U.S. patent application number 10/559512 was filed with the patent office on 2006-07-13 for drug-containing sustained release microparticle, process for producing the same and preparation containing the microparticle.
Invention is credited to Toshiyuki Ikoma, Yutaka Mizushima, Yasuaki Ogawa, Junzo Tanaka.
Application Number | 20060153930 10/559512 |
Document ID | / |
Family ID | 33534720 |
Filed Date | 2006-07-13 |
United States Patent
Application |
20060153930 |
Kind Code |
A1 |
Mizushima; Yutaka ; et
al. |
July 13, 2006 |
Drug-containing sustained release microparticle, process for
producing the same and preparation containing the microparticle
Abstract
Sustained release microparticles suitable for various types of
drugs, or drug-containing sustained release microparticles capable
of sustained release of drugs over a period of three days or more
and capable of inhibiting initial burst release; a process for
producing the same; and preparations containing the microparticles
are disclosed. The drug-containing sustained release microparticles
comprise a drug other than human growth hormone and a porous
apatite derivative, and optionally include a water-soluble bivalent
metal compound. The drug-containing sustained release
microparticles can be produced by dispersing under agitation
microparticles of a porous apatite derivative in an aqueous
solution containing a drug so that the aqueous solution infiltrates
into the porous apatite derivative; optionally adding an aqueous
solution containing a water-soluble bivalent metal compound that
may infiltrate into the porous apatite derivative; further adding
additives such as a stabilizer to the mixture; and effecting
lyophilization or vacuum drying.
Inventors: |
Mizushima; Yutaka; (Tokyo,
JP) ; Ogawa; Yasuaki; (Kyoto, JP) ; Tanaka;
Junzo; (Ibaraki, JP) ; Ikoma; Toshiyuki;
(Ibaraki, JP) |
Correspondence
Address: |
PRICE HENEVELD COOPER DEWITT & LITTON, LLP
695 KENMOOR, S.E.
P O BOX 2567
GRAND RAPIDS
MI
49501
US
|
Family ID: |
33534720 |
Appl. No.: |
10/559512 |
Filed: |
June 11, 2004 |
PCT Filed: |
June 11, 2004 |
PCT NO: |
PCT/JP04/08188 |
371 Date: |
December 5, 2005 |
Current U.S.
Class: |
424/604 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 35/00 20180101; A61P 29/00 20180101; A61K 33/42 20130101; A61K
33/30 20130101; A61P 31/12 20180101; A61K 33/42 20130101; A61K
9/1611 20130101; A61K 2300/00 20130101; A61K 31/00 20130101; A61K
2300/00 20130101; A61K 33/30 20130101 |
Class at
Publication: |
424/604 |
International
Class: |
A61K 33/42 20060101
A61K033/42 |
Claims
1. Drug-containing sustained release microparticles characterized
by comprising a drug other than human growth hormone and a porous
apatite derivative.
2. Drug-containing sustained release microparticles characterized
by comprising a drug other than human growth hormone, a porous
apatite derivative and a water-soluble bivalent metal compound.
3. The drug-containing sustained release microparticles according
to claim 1, characterized in that the porous apatite derivative is
a porous apatite derivative in which a portion of calcium as a
constituent of hydroxyapatite is substituted with zinc during
production.
4. The drug-containing sustained release microparticles according
to claim 3, characterized in that the porous apatite derivative has
a zinc substitution rate or zinc content rate of 0.1 to 2.0.
5. The drug-containing sustained release microparticles according
to claim 2, characterized in that the water-soluble bivalent metal
compound is a zinc compound.
6. The drug-containing sustained release microparticles according
to claim 5, characterized in that the water-soluble bivalent metal
compound is zinc chloride or zinc acetate.
7. A preparation for parenteral administration characterized by
comprising, drug-containing sustained release microparticles
according to claim 1.
8. The preparation according to claim 7, characterized in that the
preparation for parenteral administration is either a subcutaneous
injection or an intramuscular injection.
9. A process for producing drug-containing sustained release
microparticles characterized by comprising: dispersing under
agitation microparticles of a porous apatite derivative in an
aqueous solution containing a drug so that the aqueous solution
infiltrates into the porous apatite derivative; adding thereto an
aqueous solution containing a water-soluble bivalent metal compound
so that the water-soluble bivalent metal compound infiltrates into
the porous apatite derivative; further adding an additive such as a
stabilizer to the mixture; and effecting lyophilization or
vacuum-drying.
