U.S. patent application number 13/479508 was filed with the patent office on 2012-09-13 for method for preparing nano-scale or amorphous particle using solid fat as a solvent.
Invention is credited to Kab-Sig KIM.
Application Number | 20120231093 13/479508 |
Document ID | / |
Family ID | 36616542 |
Filed Date | 2012-09-13 |
United States Patent
Application |
20120231093 |
Kind Code |
A1 |
KIM; Kab-Sig |
September 13, 2012 |
METHOD FOR PREPARING NANO-SCALE OR AMORPHOUS PARTICLE USING SOLID
FAT AS A SOLVENT
Abstract
The present invention relates to a method for preparing
nanoscale or amorphous particles using solid fat as a solvent.
According to the present invention, nanoscale or amorphous
particles of active ingredients are prepared by using fat as a
solvent, wherein the fat is in solid phase at room temperature. The
nanoscale or amorphous particles of active ingredients can be
advantageously used in medicine, cosmetics, functional foods or the
like.
Inventors: |
KIM; Kab-Sig; (Seoul,
KR) |
Family ID: |
36616542 |
Appl. No.: |
13/479508 |
Filed: |
May 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10596178 |
Jun 2, 2006 |
8211470 |
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PCT/KR04/02914 |
Nov 11, 2004 |
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13479508 |
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Current U.S.
Class: |
424/725 ;
426/573; 426/601; 426/611; 426/655; 426/656; 426/658; 514/1;
514/1.1; 514/23; 514/492; 514/772.3; 514/773; 514/777; 514/784;
977/900; 977/902; 977/906; 977/926 |
Current CPC
Class: |
A61K 9/5123 20130101;
A61K 9/5192 20130101; A61K 9/5138 20130101; A61K 9/5089 20130101;
A61K 9/1694 20130101 |
Class at
Publication: |
424/725 ;
426/573; 426/601; 426/611; 426/655; 426/656; 426/658; 514/1;
514/1.1; 514/23; 514/492; 514/772.3; 514/773; 514/777; 514/784;
977/900; 977/906; 977/926; 977/902 |
International
Class: |
A61K 36/00 20060101
A61K036/00; A23D 9/007 20060101 A23D009/007; A23D 9/013 20060101
A23D009/013; A23L 1/28 20060101 A23L001/28; A23L 1/305 20060101
A23L001/305; A23L 1/30 20060101 A23L001/30; A61K 31/00 20060101
A61K031/00; A61K 38/00 20060101 A61K038/00; A61K 31/70 20060101
A61K031/70; A61K 31/28 20060101 A61K031/28; A61K 47/30 20060101
A61K047/30; A61K 47/42 20060101 A61K047/42; A61K 47/36 20060101
A61K047/36; A61K 47/44 20060101 A61K047/44; A23L 1/308 20060101
A23L001/308; A23L 1/052 20060101 A23L001/052 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 5, 2003 |
KR |
10-2003-0088303 |
Nov 9, 2004 |
KR |
10-2004-0090832 |
Claims
1.-2. (canceled)
3. A method for preparing nanoscale particles comprising the steps
of: (1) preparing a mixture comprising one or more active
ingredients and solid fat as a solvent in an excess amount to the
active ingredient, and (2) pressurizing the mixture comprising one
or more active ingredients and solid fat to the critical pressure
or more by adding the gas of a supercritical fluid into the
mixture, then removing the solid fat from the mixture by releasing
out the solid fat together with the gas of the supercritical fluid,
wherein the supercritical fluid is CO.sub.2 or N.sub.2 and wherein
the temperature is maintained below the melting point of the solid
fat; and, wherein the step (1) further comprises rapidly cooling
the homogeneously melt-mixed mixture for solidification;
pulverizing the solidified mixture; adding one or more surfactants
and/or one or more non-surfactant type anti-coagulating agents or
aqueous solution thereof to the pulverized powder and mixing them
homogeneously; and drying the mixed product at room
temperature.
4. A method for preparing nanoscale particles comprising the steps
of: (1) preparing a mixture comprising one or more active
ingredients and solid fat as a solvent in an excess amount to the
active ingredient, and (2) pressurizing the mixture comprising one
or more active ingredients and solid fat to the critical pressure
or more by adding the gas of a supercritical fluid into the
mixture, and then removing the solid fat from the mixture by
releasing out the solid fat together with the gas of the
supercritical fluid, wherein the supercritical fluid is CO.sub.2 or
N.sub.2 and wherein the temperature is maintained below the melting
point of the solid fat, wherein the step (1) comprises: adding one
or more surfactants and solid fat into a reactor, and melt-mixing
them homogenously; rapidly cooling the homogenously melt-mixed
mixture for solidification; pulverizing the solidified mixture;
adding one or more surfactants and/or one or more non-surfactant
type anti-coagulating agents together with one or more active
ingredients or aqueous solution thereof, to the pulverized powder
and mixing them homogenously; and drying the mixed product at room
temperature.
5.-7. (canceled)
8. The method for preparing nanoscale particles according to claim
3, wherein the active ingredient is organic compounds,
organometallic compounds, natural extracts, peptides, proteins or
polysaccharides that exhibits physiological activities.
9. The method for preparing nanoscale particles according to claim
3, wherein the solid fat is a fat or a mixture of fats maintaining
solid phase at the temperature of 30.degree. C. or less and having
40-150.degree. C. of melting point.
10. The method for preparing nanoscale particles according to claim
9, wherein the solid fat is selected from the group consisting of
saturated fatty acids, esters and alcohols with C10-C22; mono- or
di-glycerides having saturated fatty acid group with C10-C22;
hydrocarbons with C16 or more; tri-glycerides having saturated
fatty acid group with C10-C22; and a mixture thereof.
11. The method for preparing nanoscale particles according to claim
3, wherein the mixture prepared from the step (1) further comprises
one or more material selected from the group consisting of
synthetic surfactants, natural surfactants, lipids, polymers,
monosaccharides, polysaccharides, dietary fibers, gums and
proteins.
12. The method for preparing nanoscale particles according to claim
3, wherein the surfactant is at least one selected from the group
consisting of synthetic surfactants, natural surfactants, lipids
and polymers.
13. The method for preparing nanoscale particles according to claim
3, wherein the non-surfactant type anti-coagulating agent is at
least one selected from the group consisting of monosaccharides,
polysaccharides, dietary fibers, gums and proteins.
14. The method for preparing nanoscale particles according to claim
3, wherein the mixture prepared in the step (1) further comprises a
co-solvent.
15. The method for preparing nanoscale particles according to claim
14, wherein the co-solvent is one or more alcohols with C2-C6.
16. The method for preparing nanoscale particles according to claim
3, wherein the temperature inside the reactor in the step (2) is
below the melting point of the solid fat contained in the mixture
prepared from the step (1).
17. The method for preparing nanoscale particles according to claim
3, wherein the temperature inside the reactor in the step (2) is
20-40.degree. C.
18. The method for preparing nanoscale particles according to claim
3, wherein, in the step (2), the solid fat is removed from the
mixture comprising one or more active ingredients and solid fat
under 70-400 atm by adding the gas of a supercritical fluid to the
mixture.
19. The method for preparing nanoscale particles according to claim
4, wherein the active ingredient is organic compounds,
organometallic compounds, natural extracts, peptides, proteins or
polysaccharides that exhibits physiological activities.
20. The method for preparing nanoscale particles according to claim
4, wherein the solid fat is a fat or a mixture of fats maintaining
solid phase at the temperature of 30.degree. C. or less and having
40-150.degree. C. of melting point.
