radish radish radish radish

From the results shown in Tables 13 and 14, it can be seen that the eye drops prepared according to the present invention have no change in properties during a long period of time under room temperature and accelerated storage conditions, and no phenomenon such as precipitation occurs.

Test Example 4. An irritant test

An eye irritation test was performed on the composition obtained according to the present invention. Approximately 30 uL (1 drop) of each composition was dispensed into one eye of 28 healthy adults, and the degree of irritation was evaluated according to the criteria of Table 15 according to the Draize test (Skin irritation scores) method. Resistis ^TM was used as a positive control.

score Degree of irritation 0 No irritation / discomfort One A slight irritation / discomfort feeling 2 Stimulation / discomfort (less than 5 minutes) 3 Stimulation / discomfort (over 5 minutes) 4 Strong Stimulation (Tear) / Unpleasant Feeling

As a result of the evaluation of the irritant property as described above, most of the compositions showed a total irritancy of more than 50 in comparison with the positive control (Resistis ^TM ). However, the composition of Example 43 significantly decreased the irritant property as compared with the positive control. It is very interesting that the composition of Example 43 can significantly reduce anti-irritancy, even though the composition of Example 43 and the composition of Example 48 have some differences in ingredients. The results of the evaluation of the eye irritation for the compositions of the positive control, Example 43, and Example 48 are shown in Table 16 below.

Fish
Subject
Test composition Fish
Subject
Test composition Positive control group
(Restasis ^TM ) Example 43
Composition Example 48
Composition Positive control group
(Restasis ^TM ) Example 43
Composition Example 48
Composition One One One One 15 0 One One 2 2 One One 16 3 3 2 3 3 One 4 17 One One One 4 2 One One 18 One One One 5 3 One 4 19 0 One One 6 One 0 One 20 One 0 One 7 2 3 3 21 2 One 2 8 2 2 2 22 0 0 One 9 0 2 2 23 4 2 2 10 2 One One 24 0 One One 11 One One One 25 One One One 12 0 One One 26 One One 2 13 2 3 4 27 3 2 3 14 2 2 2 28 3 2 2 Sum 43 37 49 Average 1.54 1.32 1.75

Claims (11)

delete delete delete delete delete delete delete delete 0.05 w / v% cyclosporin A; 0.05 v / v% propylene glycol dicaprylroccaprate; 0.37 v / v% of a medium chain triglyceride having 8 to 10 carbon atoms; A composition for ophthalmic use in the form of a nanoemulsion having a particle size of 200 nm or less, comprising 1.15 v / v% of polyoxyxyl 35 hydrogene castor oil in an aqueous medium. The ophthalmic composition according to claim 9, further comprising sodium hydrogen phosphate or a hydrate thereof, sodium dihydrogenphosphate or a hydrate thereof, or a mixture thereof as a buffer. 0.05 w / v% cyclosporin A; 0.05 v / v% propylene glycol dicaprylroccaprate; 0.37 v / v% of a medium chain triglyceride having 8 to 10 carbon atoms; Polyoxyl 35 Hydrogenate castor oil 1.15 v / v%; 2.72 w / v% sodium hydrogen phosphate or its hydrate; And 0.84 w / v% of sodium dihydrogenphosphate or hydrate thereof in an aqueous medium, in the form of a nanoemulsion having a particle size of 200 nm or less.

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