10. The production process according to claim 9, characterized in
that the porous apatite derivative is a porous apatite derivative
in which a portion of calcium as a constituent of hydroxyapatite is
substituted with zinc during production.
11. The production process according to claim 10, characterized in
that the porous apatite derivative has a zinc substitution rate or
zinc content rate of 0.1 to 2.0
12. The process according to claim 9, characterized in that the
water-soluble bivalent metal compound is zinc chloride or zinc
acetate.
Description
TECHNICAL FIELD
[0001] The present invention relates to drug-containing sustained
release microparticles comprising, as a base, microparticles of a
porous apatite derivative that disappears in a living body; a
process for producing the same; and a preparation containing the
microparticles.
BACKGROUND ART
[0002] Investigation has heretofore been made on particulate
injections that provide the sustained release of drugs for a long
period, most of which comprise poly-lactic-co-glycolic acid (PLGA)
as a base (see Japanese Patent Laid-Open Nos. 11-286403,
2000-239104 and 2002-326960). Alternatively, sustained release
microcapsules that contain human growth hormone (hGH) and comprise
PLGA as a base have been reported (Nature Medicine, 2: 795-799,
1996). Sustained release microcapsules that contain leuprorelin, a
LHRH agonist, and comprise PLGA as a base have also been reported
(Chemical Pharmaceutical Bulletin, 36: 1095-1103, 1988). PLGA is a
biodegradable base that hydrolyzes and disappears in a living body,
and this property is preferable for a base of an injection.
However, if drugs encapsulated in typical sustained release
particulate preparations that use PLGA are highly soluble in water,
there is an inevitable problem with excessive release in the early
stage of administration (initial burst). In addition, organic
solvents must be used for its production. In this case,
inactivation becomes a problem for protein drugs. Furthermore, if a
solvent evaporation method typically used as a production process
is adopted, the amount of drugs encapsulated, in the case of
water-soluble drugs, is 10% or less by weight, and the amount of
the whole preparation administered, in the case of drugs with low
activity, is increased. Such a preparation is difficult to
administer. Because the preparation has a relatively large average
particle size of 20 .mu.m or more, an injection needle as thick as
21 to 23 G is required. Some sustained release particles of drugs
that use hydroxyapatite have already been reported (H. Gautier et
al., Journal of Biomedical Material Research, 40, 606-613, 1998;
and J. Guicheux et al., Journal of Biomedical Material Research,
34, 165-170, 1997). However, all of the sustained release particles
are two-component systems having the drug and hydroxyapatite, in
which hydroxyapatite has a large particle size of 40 to 80 .mu.m or
200 .mu.m and their in-vivo sustained release effect is unknown.
Besides, the amount of the drug adsorbed into the apatite particle
(the amount of the drug encapsulated) was as low as 1% or less.
DISCLOSURE OF THE INVENTION
[0003] A material having so-called biodegradability or a property
of disappearing in a living body, which disappears from a living
body within a period of time near the end of the release of drugs
after administration, must be selected as a sustained release base.
Initial burst release (the excessive release of drugs in the early
stage of administration), with respect to highly water-soluble
drugs as well, must be small. Taking protein drugs into
consideration, a sustained release base and a process for producing
drug-containing sustained release microparticles, which allow
production with the minimal use of organic solvents, must be found.
Particulate preparations capable of easily passing through a thin
injection needle of 23 G or less and capable of sustained release
of drugs over a period of three days must be prepared, wherein the
amount of drugs encapsulated in the drug-containing microparticle
is brought to 10% or more by weight.
[0004] In order to solve these problems, the present inventors have
found that sustained release microparticles suitable for various
types of drugs can be obtained by use of microparticles of a porous
apatite derivative. The present inventors have further found that
the use of a water-soluble bivalent metal compound in combination
with a drug other than human growth hormone achieves the sustained
release of the drug over a period of three days or more and
inhibits, with respect to highly water-soluble drugs as well,
initial burst release. In addition, the present inventors have
found that when the water-soluble bivalent metal compound is not
used, the same effect can be obtained.
