U.S. patent application number 09/988367 was filed with the patent office on 2002-05-02 for lotions containing vitamin d3 derivatives.
This patent application is currently assigned to CHUGAI SEIYAKU KABUSHIKI KAISHA. Invention is credited to Miyauchi, Eiichi, Sakai, Yasuyuki, Sano, Keiko.
Application Number | 20020051803 09/988367 |
Document ID | / |
Family ID | 26576227 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020051803 |
Kind Code |
A1 |
Miyauchi, Eiichi ; et
al. |
May 2, 2002 |
Lotions containing vitamin D3 derivatives
Abstract
The present invention aims to provide a lotion stably
maintaining maxacalcitol and having excellent percutaneous
absorption. The present invention provides lotions comprising
maxacalcitol as an active ingredient and a nonionic surfactant as
an additive, as well as lotions which further contains a polyhydric
alcohol and a solubilizer as additives besides a nonionic
surfactant.
Inventors: |
Miyauchi, Eiichi; (Tokyo,
JP) ; Sakai, Yasuyuki; (Tokyo, JP) ; Sano,
Keiko; (Tokyo, JP) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
SUITE 300
624 NINTH STREET, N.W.
WASHINGTON
DC
20001-5303
US
|
Assignee: |
CHUGAI SEIYAKU KABUSHIKI
KAISHA
5-1, Ukima 5-chome Kita-ku
Tokyo
JP
115-8543
|
Family ID: |
26576227 |
Appl. No.: |
09/988367 |
Filed: |
November 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09988367 |
Nov 19, 2001 |
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09555815 |
Jun 5, 2000 |
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09555815 |
Jun 5, 2000 |
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PCT/JP98/05535 |
Dec 8, 1998 |
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Current U.S.
Class: |
424/401 ;
514/167 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/593 20130101; A61K 47/10 20130101; A61K 47/26 20130101;
A61K 9/08 20130101 |
Class at
Publication: |
424/401 ;
514/167 |
International
Class: |
A61K 031/59; A61K
007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 9, 1997 |
JP |
338813/1997 |
Dec 9, 1997 |
JP |
338814/1997 |
Claims
What is claimed is:
1. A lotion comprising (1) maxacalcitol as an active ingredient;
and (2) polyoxyethylene cetyl ether in an amount of 0.5-2% by
weight.
2. A lotion comprising (1) maxacalcitol as an active ingredient;
and (2) polyoxyethylene/polyoxypropylene glycol in an amount of
0.1-20% by weight.
3. The lotion of claim 2, wherein said
polyoxyethylene/polyoxypropylene glycol is
polyoxyethylene(160)/polyoxypropylene(30) glycol.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to lotions stably containing
maxacalcitol, which are useful as external medicines. More
specifically, the present invention relates to lotions useful as
external medicines wherein chemical stability and percutaneous
absorption of maxacalcitol as an active ingredient can be
controlled by regulating the composition of components.
BACKGROUND ART
[0002] Some classes of active vitamin D.sub.3 derivatives such as
1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-se-
co-5,7,10(19)-pregnatriene (22-oxa-1.alpha.,25-dihydroxyvitamin
D.sub.3; herein also referred to as maxacalcitol) have skin
epidermal cell growth-inhibiting and differentiation-inducing
effects and are expected to have pharmacological effects against
psoriasis (JPA Nos. 267550/86 and 183534/88).
[0003] Maxacalcitol is known to be chemically unstable and rapidly
decompose especially in aqueous solutions. Generally, the following
techniques have been proposed to improve stabilization of vitamin
D-related derivatives.
[0004] (1) stabilization by adding various amino acids (alanine,
valine, lysine, etc.: JPA No. 17/87);
[0005] (2) stabilization by combination of ascorbic acid or a salt
thereof with a chelating agent (JPA No. 44845/86);
[0006] (3) stabilization by adding ascorbic acid alone (JPA No.
238936/93); and
[0007] (4) stabilization by inclusion in cyclodextrin (JPA Nos.
83021/88 and 128417/76).
[0008] However, these techniques have disadvantages such as they
involve a complex procedure or have an insufficient stabilization
effect, and do not suffice to prepare a lotion stably maintaining
maxacalcitol.
[0009] As to percutaneous absorption in the category of biological
properties, the use of absorption promoters is recommended and the
addition of unsaturated fatty acids such as oleic acid or the-use
of chemicals such as AZONEs has been reported (Morimoto et al. in
the program and abstracts of lectures, p. 21, Proceedings of the
eighth transdermal therapeutic system symposium, Tokyo, Feb. 21,
1996).
[0010] However, these absorption enhancers are not preferable for
use in preparations that are often administered (applied)
repeatedly, because their enhancing mechanisms depend on providing
high absorption efficiency by damaging the skin.