21. The method for preparing nanoscale particles according to claim
20, wherein the solid fat is selected from the group consisting of
saturated fatty acids, esters and alcohols with C10-C22; mono- or
di-glycerides having saturated fatty acid group with C10-C22;
hydrocarbons with C16 or more; tri-glycerides having saturated
fatty acid group with C10-C22; and a mixture thereof.
22. The method for preparing nanoscale particles according to claim
4, wherein the mixture prepared from the step (1) further comprises
one or more material selected from the group consisting of
synthetic surfactants, natural surfactants, lipids, polymers,
monosaccharides, polysaccharides, dietary fibers, gums and
proteins.
23. The method for preparing nanoscale particles according to claim
4, wherein the surfactant is at least one selected from the group
consisting of synthetic surfactants, natural surfactants, lipids
and polymers.
24. The method for preparing nanoscale particles according to claim
4, wherein the non-surfactant type anti-coagulating agent is at
least one selected from the group consisting of monosaccharides,
polysaccharides, dietary fibers, gums and proteins.
25. The method for preparing nanoscale particles according to claim
4, wherein the mixture prepared in the step (1) further comprises a
co-solvent.
26. The method for preparing nanoscale particles according to claim
25, wherein the co-solvent is one or more alcohols with C2-C6.
27. The method for preparing nanoscale particles according to claim
4, wherein the temperature inside the reactor in the step (2) is
below the melting point of the solid fat contained in the mixture
prepared from the step (1).
28. The method for preparing nanoscale particles according to claim
4, wherein the temperature inside the reactor in the step (2) is
20-40.degree. C.
29. The method for preparing nanoscale particles according to claim
4, wherein, in the step (2), the solid fat is removed from the
mixture comprising one or more active ingredients and solid fat
under 70-400 atm by adding the gas of a supercritical fluid to the
mixture.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for preparing
nanoscale or amorphous particles using solid fat as a solvent.
Specifically, the present invention relates to a method for
preparing nanoscale or amorphous particles of active ingredients
which are advantageously used in medicine, cosmetics, functional
foods or the like, by using fat in solid phase at room temperature
as a solvent.
BACKGROUND ART
[0002] A demand for a technique of an effective and rapid
preparation of very fine particles in regular size has been
constantly required in various industrial fields. Such fine
particles in regular size have many advantages, particularly among
which good flowability and little deviation in particle interaction
are very advantageous in industrial application. In medical field,
the particle size of a therapeutic agent greatly affects to the
dissolution rate, bioavailability, formulation and the like, and
for example, the smaller the deviation in the interaction between
the particles of a therapeutic agent is, the better the whole
stability of the therapeutic agent becomes.
[0003] When the particle of a therapeutic agent is made into
nanoscale size in medicinal products, following advantages may be
obtained. First of all, in a drug having a small enteral absorption
rate in oral administration, one having a smaller size can be
absorbed more than one having a bigger size, thereby increasing the
bioavailability of the therapeutic agent. Further, the dosage form
of drugs can be varied, for instance a drug being possibly
administered only via oral route can be administered by inhalation.
In a controlled-release drug formulation, the release rate of a
therapeutic agent is a very important factor. When the particle
size of the therapeutic agent is formed to be in nanoscale, the
particle size becomes relatively more uniform, thus the release
rate can become more expectable, thereby being possible to provide
more effective therapeutic agent.
[0004] In order to take various advantages of regular nanoparticles
as described above, many attempts have been made to prepare an
active ingredient as a nanoparticle. For this object, mechanical
techniques such as crushing, grinding, milling and the like have
been conventionally employed to make relatively large particles
smaller. In the pharmaceutical industry, a method of milling a mass
amount of drugs to the size range being suitable for the medicinal
or pharmaceutical use with an air-jet mill has been commonly used.
However, such mechanical process involves the risk of contamination
and had a limitation on decreasing the particle size to about tens
of micrometers.
[0005] U.S. Pat. No. 5,145,684 discloses a method for preparing
particles of poorly water-soluble drugs in the size of hundreds of
nanometers by wet milling the poorly water-soluble drugs in the
presence of a surface modifier. This technique should be applied
after a preparation of the drugs in the particle size of not more
than 100 micrometer by using a conventional milling process.
Generally in this method, the time taken for the preparation of
particles having a targeted size range depends on the particular
mechanical device used thereto. For example, when using a ball
mill, processing times of up to 5 days or longer may be required,
however, when using a high shear media mill, 1 day would be enough
to provide particles of a desired size. However, in connection with
the use of a high shear media mill, contamination associated with
the high corrosion of grinding media and grinding vessel should be
concerned. Further, a drying process such as spray or freeze drying
should be conducted for getting powder form, because the resulted
nanoparticles from the wet milling method are in liquid phase.
During the drying process, coagulation of the particles is occurred
due to interparticle attraction forces, hence it is substantially
difficult to obtain a dispersion of particles in a nanometer scale
by redispersing the resulted powder into a liquid. In order to
solve such problem, U.S. Pat. No. 5,302,401 describes an
anti-coagulating agent employed during lyophilization.
Additionally, U.S. Pat. No. 6,592,903 B2 describes an invention
comprising a stabilizer, a surfactant and an anti-coagulating agent
used during a spray dry process. Further, US Patent No.
2003/0185869 A1 describes an application of a wet milling technique
for some poorly soluble drugs, with using lysozyme as a surface
stabilizer. However, such protein surface stabilizer used therein
has many restrictions in a drying process, accordingly it only
describes the preparation in liquid phase.
[0006] Other conventionally available methods include a
recrystallization technique which provides fine particles of an
active ingredient by changing the environment of a solution
containing dissolved active ingredient to cause the precipitation
or crystallization of solutes. The recrystallization technique can
be practiced in two different ways: the one being comprised of
dissolving a therapeutic agent in a suitable solvent and lowering
the temperature, thereby changing the solubility of the therapeutic
agent to precipitate particles; and the other being comprised of
adding antisolvent to a solution containing dissolved therapeutic
agent, thereby decreasing the solubility of the solute to
precipitate particles. However, the recrystallization technique
usually requires the use of toxic organic solvent and often causes
flocculation or coagulation of the particles during a drying
process in wet condition, following after the filtration of the
precipitated particles. As a result, the final particles may be
irregular in their size.
[0007] US Patent No. 2003/0104068 A1 discloses a method for
preparing fine particles comprising: dissolving polymers into an
organic solvent; dissolving or dispersing a proteineous drug
thereto; then rapidly cooling the solution to ultra-low temperature
for solidification; and lyophilizing the resulted product to
provide a fine powder. In this case, however, there are concerns
for the denaturation of a proteineous drug by the contact with an
organic solvent and the process economy owing to the rapid cooling
and lyophilizing process.
[0008] Other techniques for reducing particle size include
emulsification. The emulsifying method is commonly used in cosmetic
field, which comprises melting poorly water soluble substances with
heat or dissolving them in an organic solvent, and then adding the
melted or dissolved substances to an aqueous solution containing a
surfactant dissolved therein, with stirring at high speed or with
sonication to disperse the added substances and provide fine
particles. However, in this emulsification method, a step for
removing water is required for providing the fine particles in a
powdered form, and the step gives variously restrictions to the
process. Further, when using an organic solvent to dissolve the
poorly water-soluble substance, there always has been a concern for
residual toxic organic solvent.
[0009] US Patent No. 2004/0067251 A1 discloses a method for
preparing fine particles by dissolving active ingredients into an
organic solvent and spraying the resulted solution to an aqueous
solution containing a surfactant dissolved therein. The invention
involves the use of an organic solvent, and requires a drying
process for removing the water used, to provide the particles as a
powdered form, since the resulted particles are present in aqueous
phase. During the drying process, the coagulation of the particles
is likely to be occurred, hence the coagulated particles are hardly
redispersed with maintaining the particle size to a nanoscale.