[0005] Thus, an object of the present invention is to provide
sustained release microparticles suitable for various types of
drugs, or drug-containing sustained release microparticles capable
of sustained release of drugs over a period of three days or more
and capable of preventing, with respect to highly water-soluble
drugs as well, initial burst release; a process for producing the
same; and preparations containing the microparticles.
[0006] The drug-containing sustained release microparticles of the
present invention comprise a drug other than human growth hormone
and a porous apatite derivative, or comprise a drug other than
human growth hormone, a porous apatite derivative and a
water-soluble polyvalent metal compound. The water-soluble
polyvalent metal compound includes zinc chloride, calcium chloride,
calcium hydroxide, iron chloride, iron hydroxide, cobalt chloride,
aluminum chloride and zinc acetate. Among others, a water-soluble
bivalent compound is most preferred. The preferred water-soluble
bivalent compound includes a zinc compound and a calcium compound,
with zinc chloride most preferred. In addition, zinc acetate,
calcium chloride, and the like are also preferred.
[0007] The preparation for parenteral administration of the present
invention comprises the drug-containing sustained release
microparticles.
[0008] It is preferred that the preparation for parenteral
administration should be a subcutaneous injection or an
intramuscular injection.
[0009] It is also preferred that the porous apatite derivative
should be a porous apatite derivative in which a portion of calcium
as a constituent in the composition of hydroxyapatite is
substituted with zinc during production.
[0010] Moreover, it is preferred that the zinc substitution rate or
zinc content rate in the porous apatite derivative should be 0.1 to
2.0.
[0011] The process for producing the drug-containing sustained
release microparticles of the present invention comprises:
dispersing under agitation microparticles of a porous apatite
derivative in an aqueous solution containing a drug so that the
aqueous solution infiltrates into the porous apatite derivative;
adding thereto an aqueous solution containing a water-soluble
bivalent metal compound so that the water-soluble bivalent metal
compound infiltrates into the porous apatite derivative; further
adding an additive such as a stabilizer to the mixture; and
effecting lyophilization or vacuum drying.
[0012] In some cases, the process for producing drug-containing
sustained release microparticles does not involve the addition of
the aqueous solution containing the water-soluble bivalent metal
compound. Therefore, the water-soluble bivalent metal compound does
not infiltrate in the porous apatite derivative.
[0013] Likewise, it is preferred for the process for producing
drug-containing sustained release microparticles that: the porous
apatite derivative should be a porous apatite derivative in which a
portion of calcium as a constituent of hydroxy apatite is
substituted with zinc during production; the zinc substitution rate
or zinc content rate in the porous apatite derivative should be 0.1
to 2.0; and the water-soluble bivalent metal compound should be
zinc chloride or zinc acetate.
[0014] The drug other than human growth hormone used herein is not
particularly limited and is preferably a water-soluble drug. For
example, a protein drug includes interferons, interleukins, G-CSF,
BDNF, FGF, EGF and a variety of antibodies. A peptide drug includes
GnRH and its derivatives, TRH, enkephalins, PTH and calcitonin. A
DNA-associated substance includes antisense and ribozyme. In
addition, anti-inflammatory drugs, steroids, anti-dementia drugs
and drugs for circulatory diseases are encompassed.
[0015] In the basic process for producing drug-containing sustained
release microparticles, microparticles of a porous apatite
derivative is dispersed under agitation in an aqueous solution
containing a drug so that the aqueous solution sufficiently
infiltrates into the porous apatite derivative. An aqueous solution
containing a water-soluble bivalent metal compound is further added
thereto so that the water-soluble bivalent metal compound
sufficiently infiltrates into the porous apatite derivative. Then,
appropriate additives such as a stabilizer are added to the
mixture. Lyophilization or vacuum drying is effected, thereby
obtaining a powder of drug-containing sustained release
microparticles comprising the drug and the microparticles of the
porous apatite derivative as a base. When actually administered,
this obtained powder is dispersed in an appropriate dispersion
medium and injected, for example, subcutaneously or
intramuscularly. When the desorption of the encapsulated drug is
measured by dispersing the microparticles thus obtained in a large
amount of purified water at room temperature, the drug up to a
certain amount relative to porous apatite derivatives was not
desorbed, though depending on the type of the drug. That is, the
drug probably infiltrates and is adsorbed in the fine pores of the
porous apatite derivatives.