[0011] Thus, the need to develop lotions stably maintaining
maxacalcitol and having excellent percutaneous absorption continue
to exist.
DISCLOSURE OF THE INVENTION
[0012] As for the behavior of its stability in aqueous solutions,
maxacalcitol is known to remain stable if the pH of the solutions
is shifted to an alkaline side. However, alkaline preparations are
highly irritant to skin and side effects possibly increase.
Therefore, when maxacalcitol is formulated in preparations for
external medication, it is desirable to attain stabilization of
maxacalcitol in a solution at or around neutral pH.
[0013] An object of the present invention is to provide a lotion
wherein maxacalcitol as an active ingredient is stably maintained,
especially a lotion having a pH at or around neutrality.
[0014] Another object of the present invention is to simply solve
the problem of chemical stabilization of maxacalcitol, which could
not be readily attained in the prior art, by a convenient method of
adding a specific type of nonionic surfactant and a polyhydric
alcohol.
[0015] Still another object of the present invention is to provide
a lotion having particularly excellent percutaneous absorption by
regulating the compounded amount of a less skin-irritating
polyhydric alcohol to control the percutaneous absorption.
[0016] As a result of careful studies conducted to solve the above
problems, we unexpectedly found that a lotion containing
maxacalcitol as an active ingredient stably maintains the active
ingredient even at or around neutral pH upon addition of a specific
nonionic surfactant. The present invention successfully achieved
not only solubilization of oil-soluble materials but also a high
stabilization effect by using a specific type of nonionic
surfactants among which have heretofore been used as solubilizers
for materials that are slightly soluble in water. This was a quite
unexpected discovery because no report had been made of the ability
of any nonionic surfactants to simultaneously achieve both
solubilization and stabilization of oil-soluble materials
(maxacalcitol in the specification). Moreover, we succeeded in
controlling both of heat stability and percutaneous absorption of
the active ingredient maxacalcitol by selecting a polyhydric
alcohol, a nonionic surfactant and a solubilizer as additives in a
lotion, and also succeeded in establishing an optimal composition
for both heat stability and percutaneous absorption in a lotion
prepared from specific components. The present invention was
completed based on these findings.
[0017] Accordingly, the present invention provides a lotion
comprising maxacalcitol as an active ingredient and a nonionic
surfactant as an additive.
[0018] According to a preferred embodiment of the present
invention, an ether-type surfactant is used as a nonionic
surfactant.
[0019] According to a more preferred embodiment of the present
invention, a block copolymer-type nonionic surfactant or a
polyoxyethylene alkyl ether is used as an ether-type
surfactant.
[0020] According to a still more preferred embodiment of the
present invention, a Pluronic-type or polyoxyethylene cetyl
ether-type surfactant is used as an ether-type surfactant.
[0021] Preferably, Pluronic.TM. F-68 or Cetomacrogol.TM. 1000 is
used as a Pluronic-type or polyoxyethylene cetyl ether-type
surfactant, respectively.
[0022] More preferably, a lotion of the present invention contains
0.1-20% by weight of Pluronic F-68 or 0.1-2% by weight of
Cetomacrogol 1000 as a surfactant.
[0023] Most preferably, a lotion of the present invention contains
1-5% by weight of Pluronic F-68 or 0.5-2% by weight of Cetomacrogol
1000 as a surfactant.
[0024] According to one embodiment of the present invention, there
is provided a lotion which, besides a nonionic surfactant, further
comprises a polyhydric alcohol and a solubilizer as additives.
[0025] Preferably, a lotion of the present invention contains a
glycol as a polyhydric alcohol, an ether-type surfactant as a
nonionic surfactant and a monohydric alcohol as a solubilizer.
[0026] More preferably, a lotion of the present invention contains
propylene glycol and/or 1,3-butylene glycol as a polyhydric
alcohol, a polyoxyethylene alkyl ether or a Pluronic-type
surfactant as a nonionic surfactant and ethanol or isopropanol as a
solubilizer.
[0027] More preferably, a lotion of the present invention contains
propylene glycol and 1,3-butylene glycol as polyhydric alcohols,
Cetomacrogol 1000 as a nonionic surfactant and ethanol as a
solubilizer.
[0028] An especially preferred lotion of the present invention
contains 1-70% by weight of propylene glycol, 1-45% by weight of
1,3-butylene glycol, 0.1-5% by weight of Cetomacrogol 1000, 1-20%
by weight of ethanol, and the balance being water.
[0029] An especially preferred lotion of the present invention
contains 50-70% by weight of propylene glycol, 1-20% by weight of
1,3-butylene glycol, 0.1-2% by weight of Cetomacrogol 1000, 1-20%
by weight of ethanol, and the balance being water.
[0030] Most preferably, a lotion of the present invention contains
50-70% by weight of propylene glycol, 1-20% by weight of
1,3-butylene glycol, 1% by weight of Cetomacrogol 1000, 1% by
weight of ethanol, and the balance is water.
