U.S. patent application number 11/915922 was filed with the patent office on 2010-02-25 for injectable drug carrier comprising layered double hydroxide.
This patent application is currently assigned to NANOHYBRID CO., LTD.. Invention is credited to Jin-ho Choy, Ji-Sun Jung, Jae-Min Oh, Taeun Park.
Application Number | 20100047307 11/915922 |
Document ID | / |
Family ID | 37481792 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100047307 |
Kind Code |
A1 |
Park; Taeun ; et
al. |
February 25, 2010 |
INJECTABLE DRUG CARRIER COMPRISING LAYERED DOUBLE HYDROXIDE
Abstract
Provided is an injectable drug carrier including a non-toxic
Layered Double Hydroxide (LDH) and pharmaceutically acceptable
excipients. Provided is also a method of preparing the injectable
drug carrier, the method including: synthesizing LDH with various
compositions and controlling the size and shape of the LDH at a
level that the LDH has no adverse effect in vivo. A solution
obtained by dispersing the LDH in a solvent is injected in vivo.
According to the method, nano-size LDH that does not affect a blood
vessel in vivo can be synthesized. The LDH thus synthesized has no
adverse effect in vivo even at a concentration of 400 mg/kg, and
thus can contribute to establishment of a drug delivery system
capable of improving the delivery efficiency of a specific
drug.
Inventors: |
Park; Taeun; (Seoul, KR)
; Choy; Jin-ho; (Seoul, KR) ; Oh; Jae-Min;
(Seoul, KR) ; Jung; Ji-Sun; (Seoul, KR) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W., SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
NANOHYBRID CO., LTD.
Seoul
KR
|
Family ID: |
37481792 |
Appl. No.: |
11/915922 |
Filed: |
June 3, 2005 |
PCT Filed: |
June 3, 2005 |
PCT NO: |
PCT/KR2005/001667 |
371 Date: |
November 29, 2007 |
Current U.S.
Class: |
424/423 ;
514/262.1 |
Current CPC
Class: |
A61K 47/02 20130101;
A61K 9/0019 20130101; A61P 35/00 20180101; A61K 9/143 20130101 |
Class at
Publication: |
424/423 ;
514/262.1 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/519 20060101 A61K031/519; A61P 35/00 20060101
A61P035/00; A61P 37/02 20060101 A61P037/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 2, 2005 |
KR |
10-2005-0047235 |
Claims
1. An injectable drug carrier comprising a non-toxic Layered Double
Hydroxide (LDH) and a pharmaceutically acceptable excipients.
2. The injectable drug carrier of claim 1, wherein the LDH has a
particle size of 100 to 300 nm.
3. A method of preparing the injectable drug carrier of claim 1,
the method comprising: titrating a divalent and trivalent metal
salts-containing aqueous solution with a base solution and
incubating the resultant solution at room temperature or under
hydrothermal synthesis condition to obtain LDH; and controlling a
particle size of the LDH.
4. The method of claim 3, wherein the divalent metal is selected
from the group consisting of magnesium (Mg.sup.2+), calcium
(Ca.sup.2+), and zinc (Zn.sup.2+), and the trivalent metal is
selected from the group consisting of aluminum (Al.sup.3+) and iron
(Fe.sup.3+).
5. The method of claim 3, wherein the base solution is selected
from the group consisting of sodium hydroxide (NaOH) and ammonia (N
H.sub.3).
6. An injectable drug delivery system comprising the drug carrier
of claim 1 and a drug.
7. The injectable drug delivery system of claim 6, wherein the drug
is loaded into the drug carrier by ion exchange or
coprecipitation.
8. The injectable drug delivery system of claim 6, wherein the drug
is methotrexate (MTX).
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATION(S)
[0001] This application is a 35 U.S.C. .sctn.371 National Phase
Entry Application from PCT/KR2005/001667, filed Jun. 3, 2005, and
designating the United States and claims the benefit of Korean
Patent Application No. 10-2005-0047235, filed on Jun. 2, 2005, in
the Korean Intellectual Property Office, the disclosure of which is
incorporated herein in its entirety by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a use of Layered Double
Hydroxide (LDH) as a drug carrier, and more particularly, to a
method of loading a drug onto the LDH drug carrier, a method of
improving drug delivery efficiency using the LDH drug carrier, and
establishment of a safe dose range of LDH that has no adverse
effect in vivo when LDH is administered through injection.
