KR102160974B1 - Nanodiamond-drug complex and method for preparing the same - Google Patents

Abstract

The present invention relates to a nanodiamond-drug complex for drug delivery and a method for preparing the same, and more particularly, to a nanodiamond-drug complex for sustained-release drug delivery and a method for preparing the same. The method for preparing a nanodiamond-drug complex according to the present invention comprises the steps of: obtaining a surface-treated nanodiamond-containing mixture by mixing a surface treatment agent in a nanodiamond-containing solution; Classifying surface-treated nanodiamonds from the mixture; And mixing the classified surface-treated nanodiamond and a drug.

Description

Nanodiamond-drug complex and method for preparing the same}

The present invention relates to a nanodiamond-drug complex for drug delivery and a method for preparing the same, and more particularly, to a nanodiamond-drug complex for sustained-release drug delivery and a method for preparing the same.

In recent years, the dosing cycle of many active pharmaceutical drugs, including drugs and prodrugs, has improved, for example sustained release (slow release, sustained release, or sustained release over time to allow once a day or once a week). Studies on formulations of modified release form) are on the rise, but studies on such sustained release formulations tend to be limited to formulations administered orally or administered through injection.

In addition, Ketoprofen, Ibuprofen, Naproxen, Fluriprofen, Diclofenac, Aceclofenac, Ketorolac, Indomethacin, Nonsteroidal anti-inflammatory drugs (NSAIDs) such as Meloxicam, Nimensulide, Celecoxib, Etoricoxib, and Piroxicam It is reported that various side effects occur in the stomach, kidneys, liver, etc. when formulated and administered as an oral formulation or injection. Therefore, it is necessary to develop a formulation that can minimize the side effects of the above NSAIDs. Actually.

On the other hand, nanodiamond (ND) is also referred to as ultra-nano crystalline diamond or ultra-dispersed diamond (UDD), and is a unique nanomaterial that can be easily manufactured in tens of kg by detonation synthesis. Recently, the above nanodiamonds have been used in various fields such as electroplating, polishing, various polymer engineering and thermal composites, CVD-seeding, oil and lubricant additives, luminescence imaging, and quantum engineering. Attempts to communicate are also continuing.

However, the nanodiamonds as described above are typically present in agglomerates with a diameter of about 1 mm. Therefore, in order to utilize nanodiamonds, there is inconvenience in that the above aggregates must be pulverized or separately purified and used, and nanodiamonds obtained through such pulverization or purification have a very wide distribution of particle sizes, and thus various fields It is a situation in which it is difficult to use nanodiamonds of a more uniform size. In addition, nanodiamonds obtained through pulverization or purification as described above have a property of being re-aggregated during distribution or when stored and used instead of immediately after pulverization or purification. However, when the re-aggregated nanodiamonds are pulverized or purified again as described above, not only are they not separated into previously separated sizes, but also there is a problem of poor redispersibility in the solution.

The inventors of the present invention were conducting research on a formulation that can deliver various drugs such as NSAIDs into the body by minimizing conventional side effects by using nanodiamonds, while the drug has excellent sustained-release delivery effect, The present invention was completed by discovering a method for preparing a drug complex that exhibits a surprising effect that can exhibit excellent redispersibility even after re-aggregation of nanodiamonds.

Korean Patent Application Publication No. 10-2013-0051040 (published on May 20, 2013)

Nano letter., 7(11), 3305-3314, 2007. (released on October 5, 2007)

The present invention is to provide a drug complex capable of sustained release of a drug.

In addition, the present invention is to provide a method for preparing a drug complex as described above.

In order to achieve the above object, the present invention is to obtain a surface-treated nanodiamond-containing mixture by mixing a surface treatment agent in a nanodiamond-containing solution; Classifying surface-treated nanodiamonds from the mixture; And mixing the classified surface-treated nanodiamond and a drug; and a method for preparing a nanodiamond-drug complex.

In addition, the present invention provides a nanodiamond-drug complex formed by combining a classified surface-treated nanodiamond and a drug.

Using the method for preparing a nanodiamond-drug complex of the present invention, a nanodiamond-drug complex having excellent sustained-release effect of a drug can be prepared. In addition, by preparing a nanodiamond-drug complex using nanodiamonds having a more uniform size, the drug content and storage stability of the nanodiamond-drug complex may be improved.