PREFERRED EMBODIMENTS OF THE INVENTION
[0031] The present invention relates to lotions comprising
maxacalcitol as an active ingredient and a nonionic surfactant as
an additive, as well as lotions which, besides a nonionic
surfactant, further contain a polyhydric alcohol and a solubilizer
as additives.
[0032]
1.alpha.,3.beta.-Dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9-
,10-seco-5,7,10(19)-pregnatriene
(22-oxa-1.alpha.,25-dihydroxyvitamin D.sub.3; herein also referred
to as maxacalcitol) contained as an active ingredient in lotions of
the present invention is a known vitamin D.sub.3 derivative and can
be synthesized by the process described in JPA No. 267550/86, for
example.
[0033] The amount of maxacalcitol contained in lotions of the
present invention is a therapeutically effective amount for the
skin disease to be treated, normally within the range of from about
1 .mu.g/g to about 200 .mu.g/g, preferably about 2 .mu.g/g to about
100 .mu.g/g.
[0034] Nonionic surfactants used in the present invention have
generally been used as solubilizers for slightly soluble materials.
According to the present invention, however, nonionic surfactants
are added not only to solubilize oil-soluble materials but also to
improve heat stability of the active ingredient maxacalcitol.
Therefore, the type of nonionic surfactants is not specifically
limited in so far as they can simultaneously achieve solubilization
and stabilization of the active ingredient maxacalcitol, but
ether-type surfactants are preferred.
[0035] Among ether-type surfactants, Pluronic-type surfactants
(polyoxyethylene/polyoxypropylene glycol) classified into block
copolymer-type nonionic surfactants or polyoxyethylene alkyl ethers
are especially preferred.
[0036] Specific examples of Pluronic-type surfactants include F-68
(trade name of polyoxyethylene (160)/polyoxypropylene (30) glycol
available from Asahi Denka Kogyo K.K.) having hydrophilic physical
properties. F-68 brings about advantageous effects typically at
0.1-20% by weight, preferably at 1-5% by weight.
[0037] Specific examples of polyoxyethylene alkyl ethers include
Cetomacrogol 1000 belonging to cetyl ethers. Cetomacrogol 1000
brings about advantageous effects typically at 0.1-2% by weight,
preferably at 0.5-2% by weight.
[0038] As described above, nonionic surfactants function to both
stabilize and solubilize the active ingredient maxacalcitol in
lotions of the present invention.
[0039] Moreover, by adding the above nonionic surfactants in lotion
the pH of preparations can be adjusted to at or around neutrality
without decreasing thermal stability of maxacalcitol. The above
nonionic surfactants act to physically stabilize external medicines
in general, and emulsion-type medicines in particular, so that they
are well suitable for incorporation into lotions from both aspects
of widely usage as pharmaceutical excipient and material cost.
[0040] However, the other class of nonionic surfactants, i.e.
ester-type surfactants (polyoxyethylene fatty acid esters) showed
contrastive results in maxacalcitol stabilization effect as
compared to their satisfactorily solubilization effect. Thus,
surfactants can be differentiated by differences of properties in
terms of chemical structures.
[0041] According to one embodiment of the present invention, the
lotion further comprises a polyhydric alcohol and a solubilizer as
additives besides a nonionic surfactant.
[0042] Polyhydric alcohols suitable for lotions of the present
invention have such physical properties that they are generally
added as wetting (moisturizing) agents in conventional external
preparations. In the present invention, they are added not only for
this function but also to control or improve thermal stability of
the active ingredient maxacalcitol.
[0043] The type of polyhydric alcohols is not specifically limited
so far as they can control or improve thermal stability of the
active ingredient maxacalcitol, but dihydric alcohols are
preferred. Examples of dihydric alcohols include glycols such as
propylene glycol, 1,3-butylene glycol, etc.
[0044] Solubilizers suitable for lotions of the present invention
are reagents for solubilizing the active ingredient maxacalcitol.
Solubilizers include, for example, monohydric alcohols such as
ethanol or isopropanol. A preferred solubilizer is ethanol.
[0045] The ranges of the proportions of specific components in
which both thermal stability and percutaneous absorption can be
controlled in lotions of the present invention are as follows.
[0046] As to Cetomacrogol 1000 among polyoxyethylene cetyl ethers,
both of the above properties can be controlled at a proportion of
0.1-5% by weight.
[0047] As to ethanol, both of the above properties can be
controlled at a proportion of 1-20% by weight.
[0048] As to propylene glycol, both of the above properties can be
controlled at a proportion of 0-70% by weight.
[0049] As to 1,3-butylene glycol, both of the above properties can
be controlled at a proportion of 0-45% by weight.
[0050] Pharmaceutical properties and specific proportions of
various additives are described below as a guide to a proposal of
optimal pharmaceutical formulations.