[0004] 2. Description of the Related Art
[0005] Generally, currently available medications have possibility
of destroying normal cells as well as diseased cells. Thus, many
drugs are limitedly used. There also exist drugs that cannot be
used in actual medication due to poor stability in spite of good
medicinal activity. In addition, since a single dose is consumed
rapidly in the human body during medication, some drugs have
inconvenience to be administered several times. In view of these
problems of existing drugs, various drug delivery systems capable
of assuring good drug delivery efficiency, stability and controlled
release rate have been developed.
[0006] Basic requirements of drug delivery systems variously depend
on desired objectives. Preferentially, drug delivery systems must
satisfy the following requirements: 1) drug stability, 2) drug
targeting to a specific tissue, 3) regulation of drug release rate
and 4) in vivo safety of delivery carriers. Development of organic,
inorganic, or polymer drug delivery systems, etc. satisfying these
various requirements has been carried out. Internationally
developed drug delivery systems are as follows. U.S. Pat. No.
6,361,780, entitled "Microporous Drug Delivery System", discloses a
drug delivery device using porous inorganic oxides, metals, etc.
International Patent WO9407468, entitled "Two Phase Matrix for
Sustained Release Drug Delivery", discloses a polymer-silicate
phase-based drug delivery system for use as a transdermal patch.
U.S. Pat. No. 6,558,703, entitled "Porous Hydroxyapatite Particles
as a Carrier for Drug Substances", discloses a drug delivery system
for oral administration which utilizes porous inorganic particles
loaded with a sticky/greasy/oily drug substance. U.S. Pat. No.
5,846,952, entitled "Methods and Compositions for Poly-, Beta-,
-1-4-N-Acetyl Glucosamine Drug Delivery", discloses
poly-.-1.4-N-acetylglucosamine (p-GlcNAc) polysaccharide as a drug
delivery system. In addition, U.S. Pat. No. 5,904,718, entitled
"Delayed Drug Delivery System", discloses a sustained release drug
delivery system using inorganic materials. U.S. Pat. No. 5,648,097,
entitled "Calcium Mineral-Based Microparticles and Method for the
Production thereof", discloses biodegradable inorganic calcium salt
particles used as a drug carrier capable of controlling a drug
release rate in the human body. European Patent No. EP1,067,971,
entitled "Inorganic Materials for Radioactive Drug Delivery",
discloses an inorganic drug delivery system. Recently, Korean
Patent No. 10-0359715, entitled "Bio-inorganic Hybrid Complexes as
Gene Reservoir and Potential Delivery Carrier and their
Preparation", and U.S. Pat. No. 6,329,515, entitled "Bio-inorganic
Compound Capable of Stable, Solid-State Storage of Genes and
Preparation thereof", disclose that Layered Double Hydroxide (LDH)
has the possibility of serving as a reservoir which safely stores
DNAs and serving as a gene or drug delivery carrier. In addition,
Korean Patent Application No. 2003-00676, entitled "Method of
Preventing the Proliferation of Tumor Cells Using MTX-LDH Hybrid",
discloses the prevention of proliferation of osteosarcoma cells
using LDH incorporated with MTX which is an anticancer agent.
[0007] As described above, research and study on drug delivery
systems have been currently actively carried out. In particular,
research on drug delivery systems capable of controlling drug
stability and release characteristics using polymers or inorganic
materials has been most actively carried out. Research on drug
delivery systems which increase drug efficacy at a cellular level
is also carried out. However, drug delivery systems which is able
to be directly used in vivo have not been sufficiently studied. In
particular, injectable inorganic drug delivery carriers have been
hardly studied.
[0008] The present invention is directed to a preparation of a LDH
as a drug carrier capable of maximizing in vivo drug delivery
efficiency and a use of it in an injectable formulation.
[0009] LDH, which is also called "hydrotalcite-like compound", is a
compound having a similar structure to magnesium (Mg)-aluminum (Al)
layered double hydroxide known as hydrotalcite, wherein magnesium
or aluminum can be substituted by other divalent or trivalent
metal. The LDH structure consists of positively charged hydroxide
layers due to the presence of trivalent metal ions in substitution
of divalent metal ions, and thus various anions can be intercalated
between the positively charged hydroxide layers. Thus, a complex
obtained by the intercalation of a negatively charged drug between
the hydroxide layers of LDH can be used as a drug delivery system.
