U.S. patent number 3,881,012 [Application Number 05/337,476] was granted by the patent office on 1975-04-29 for pharmaceutical preparations of penicillin compounds for rectal use.
This patent grant is currently assigned to Takeda Chemical Industries, Ltd.. Invention is credited to Katsuo Aoki, Shin-Ichiro Hirai, Toshiaki Ikenaga, Tai Matsuzawa, Hiroyuki Mima, Yoshihiro Okada.
United States Patent |
3,881,012 |
Mima , et al. |
April 29, 1975 |
Pharmaceutical preparations of penicillin compounds for rectal
use
Abstract
Pharmaceutical compositions for rectal administration,
containing an alkali metal disalt of sulbenicillin or
carbenicillin, a specified amount of an oily or fatty suppository
base and a specified amount of a nonionic surfactant, for example,
a polyoxyethylene higher alcohol ether.
Inventors: |
Mima; Hiroyuki (Hyogo,
JA), Matsuzawa; Tai (Osaka, JA), Aoki;
Katsuo (Hyogo, JA), Hirai; Shin-Ichiro (Kyoto,
JA), Ikenaga; Toshiaki (Osaka, JA), Okada;
Yoshihiro (Osaka, JA) |
Assignee: |
Takeda Chemical Industries,
Ltd. (Osaka, JA)
|
Family
ID: |
12106148 |
Appl.
No.: |
05/337,476 |
Filed: |
March 2, 1973 |
Foreign Application Priority Data
|
|
|
|
|
Mar 6, 1972 [JA] |
|
|
47-23279 |
|
Current U.S.
Class: |
514/197;
514/966 |
Current CPC
Class: |
A61K
9/02 (20130101); A61K 31/43 (20130101); Y10S
514/966 (20130101) |
Current International
Class: |
A61K
9/02 (20060101); A61K 31/429 (20060101); A61K
31/43 (20060101); A61k 021/00 (); A61k
027/00 () |
Field of
Search: |
;424/271 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rosen; Sam
Attorney, Agent or Firm: Wenderoth, Lind & Ponack
Claims
What is claimed is:
1. A pharmaceutical composition for rectal use which comprises (1)
a penicillin compound of the formula ##SPC3##
wherein R is --SO.sub.2 --O-- or --CO--O-- and M.sup.1 and M.sup.2
are the same or different and each represents an alkali metal, (2)
an oily or fatty suppository base in an amount of 0.5 to 15 times
the weight relative to the weight of the penicillin compound and
(3) at least one nonionic surfactant selected from the group
consisting of (a) polyoxyethylene higher alcohol ethers, wherein
the average number of polyoxyethylene units is 5-30 and the higher
alcohol has 8-18 carbon atoms, (b) polyoxyethylene fatty acid
esters, wherein the average number of polyoxyethylene units is 5-30
and the fatty acid has 12-18 carbon atoms and (c) polyoxyethylene
sorbitan fatty acid esters, wherein the average number of
polyoxyethylene units is 4,5 or 20 and the fatty acid has 12-18
carbon atoms, in an amount of 0.01 to 0.5 time the weight relative
to the weight of the oily or fatty base, the HLB value of the
nonionic surfactant being within the range of 7 to 18.
2. A pharmaceutical composition as claimed in claim 1 wherein both
of M.sup.1 and M.sup.2 are sodium.
3. A pharmaceutical composition as claimed in claim 1 wherein the
nonionic surfactant is a polyoxyethylene higher alcohol ether.
4. A pharmaceutical composition as claimed in claim 3 wherein the
nonionic surfactant is a polyoxyethylene higher alcohol ether
having an HLB value of from 9 to 14.
5. A pharmaceutical composition as claimed in claim 1 wherein the
nonionic surfactant is a mixture of a polyoxyethylene higher
alcohol ether and a polyoxyethylene fatty acid ester.
6. A pharmaceutical composition as claimed in claim 4 wherein the
polyoxyethylene higher alcohol ether is polyoxyethylene lauryl
ether having an HLB value of about 11.5.
7. A pharmaceutical composition as claimed in claim 4 wherein the
polyoxyethylene higher alcohol ether is polyoxyethylene lauryl
ether having an HLB value of about 13.0.
8. A pharmaceutical composition as claimed in claim 4 wherein the
polyoxyethylene higher alcohol ether is polyoxyethylene cetyl ether
having an HLB value of about 12.8.