[0051] As to Cetomacrogol 1000, 0.1-2% by weight is a suitable
proportion considering both stability and percutaneous
absorption.
[0052] As to ethanol, 1-20% by weight is a suitable proportion
considering both stability and percutaneous absorption.
[0053] Propylene glycol mainly has effect on percutaneous
absorption and may be added at a variable proportion up to 70% by
weight based on actual application in external medicines.
Proportions of 0-50% by weight are suitable for preparations that
are required to have low absorption, while proportions of 50-70% by
weight are suitable for preparations that are required to have high
absorption. However, it should be noted that propylene glycol has a
concentration-dependent negative effect on thermal stability of
maxacalcitol in contrast with its percutaneous absorption.
[0054] 1,3-Butylene glycol mainly has effect on thermal stability
and may be added at any concentration up to 45% by weight based on
actual application in external medicines. However, it should be
noted that considering percutaneous absorption, 1,3-butylene glycol
has no effect when high percutaneous absorption is required.
[0055] As described above, propylene glycol and 1,3-butylene glycol
have conflicting pharmaceutical properties, so they can be added
either alone or in combination in any proportions based on their
contributory properties described above in accordance with the
method and purpose of use.
[0056] For example, preparations having both high chemical
stability and high percutaneous absorption as recommended herein
contain, as base material, 50-70% by weight of propylene glycol,
0-20% by weight of 1,3-butylene glycol, 0.1-2% by weight,
preferably 1% by weight, of Cetomacrogol 1000, and 1-20% by weight,
preferably 1% by weight, of ethanol.
[0057] The above formulations are generally applicable in the field
of external medicines from both aspects of application in products
and product economy and their practical feasibility is very
high.
[0058] If necessary, lotions of the present invention may further
contain preservatives such as paraoxybenzoic acid esters and sorbic
acids, or additives for improving commercial quality including
thickeners such as CMC-Na, wetting (moisturizing) agents,
organoleptic agents such as menthol, isopropanol, etc.
[0059] The process for preparing lotions of the present invention
is not specifically limited. For example, a specific amount of
maxacalcitol is dissolved in a specific amount of a solubilizer
such as ethanol. In a separate step, a specific amount of a
nonionic surfactant is dissolved in an appropriate buffer (such as
phosphate buffer). Then, the above two solutions are mixed into a
lotion. Alternatively, a mixture of the above two solutions may
optionally be combined with a specific amount of a polyhydric
alcohol and finally made up-with the same buffer to give a
lotion.
[0060] Lotions of the present invention can be used to treat
various cases of psoriasis such as psoriasis vulgaris, psoriasis
pustulosa, psoriasis guttata, erythroderma psoriaticum, psoriasis
arthropathica, psoriasis gravis. The dose depends on the condition
of the disease or other factors, but preferably a lotion containing
1 .mu.g/g to 200 .mu.g/g of maxacalcitol is administered once to
several times per day.
[0061] The following examples further illustrate the present
invention without limiting the same thereto.
EXAMPLES
Example A-1
Lotions containing a nonionic surfactant as an additive
[0062] General preparation process
[0063] A process for preparing a lotion of the present invention is
described below. At first, a specified amount of maxacalcitol stock
is dissolved in a specified amount of ethanol in accordance with
Test formulations in the following Table A-1 (solution 1). In a
separate step, a specified amount of each surfactant is
dissolved-in 25 mM phosphate buffer (pH 8) (solution 2). Then,
solution 1 is mixed into solution 2 to prepare a test sample.
[0064] Test formulations
[0065] Test formulations are shown in the following Table A-1.
1TABLE A-1 Test Cetomacrogol PBS example Maxacalcitol EtOH F-68*
1000 TL-10** TO-10M*** (to make) A-1 10 .mu.g 10 .mu.l 0 g 0 g 0 g
0 g 1 g A-2 10 .mu.g 10 .mu.l 1 mg 0 g 0 g 0 g 1 g A-3 10 .mu.g 10
.mu.l 5 mg 0 g 0 g 0 g 1 g A-4 10 .mu.g 10 .mu.l 10 mg 0 g 0 g 0 g
1 g A-5 10 .mu.g 10 .mu.l 0 g 1 mg 0 g 0 g 1 g A-6 10 .mu.g 10
.mu.l 0 g 5 mg 0 g 0 g 1 g A-7 10 .mu.g 10 .mu.l 0 g 10 mg 0 g 0 g
1 g A-8 10 .mu.g 10 .mu.l 0 g 0 g 1 mg 0 g 1 g A-9 10 .mu.g 10
.mu.l 0 g 0 g 5 mg 0 g 1 g A-10 10 .mu.g 10 .mu.l 0 g 0 g 10 mg 0 g
1 g A-11 10 .mu.g 10 .mu.l 0 g 0 g 0 g 1 mg 1 g A-12 10 .mu.g 10
.mu.l 0 g 0 g 0 g 5 mg 1 g A-13 10 .mu.g 10 .mu.l 0 g 0 g 0 g 10 mg
1 g *F-68: Trade name of polyoxyethylene (160)/polyoxypropylene
(30) glycol available from Asahi Denka Kogyo K.K. **TL-10: Trade
name of polysorbate 20 available from Nikko Chemicals Co., Ltd.