Most of negatively charged drugs can be used herein, which includes
various drugs such as methotrexate, vitamins (e.g., vitamin C or
retinoic acid), genes with a negatively charged phosphate group,
and antisense for gene therapy. It is anticipated that when
administered in vivo through injection, LDH containing a negatively
charged drug will provide advantages such as drug stability,
sustained drug release, and improved drug delivery efficiency, with
no harmful side effects along with pharmacological activity.
[0010] The present invention relates to the hybridization of
nanotechnology and biotechnology. LDH used herein as an injectable
drug carrier is an inorganic solid compound and is applied in
various fields, including catalysts, supports, thermal stabilizers,
antiacids, etc. Depending on the purpose of LDH in these
applications, metal composition, particle shape, particle size,
etc. must be diversely controlled. Such a control belongs to the
category of nanotechnology since it requires microscale or
nanoscale particle control and molecular or atomic level
modification in composition or physical property. Also for the
intercalation of a physiologically active drug molecule into LDH,
the interaction between the drug molecule and the LDH is to be
controlled. Thus, the present invention also relates to a novel
technology which converges medical technology, biotechnology, and
nanotechnology. The present invention also relates to biotechnology
in the respect that drug efficacy is evaluated after a drug
delivery carrier is injected in vivo. Therefore, the present
invention is a novel technology that can be accomplished by
fusioning nanotechnology and biotechnology.
SUMMARY OF THE INVENTION
[0011] The present invention provides a non-toxic, injectable
inorganic drug delivery system using Layered Double Hydroxide (LDH)
with an appropriate physicochemical property as a drug carrier.
[0012] In view of the above objectives of the present invention,
there is provided an injectable drug carrier including a non-toxic
Layered Double Hydroxide (LDH) and a pharmaceutically acceptable
excipients. LDH has possibility of having an adverse effect in vivo
since the control of its size and shape is difficult. Furthermore,
it has not been determined whether LDH is toxic or non-toxic in
vivo because the LDH has not been administered through injection.
However, the present inventors found that LDH was non-toxic and had
no harmful side effects in vivo when administered through injection
and thus first demonstrated that LDH could be used as an injectable
drug carrier.
[0013] The present invention is characterized in that the LDH of
particle size of 100 to 300 nm is preferred.
[0014] The present invention also provides a method of preparing an
injectable drug carrier, the method which includes titrating a
divalent and trivalent metal salts-containing aqueous solution with
a base solution, incubating the resultant solution at room
temperature or under hydrothermal synthesis condition to obtain
LDH; and controlling a particle size of the LDH. Here, the
"hydrothermal synthesis" refers to a synthesis method performed at
a temperature higher than the boiling point of water (100.degree.)
in a hermetically sealed reactor under a vapor-phase pressure
greater than atmospheric pressure.
[0015] In the present invention, the divalent metal may be selected
from the group consisting of magnesium (Mg.sup.2+), calcium
(Ca.sup.2+), and zinc (Zn.sup.2+), the trivalent metal may be
selected from the group consisting of aluminum (Al.sup.3+) and iron
(Fe.sup.3+), and the base solution may be selected from the group
consisting of sodium hydroxide (NaOH) and ammonia (NH.sub.3).
[0016] The present invention also provides an injectable drug
delivery system including the injectable drug carrier and a drug.
Here, the drug may be any negatively charged drug that can be
intercalated between hydroxide layers of LDH. Examples of the drug
include various drugs such as methotrexate, vitamins (e.g., vitamin
C or retinol acid), genes with a negatively charged phosphate
group, and antisense for gene therapy. The drug can be loaded in
the LDH by a method previously well known in the art, e.g., ion
exchange or coprecipitation.
[0017] An injectable drug delivery system according to an
embodiment of the present invention can be prepared by 1)
synthesizing LDH with various compositions and controlling the size
and shape of the LDH at a level suitable for use in a drug delivery
system, and 2) processing the LDH into an injectable
formulation.