In addition, the surface-treated nanodiamonds according to the present invention may exhibit excellent redispersibility effects.

The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the content of the above-described invention, so the present invention is limited to the matters described in such drawings. It is limited and should not be interpreted.
1 shows an embodiment of a classification step in the preparation of a nanodiamond-drug complex of the present invention.
Figure 2 shows a graph showing the drug-binding ability of the surface-treated RND and diclofenac. The graph shows a graph of the drug binding capacity (y-axis) versus the mass ratio (x-axis) of diclofenac/RND.
3 is a graph showing the drug-binding ability of RND-COOH and diclofenac further modified with COOH to surface-treated RDN. Graph? Shows a graph of the drug binding capacity (y-axis) to the mass ratio (x-axis) of diclofenac/RND-COOH.
4 is a graph showing the drug release characteristics of a diclofenac solution and an RND-COOH/diclofenac complex.

Hereinafter, a method for preparing a nanodiamond-drug complex of the present invention and a nanodiamond-drug complex will be described in detail.

[Method for preparing nanodiamond-drug complex]

The method for preparing a nanodiamond-drug complex of the present invention comprises the steps of obtaining a surface-treated nanodiamond-containing mixture by mixing a surface treatment agent in a nanodiamond-containing solution; Classifying surface-treated nanodiamonds from the mixture; And mixing the classified surface-treated nanodiamond and a drug.

Obtaining a surface-treated nanodiamond-containing mixture

First, in the method for preparing a nanodiamond-drug complex according to the present invention, a mixture containing nanodiamonds surface-treated is prepared by mixing nanodiamonds and a surface treatment agent as raw materials.

As the raw material, the nanodiamond may use pure nanodiamond particles, for example, a nanodiamond having a nanodiamond content of 90% by weight or more or a nanodiamond content of 95% by weight or more, more preferably a nanodiamond content of 99% by weight. You can use As the raw material, the nanodiamond may include 0.5-1.2% by weight of residual metal impurities contained in the production of the nanodiamond. The residual metal impurities are not limited thereto, but may represent, for example, at least one metal selected from the group consisting of Al, Si, P, Ca, Fe, Ni, Cu, and Zn, and salts thereof. More specifically, the nanodiamond as the raw material of the present invention may be a detonation nanodiamond prepared by a known method, and a commercially available nanodiamond may be obtained and used.

The surface treatment agent is hydroxide ion (OH ^-) in an aqueous solvent, bicarbonate ion (HCO ₃ ^-), carbonate ions (CO ₃ ^2-), chloride ion (Cl ^-), bromide ion (Br ^-), nitrate ion ( NO ₃ ^-), phosphate ion (PO ₃ ^-), and can emit at least one of the ions can be used a compound which is selected from the group consisting of sulfate ion (SO ₄ ^2-). More specifically, the surface treatment agent is not limited thereto, but, for example, an alkali metal compound capable of releasing the ions may be used, and more specifically NaOH, NaHCO ₃ , Na ₂ CO ₃ , NaCl, NaBr, NaNO ₃ , NaPO ₃ , KOH, KHCO ₃ , KCO ₃ , KCl, KBr, KNO ₃ , KPO ₃ or mixtures thereof may be used. In addition, it may be most preferable to use NaHCO ₃ , Na ₂ CO _3, or a mixture thereof in terms of the drug-containing capacity of the nanodiamond-drug complex and the redispersion of the nanodiamond.

The surface treatment agent may be mixed in an amount of 0.1 to 10 parts by weight based on 100 parts by weight of the nanodiamond-containing saturated solution, and more specifically, it may be mixed in an amount of 1 to 5 parts by weight.

In one embodiment, the nanodiamond may be mixed in an amount of 3 to 4 parts by weight based on 100 parts by weight of the saturated solution containing the surface treatment agent.

In one embodiment, when the surface treatment agent is NaCl, the saturated solution containing NaCl may contain 0.00036 g of NaCl per 1 mL of H ₂ O.

In one embodiment, when the surface treatment agent is NaHCO _{3, the} saturated solution containing NaHCO ₃ may contain 0.09 g of NaHCO ₃ per 1 mL of H ₂ O.