[0010] Recently, many attempts have been made to use a
supercritical fluid in the amorphous or nanoscale particle
preparation. Supercritical fluid is a fluid existing in liquid form
at a temperature higher than its critical temperature and under
pressure higher than its critical pressure. Commonly used
supercritical fluid is carbon dioxide. As one of techniques
involving the use of supercritical fluids in a nanoparticle
preparation, the rapid expansion of a supercritical solution
(hereinafter, RESS) is known from the following literatures: Tom et
al. Biotechnol. Prog. 7(5):403-411. (1991); U.S. Pat. No. 6,316,030
B1; U.S. Pat. No. 6,352,737 B1; and U.S. Pat. No. 6,368,620 B2.
According to RESS, an object solute is firstly dissolved in a
supercritical fluid, and then the supercritical solution is rapidly
sprayed into a relatively low-pressure condition via nozzle. Then,
the density of the supercritical fluid rapidly falls down. As a
result, the ability of the supercritical fluid to solubilize the
solute is also rapidly reduced, and the solutes are formed into
very minute particles or crystallines.
[0011] Other techniques using a supercritical fluid include a
gas-antisolvent recrystallization (hereinafter, GAS) (Debenedetti
et al. J. Control. Release 24:27-44. (1993); WO 00/37169). The
method comprises dissolving a therapeutic agent in a conventional
organic solvent to prepare a solution and spraying the resulted
solution into a supercritical fluid served as an antisolvent,
through a nozzle. Then, the volume becomes rapidly expanded upon
the contact between the solution and the supercritical fluid. As a
result, the density and capacity of the solvent become so much
lower to cause excessive supersaturation, hence the solutes form
seeds or particles.
[0012] U.S. Pat. No. 6,630,121 describes a method for preparing
fine particles by nebulizing a solution containing active
ingredients to provide fine particles with the use of a
supercritical fluid, and drying the resulted particles with a dry
gas. The method can be used regardless of the solubility of the
active ingredients to the supercritical fluid. WO 02/38127 A2
describes a method using SEDS (Solution Enhanced Dispersion by
Supercritical fluids) technique for preparing fine particles of
active ingredients and coating the resulted fine particles with an
additive such as a polymer. Further, U.S. Pat. No. 6,596,206 B2
describes a technique of preparing fine particles of active
ingredients by dissolving the active ingredients in an organic
solvent and focusing acoustic energy to the resulted solution so
that the solution can be ejected into a supercritical fluid as a
form of fine particles.
DISCLOSURE
Technical Problem
[0013] Those above-mentioned prior arts propose a method for
producing very fine particles with relatively uniform size, but
have several disadvantages.
[0014] The first disadvantage is likely to occur in a tube for
transferring a solution and a nozzle. In a preparation method of
fine particles using a supercritical fluid, the particle size
generally determined by the diameter of a nozzle used in the
method, accordingly the diameter of a nozzle ought to be very fine
and precise. However, upon the repeated use of a nozzle, the
diameter of the nozzle becomes changed, hence the particle size
becomes irregular as time elapses. Moreover, due to the use of a
nozzle having an ultra-fine diameter for the preparation of
ultra-fine particles, the clogging of the nozzle is likely to occur
very often. Further, during unclogging of the nozzle, caking of the
particles remained in the tube is frequently occurred.
[0015] The second disadvantage of the prior arts is that the
species of solutes applicable and solvents available are very
limited. The RESS technique can be suitably applied only provided
that the solutes are well dissolved in a supercritical fluid.
Depending on the solutes, the solubility thereof is possibly
increased with the use of a co-solvent, however, if the amount of
co-solvent increases, the existence of the residual solvent after
the particle generation would cause the growth of crystals, which
obstructs the preparation of the particles in regular size. In the
GAS technique, a solvent should be selected with great concern.
Only provided that the solvent containing the solutes dissolved
therein is rapidly diffused into the supercritical fluid as being
contacted together, fine particles can be generated. Further, the
growth of particles can be prevented, provided that the amount of
solvent remained between the particles during filtration is
minimized. In addition, the GAS technique requires a special
filtration device for filtering the resulted fine particles from
the solvent.
[0016] The third disadvantage of the prior arts is that there are
many restrictions in commercial scale production of nanoparticles
by those conventional methods using a supercritical fluid. For the
commercial scale use of RESS, solutes used should be very soluble
in a supercritical fluid, which are very rare. Further, the
preparation of nanoscale fine particles of a single species of
material involves the coagulation of the particles, hence an
anti-coagulating material such as an emulsifier, cellulose or
lipids should be dissolved together, and the mixture thereof should
be made into fine particles in nanoscale. However, most of the
anti-coagulating materials would not be soluble in carbon dioxide
which is mainly used as a supercritical fluid. In preparing
nanoparticles using GAS, the solution containing solutes dissolved
therein is injected into a reactor containing a supercritical
fluid, but the injection rate is so slow that the preparation of
uniform-sized particles is difficult. However, when increasing the
injection rate, the particle sizes become irregular and further
problems would be occurred in a filtration process. Moreover, the
resulted particles with the composition ratio, which was not
originally intended, would be obtained instead of particles with
desired composition ratio, due to the differences between the
solubility of the solutes to the solvent and the solubility of the
anti-coagulating material added thereto, for preventing the
coagulation of particles.
Technical Solution
[0017] The present invention is designed to solve those problems of
the prior arts as described above. The object of the present
invention is to provide a method for preparing nanoscale or
amorphous fine particles of active ingredients which uses a
supercritical fluid for preparation nanoparticles, wherein the
method comprises preparing a mixture including active ingredients
and solid fat and then removing solid fats therefrom with a
supercritical fluid.
Mode doe Invention
[0018] According to the present invention, provided is a method for
preparing nanoscale or amorphous particles, comprising the steps
of: (1) preparing a mixture comprising one or more active
ingredients and solid fat and (2) pressurizing the mixture
comprising one or more active ingredients and solid fat to the
critical pressure or more by adding the gas of a supercritical
fluid into the mixture, and then removing the solid fat from the
mixture by releasing out the solid fat together with the gas of the
supercritical fluid.
[0019] According to one preferred embodiment of the present
invention, the step (1) comprises: adding one or more active
ingredients, solid fat and optionally one or more surfactants into
a reactor and melt-mixing them homogeneously.
[0020] According to other preferred embodiment of the present
invention, the step (1) comprises: adding one or more active
ingredients, solid fat and optionally one or more surfactants into
a reactor and melt-mixing them homogeneously; rapidly cooling the
mixture for solidification; pulverizing the solidified mixture;
adding one or more surfactants and/or one or more non-surfactant
type anti-coagulating agents or aqueous solution thereof to the
pulverized powder and mixing them homogeneously; and drying the
mixed product at room temperature.
[0021] According to another preferred embodiment of the present
invention, the step (1) comprises: adding one or more surfactants
and solid fat into a reactor, and melt-mixing them homogeneously;
rapidly cooling the mixture for solidification; pulverizing the
solidified mixture; adding one or more surfactants and/or one or
more non-surfactant type anti-coagulating agents together with one
or more active ingredients or aqueous solution thereof, to the
pulverized powder and mixing them homogeneously; and drying the
mixed product at room temperature.
[0022] According to another preferred embodiment of the present
invention, the step (1) comprises: adding one or more active
ingredients, solid fat and optionally one or more surfactants into
a reactor, further adding the gas of a supercritical fluid so as to
provide a subcritical or supercritical condition, and then
melt-mixing the mixture by heating.
[0023] According to another preferred embodiment of the present
invention, the step (1) comprises: adding one or more active
ingredients, solid fat and optionally one or more surfactants into
a reactor, pressurizing the mixture to the critical pressure or
more by adding the gas of a supercritical fluid into the mixture
and then melt-mixing the mixture by heating, and spraying the
melted mixture to the atmospheric pressure.