[0018] Generally, LDH is synthesized by titrating a divalent and
trivalent metal salts-containing solution with a base solution. The
divalent metal may be magnesium (Mg.sup.2+), calcium (Ca.sup.2+),
or zinc (Zn.sup.2+), the trivalent metal may be aluminum
(Al.sup.3+) or iron (Fe.sup.3+), and the base solution may be
sodium hydroxide (NaOH) or ammonia (NH.sub.3). LDH synthesized by
precipitation can be obtained in the form of particles with desired
composition, shape, and size by adjusting the concentration and
ratio of metal ions, the titration rate, the total reaction time,
etc. Preferably, LDH may be processed into fine particles with a
particle size of 300 nm or less to prevent clogging of capillary
blood vessels and to eliminate a physical impact when administered
in vivo through injection. In the present invention, incubation for
24 hours after titration of NaOH solution into the solution
containing magnesium and aluminum ions can produce uniform LDH
particles.
[0019] The loading of a drug into LDH can be performed by ion
exchange or coprecipitation. According to the ion exchange method,
ions such as nitrate (NO.sub.3.sup.-), chloride (Cl.sup.-), or
carbonate (CO.sub.3.sup.2-) in the interlayers of LDH are
substituted by ionized drug molecules. According to the
coprecipitation method, ionized drug molecules are added to a mixed
metal solution during titration, and encapsulation of the drug
molecules occurs simultaneously with formation of LDH. Most of
negatively charged drugs can be intercalated into LDH. Examples of
the drug include various drugs such as methotrexate, vitamins
(e.g., vitamin C or retinoic acid), genes with a negatively charged
phosphate group, and antisense for gene therapy.
[0020] A drug-loaded LDH, i.e., a drug-LDH hybrid complex is
represented by formula 1 below:
[M.sup.2+.sub.1-xN.sup.3+.sub.x(OH).sub.2][A.sup.n-].sub.x/nyH.sub.2O
wherein M.sup.2+ is a divalent metal cation selected from the group
consisting of Mg.sup.2+, Ni.sup.2+,Cu.sup.2+, and Zn.sup.2+,
N.sup.3+is a trivalent metal cation selected from the group
consisting of Al.sup.3+, Fe.sup.3+, V.sup.3+, Ti.sup.3+ and
Ga.sup.3+, x is 0.1 to 0.4, A is an anionic drug, n is a charge
number of the drug, and y is a positive number.
[0021] In formula 1, the x related to a metal composition ratio may
range from 0.1 to 0.4, and more preferably from 0.25 to 0.33. If
the x value is outside of this range, encapsulation of a drug in
LDH carrier, i.e., the intercalation of a drug between the
hydroxide layers of the LDH carrier may not occur, which renders
the production of a desired drug-LDH hybrid difficult.
[0022] The drug-LDH hybrid of the present invention may be used in
a hydrate form. The degree of hydration can be expressed as the y
value. The y value can be changed according to various factors such
as moisture content in air, and can be represented by a positive
number since it can be generally selected within a broad range.
[0023] LDH thus synthesized is dispersed in distilled water and
further diluted with injectable distilled water. A finally obtained
LDH-containing solution is injected intraperitoneally to Balb/c
mice, and a change in body weight of mice and a death rate are
measured for a month to evaluate an effect (e.g., toxicity) of LDH
in vivo.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The above and other features and advantages of the present
invention will become more apparent by describing in detail
exemplary embodiments thereof with reference to the attached
drawings in which:
[0025] FIG. 1 is X-ray diffraction patterns of Layered Double
Hydroxides (LDHs) synthesized at room temperature (a), and
hydrothermally synthesized at 125, 150, and 180.degree. (b, c, and
d);
[0026] FIG. 2A is a Scanning Electron Microscope (SEM) image of LDH
synthesized at room temperature, and FIGS. 2B, 2C, and 2D are SEM
images of LDHs hydrothermally synthesized at 125.degree.,
150.degree., and 180.degree., respectively;
[0027] FIG. 3 is a graph illustrating a change in body weight of
mice with respect to the concentration of LDH administered to mice
intraperitoneally;
[0028] FIG. 4 is a graph illustrating the total survival of mice
with respect to the concentration of LDH administered to the mice
intraperitoneally;
[0029] FIG. 5 is X-ray diffraction patterns of (a) LDH and (b) a
LDH-methotrexate (MTX) hybrid synthesized by ion exchange;
[0030] FIG. 6a is a graph illustrating cell viability with respect
to the concentration of MTX and a LDH-MTX hybrid 24 hours after
osteosarcoma cell line, SAOS-2, was treated with the MTX and the
LDH-MTX hybrid and FIG. 6b is a graph illustrating cell viability
with respect to the time after osteosarcoma cell line, SAOS-2, was
treated with LDH, MTX, and a LDH-MTX hybrid (each at a
concentration of 500 .degree./ml); and
[0031] FIG. 7 is a graph illustrating the total survival of mice
with respect to the concentration of MTX (7a) and a LDH-MTX hybrid
(7b) administered to the mice intraperitoneally.