In one embodiment, the nanodiamond and the surface treatment agent are contained in a concentration of 3 to 10% by weight, preferably 3 to 5% by weight, in 10 to 100 ml of a solution containing a surface treatment agent having a saturation concentration at 25°C. Nanodiamond-containing solution may be mixed in 1 to 10 ml, and more specifically, in 30 to 80 ml of a solution containing a saturated surface treatment agent, a nanodiamond-containing solution containing a nanodiamond in a concentration of 4 to 6% by weight It can be mixed at a mixing ratio of 1 to 3 ml. When the mixing ratio is within the above range, it may be preferable in terms of surface treatment of nanodiamonds, binding force with drugs, redispersibility of nanodiamonds, and uniform classification of nanodiamonds. For example, when the mixing ratio is less than the above range, the degree of surface modification of the nanodiamond may be insignificant, resulting in a problem that the binding force with the drug is lowered.If the mixing ratio exceeds the above range, on the surface of the surface-treated nanodiamond There may be a problem in that the uniformity of the size of the nanodiamond is deteriorated due to aggregation between the surface treatment agents or aggregation with moisture.

The mixing of the nanodiamond and the surface treatment agent may be appropriately adjusted according to mixing conditions such as temperature and humidity, and the mixed solvent is not limited thereto, but for example, water, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide, Aqueous solvents such as dimethylformamide, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, diethyl ether, diisopropyl ether, 1,4-dioxane, benzene, hexane, chloroform, or mixtures thereof , An oily solvent or a mixed solvent thereof may be used. The mixing may be preferably performed in an aqueous solvent in order to improve the dispersibility of the nanodiamond and the surface treatment agent.

In addition, in the method for preparing a nanodiamond-drug complex of the present invention, the nanodiamond and the surface treatment agent may be added to an aqueous solvent and then mixed using known means such as stirring and ultrasonic treatment, but the surface treatment in the solution In terms of improving the purity of the nanodiamond, it may be desirable to mix through stirring. For example, when mixing by ultrasonic treatment, there may be a problem that the purity of the surface-treated nanodiamond in the solution decreases due to the generation of the ultrasonic metal residue in the solution.

In addition, the method for preparing a nanodiamond-drug complex of the present invention may further include a step of mixing the nanodiamond and the surface treatment agent as described above, and then standing at room temperature, for example, 25 to 30°C. In the case of further performing the stationary step, it is possible to improve the surface treatment rate of the nanodiamond and the purity of the solution containing the surface treatment nanodiamond. For example, in the case of performing the stationary step, the remaining amount of nanodiamond particles that are not surface-treated may precipitate and settle, and a surface-treated nanodiamond may be obtained from the supernatant.

The stationary step is not limited thereto, but may be preferably performed for 30 minutes to 120 minutes, such as 50 to 100 minutes in terms of overall process efficiency.

Classification of surface-treated nanodiamonds

The method for preparing a nanodiamond-drug complex of the present invention includes the step of classifying the surface-treated nanodiamond prepared above. Accordingly, the present invention can select and use a surface-treated nanodiamond having a more uniform particle size and a more uniform zeta potential. In addition, by using a surface-treated nanodiamond having a more uniform particle size and a more uniform zeta potential, the drug content of the prepared nanodiamond-drug complex can be uniformly prepared, thereby improving the quality of the product excellently. have.

In addition, the nanodiamond surface-treated according to the present invention may exhibit excellent redispersibility in a solution after drying.

Nanodiamonds classified by conventionally known pulverization or purification with an acid solution have a problem in that they aggregate and are not redispersed when redispersed in a solution after drying.

In one embodiment, it was confirmed that the dispersibility was excellent even when the process of re-dispersing in distilled water after drying the nanodiamond surface-treated according to the present invention was repeated 10 times.

In the classification step, the surface-treated nanodiamond-containing mixture is allowed to stand to separate the supernatant, and the precipitate is washed with water, stirred and allowed to stand, to obtain a nanodiamond having a desired particle size.

In addition, the classification step is to obtain the classified nanodiamonds from the supernatant produced by centrifuging the surface-treated nanodiamond-containing mixture, washing the recovered precipitate with water, stirring and centrifuging the desired particle size. Nanodiamonds of can be obtained.