[0024] According to another preferred embodiment of the present
invention, the step (1) comprises: adding one or more active
ingredients, solid fat and optionally one or more surfactants into
a reactor, pressurizing the mixture to the critical pressure or
more by adding the gas of a supercritical fluid and then
melt-mixing the mixture by heating, and pulverizing the melted
mixture by spraying it to the atmospheric pressure; adding one or
more surfactants and/or one or more non-surfactant type
anti-coagulating agents or aqueous solution thereof to the
pulverized mixture and mixing them homogeneously; and drying the
mixture at room temperature.
[0025] The term "gas of a supercritical fluid" used herein, refers
to an inert gas, which has no reactivity such as a carbon dioxide
gas or a nitrogen gas, but can be a supercritical fluid under
specific temperature and pressure conditions, i.e. beyond their
critical point.
[0026] "Critical pressure" used herein, refers to a specific
pressure at least under which the gas of a supercritical fluid can
be liquefied as a supercritical fluid.
[0027] The active ingredients useful in the method for preparing
nanoscale or amorphous particles (hereinafter, referred as
"nanoparticles") according to the present invention include, for
example, organic compounds, organometallic compounds, natural
extracts, peptides, proteins, polysaccharides and the like, which
exhibit specific physiological activities in medicinal products,
functional foods, cosmetics and the like, and there is no specific
restriction on their phase at room temperature such as solid or
liquid phase and electrical properties such as being neutral or
ionic.
[0028] "Nanoparticles" used herein, refers to particles wherein 90%
or more of the particles have a size of 5 .mu.m or less, preferably
2 .mu.m or less, more preferably 1 .mu.m or less, still more
preferably 0.5 .mu.m or less.
[0029] The solid fat useful in the method for preparing
nanoparticles according to the present invention, is a fat or a
mixture of fats maintaining solid phase at room temperature, i.e.
at 30.degree. C. or less, having a relatively low melting point as
being 40.about.150.degree. C. Thereby, the solid fat is easily
melted with heat and is served as a solvent for the active
ingredients. Also, the solid fat is highly soluble in the
supercritical fluid. The solid fat includes, for instance,
saturated fatty acids, esters and alcohols with C10.about.C22;
mono- or di-glycerides having saturated fatty acid group with
C10.about.C22; hydrocarbons with C16 or more; or a mixture thereof.
Further, tri-glycerides with C10.about.C22 may be used after
solidifying them by reducing the fatty acid.
[0030] According to the method for preparing nanoparticles of the
present invention, the nanoparticles may be prepared by using the
active ingredients as a single component. Optionally, an
anti-coagulating agent may be further used for preventing the
coagulation of the resulted nanoparticles. Such anti-coagulating
agents useful in the present invention may be classified into a
surfactant type and a non-surfactant type. As the surfactant type
anti-coagulating agent, various synthetic and natural surfactants,
lipids, polymers and the like may be used. As the non-surfactant
type anti-coagulating agent, monosaccharides, polysaccharides,
dietary fibers, gums, proteins and the like may be used.
Phospholipids such as lecithin, lysolecithin, phosphatidyl choline,
phosphatidyl ethylamine and the like are referred herein as a
surfactant, though it may be classified as lipids in general.
Surfactants may be generally divided, upon their affinity to water,
into a hydrophilic and a lipophilic type, which are determined by
the HLB (hydrophilic-lipophilic balance) value. Upon the functional
groups, there are four types of surfactants such as cationic,
anionic, neutral and zwitterionic. A surfactant useful in the
present invention is not specifically restricted to a certain type
or species, as long as it prevents the coagulation of the active
ingredients, and it is well dissolved in the solid fats and is not
readily removed by a supercritical fluid.
[0031] Further, when sufficient dissolution of the active
ingredients and surfactants is not achieved by using only solid
fats, one or more alcohols may be further used as a co-solvent in
the method of the present invention, wherein the co-solvent is
preferably one or more lower alcohols with C2.about.C6, and ethanol
is the most preferred.
[0032] Hereinafter, the method for preparing nanoparticles of the
present invention is now illustrated step by step with more
details.
[0033] In the step (1) of the method for preparing nanoparticles
according to the present invention, a mixture comprising one or
more active ingredients and solid fat is prepared. The details
thereof are now described as follows.
[0034] According to one preferred embodiment of the present
invention, one or more active ingredients and solid fat are added
into a reactor wherein the amount of the solid fat is.
0.1.about.1000 parts by weight per 1 part by weight of the active
ingredients. At this stage, when necessary, 0.001.about.10 parts by
weight of surfactant or 0.001.about.10 parts by weight of lower
alcohol, or a mixture of 0.001.about.10 parts by weight of
surfactant and 0.001.about.10 parts by weight of lower alcohol,
based on 1 part by weight of the active ingredients may be
optionally added to the reactor.
[0035] The optionally added surfactant should have relatively large
solubility to the solid fats so as to form a homogeneous solution
when being dissolved together with the active ingredients in solid
fat, or in solid fat containing a lower alcohol described above.
Further, different surfactants may be selected, depending on the
properties of the active ingredients and the use or the purpose of
use of the resulted nanoparticles. When the resulted nanoparticles
are used finally in the form of a water dispersion, a surfactant
with a high HLB value is preferably selected, and when the purpose
is to increase the internal absorption rate, a surfactant with a
relatively low HLB value is preferably selected.
[0036] As mentioned above, the active ingredients and solid fat are
added to a reactor and when being necessary, surfactant or lower
alcohol or a mixture thereof is further added to the reactor, and
then the mixture in the reactor is gradually melted as being
heated.
[0037] As the temperature inside the reactor rises, the solid fat
becomes melt, and the active ingredients and surfactant are
dissolved or dispersed therein. The temperature is raised until a
homogeneous solution or dispersion is formed. It is preferred to
start stirring from the point when it becomes possible, since it
will make the solution or dispersion of the mixture more
homogeneously and reduce the working time. The point when stirring
becomes possible, depends on the specific species of the active
ingredients, surfactant and solid fat used in the method, however
the determination of the starting point of stirring will be easily
made at the working site by the skilled person in this field.
[0038] According to other preferred embodiment of the present
invention, as it has been mentioned above, a mixture comprising one
or more active ingredients and solid fat is prepared by: adding the
one or more active ingredients, solid fat and optionally one or
more surfactants to a reactor; melt-mixing them together
homogeneously; rapidly cooling the resulted mixture for
solidification; pulverizing the solidified mixture; adding one or
more surfactants and/or one or more non-surfactant type
anti-coagulating agents or aqueous solution thereof to the resulted
powder, and mixing them homogeneously; and drying the resulted
mixture at room temperature. In the above processes, the drying
process is not particularly restricted to a certain method, but it
should be conducted below the melting point of the solid fat
used.
[0039] According to another preferred embodiment of the present
invention, when the active ingredients are those sensitive to the
temperature or soluble in water such as peptides, proteins or
polysaccharides, the mixture comprising the active agents and solid
fats is prepared by: firstly, adding one or more surfactants and
solid fat into a reactor and melt-mixing them homogeneously;
rapidly cooling the melted mixture for solidification; pulverizing
the solidified mixture; then adding the active ingredients together
with one or more surfactants and/or one or more non-surfactant type
anti-coagulating agents or aqueous solution thereof, to the
resulted powder, and mixing them homogeneously; and drying the
resulted mixture at room temperature. In the above processes, the
drying process is not particularly restricted to a certain method,
but it should be conducted below the melting point of the solid fat
used.