[0016] The microparticles of the porous apatite derivative used
herein can be obtained by a known method including a method
described in, for example, T. Yamaguchi, H. Yanagida, A. Makishima,
H. Aoki, Ceramic Science Series 7 Bioceramics, GIHODO SHUPPAN Co.,
Ltd., pp. 7-9, 1984. The most preferable porous apatite derivative
is any of those in which a portion of Ca in the composition of
hydroxyapatite is substituted with zinc (Zn). The rate of
substitution (the number of a Zn atom relative to 10 Ca atoms) is
preferably 0.1 to 5.0, more preferably 0.1 to 2.0. In this case,
the disappearing velocity of the porous apatite derivative in a
living body differs depending on the ratio of (Ca+Zn)/P. If the
ratio is smaller than 1.67, the porous apatite derivative is more
likely to be soluble in water, that is, the disappearing velocity
of the porous apatite derivative in a living body is accelerated.
It is preferred that the ratio of (Ca+Zn)/P should fall within the
range of 1.67 to 1.51. When the porous apatite derivative is used
within this range, the porous apatite derivative disappears in a
living body within a few weeks to a few months. The substitution
rate or content rate(the number of a Zn atom relative to 10 Ca
atoms ) is preferably 0.1 to 5.0, more preferably 0.1 to 2.0. A
lower treating temperature at which the porous apatite derivative
is produced renders the porous apatite derivative more soluble in
water and therefore accelerates the disappearing velocity of the
porous apatite derivative in a living body. The treating
temperature used is room temperature to 800.degree. C., preferably
150.degree. C. to 600.degree. C. More preferable is a treating
temperature of 150.degree. C. to 400.degree. C. If the porous
apatite derivative is treated at 800.degree. C. or higher, the
resulting porous apatite derivative does not disappear in a living
body. The particle size of the microparticle can be controlled by a
treating temperature and can be used in the range of 0.1 .mu.m to
100 .mu.m. Of these sizes, preferred is 0.1 .mu.m to 20 .mu.m. The
microparticle having a particle size of 0.2 .mu.m to 10 .mu.m can
be utilized more preferably.
[0017] The rate of the drug adsorbed into the porous apatite
derivative is much larger than the rate of the drug adsorbed into
hydroxyapatite without Zn substitution. This is attributed to the
specific surface and porosity of the porous apatite derivative that
are significantly increased by allowing the porous apatite
derivative to undergo zinc substitution or to contain zinc. The
larger rate of the drug adsorbed is preferred because the gross
amount of the drug-containing sustained release microparticles
administered is rendered smaller. The preferred rate of the drug
adsorbed differs depending on the optimal amount of the drug
administered and however, is generally 2 to 30% by weight relative
to porous apatite derivatives. Of these rates, 5 to 25% by weight
is preferably used. More preferred is any of those adsorbing 10% or
more by weight of the drug therein.
[0018] The water-soluble bivalent metal compound that is added
after drugs are adsorbed into porous apatite derivatives is
preferably a Zn or Ca compound. Of them, the Zn compound is most
preferable. The amount of its usage, which varies depending on the
physicochemical property of the drug, is generally in the range of
1 to 70% by weight relative to the porous apatite derivative and is
preferably in the range of 5 to 70% by weight for sufficiently
maintaining the sustained release of drugs. A chloride or a salt of
an organic acid is preferably selected as the water-soluble
bivalent metal compound used. Examples thereof include zinc
chloride, zinc acetate and calcium chloride.
[0019] The duration of sustained release of drugs from the
drug-containing sustained release microparticles thus obtained, can
be controlled by the treating temperature of a hydroxyapatite
derivative and the amount of the bivalent metal compound used, and
may extend a period of three days or more. The sustained release of
drugs over a period of one week or more is also made possible and
is preferable in practice.