In one embodiment, in the classification step, the nanodiamonds may be separated according to the particle size by performing one or more centrifugation, and the supernatant generated after each centrifugation includes the classified surface-treated nanodiamonds, and the precipitate Contains a mixture of unclassified nanodiamonds and surface treatment agents.

The temperature of the centrifugation is not limited thereto, but when the temperature increases due to convection during centrifugation, a problem of lowering the dispersion effect may occur, and thus, for example, it may be performed at 25°C or less. In addition, it may be more preferable to perform the centrifugation at 10° C. or lower, in consideration of the binding force with a bio-material, for example, a drug as the temperature increases, and may be performed at 4 to 10° C., for example.

In addition, the centrifugation may be performed at a speed of 2,000 to 3,000 G (gravity), but is not limited thereto.

In one embodiment, the centrifugation was performed at 10° C. at a speed of 2,000 to 15,000 rpm (SUPRA 30K centrifuge) for 30 minutes.

Through the classification step, it is possible to obtain a classified surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 30 to 150 nm. For example, surface-treated nanodiamonds having an average particle diameter (D ₅₀ ) of less than 30 nm can be obtained from the supernatant prepared first through the above classification step, and through repetition of the above process, in turn, 30 nm or more and less than 60 nm. , It is possible to obtain a surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 60 nm or more and less than 150 nm and 150 nm or more. When considering the size of the prepared nanodiamond-drug complex, a surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 60 nm or more, for example 60 to 150 nm, 60 to 100 nm or 60 to 80 nm was obtained. It may be desirable to do.

In one embodiment, when using a surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 60 nm or more, it is preferable in terms of drug-containing dose while not passing through the blood-brain barrier. can do.

In addition, the obtained classified surface-treated nanodiamond may have a zeta potential (ζ) ≤ -30 mV, and a zeta of -60 to -40 mV in terms of binding force and sustained release of the prepared nanodiamond-drug complex It may be desirable to obtain one having a potential.

The zeta potential may represent a zeta potential at 25° C. of an aqueous suspension of 0.05 to 1% by weight containing the classified surface-treated nanodiamonds, and the zeta potential may be measured by a known device and method.

Mixing the classified surface-treated nanodiamond and the drug

The method for preparing a nanodiamond-drug complex of the present invention includes mixing the surface-treated nanodiamond classified above and a drug. By mixing the classified surface-treated nanodiamond and the drug, a nanodiamond-drug complex in which the classified surface-treated nanodiamond and the drug are physically bonded can be prepared.

It is preferable that the drug can bind to the classified surface-treated nanodiamonds exhibiting a negative zeta potential as an electrostatic attraction. The drug is not limited thereto, but may include, for example, one or more selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids.

The nonsteroidal anti-inflammatory agent is not limited thereto, for example, aspirin, salicylic acid, ibuprofen, naproxen, dexketoprofen, loxoprofen, dexibuprofen, ketoprofen, phenoprofen, flubiopro Pen, oxaprozin, indomethacin, tolmethine, sulidac, etodolac, ketorolac, diclofenac, aceclofenac, or mixtures thereof may be used.

The steroid is not limited thereto, for example, dexamethasone, clobetasol, desoxymethasone, hypokinoid, anticinolide, betamethasone, butesonide, flucinonide, prednicarbonate, diflucortorone, or Mixtures of these can be used.

In the present invention, the mixing ratio of the classified surface-treated nanodiamond and the drug is not particularly limited, and the mixing ratio may be adjusted in consideration of the binding capacity of the drug to the classified surface-treated nanodiamond.

In one embodiment, 0.5 to 1 g of the drug may be bound per 1 g of the classified surface-treated nanodiamond, but the binding capacity is not limited thereto.

In one embodiment, the inventors of the present invention confirmed that 0.511 g of diclofenac can be bound per 1 g of the classified surface-treated nanodiamond.

The method for preparing a nanodiamond-drug complex of the present invention comprises the classified surface-treated nanodiamonds by known means within a range that does not impair the object of the present invention before mixing the classified surface-treated nanodiamonds with a drug. It may further include a step of purifying. Even after purification, it is preferable that the average particle diameter and zeta potential of the classified surface-treated nanodiamonds do not substantially change.