[0040] In the solidification of the mixture by rapid cooling, it is
preferred to rapidly decrease the temperature of the solution of
the melted mixture to the temperature of 10.degree. C. or less.
When cooling is conducted slowly, crystal growth of the active
ingredients may occur, and under such circumstances, the
nanoparticles of the active ingredients are hardly achieved and the
obtained particles are likely to have a broad particle
distribution.
[0041] The solid product obtained from the rapid cooling, is
conventionally milled by, for example, dry milling and the like.
The smaller the size of the milled particles is, i.e. the larger
the surface area of the particles is, the more it is advantageous
in later processes such as a fat removal process. The particle size
after the milling process is preferably 100 micrometer or less, but
not limited thereto.
[0042] According to another preferred embodiment of the present
invention, the mixture comprising one or more active ingredients
and solid fat is prepared by: adding the one or more active
ingredients, solid fat and optionally one or more surfactants to a
reactor; further adding the gas of a supercritical fluid(for
instance, CO.sub.2 gas) to the mixture so as to form subcritical or
supercritical conditions; and then melting the resulted mixture by
heating.
[0043] According to another preferred embodiment of the present
invention, the mixture comprising one or more active ingredients
and solid fat is prepared by: adding the one or more active
ingredients, solid fat and optionally one or more surfactants to a
reactor; adding thereto the gas of a supercritical fluid up to the
pressure over the critical pressure and melting the mixture; and
then spraying the melted mixture to the atmospheric pressure.
[0044] According to another preferred embodiment of the present
invention, a mixture comprising one or more active ingredients and
solid fat is prepared by: adding the one or more active
ingredients, solid fat and optionally one or more surfactants to a
reactor; adding thereto the gas of a supercritical fluid up to the
pressure over the critical pressure and melting the mixture; then
spraying the melted mixture to the atmospheric pressure for
pulverization; adding one or more surfactants and/or one or more
non-surfactant type anti-coagulating agents or aqueous solution
thereof to the resulted mixture and mixing homogeneously; and
drying the mixture at room temperature. In the above processes, the
drying process is not particularly restricted to a certain method,
but it should be conducted below the melting paint of the solid fat
used.
[0045] In the case of using a supercritical fluid in the step (1)
of the present invention, after the components of the mixture are
completely melted and homogeneously mixed, a supercritical fluid
such as CO.sub.2 is slowly added into a reactor to pressurize the
mixture up to the pressure under which the gas of a supercritical
fluid is liquefied as a supercritical fluid, i.e. the critical
pressure(for CO.sub.2, 70 atm) or more. The pressure inside the
reactor at this stage depends on the reactor size and the amount of
the mixture, but generally preferred is 50.about.200 atm. The
temperature at this stage is a temperature that can provide the
sufficient fluidity to the solution of the mixture for
stirring.
[0046] Once the critical pressure or more is achieved by rising the
pressure inside the reactor with the gas of a supercritical fluid,
it is preferred to carry out stirring for additional 10 minutes or
more at that condition, so that the supercritical fluid may be
sufficiently permeated into the solution of the mixture.
[0047] In completing the additional stirring, while slowly adding
thereto the gas of the supercritical fluid further, the exhaust
port connected to another reactor under atmospheric pressure, is
opened to the full for spraying the resulted solution of the
mixture into the reactor under atmospheric pressure. At this
moment, the supercritical fluid is instantly vaporized, thereby
rapidly cooling down the surroundings and causing the
solidification of the resulted solution of the mixture in an
instant. The solidification of the solution of the mixture is so
instantaneous that it becomes short of energy and time demanded for
crystal growth, therefore it is possible to obtain solid products
in which the solutes including the active ingredients, surfactant
and the like and the solid fat are homogeneously mixed in the form
of very fine particles. In the solid products obtained therefrom,
the very fine nanoscale particles of the active ingredients are
dispersed uniformly. Further, since the surfactant is also
uniformly mixed with the active ingredients, the dispersability and
stability of the finally produced fine particles become
significantly improved.
[0048] The purpose of this step is to make the particles of active
ingredients be finer and more uniform in the solid product.
Therefore, as long as the particle size of the solid product
containing the active ingredients is in the range that does not
cause any problem to the workability in later processes, it is not
necessary to specifically adjust the particle size of the solid
product itself. Accordingly, it is not necessary to adjust the
spray nozzle diameter or the spraying rate, in order to adjust the
particle size of the solid product itself produced by spraying into
the atmospheric pressure condition. Therefore, the risk of
deformation or clogging of the spray nozzle does not need to be
concerned any more.
[0049] In spraying the solution of the mixture into another reactor
under the atmospheric pressure condition, a conical supporting
plate is preferably placed inside the reactor under the atmospheric
pressure condition, at a distance from the spray outlet such as
nozzle, in order to solidify the sprayed solution into the form of
finer powders. By doing so, the solids can be formed into finer
particles, and in the next step, the solid fat can be more easily
removed with the supercritical fluid.
[0050] According to the preferred embodiment of the present
invention, to the powdered mixture obtained by using a
supercritical fluid or milling, when being necessary, one or more
surfactants and/or one or more non-surfactant type anti-coagulating
agents or aqueous solution thereof can be added, or alternatively
when the active ingredients are those temperature sensitive or
water soluble such as peptides, proteins or polysaccharides, the
surfactant and/or the non-surfactant type anti-coagulating agent
together with the active ingredients or aqueous solution thereof
can be added. The resulted mixture may be homogeneously mixed by
using a general mixer. In the above, when necessary, the
non-surfactant type anti-coagulating agent is added in the amount
of 0.001.about.10 parts by weight per 1 part by weight of the
active ingredients. When the aqueous solution of surfactant or the
non-surfactant type anti-coagulating agent is added, the physical
state of the resulted mixture may be varied upon the amount of
water used and the species of the surfactant and anti-coagulating
agent, but if the amount of water added is generally 30% (w/w) or
less of the amount of fats used, the mixture will be readily formed
into a powder. The amount of water added is not specifically
limited, as long as it can sufficiently disperse the water-soluble
components into the mixture prepared. When 40% (w/w) or more of
water is used, the mixture becomes the form of dough or paste,
which can be dried easily at room temperature by various
conventional methods. The drying process is not particularly
restricted to a certain method, but it should be conducted below
the melting point of the solid fat used. Further, it would be
readily understood by the skilled person in this field that, the
smaller the particle size used is, the more water can be easily
removed by a conventional drying process under reduced pressure.
After completing the drying process, the residual water content
relative to the solid fat content is preferably not more than
30%.
[0051] In the step (2) according to the method for preparing
nanoparticles of the present invention, the solid fat is removed
from the mixture comprising one or more active ingredients and the
solid fat, by using a supercritical fluid. The details thereof are
described as follows.
[0052] While maintaining the temperature of the reactor containing
the mixture obtained from the preceding steps including the step
(1), in maintaining the temperature below the melting point of the
solid fat present in the mixture, preferably maintaining the
temperature in the range of 20.about.40.degree. C., the gas of a
supercritical fluid is added to the reactor to pressurize it to
70.about.400 atm. Then, under said pressure, the gas of a
supercritical fluid is gradually released out, wherein the reactor
pressure is constantly maintained by controlling an input valve and
an output valve for the gas of a supercritical fluid such as carbon
dioxide. Along with the release of the gas of the supercritical
fluid, the solid fat is also released out, i.e. removed from the
reactor. At this stage, if the temperature inside the reactor is
too high, the solid fat becomes melt, hence causing the growth of
crystal of the active ingredient, surfactant, anti-coagulating
agent and the like which were uniformly dispersed in the mixture.
As a result, regular nanoparticles are not possibly obtained. For
above reason, the reactor temperature is preferably maintained
below the melting point of the solid fat present in the mixture,
and in terms of workability, more preferred is in the range of
20.about.40.degree. C.