***TO-10M: Trade name of polysorbate 80 available from Nikko
Chemicals Co., Ltd.
[0066] Test examples
[0067] In order to verify and examine the effect of nonionic
surfactants, test examples having the above formulations were
evaluated for the residual maxacalcitol ratios in percentages vs.
initial amount over time (1, 2 and 4 weeks) at a constant
temperature of 60.degree. C. in a ventilated incubator. The results
are shown in Table A-2.
2 TABLE A-2 Residual ratio Test (percentage vs. initial amount)
example 1 week 2 weeks 3 weeks A-1 94.22 92.29 83.52 A-2 91.64
92.34 86.74 A-3 92.29 92.25 89.13 A-4 92.98 93.16 92.63 A-5 98.64
95.67 91.78 A-6 98.01 99.05 94.25 A-7 98.28 99.44 95.88 A-8 89.86
89.84 84.43 A-9 83.46 72.20 56.64 A-10 63.52 6.52 3.20 A-11 91.11
74.34 44.23 A-12 72.07 3.95 0.00 A-13 49.01 3.32 0.00
[0068] The above test examples show that addition of nonionic
surfactants, especially ether-type surfactants (Test examples
A2-A7) has dramatic effect for improving stability as compared with
ester-type surfactants (Test examples A8-A13) and a control
containing no surfactant (Test example A-1).
Example B-1
[0069]
[0070] Example B-1 relates to various classes of polyhydric
alcohols.
[0071] (1) Preparation process
[0072] A process for preparing a lotion of the present invention is
described below. At first, a specific amount of maxacalcitol is
dissolved in a specific amount of ethanol (solution 1). In a
separate step, a specific amount of a surfactant (Cetomacrogol
1000) is dissolved in 25 mM phosphate buffer (pH 8) (solution 2).
Then, solution 1 is mixed into solution 2 (solution 3). Solution 3
is combined with a specific amount of a polyhydric alcohol and made
up with the same buffer to give a test sample.
[0073] Test formulations as prepared are shown in the following
Table B-1.
3TABLE B-1 1,3- Test Cetomacrogol butylene Buffer example
Maxacalcitol EtOH 1000 PG glycol Glycerin (to make) B-1 50 .mu.g 10
.mu.l 10 mg 450 mg -- -- 1 g E-2 50 .mu.g 10 .mu.l 10 mg -- 450 mg
-- 1 g B-3 50 .mu.g 10 .mu.l 10 mg -- -- 450 mg 1 g EtOH: Ethanol
PG: Propylene Glycol
[0074] (2) Thermal stability test
[0075] Then, a thermal stability test was performed as follows. In
this test, test samples as prepared above were evaluated for the
residual maxacalcitol ratios in percentage vs. initial amount over
time at each temperature setting in a ventilated incubator.
[0076] The obtained thermal stability data are shown in the
following Table B-2.
4TABLE B-2 Evaluation of thermal stability: residual ratio vs.
initial amount (%) Storage Test example conditions B-1 B-2 B-3 1
week, 80.degree. C. 61.8 76.7 14.3 2 weeks, 60.degree. C. 89.1 99.5
84.0 4 weeks, 60.degree. C. 75.0 89.4 62.7
[0077] The data in Table B-2 show that the order of contribution to
stabilization in terms of thermal stability is 1,3-butylene
glycol>propylene glycol>glycerin. Especially effective was
1,3-butylene glycol.
[0078] (3) Percutaneous absorption test
[0079] A percutaneous absorption test was performed as follows. As
test animals, 6-week old male SD rats were conditioned at a
constant temperature and a constant humidity (25.degree. C., 50-60%
RH) for a week and subjected to experiments at the age of 7
weeks.
[0080] The administration method is as follows. On the day before
administration, rats are cervicodorsally shaved with a clipper and
a shaver and conditioned in separate cages for a day. On the day of
administration, a single dose of 15 .mu.g/0.3 g lotion/kg of each
test sample is percutaneously administered at an area of 3.times.4
cm on the shaved part. At hours 4 and 24 after administration, the
lotion is wiped off with absorbent cotton soaked in 70% ethanol and
a skin section is cut out from the wiped site as a test sample.
[0081] The absorbent cotton was assayed for the amount of
unabsorbed maxacalcitol. Unabsorbed ratios were expressed as the
percentages of the amounts recovered vs. administered amount and
evaluated.