In addition, the method for preparing the nanodiamond-drug complex of the present invention is to improve the zeta potential of the surface of the nanodiamond within a range that does not impede the object of the present invention before mixing the classified surface-treated nanodiamond with a drug. It may further include the step of modifying the surface of the diamond. For example, it is possible to perform additional surface modification by conjugating a compound containing a carboxyl group to the surface of the classified surface-treated nanodiamond, but the simplification of the process and the size of the prepared nanodiamond-drug complex and the sustained release of the drug In terms it may be desirable to not include an additional surface modification step.

[Nanodiamond-drug complex]

The nanodiamond-drug complex of the present invention is formed by combining the classified surface-treated nanodiamond and the drug.

The nanodiamond-drug complex of the present invention is formed by bonding the nanodiamond surface-treated using the above-described surface treatment agent and the electrostatic attraction of the drug.

The average particle diameter (D50) of the surface-treated nanodiamond is 30 to 150 nm, for example, 35 to 140 nm, 40 to 130 nm, 45 to 120 nm, 50 to 110 nm, 55 to 100 nm, 60 to 90 nm, 60 to 80 nm may be preferred in terms of the drug content and sustained release of the drug.

The zeta potential (ζ) of the surface-treated nanodiamond may be ζ ≤ -30 mV, and for example, the drug content and It may be desirable in terms of sustained release of the drug.

The surface of the surface-treated nanodiamond may be further surface-modified by a compound having a carboxyl group, but in terms of the size of the nanodiamond-drug complex and the sustained release of the drug, the surface is additionally surfaced by a compound having a carboxyl group. It may be desirable to use one that has not been modified.

It is preferable that the drug can bind to the classified surface-treated nanodiamonds exhibiting a negative zeta potential as an electrostatic attraction. The drug is not limited thereto, but may include, for example, one or more selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs,) and steroids.

The nonsteroidal anti-inflammatory agent is not limited thereto, for example, aspirin, salicylic acid, ibuprofen, naproxen, dexketoprofen, loxoprofen, dexibuprofen, ketoprofen, phenoprofen, flubiopro Pen, oxaprozin, indomethacin, tolmethine, sulidac, etodolac, ketorolac, diclofenac, aceclofenac, or mixtures thereof may be used.

The steroids are not limited thereto, for example, dexamethasone, clobetasol, desoxymethasone, hypokinoids, antisinorides, betamethasone, butesonide, flucinonide, prednicarbonate, diflucortorone or these Mixtures of can be used.

[Applications of nanodiamond-drug complex]

The present invention can provide a pharmaceutical formulation comprising the nanodiamond-drug complex according to the present invention. The pharmaceutical formulation according to the present invention can be provided in various known forms of pharmaceutical formulations. For example, the present invention can provide a pharmaceutical composition comprising a nanodiamond-drug complex and a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated as an oral formulation, a parenteral formulation, or the like, but is not particularly limited thereto.

In the present invention, the pharmaceutical preparation containing the nanodiamond-drug complex is preferably a preparation for transdermal administration, and the preparation for transdermal administration is more preferably an ointment and a patch, and most preferably may be a medical patch.

The medical patch may be a patch prepared by applying a composition including a nanodiamond-drug complex according to the present invention on a support and then drying it.

In addition, the medical patch may be a patch composed of the hydrogel after preparing a hydrogel including the nanodiamond-drug complex without the support.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely describe the present invention to those with average knowledge in the field to which the present invention belongs.

Preparation and classification of surface-treated nanodiamonds

NaHCO in a suspension containing 5% by weight of nanodiamonds (RND (Real Dzerzhinksy Ltd, Russia), CND (Carbodeon Ltd, Finland, Snezhinsk, Russia) and SND (Snezhinsk, Russia)) in an amount of 5 μl each per 1 ml of suspension. ₃ and NaCl were added and stirred at room temperature to prepare an initial hydrosol.