[0053] The time taken for removing the solid fats with a
supercritical fluid is quite dependant on the species and amount of
the solid fat used. In order to obtain the particles of active
ingredients with higher purity, it is preferred to take time in
removing the solid fats as long as possible, thereby minimizing the
residual amount of the solid fats. The solid fats preferably used
in the present invention are non-toxic to a human body, therefore
the residual amount is not particularly limited to a specific
range. However, considering the purity of the resulted active
ingredients, the residual amount is preferably not more than 10 wt
% of the total weight. As for exception, when the solid fat such as
mono-, di- or tri-glyceride type compounds, which is also generally
used as a surfactant, is used, it would be no problem even if the
residual amount of the solid fat is more than 10% of the total
weight.
[0054] The solid fat removed from the mixture by the method
described above, can be collected in a separate reactor and then
used again in future.
[0055] Hereinafter, the present invention is illustrated in detail
with a reference to the examples as follows, however the present
invention is by no means limited to those examples.
EXAMPLE 1
[0056] A 80 ml pressure-resistant reactor was charged with 2 g of
ketoconazole as an active ingredient and 18 g of cetyl alcohol as a
solid fat and slowly heated, and stirring was started when the
temperature inside the reactor reached to 70.degree. C. When the
temperature inside the reactor reached to 80.degree. C. by further
heating, the mixture became a homogeneous solution in transparent
liquid phase.
[0057] Next, the pressure inside the reactor was elevated by adding
a carbon dioxide gas as a gas of a supercritical fluid, by opening
an input valve for feeding a supercritical fluid. The carbon
dioxide gas was continuously added into the reactor until the
pressure inside the reactor reached to 120 atm which is over the
critical pressure of the carbon dioxide gas. Then, the input valve
for feeding a supercritical fluid was closed, and additional
stirring was carried out for 20 minutes. Completing the additional
stirring, while the carbon dioxide gas was slowly added again by
opening the input valve for feeding a supercritical fluid, a spray
valve that is connected to a collecting reactor under atmospheric
pressure was widely opened all at once so as to spray the solution
of the mixture completely. At this stage, a vent valve equipped to
a collecting reactor was remained wide open, in order to maintain
the atmospheric pressure condition of the collecting reactor.
Further, the inside of the collecting reactor was equipped with a
conical plate placed in front of the spray nozzle, for providing
finer powders from the solution sprayed out from the nozzle. After
completing the spraying of the solution, carbon dioxide gas was
still fed for additional 10 minutes and then the input and spray
valve of the supercritical fluid were closed.
[0058] Next, the pressure inside the collecting reactor containing
the sprayed solid powders was elevated to about 150 atm by adding
carbon dioxide gas into the collecting reactor. The pressure inside
the collecting reactor was constantly maintained to the pressure of
100 atm or more by controlling a vent valve of the collecting
reactor, while continuously adding the carbon dioxide gas. Under
the constantly maintained pressure, the cetyl alcohol used as a
solid fat was extracted for 8 hours with the gas of the
supercritical fluid to obtain 1.8 g of fat-removed fine solid
particles. The particle size of the obtained powdered mixture was
determined by a particle size analyzer (Mastersizer Microplus) by
dispersing the obtained powdered mixture into distilled water, and
the result was shown in Table 1.
EXAMPLE 2
[0059] 30 g of cetyl alcohol and 2 g of ketoconazole were placed
into a 250 ml volume beaker and heated to 80.degree. C. with
stirring until the mixture became completely melt to form a
transparent liquid. After completely melting the mixture,
additional stirring for about 10 minutes was further carried out
for homogeneous mixing. Then, the melted mixture was poured into a
stainless steel plate which was precooled to 10.degree. C. or less
for rapid cooling and solidifying, thereby obtaining the solid
product in which the active ingredient was dispersed uniformly into
the fat in the form of fine particles. The resulted solid product
was milled into fine particles, together with 2 g of D-(+)-sucrose
as an anti-coagulating agent by a domestic milling device, to
provide fat powder. 5.5 g of the fat powder was placed into a
pressure resistant reactor, and cetyl alcohol used as a solid fat
was removed therefrom by the same method as in Example 1 to obtain
0.6 g of a powdered mixture of ketoconazole and sucrose. The
powdered mixture was dispersed into distilled water for measuring
the particle size thereof with a particle size analyzer
(Mastersizer Microplus). The results were shown in Table 1.
EXAMPLE 3
[0060] 20 g of cetyl alcohol and 1 g of ketoconazole were placed
into a 250 ml volume beaker and heated to 80.degree. C. with
stirring until the mixture became completely melt to form a
transparent liquid. After completely melting the mixture,
additional stirring for about 10 minutes was further carried out
for homogeneous mixing. Then, the melted mixture were poured into a
stainless steel plate which was precooled to 10.degree. C. or less
for rapid cooling and solidifying, thereby obtaining the solid
product in which the active ingredient was dispersed uniformly into
the fat in the form of fine particles. The resulted solid product
was milled into fine particles with about 100 .mu.m particle size,
by a domestic milling device, to provide fat powder. To the
resulted fat powder, a solution of 1 g of sucrose as an
anti-coagulating agent in 5 ml of water was added and stirred with
a spatula for uniform mixing of the fat powder and the sucrose
solution, thereby obtaining a mixture of the fat powder and
sucrose. Since the resulted mixture of the fat powder and sucrose
had small water content, it easily turned into a powder form. 13.5
g of the mixture of the fat powder and sucrose was placed into a
pressure resistant reactor, and cetyl alcohol used as a solid fat
was removed therefrom by the same method as in Example 1 to obtain
0.9 g of a powdered mixture of ketoconazole and sucrose. The
powdered mixture was dispersed to distilled water for measuring the
particle size thereof with a particle size analyzer (Mastersizer
Microplus). The results were shown in Table 1.
EXAMPLE 4
[0061] A mixture of a fat powder and sucrose was prepared by the
same method as in
[0062] Example 3, except that a solution of 2 g of sucrose as an
anti-coagulating agent in 5 ml of water was added to 21 g of the
fat powder comprised of ketoconazole and cetyl alcohol (1 g and 20
g, respectively). 10.4 g of the mixture of the fat powder and
sucrose was placed into a pressure resistant reactor, and cetyl
alcohol used as a solid fat was removed therefrom by the same
method as in Example 1, thereby obtaining 1.0 g of a powdered
mixture of ketoconazole and sucrose. The resulted powdered mixture
was dispersed into distilled water for measuring the particle size
with a particle size analyzer (Mastersizer Microplus). The results
were shown in Table 1.
EXAMPLE 5
[0063] A mixture of a fat powder and sucrose was prepared by the
same method as in Example 3, except that a solution of 1 g of
sucrose as an anti-coagulating agent in 8 ml of water was added to
21 g of the fat powder comprised of ketoconazole and cetyl alcohol
(1 g and 20 g, respectively). 10.0 g of the mixture of the fat
powder and sucrose was placed into a pressure resistant reactor,
and cetyl alcohol used as a solid fat was removed therefrom by the
same method as in Example 1, thereby obtaining 0.4 g of a powdered
mixture of ketoconazole and sucrose with excellent flowability. The
resulted powdered mixture was found to be adsorbed to the inner
wall of the reactor in a significant amount. The resulted powdered
mixture was dispersed into distilled water for measuring the
particle size with a particle size analyzer (Mastersizer
Microplus). The results were shown in Table 1.