[0082] The results are shown in Table B-3. Evaluation was made for
unabsorbed maxacalcitol ratios (%) at hours 4 and 24. Each value
represents mean.+-.SE.
5TABLE B-3 Evaluation of percutaneous absorption: unabsorbed
maxacalcitol ratio (%) Period after Test example administration B-1
B-2 B-3 4 hours 69.77 .+-. 4.76 81.74 .+-. 1.89 80.38 .+-. 3.16 24
hours 41.56 .+-. 3.98 not evaluated 50.53 .+-. 2.38
[0083] As is apparent from Table B-3, percutaneous absorption as
demonstrated by the order of contribution to initial uptake (up to
4 hours) among various base materials showed that glycerin and
1,3-butylene glycol have comparable effects while propylene glycol
has more positive effects than the other two base materials.
Example B-2
[0084] Example B-2 examines the amount of propylene glycol, which
was shown to have good percutaneous absorption in Example B-1.
[0085] The process for preparation of test formulations, thermal
stability test method, percutaneous absorption test method and the
like were as described in Example B-1.
[0086] Test formulations of Example B-2 are shown in the following
Table B-4.
6TABLE B-4 Test Maxacal- Cetomacrogol Propylene PBS example citol
Ethanol 1000 glycol (to make) B-4 50 .mu.g 10 .mu.l 10 mg 200 mg 1
g B-5 50 .mu.g 10 .mu.l 10 mg 450 mg 1 g B-6 50 .mu.g 10 .mu.l 10
mg 700 mg 1 g
[0087] The data for thermal stability of the formulations of
Example B-2 are shown in the following Table B-5.
7TABLE B-5 Evaluation of thermal stability: residual ratio vs.
initial amount (%) Storage Test example conditions B-4 B-5 B-6 2
weeks, 60.degree. C. 94.0 89.1 85.4 4 weeks, 60.degree. C. 90.1
75.0 69.3
[0088] As for the contribution to stabilization in terms of thermal
stability, propylene glycol showed a concentration-dependent
negative effect on chemical stability of maxacalcitol.
[0089] The results of percutaneous absorption test are shown in
Table B-6. Evaluation was made for unabsorbed maxacalcitol ratios
(%) 4 hours after administration. Each value represents
mean.+-.SE.
8TABLE B-6 Evaluation of percutaneous absorption: Test example B-4
B-5 B-6 Unabsorbed 71.44 .+-. 1.479 69.77 .+-. 4.764 62.21 .+-.
3.800 maxacalcitol ratio (%)
[0090] As to percutaneous absorption, the order of contribution to
initial uptake (up to 4 hours) among base materials was in contrast
with the results of thermal stability test and this shows the
tendency that the amount of addition of propylene glycol has a
positive effect on percutaneous absorption.
Example B-3
[0091]
[0092] Example B-3 is intended to make a closer investigation of a
70% propylene glycol formulation.
[0093] The formulation was as shown in Test example B-6 of Example
B-2, and the preparation process, thermal stability test and
percutaneous absorption test were as described in Example B-1.
During percutaneous absorption test, the amount of unabsorbed
maxacalcitol was determined from the absorbent cotton used for
wiping off maxacalcitol and the amount of maxacalcitol in the skin
was determined from the skin section cut out. Unabsorbed ratios and
skin residual ratios were expressed as the percentages of the
respective amounts recovered vs. administered amount and evaluated
by comparison.
[0094] Formulations of Example B-3 are shown in the following Table
B-7.
9TABLE B-7 Test Maxacal- Cetomacrogol Propylene PBS example citol
Ethanol 1000 glycol (to make) B-7 50 .mu.g 10 .mu.l 10 mg 700 mg 1
g
[0095] The data for thermal stability of the formulation of Example
B-3 are shown in-the following Table B-8.
10TABLE B-8 Evaluation of thermal stability: residual ratio (% vs.
initial amount) Storage temperature and residual ratio Period (%
vs. initial amount) (weeks) 80.degree. C. 60.degree. C. 40.degree.
C. 25.degree. C. 2 45.3 85.4 99.2 -- 4 -- 69.3 98.3 -- 12 -- 69.3
96.0 -- 24 -- 53.6 91.4 101.0
[0096] Long-term prediction from the above data by Arrhenius
calculation indicated that the expected period for 95% storage at
25.degree. C. was 2.7 years whereas the expected residual ratio at
25.degree. C. for 2 years was 98.1%. Thus, the results of Arrhenius
prediction on thermal stability suggest that the tested formulation
can be stored at room temperature.
[0097] The data from the percutaneous absorption test on the
formulation of Example B-3 are shown in Table B-9. Evaluation was
made for unabsorbed maxacalcitol ratios and maxacalcitol ratios in
skin after 4 and 24 hours.