Surface-treated nanodiamonds having an average particle diameter (D ₅₀ ) of less than 30 nm by centrifuging (SUPRA 30K) for 10 minutes at 30,000 G (15,000 rpm) at 10°C after allowing the prepared initial hydrosol to stand at room temperature for 1 hour Was obtained. After adding 25 ml of distilled water to the precipitate, a homogeneous solution was prepared by stirring. The prepared solution is stirred for 10-20 seconds using a stirrer. After stirring, it was centrifuged at 30,000 G at 10° C. for 15 minutes to obtain a surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 30 to 60 nm. After adding 25 ml of distilled water to the precipitate, a homogeneous solution was prepared by stirring. The prepared solution is stirred for 10-20 seconds using a stirrer. After stirring, it was centrifuged at 30,000 G at 10° C. for 15 minutes to obtain a surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 60 to 90 nm. After adding 25 ml of distilled water to the precipitate, a homogeneous solution was prepared by stirring. The prepared solution is stirred for 10-20 seconds using a stirrer. After stirring, centrifugation at 5,500 G (6,000 rpm) at 10° C. for 10 minutes to obtain surface-treated nanodiamonds having an average particle diameter (D ₅₀ ) of 90 to 150 nm.

The above method was repeated 7 times to classify surface-treated nanodiamonds of less than 30 nm, 30 to 60 nm, 60 to 90 nm, and 90 to 150 nm, respectively.

[Evaluation of physical properties of surface-treated nanodiamond]

The prepared and classified surface-treated nanodiamonds were dried and prepared in a powder form. Then, the weight and weight% of the powder were measured for each fraction.

color

The prepared nanodiamonds exhibited the characteristics of detonation nanodiamonds, and the color of the powder was different according to the average size of the particles. The color was changed in the following order: the fraction with the smallest particle size represents dark black, the fraction with the medium particle size represents gray, and the fraction with the largest particle size represents milk white or beige.

Average particle size

The particle size of the classified surface-treated nanodiamonds was measured using Equation 1 below.

[Equation 1]

In Equation 1, η represents the viscosity of the dispersion medium, and the unit is Pa.s. For example, it may represent the viscosity measured using a Brookfield viscometer (spindle #4-6) at 25°C; ρ ₀ represents the density of the dispersion medium, and the unit is g/cm ³ ; ρ represents the apparent density of the dispersed phase, the unit is g/cm ³ (the apparent density is a tap density meter (measured using the German Englesmann STAV II)), ω represents the speed of the rotor, and the unit is rad/s. ; τ is the time, the unit is seconds (s); and l ₁ and l ₂ represent the distance from the rotation axis to the center of each of the sediment and liquid columns, the unit is m.

The average diameter and weight% according to the fraction of the surface-treated nanodiamonds classified above are shown in Table 1 below.

Fraction number Average diameter, nm weight% One 28.6 21 2 36.5 28 3 47.3 16 4 68.8 13 5 73.1 6 6 94.3 12 7 105.7 4

Modification of carboxylate of surface-treated nanodiamonds

Using the surface-treated nanodiamond classified above, a nanodiamond whose surface was further modified with a carboxylate group was prepared through the following process.

First, after adding 3 g of the surface-treated nanodiamond (hereinafter referred to as'RND') classified by 60 to 90 nm to a preheated mixture of 100 mL of H ₂ SO ₄ :HNO ₃ (mixing ratio 3:1), 48 hours While stirring. Thereafter, 50 mL of 0.1 M NaOH aqueous solution was added to the mixture, and the mixture was stirred at 80° C. for 3 hours, and then 0.1 M HCl aqueous solution was added dropwise over 2 hours to remove excess acid. Finally, the resulting mixture was washed by centrifugation several times using deionized water, and the obtained precipitate was dried and dispersed in deionized water to prepare a carboxylate-modified surface-treated nanodiamond (hereinafter'RND-COOH'). I did.

[Evaluation of physical properties of RND and RND-COOH]

Z-average, polydiversity, and Z-potential of RND and RND-COOH prepared above using a particle size analyzer (Zetasizer Nano ZS, Malvern Instruments Ltd, UL) The measurement results are shown in Table 2 below.

The results are expressed as the average value of the results of three measurements on an aqueous suspension solution containing nanodiamonds at a concentration of 0.1 wt% at 25°C.

Z-average, nm Polydispersity Z-potential, mV RND 80.7 0.17 -49.5 RND-COOH 82.9 0.21 -50.5

Preparation of nanodiamond-drug complex

A nanodiamond-drug complex in which Diclofenac was bound to RND and RND-COOH prepared above was prepared using the following method (RND/Diclofenac, RND-COOH/Diclofenac, respectively).