TABLE-US-00001 TABLE 1 Average particle size (.mu.m) of the final
powders obtained from Examples 1~5 Raw material (Active Exam- Exam-
Exam- ingredient) ple 1 ple 2 Example 3 ple 4 Example 5 Average
10.41 1.79 1.02 1.04 1.10 0.75 particle size
EXAMPLE 6
[0064] A mixture of a fat powder, polyvinylpyrrolidone and sucrose
was prepared by the same method as in Example 3, except that a
solution of 0.1 g of polyvinylpyrrolidone
[0065] (Polyvinylpyrrolidone K 30) as a surfactant and 1 g of
sucrose as a non-surfactant type anti-coagulating agent in 8m1 of
water, was added to 21 g of the fat powder comprised of
ketoconazole and cetyl alcohol (1 g and 20 g, respectively). 10.0 g
of the mixture of the fat powder, polyvinylpyrrolidone and sucrose
was placed into a pressure resistant reactor, and cetyl alcohol
used as a solid fat was removed therefrom by the same method as in
Example 1, thereby obtaining 0.64 g of a powdered mixture of
ketoconazole, sucrose and polyvinylpyrrolidone with excellent
flowability. The resulted powdered mixture was found to be adsorbed
to the inner wall of the reactor in a significant amount. The
resulted powdered mixture was dispersed into distilled water for
measuring the particle size with a particle size analyzer (Horiba
LA910S). The results were shown in Table 2.
EXAMPLE 7
[0066] A mixture of a fat powder and sucrose was prepared by the
same method as in Example 3, except that the fat powder containing
ketoconazole and polyvinylpyrrolidone dispersed uniformly therein
as fine particles, was prepared by dissolving 0.1 g of
polyvinylpyrrolidone and 1 g of ketoconazole together with 20 g of
cetyl alcohol, and to the fat powder prepared above, a solution of
1 g of sucrose as an anti-coagulating agent in 8 ml of water was
added. 10.0 g of the mixture of the fat powder and sucrose was
placed into a pressure resistant reactor, and cetyl alcohol used as
a solid fat was removed therefrom by the same method as in Example
1, thereby obtaining 0.62 g of a powdered mixture of ketoconazole,
sucrose and polyvinylpyrrolidone with excellent flowability. The
resulted powdered mixture was found to be adsorbed to the inner
wall of the reactor in a significant amount. The resulted powdered
mixture was dispersed into distilled water for measuring the
particle size with a particle size analyzer (Horiba LA910S). The
results were shown in Table 2.
EXAMPLE 8
[0067] A fat powder containing ketoconazole and
polyvinylpyrrolidone uniformly dispersed therein as fine particles
was prepared by dissolving 0.1g of polyvinylpyrrolidone and 1 g of
ketoconazole together with 20 g of cetyl alcohol by the same method
as in the Example 3. To the resulted fat powder, a solution of 1 g
of sucrose as an anti-coagulating agent in 14 ml of water was added
and mixed homogeneously. The resulted mixture was dried in a vacuum
drier until the water content became 5% (w/w) or less relative to
the amount of the cetyl alcohol. 9 g of the dried mixture prepared
above was placed into a pressure resistant reactor, and cetyl
alcohol was removed therefrom by the same method as in Example 1,
thereby obtaining 0.8 g of a powdered mixture with excellent
flowability. The resulted powdered mixture was dispersed into
distilled water for measuring the particle size with a particle
size analyzer (Horiba LA910S). The results were shown in Table
2.
EXAMPLE 9
[0068] A mixture of a fat powder and sucrose was prepared by the
same method as in Example 8, except that a solution of 2 g of
sucrose as an anti-coagulating agent in 14 ml of water was added to
the fat powder prepared by dissolving 0.1 g of polyvinylpyrrolidone
and 1 g of ketoconazole together with 20 g of cetyl alcohol. Cetyl
alcohol was removed from 9 g of the resulted mixture of the fat
powder and sucrose by the same method as in Example 1, thereby
obtaining 1.1 g of a powdered mixture with excellent flowability.
The resulted powdered mixture was dispersed into distilled water
for measuring the particle size with a particle size analyzer
(Horiba LA910S). The results were shown in Table 2.
EXAMPLE 10
[0069] A mixture of a fat powder and xylitol was prepared by the
same method as in Example 8, except that a solution of 1 g of
xylitol as an anti-coagulating agent in 14 ml of water was added to
the fat powder prepared by dissolving 0.1 g of polyvinylpyrrolidone
and 1 g of ketoconazole together with 20 g of cetyl alcohol. Cetyl
alcohol was removed from 9 g of the resulted mixture of the fat
powder and xylitol by the same method as in Example 1, thereby
obtaining 0.8 g of a powdered mixture with excellent flowability.
The resulted powdered mixture was dispersed into distilled water
for measuring the particle size with a particle size analyzer
(Horiba LA910S). The results were shown in Table 2.
EXAMPLE 11
[0070] A mixture of a fat powder, xylitol, sodium dioctyl
sulfosuccinate (DOSS) and sodium dodecylsulfate (SLS) was prepared
by the same method as in Example 8, except that a solution of 1 g
of xylitol as an anti-coagulating agent and 0.08 g of DOSS and
0.008 g of SLS as additional surfactants in 14 ml of water, was
added to the fat powder prepared by dissolving 0.1 g of
polyvinylpyrrolidone and 1 g of ketoconazole together with 20 g of
cetyl alcohol. Cetyl alcohol was removed from 10 g of the resulted
mixture of the fat powder, xylitol, DOSS and SLS by the same method
as in Example 1, thereby obtaining 0.9 g of a powdered mixture with
excellent flowability. The resulted powdered mixture was dispersed
into distilled water for measuring the particle size with a
particle size analyzer (Horiba LA910S). The results were shown in
Table 2.
EXAMPLE 12
[0071] 0.25 g of polyvinylpyrrolidone and 1 g of ketoconazole were
dissolved together with 20 g of cetyl alcohol, to prepare a fat
powder containing ketoconazole and polyvinyl pyrrolidone uniformly
dispersed therein as a form of fine particles. To the resulted fat
powder, a solution of 1 g of xylitol as an anti-coagulating agent
in 14 ml of water was added and mixed uniformly. Then, the mixture
was dried in a vacuum drier until the water content became 5 %
(w/w) or less relative to the amount of cetyl alcohol. 9 g of the
dried mixture prepared above was placed into a pressure resistant
reactor, and cetyl alcohol was removed therefrom by the same method
as in Example 1, thereby obtaining 0.88 g of a powdered mixture
with excellent flowability. The resulted powdered mixture was
dispersed into distilled water for measuring the particle size with
a particle size analyzer (Horiba LA910S). The results were shown in
Table 2.
EXAMPLE 13
[0072] A fat powder containing ketoconazole and
polyvinylpyrrolidone uniformly dispersed therein as fine particles,
was prepared by dissolving 0.25 g of polyvinylpyrrolidone and 1 g
of ketoconazole together with 20 g of cetyl alcohol by the same
method as in Example 2. To the resulted fat powder, a solution of 1
g of sucrose as an anti-coagulating agent in 14 ml of water was
added and mixed homogeneously. The resulted mixture was dried in a
vacuum drier until the water content became 5 % (w/w) or less
relative to the amount of cetyl alcohol. 9 g of the dried mixture
prepared above was placed into a pressure resistant reactor, and
cetyl alcohol was removed therefrom by the same method as in
Example 1, thereby obtaining 0.87 g of a powdered mixture with
excellent flowability. The resulted powdered mixture was dispersed
into distilled water for measuring the particle size with a
particle size analyzer (Horiba LA910S). The results were shown in
Table 2.