DETAILED DESCRIPTION OF THE INVENTION
[0032] According to the present invention, Layered Double Hydroxide
(LDH) can be used as a biocompatible injectable drug carrier that
has little toxicity and adverse effect in vivo. Furthermore, LDH
can also be used as a non-toxic injectable drug carrier maximizing
drug efficacy and drug delivery efficiency when it is injected in
vivo in the form of a hybrid with various drugs. In addition, LDH
is suitable for use as an injectable drug carrier with regard to a
particle size and shape. An actual animal test shows that LDH has
no adverse effect in vivo on intraperitoneal application.
[0033] Hereinafter, the present invention will be described more
specifically with reference to the following examples. The
following examples are for illustrative purposes and are not
intended to limit the scope of the invention.
Example 1
Synthesis of Layered Double Hydroxide (LDH)
[0034] LDH's were synthesized as follows. A mixture of magnesium
nitrate and aluminum nitrate (2:1) was dissolved in distilled water
and sodium carbonate was then added in an amount of 1.5 times of
the molar ratio of aluminum. The reaction solution was titrated
with a 0.5 M sodium hydroxide solution until pH was 9.5. Then, some
samples of the resultant solution were incubated at room
temperature for 24 hours and some samples were incubated at 125,
150, and 180.degree. under hydrothermal synthesis condition for 24
hours. X-ray diffraction patterns of LDH's thus obtained are shown
in FIG. 1 and Scanning Electron Microscope(SEM) images showing
particle shape and size are shown in FIG. 2. In FIG. 1, (a) is an
X-ray diffraction pattern of the LDH synthesized at room
temperature, (b), (c), and (d) are X-ray diffraction patterns of
the LDHs hydrothermally synthesized at 125, 150, and 180.degree.,
respectively. FIG. 2a is a SEM image of the LDH synthesized at room
temperature, and FIGS. 2b, 2c, and 2dare SEM images of the LDHs
hydrothermally synthesized at 125.degree., 150.degree., and
180.degree., respectively. Referring to FIGS. 1, 2a, 2b, 2c, and
2d, the hydrothermally synthesized LDHs had a particle size ranging
from 100 to 300 nm, which did not greatly depend on temperature.
Thus, it can be seen that it is efficient to synthesize LDH at a
low temperature (100-125.degree.) if possible.
Example 2
In vivo Toxicity Test of LDH
[0035] Small animal models, Balb/c mice (6-7 weeks old) were
purchased and managed in cages (5 mice/cage). The LDH synthesized
by hydrothermal process at 125.degree. as described in Example 1
was administered intraperitoneally to 10 mice at each concentration
of 100, 200, 300, and 400 mg per 1 kg of body weight. The body
weight of each mouse was measured prior to administration, and
every week for three weeks, and a dose of the drug adjusted
according to newly measured weight was administered.
[0036] A change in the average of body weight of the 10 mice is
shown in FIG. 3, and the body weights of the mice died during the
test were excluded from statistical analysis. As shown in FIG. 3,
weight loss was not observed even when a LDH level was 0.4% of the
body weight (400 mg/kg). Rather, a gradual increase in body weight
was observed. This shows that the mice grew normally.
[0037] In FIG. 4, the death rate of the mice with respect to the
concentration of administered LDH is represented by total number of
mice survived. As shown in FIG. 4, only one mouse died upon
administration of 200 mg/kg of LDH for three weeks, and all mice
were alive upon administration of 300 and 400 mg/kg of LDH for
three weeks. This shows that LDH has no adverse effect in vivo even
at a concentration of 400 mg/kg and thus can be used as an
injectable drug carrier up to this dosage level.