100 μl of RND and RND-COOH suspension, each containing 5 mg of nanodiamond powder, was added to a vial containing 1000 μl of aqueous diclofenac solution. The vial was shaken at ambient temperature for 10 minutes to reach equilibrium. Then, 2 μl of 0.25M NaCl was added to the mixture, maintained for 5 minutes while stirring, and then centrifuged at 16,000 G for 10 minutes at 10° C. to prepare a nanodiamond-drug complex.

The physical properties of the prepared nanodiamond-drug complex were measured as described above, and the results are shown in Table 3 below.

In addition, after centrifugation at 16,000 G for 10 minutes above, the supernatant containing unadsorbed diclofenac was diluted at a ratio of 1:400, and then at 276 nm using a UV spectrometer (UV-1800, Shimadzu, Japan). The absorbance of the supernatant was measured. The drug concentration was measured according to Beer's law using linear calibration. The drug binding (adsorption) ability of the nanodiamond was calculated using the following equation, and the results are shown in Table 4, FIGS. 2 and 3 below.

Drug binding capacity = W _d /W _nd x 100%

In the above formula, W _d is the weight of the adsorbed drug, and W _nd is the weight of the nanodiamond nanoparticles.

In order to compare the drug-binding ability of nanodiamonds, diclofenac was bound as described above using nanodiamonds (Carbodeon Ltd Oy, Finland, hereinafter'CND') showing a zeta potential of (+) without surface treatment as a nanodiamond. The results for the composite are shown together.

In addition, CND/Ketorolac bound to CND was prepared using ketorolac as a drug, and the results are shown together.

Z-average, nm Polydispersity Z-potential, mV RND/Diclofenac 121.5 0.18 -35.6 RND-COOH/Diclofenac 66.5 0.17 -29.7 CND 75.5 0.190 +39.3 CND/Ketorolac 5563 ^* 0.430 +19.9

^* Represented as a muldimodal distribution.

ND/Drug (μg/mg) RND RND-COOH CND Diclofenac 511 524 260

Evaluation of drug release characteristics of nanodiamond-drug complex

The drug release characteristics were evaluated using the RND-COOH/Diclofenac and CND/Ketorolac complexes prepared above.

The drug release characteristics were evaluated in vitro at 26°C by preparing a cell having a semi-permeable membrane between the donor chamber and the receptor chamber. As the semipermeable membrane, a dialysis tube (36/32 VISKING, SERVA, Germany) having a pore radius of 24Å and a permeation limit of 8-15 kDa was used, and before the experiment, a dialysis bag was placed at 50° C. for 1 hour at 10 Mm EDTA-Na After activation with salt (pH 7), it was used after washing several times with deionized water. The donor compartment was a plastic ring (27 mm in diameter) covered with a dialysis bag, and in the test, 2 mL of sample was introduced into the donor compartment, and one side was immersed in a glass beaker filled with 30 mL of deionized water (aqueous solution, receptor solution). . Stirring was continued during the test using a magnetic bar. The aqueous solution was replaced with an equal amount of deionized water every 12 hours for the first 24 hours. The drug concentration in the aqueous solution was measured as the maximum absorption using a calibration curve. As a control, the release characteristics of the free drug dissolved in 2 mL of deionized water under the same conditions were evaluated. The release characteristics were evaluated and shown in FIG. 4.

Experiment result

Through the above experiments, the nanodiamonds surface-treated according to the present invention showed excellent solution stability, and more specifically, the nanodiamonds as obtained without surface treatment showed that they aggregated and precipitated in the solution after 1 hour. , Nanodiamonds surface-treated according to the present invention showed excellent solution stability for at least 6 months. In addition, it was confirmed that the stability of the colloid solution was maintained when water was added to the nanodiamond in the surface-treated powder state and then dried several times (at least 10 times), indicating that redistribution was possible. Accordingly, it was confirmed that the intrinsic properties of the detonation nanodiamond were maintained by showing a color change.

In addition, as can be seen in Table 4, it was confirmed that RND and RND-COOH form a complex with diclofenac, and as a comparative example, CND, which has a positive surface charge, forms a complex with ketorolac, whereas diclofenac and It was confirmed that the complex could not be formed.