EXAMPLE 14
[0073] A mixture of a fat powder, xylitol, DOSS and SLS was
prepared by the same method as in Example 12, except that a
solution of 1 g of xylitol as an anti-coagulating agent and 0.2 g
of DOSS and 0.004 g of SLS as additional surfactants in 14 ml of
water was added to the fat powder prepared by dissolving 0.25 g of
polyvinylpyrrolidone and 1 g of ketoconazole together with 20 g of
cetyl alcohol. Cetyl alcohol was removed from 9.06 g of the
resulted mixture of the fat powder, xylitol, DOSS and SLS by the
same method as in Example 1, thereby obtaining 0.96 g of a powdered
mixture with excellent flowability. The resulted powdered mixture
was dispersed into distilled water for measuring the particle size
with a particle size analyzer (Horiba LA910S). The results were
shown in Table 2.
EXAMPLE 15
[0074] A mixture of a fat powder and sucrose was prepared by the
same method as in Example 3, except that the fat powder containing
ketoconazole and sucrose fatty acid ester uniformly dispersed
therein as fine particles was prepared by dissolving 0.13 g of
sucrose fatty acid ester and 1 g of ketoconazole together with 20 g
of cetyl alcohol by the same method as in Example 2, and to the fat
powder prepared above, a solution of 1 g of sucrose as an
anti-coagulating agent in 9 ml of water was added. 9.0 g of the
mixture of the fat powder and sucrose was placed into a pressure
resistant reactor, and cetyl alcohol used as a solid fat was
removed therefrom by the same method as in Example 1, thereby
obtaining 1.18 g of a powdered mixture of sucrose fatty acid ester,
sucrose and ketoconazole with excellent flowability. The resulted
powdered mixture was dispersed into distilled water for measuring
the particle size with a particle size analyzer (Horiba LA910S).
The results were shown in Table 2.
EXAMPLE 16
[0075] A fat powder containing ketoconazole and sucrose fatty acid
ester uniformly dispersed therein as fine particles was prepared by
dissolving 0.25 g of sucrose fatty acid ester and 1 g of
ketoconazole together with 20 g of cetyl alcohol by the same method
as in Example 2. To the resulted fat powder, a solution of 1 g of
sucrose as an anti-coagulating agent in 14 ml of water was added
and mixed homogeneously. The resulted mixture was dried in a vacuum
drier until the water content became 5% (w/w) or less relative to
the amount of cetyl alcohol. 10 g of the dried mixture prepared
above was placed into a pressure resistant reactor, and cetyl
alcohol was removed therefrom by the same method as in Example 1,
thereby obtaining 0.89 g of a powdered mixture with excellent
flowability.
[0076] The resulted powdered mixture was dispersed into distilled
water for measuring the particle size with a particle size analyzer
(Horiba LA910S). The results were shown in Table 2.
EXAMPLE 17
[0077] A fat powder containing ketoconazole and sucrose fatty acid
ester uniformly dispersed therein as fine particles, was prepared
by dissolving 0.25 g of sucrose fatty acid ester and 1 g of
ketoconazole together with 20 g of cetyl alcohol by the same method
as in Example 2. To the resulted fat powder, a solution of 1 g of
xylitol as an anti-coagulating agent in 14 ml of water was added
and mixed homogeneously. The resulted mixture was dried in a vacuum
drier until the water content became 5 % (w/w) or less relative to
the amount of cetyl alcohol. 10 g of the dried mixture prepared
above was placed into a pressure resistant reactor, and cetyl
alcohol was removed therefrom by the same method as in Example 1,
thereby obtaining 0.87 g of a powdered mixture with excellent
flowability. The resulted powdered mixture was dispersed into
distilled water for measuring the particle size with a particle
size analyzer (Horiba LA910S). The results were shown in Table
2.
EXAMPLE 18
[0078] A fat powder containing lovastatin and polyvinylpyrrolidone
uniformly dispersed therein as fine particles, was prepared by
dissolving 0.25 g of polyvinylpyrrolidone and 1 g of lovastatin
together with 20 g of cetyl alcohol by the same method as in
Example 2. To the resulted fat powder, a solution of 1 g of xylitol
as an anti-coagulating agent in 14 ml of water was added and mixed
homogeneously. The resulted mixture was dried in a vacuum drier
until the water content became 5% (w/w) or less relative to the
amount of cetyl alcohol. 10 g of the dried mixture prepared above
was placed into a pressure resistant reactor, and cetyl alcohol was
removed therefrom by the same method as in Example 1, thereby
obtaining 0.85 g of a powdered mixture with excellent flowability.
The resulted powdered mixture was dispersed into distilled water
for measuring the particle size with a particle size analyzer
(Horiba LA910S). The results were shown in Table 2.
EXAMPLE 19
[0079] A fat powder containing paclitaxel and polyvinylpyrrolidone
uniformly dispersed therein as fine particles, was prepared by
dissolving 0.25 g of polyvinylpyrrolidone and 1 g of paclitaxel
together with 20 g of cetyl alcohol by the same method as in
Example 2. To the resulted fat powder, a solution of 1 g of xylitol
as an anti-coagulating agent in 14 ml of water was added and mixed
homogeneously. The resulted mixture was dried in a vacuum drier
until the water content became 5% (w/w) or less relative to the
amount of cetyl alcohol, 10 g of the dried mixture prepared above
was placed into a pressure resistant reactor, and cetyl alcohol was
removed therefrom by the same method as in Example 1, thereby
obtaining 1.02 g of a powdered mixture with excellent flowability.
The resulted powdered mixture was dispersed into distilled water
for measuring the particle size with a particle size analyzer
(Horiba LA910S). The results were shown in Table 2.
EXAMPLE 20
[0080] A fat powder containing itraconazole and
polyvinylpyrrolidone uniformly dispersed therein as fine particles,
was prepared by dissolving 0.25 g of polyvinylpyrrolidone and 1 g
of itraconazole together with 20 g of cetyl alcohol by the same
method as in Example 2. To the resulted fat powder, a solution of 1
g of xylitol as an anti-coagulating agent in 14 ml of water, was
added and mixed homogeneously. The resulted mixture was dried in a
vacuum drier until the water content became 5% (w/w) or less
relative to the amount of cetyl alcohol. 10 g of the dried mixture
prepared above was placed into a pressure resistant reactor, and
cetyl alcohol was removed therefrom by the same method as in
Example 1, thereby obtaining 1.05 g of a powdered mixture with
excellent flowability. The resulted powdered mixture was dispersed
into distilled water for measuring the particle size with a
particle size analyzer (Horiba LA910S). The results were shown in
Table 2.
TABLE-US-00002 TABLE 2 Particle size distribution(.mu.m) of the
final powdered mixtures obtained from Examples 6~20 Example D50 D70
D90 Average 6 0.4796 0.6785 1.0873 0.5941 7 0.4678 0.6346 1.1100
0.7205 8 0.4787 0.6983 1.4772 0.9289 9 0.5114 0.7515 1.3731 0.7695
10 0.5045 0.7341 1.3185 0.7565 11 0.5966 0.8978 1.4914 0.8793 12
0.4528 0.6064 1.0082 0.6542 13 0.4630 0.6223 1.0392 0.6603 14
0.5061 0.6921 1.0850 0.6191 15 0.5243 0.7500 1.2812 0.9024 16
0.5278 0.8728 1.6520 0.8335 17 0.5702 0.8982 1.5235 0.7759 18
0.4452 0.6164 1.0012 0.5954 19 0.4764 0.6074 1.0068 0.6052 20
0.5164 0.6257 1.1200 0.7021
INDUSTRIAL AVAILABILITY
[0081] According to the present invention, nanoscale or amorphous
fine particles of active ingredients are obtained, by removing
solid fats from a mixture comprising active ingredients and solid
fats with a supercritical fluid. The nanoparticles prepared by the
present invention may be suitably used in medicinal products,
functional or general foods, cosmetics and the like, due to their
excellent dispersability, absorbing property, physiological
activity and the like.
* * * * *