Example 3
Synthesis of LDH-MTX (Methotrexate) Hybrid
[0038] To synthesize a hybrid of LDH and MTX, the LDH synthesized
at room temperature in Example 1 was filtered with a filter of pore
size of 450 nm and then dispersed in an excess MTX-containing
solution at 60.degree. under a nitrogen atmosphere for four days
(ion exchange method). The LDH-MTX hybrid thus synthesized was
washed with distilled water and dried in vacuum. The termination of
the synthesis was confirmed by X-ray diffraction analysis. In FIG.
5, (a) is an X-ray diffraction pattern of LDH and (b) is an X-ray
diffraction pattern of the LDH-MTX hybrid.
Example 4
Anticancer Effect and in vivo Toxicity Test of LDH-MTX Hybrid
[0039] An anticancer effect of the LDH-MTX hybrid relative to MTX
was evaluated on human osteosarcoma cell lines, SAOS-2. An
anticancer effect was evaluated using MTT [MTT:
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]
assay. The concentration of each MTX and LDH-MTX hybrid used was as
follows: 5.times.10.sup.-6, 5.times.10.sup.-5, 5.times.10.sup.-4,
5.times.0.sup.-3, 5.times.10.sup.-2, 5.times.10.sup.-1, 5, 50, and
500.degree./ml. Cell viability with respect to each concentration
at 24 hours after administration is illustrated in FIG. 6a, and
cell viability with respect to the time after administration with
LDH, MTX, and the LDH-MTX hybrid (each at a concentration of 500
.degree./ml) is illustrated in FIG. 6b. Referring to FIG. 6a, the
LDH-MTX hybrid exhibited the same anticancer effect as pure MTX
even when administered at a lower concentration than that of MTX,
and in particular, reached a maximal anticancer effect in a short
time. This shows that LDH can be used as a carrier for an
anticancer agent unless toxicity of LDH is a problem in vivo.
Example 5
In vivo Toxicity Test of LDH-MTX Hybrid
[0040] Like in the in vivo toxicity test of LDH of Example 2, small
animal models, Balb/c mice (6-7 weeks old) were purchased and
managed in cages (5 mice/cage). MTX was administered
intraperitoneally to 10 mice at each concentration of 50, 75, and
100 mg/kg and the LDH-MTX hybrid synthesized in Example 3 was
administered intraperitoneally to 10 mice at each concentration of
3, 6, 12.5, 25, 50, 75, and 100 mg/kg. The body weight of each
mouse was measured every week for three weeks and a dosage of drug
adjusted to the newly measured weight was administered. The body
weights of the mice died during the test were excluded from
statistical analysis. A death rate with respect to the
concentration of MTX is represented by total number of mice
survived in FIG. 7a and a death rate with respect to the
concentration of the LDH-MTX hybrid is represented by the total
number of mice survived in FIG. 7b. Referring to FIGS. 7a and 7b,
LD.sub.50 of MTX was 75 mg/kg, whereas LD.sub.50 of the LDH-MTX
hybrid was 25 mg/kg. That is, the lethal dose of the LDH-MTX hybrid
was equal to 1/3 of that of MTX. Thus, considering that the
anticancer effect of the LDH-MTX hybrid is 10 times higher than
that of MTX as shown in FIG. 6a, the LDH-MTX hybrid can be
effectively used in a smaller amount for anticancer therapy. This
result shows that the LDH-MTX hybrid can be used as an injectable
drug delivery system without having an adverse effect in vivo.
[0041] According to the present invention, Layered Double Hydroxide
(LDH) can be used as a biocompatible injectable drug carrier that
has little toxicity and adverse effect in vivo. Furthermore, LDH
can also be used as a non-toxic injectable drug carrier maximizing
drug efficacy and drug delivery efficiency when it is injected in
vivo in the form of a hybrid with various drugs. In addition, LDH
is suitable for use as an injectable drug carrier with regard to a
particle size and shape. An actual animal test shows that LDH has
no adverse effect in vivo on intraperitoneal application.
[0042] While the present invention has been particularly shown and
described with reference to exemplary embodiments thereof, it will
be understood by those of ordinary skill in the art that various
changes in form and details may be made therein without departing
from the spirit and scope of the present invention as defined by
the following claims.
* * * * *