On the other hand, according to Figures 2 and 3, it was confirmed that the drug-binding ability of RND and RND-COOH changed according to the mass ratio of diclofenac and nanoparticles, and it was confirmed that the drug-binding ability increased as the mass ratio increased. It was confirmed that the maximum values were 511 and 524 μg/mg, respectively. Taking this into consideration, it was confirmed that the size of the surface-treated nanodiamond has a greater effect than the size of the drug itself.

In addition, as can be seen from the results of FIGS. 2 and 3 and above, it was confirmed that the nanodiamonds surface-modified according to the present invention exhibited conjugate properties with the same or similar drugs even if they were not further modified by carboxylate.

In addition, it was confirmed that the surface-modified nanodiamond according to the present invention exhibits excellent redispersibility effects.

As a result of evaluating the drug release characteristics of the nanodiamond-drug complex, it was possible to confirm the drug release characteristics of the nanodiamond at a constant delayed rate, and the confirmed drug release characteristics corresponded to the Michaelis-Menten equation (Michaelis-Menten eq.). It was confirmed that it was possible to calculate the amount of drug delivered to the nanodiamond.

Claims (14)

Obtaining a surface-treated nanodiamond-containing mixture by mixing a surface treatment agent with the nanodiamond-containing solution;
Classifying surface-treated nanodiamonds from the mixture; And
Including; mixing the classified surface-treated nanodiamonds, and the classified surface-treated nanodiamonds and a drug capable of binding by electrostatic attraction;
The surface treatment agent is a hydroxyl ion in the aqueous solvent (OH ^-), bicarbonate ion (HCO ₃ ^-), carbonate ions (CO ₃ ^2-), chloride ion (Cl ^-), bromide ion (Br ^-), nitrate (NO ₃ ^-), phosphate ion (PO ₃ ^- the method of the drug complex -) and sulfate ions (the NCD to emit at least one ion selected from the group consisting of SO ₄ ^2-).
The method according to claim 1,
The method of manufacturing a nanodiamond-drug complex, wherein the surface treatment agent is mixed in an amount of 0.1 to 10 parts by weight based on 100 parts by weight of the saturated solution containing nanodiamond.
The method according to claim 1,
After the mixing step and before the classification step, the method of manufacturing a nanodiamond-drug complex further comprising the step of standing the solution at room temperature.
The method according to claim 1,
The classification step includes performing centrifugation at least once,
The supernatant generated after each centrifugation is a method of producing a nanodiamond-drug complex comprising the classified surface-treated nanodiamond.
The method according to claim 1,
The classification step is a method for producing a nanodiamond-drug complex comprising the step of obtaining a classified surface-treated nanodiamond having an average particle diameter (D ₅₀ ) of 30 to 150 nm.
The method of claim 5,
The obtained classified surface-treated nanodiamond is a zeta potential (ζ) ≤ -30 mV of the nanodiamond-drug preparation method.
delete The method according to claim 1,
The drug is a method for producing a nanodiamond-drug complex comprising at least one selected from the group consisting of non-steroidal anti-inflammatory agents and steroids.
As a nanodiamond-drug complex formed by combining the classified surface-treated nanodiamond, and the classified surface-treated nanodiamond and a drug capable of binding by electrostatic attraction,
Will the said nano diamond is subjected to surface treatment by a surface treating agent, the surface treatment agent is a hydroxyl ion (OH ^-) in an aqueous solvent, bicarbonate ion (HCO ₃ ^-), carbonate ions (CO ₃ ^2-), chloride ion (Cl ^- ), bromide ion (Br ^-), nitrate ion (NO ₃ ^-), phosphate ion (PO ₃ ^-) and sulfate ions (in nm to emit at least one ion selected from the group consisting of SO ₄ ^2-) Diamond-drug complex.
The method of claim 9,
The nanodiamond-drug complex in which a drug is bound to the classified surface-treated nanodiamond by electrostatic attraction.
The method of claim 9,
The average particle diameter (D ₅₀ ) of the classified surface-treated nanodiamonds is 30 to 150 nm nanodiamond-drug complex.
The method of claim 9,
The classified surface-treated nanodiamonds have a zeta potential (ζ) ≤ -30 mV. The nanodiamond-drug complex.
The method of claim 9,
The drug is a nanodiamond-drug complex comprising at least one or more selected from the group consisting of non-steroidal anti-inflammatory agents and steroids.
A medical patch comprising a nanodiamond-drug complex according to any one of claims 9 to 13.

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