[0020] The drug-containing sustained release microparticle finally
obtained may have a size that allows the microparticle to pass
through an injection needle used in typical administration. In
reality, the smaller size an injection needle has, the less a
patient is scared. It is preferred that the drug-containing
sustained release microparticle should pass through an injection
needle with a thickness of 25 G or smaller (the larger the number
is, the thinner an injection needle gets) defined by the
international standard that specifies the thickness of an injection
needle. For this reason, a drug-containing sustained release
microparticle having a smaller particle size is more preferable.
However, a drug-containing sustained release microparticle having a
particle size rendered small to the extreme reduces the amount of
drugs retained therein and increases initial burst release.
Actually, the particle size is preferably 0.5 .mu.m to 20 .mu.m,
more preferably 0.5 .mu.m to 10 .mu.m. A microparticle having a
particle size of 10 .mu.m or less easily passes through a 27-G
injection needle. The drug used herein is not particularly limited
as long as the drug is water-soluble and may be adsorbed into
porous apatite derivatives. A water solubility index can be
evaluated by solubility in water. As long as the solubility is 100
.mu.g/mL or more, the drug-containing sustained release
microparticle can be prepared in general. The solubility is more
preferably 500 .mu.g/mL or more, even more preferably 1 mg/mL.
EXAMPLES
[0021] Hereinafter, the present invention will be described in
detail with reference to Examples. However, the present invention
is not intended to be limited to these Examples.
Example 1
[0022] A betamethasone phosphate or hydrocortisone phosphate
aqueous solution (100 .mu.L, 100 .mu.g/mL) was mixed with a water
suspension (100 .mu.L) of a given amount of porous hydroxyapatite
(HAP) or porous apatite derivative with substitution by 0.5 mol of
zinc (HAP-Zn-0.5) and left at room temperature for 10 minutes,
followed by centrifugation at 2500 G. to determine betamethasone
phosphate or hydrocortisone phosphate liverated in the resulting
supernatant from the absorbance of the supernatant at 230 nm. The
amount of the drug remaining after the given amount of the drug
initially applied was washed away in the supernatant was used as
the amount of the drug adsorbed. The result is shown in Table 1. As
can be seen from Table 1, a larger amount of the HAP or the porous
apatite derivative relative to the drug allowed the adsorption of
the drug into the HAP or the porous apatite derivative at a higher
ratio. The porous apatite derivative had an adsorption ratio
significantly higher than that of the HAP.
In Table 1, Beta represents betamethasone phosphate, and Hyd
represents hydrocortisone phosphate. Steroid refers to
betamethasone phosphate or hydrocortisone phosphate.
Example 2
[0023] After 45 mg of porous hydroxyapatite (HAP) or porous apatite
derivative (derivative with substitution by or content of 0.5 mol
of zinc (HAP-Zn-0.5)) was accurately weighed and supplemented with
2.4 mg/mL interferon a (IFN) solution (30 .mu.g in terms of the
amount of IFN), the resulting mixture was left for 10 minutes. This
mixture was then supplemented with 1 mL of 20 mM zinc acetate
solution and shaken for 30 minutes. This dispersion was
supplemented with 1.5 mL of water and washed to quantify IFN in the
washed solution. As a result, IFN was not detected in both of the
HAP and the HAP-Zn-0.5. Namely, it was confirmed that the whole
amount of IFN was adsorbed into the HAP or the HAP-Zn-0.5. As
described above, the drug-containing microparticle in which IFN, a
protein, was adsorbed could be obtained without the use of organic
solvents. After washing, 20 mL of a PBS solution containing 20% FCS
was. added to the obtained powder and shaken at 37.degree. C. for
16 hours. IFN eluted into the resulting supernatant was determined
to calculate the rate of elution. The result is shown in Table 2.
TABLE-US-00001 TABLE 2 Rate of elution of IFN adsorbed into HAP and
HAP-Zn-0.5 Rate of IFN eluted (%) HAP Zinc acetate 0 mM 92 Zinc
acetate 20 mM 87 HAP-Zn-0.5 Zinc acetate 0 mM 89 Zinc acetate 20 mM
78
In all of the systems, the addition of zinc acetate allowed the
inhibition of the elution of IFN and the sustained release of IFN
for a longer period as compared with no addition of zinc acetate.
When the HAP and the HAP-Zn-0.5 were compared, it was apparent that
the HAP-Zn-0.5 more delayed elution and exhibited the sustained
release of IFN for a longer time.
* * * * *