11TABLE B-9 Evaluation of percutaneous absorption: (Example B-3: on
formulation of Test example B-7) (indicated in mean .+-. SE) Time
Unabsorbed Maxacalcitol ratio (hour) maxacalcitol ratio in skin 0
100% 0% 4 49.70% .+-. 2.855 14.31% .+-. 1.077 24 34.68% .+-. 2.175
16.62% .+-. 1.032
[0098] As to percutaneous absorption, the initial uptake process
was very rapid and subcutaneous retentivity was good. The
formulation of Test example B-7 proved to well satisfy the
requirements for rapid delivery and retention at the target site,
which are essential to the contemplated type of external
medicines.
[0099] These results demonstrate that the formulation of Test
example B-7 satisfies physicochemical or biological requirements of
external medicines and therefore has a satisfactory commercial
value.
Example B-4
[0100] Example B-4 relates to mixed systems of polyhydric alcohols
(propylene glycol and 1,3-butylene glycol). The results of the
above Examples B1 to B3 showed that 1,3-butylene glycol and
propylene glycol are effective for thermal stability and
percutaneous absorption, respectively. In Example B-4, the two
components were combined so as to control both pharmaceutical
properties simultaneously with a view to constructing more ideal
formulations.
[0101] Composite experimental design was used to estimate
formulations for simultaneously optimizing both pharmaceutical
properties of thermal stability and percutaneous absorption.
Specifically, mathematical functions each obtained from a certain
matrix experiment conducted to determine the relationship between
the blend ratio of base materials and the values of the
pharmaceutical properties of the resulting formulation are
coordinated and the resulting single coordinated function is solved
to search for the required formulation. Such a technique for
formulation design may be useful in the respect of study efficiency
or the like. However, it should be noted that this composite
experimental design is generally applicable and herein constitutes
only a means for leading to the present invention but does not have
any novelty.
[0102] The preparation process, thermal stability test and
percutaneous absorption test were conducted as described in Example
B-1.
[0103] Formulations prepared in Example B-4 are shown in the
following Table B-10.
12TABLE B-10 1,3- PBS Maxacal- butylene to Test citol Cetomacrogol
EtOH PG glycol make example (.mu.g) 1000 (mg) (.mu.l) (mg) (mg) (g)
B-8 50 20 60 229 171 1 B-9 50 20 60 343 57 1 B-10 50 20 60 343 257
1 B-11 50 20 60 514 86 1 B-12 50 40 60 229 171 1 B-13 50 40 60 343
57 1 B-14 50 40 60 343 257 1 B-15 50 40 60 514 86 1 B-16 50 20 160
229 171 1 B-17 50 20 160 343 57 1 B-18 50 20 160 343 257 1 B-19 50
20 160 514 86 1 B-20 50 40 160 229 171 1 B-21 50 40 160 343 57 1
B-22 50 40 160 343 257 1 B-23 50 40 160 514 86 1 B-24 50 30 110 214
286 1 B-25 50 30 110 500 0 1 B-26 50 30 110 214 86 1 B-27 50 30 110
500 200 1 B-28 50 10 110 357 143 1 B-29 50 50 110 357 143 1 B-30 50
30 10 357 143 1 B-31 50 30 210 357 143 1 B-32 50 30 110 357 143 1
B-33 50 30 110 357 143 1 B-34 50 30 110 357 143 1 EtOH: Ethanol PC:
Propylene Glycol
[0104] The following Table B-11 shows the results of the thermal
stability test and percutaneous absorption test on the formulations
of Example B-4. The thermal stability test was based on the
evaluation of residual ratios (%) vs. initial amount at 40.degree.
C. for 12 weeks and percutaneous absorption test was based on the
evaluation of unabsorbed maxacalcitol ratios (%) vs. the initial
amount 4 hours after administration.
13TABLE B-11 Thermal Percutaneous absorption test Test stability
test Unabsorbed maxacalcitol example 40.degree. C., 12 weeks (%)
ratio after 4 hours (%) B-8 97.8 76.5 B-9 96.6 72.5 B-10 96.6 67.6
B-11 94.3 68.1 B-12 97.8 79.9 B-13 97.5 88.8 B-14 96.5 74.6 B-15
94.4 62.7 B-16 97.2 80.6 B-17 97.1 77.5 B-18 95.2 76.2 B-19 94.4
70.4 B-20 97.4 80.6 B-21 96.4 73.9 B-22 97.0 74.1 B-23 95.0 69.9
B-24 96.3 66.0 B-25 96.2 68.5 B-26 97.9 88.2 B-27 92.7 68.0 B-28
95.8 67.1 B-29 96.1 79.7 B-30 95.9 66.5 B-31 94.3 79.6 B-32 95.4
66.4 B-33 96.7 86.1 B-34 95.8 73.4
[0105] The results of Example B-4 suggested that both thermal
stability and percutaneous absorption can be improved even if the
amounts of Cetomacrogol 1000 and ethanol are held at the necessary
minimums.
Example B-5
Formulations for simultaneous optimization
[0106] Formulations shown in the following Table B-12 were prepared
to ultimately optimize the amounts of propylene glycol and
1,3-butylene glycol based on the results of Example B-4.
14TABLE B-12 1,3- PBS Maxacal- butylene to Test citol Cetomacrogol
EtOH PG glycol make example (.mu.g) 1000 (mg) (.mu.l) (mg) (mg) (g)
B-35 50 10 10 171 229 1 B-36 50 10 10 214 286 1 B-37 50 10 10 257
343 1 B-38 50 10 10 300 400 1 B-39 50 10 10 400 300 1 B-40 50 10 10
500 200 1 B-41 50 10 10 600 100 1 EtOH: Ethanol PG: Propylene
Glycol
[0107] The following Table B-13 shows the results of a percutaneous
absorption test. Evaluation was made for the unabsorbed amount of
maxacalcitol vs. the administered amount of maxacalcitol at hours 4
in percentage thereof.
15TABLE B-13 Test example B-35 B-36 B-37 B-38 B-39 B-40 B-41
Unabsorbed 78.5 70.4 65.2 70.6 66.0 52.2 51.7 rate (%)
[0108] Since optimal formulations to be proposed should have good
absorption, the above Formulations B-40 and B-41 were further
examined as follows.
[0109] A thermal stability test was conducted on the above Test
examples B-40 and B-41 over time and the results are shown in the
following Table B-14.
16TABLE B-14 Thermal stability test: residual rate vs. initial
amount (%) Test 60.degree. C., 60.degree. C., 40.degree. C.,
example 2 weeks 1 month 1 month B-40 99.0 99.7 99.7 B-41 99.0 99.9
100.1
[0110] The data for percutaneous absorption of the above Test
examples B-40 and B-41 over time are shown in Table B-15, which
represents unabsorbed ratios and residual ratios in skin of
maxacalcitol at hour 2, 4 and 24 (together with the data for the
above 70% propylene glycol formulation as a control for
comparison). Each value represents mean.+-.SE.
17TABLE B-15A Unabsorbed maxacalcitol remaining in lotions (%) Test
example Time (hour) B-40 B-41 Control 0 100 100 100 2 56.6 .+-. 2.8
66.4 .+-. 6.7 78.3 4 58.8 .+-. 3.8 54.6 .+-. 3.6 49.8 .+-. 2.8 24
40.4 .+-. 1.3 39.2 .+-. 4.1 34.7 .+-. 2.2
[0111]
18TABLE B-15B Maxacalcitol absorbed into skin (%) Test example Time
(hour) B-40 B-41 Control 0 0 0 0 2 14.0 .+-. 2.5 8.0 .+-. 0.6 19.0
4 13.0 .+-. 2.6 18.0 .+-. 0.2 14.3 .+-. 1.1 24 23.5 .+-. 3.1 20.3
.+-. 1.2 16.6 .+-. 1.0
[0112] Dramatic improvements in thermal stability were observed in
the heat acceleration test as compared with the 70% propylene
glycol formulation; percutaneous absorption was also significant as
demonstrated by very rapid initial uptake comparable to that of the
70% propylene glycol formulation and by good retention in the
target skin site. Thus, the formulations of Test examples B-40 and
B-41 were proved to well satisfy the requirements for rapid
delivery and retention at the target site, which are essential to
the contemplated type of external medicines.
[0113] INDUSTRIAL APPLICABILITIES
[0114] According to the present invention, thermal stability and
percutaneous absorption can be efficiently controlled by regulating
the amounts of common base materials; furthermore, formulations
based on the control can also be proposed. This control of
pharmaceutical properties proved to lead to efficient proposal of
desired optimal formulations in accordance with the purpose and
method of use.
[0115] Recently, some classes of activated vitamin D.sub.3
derivatives, particularly maxacalcitol, are expected to bring about
topical pharmacological effects against psoriasis based on their
skin epidermal cell growth-inhibiting and differentiation-inducing
effects; they are also expected to achieve systemic pharmacological
effects such as PTH secretion/production-inhibiting effects and
differentiation-inducing effects and immunoregulation effects. This
suggests that absorption control in external application is very
important for attaining pharmaceutical efficacy of medicines having
both systemic and topical pharmacological effects. The present
invention also proposes a solution to this technical issue.
[0116] As a result of mainly controlling percutaneous absorption by
changing the amounts of components, optimal formulations required
in the respects of pharmaceutical efficacy or side-effects can be
proposed; therefore formulations for different purposes such as
external medicines for topical or systemic application can
potentially be proposed.
[0117] Thus, the present invention provides lotions useful as
external medicines wherein chemical stability and percutaneous
absorption of maxacalcitol as an active ingredient can be
controlled by regulating the composition of components.
* * * * *