9. A pharmaceutical composition as claimed in claim 4 wherein the
polyoxyethylene higher alcohol ether is polyoxyethylene oleyl ether
having an HLB value of about 10.
10. A method of treating a disease subject to treatment with
sulbenicillin or carbenicillin which comprises administering
through the rectal tract of a patient afflicted with the disease a
composition containing (1) a penicillin compound of the formula
##SPC4##
wherein R is --SO.sub.2 --O-- or --CO--O-- and M.sup.1 and M.sup.2
are the same or different and each represents an alkali metal, (2)
an oily or fatty suppository base in an amount of 0.5 to 15 times
the weight relative to the weight of the penicillin compound and
(3) at least one nonionic surfactant selected from the group
consisting of (a) polyoxyethylene higher alcohol ethers, wherein
the average number of polyoxyethylene units is 5-30 and the higher
alcohol has 8-18 carbon atoms, (b) polyoxyethylene fatty acid
esters, wherein the average number of polyoxyethylene units is 5-30
and the fatty acid has 12-18 carbon atoms and (c) polyoxyethylene
sorbitan fatty acid esters, wherein the average number of
polyoxyethylene units is 4, 5 or 20 and the fatty acid has 12-18
carbon atoms, in an amount of 0.01 to 0.5 time the weight relative
to the weight of the oily or fatty base, the HLB value of the
nonionic surfactant being within the range of 7 to 18.
Description
This invention relates to pharmaceutical preparations of penicillin
compounds for rectal use.
While a number of penicillin compounds have been put on the market,
most of them find no other administration forms than parenteral,
particularly when systemic effects are expected, because their
absorbability by oral administration is very low.
It has been generally known that water-soluble and oil-insoluble
compounds are hardly absorbed through the rectal tract, and most of
the penicillin compounds so far put on the market are of such
nature as above. Thus, it has been believed in this art that rectal
administration of penicillin compounds is not effective for
systemic effects.
Exhaustive studies by the present inventors to find a penicillin
product for rectal use have brought quite a new and astonishing
result that certain water-soluble and oil-insoluble penicillin
compounds are well absorbed into the body even through the rectum
and can give high concentrations in blood enough to achieve
systemic effects when administered in the presence of certain
nonionic surfactants and fatty or oily bases. The new finding is
not only unexpected for even those skilled in the art but also very
interesting in the biopharmacy. These penicillin compounds are
represented by the following formula (I) ##SPC1##
wherein R stands for --SO.sub.2 --O-- group or --CO--O-- group and
M.sup.1 and M.sup.2 stand for, the same or different from each
other, alkali metal such as sodium and potassium. The compound (I)
wherein R is --SO.sub.2 --O-- group is named as "sulbenicillin
dialkali metal salt" and the compound (I) wherein R is --CO--O--
group is named as "carbenicillin dialkali metal salt."
According to this invention, the pharmaceutical preparations of the
penicillin compounds can be administered through the rectal tract,
which gives no substantial pain, although the injections of
penicillin compounds are generally accompanied by a strong pain.
Another advantage is to make the administration feasible by anyone
without resorting to administration by a physician. Needless to
state, they all have merits of a pharmaceutical preparation for
rectal use and a suppository.
This invention is concerned with the said pharmaceutical
composition for rectal use prepared by dispersing the penicillin
compounds (I) in the particular mixture of oily or fatty base of
0.5 to 15 times the weight relative to the said penicillin
compounds (I) and at least one species of nonionic surfactants
selected from a polyoxyethylene higher alcohol ether, a
polyoxyethylene fatty acid ester and polyoxyethylene sorbitan fatty
acid ester of 0.01 to 0.5 time the weight relative to the said oily
or fatty base. Hydrophile-Lipophile Balance [calculated based on W.
C. Griffin's equation] (hereinafter abbreviated as HLB) of the
nonionic surfactants is within the range of 7 to 18.
In the compound represented by the formula [I], the compounds
wherein both of M.sup.1 and M.sup.2 are sodium are desirably
employed in this invention.
The oily or fatty base employable in this invention includes any of
the bases which are commonly used in the manufacture of ointments,
suppositories, etc. Such an oily or fatty base is exemplified by
sesame oil, olive oil, soybean oil, rapeseed oil, cottonseed oil,
linseed oil (from Lini Semen), castor oil, rice bran oil, tsubaki
oil (from Camellia japonica L.), corn oil, arachis oil, coconut
oil, poppyseed oil, almond oil, avocado oil, palm oil, palm kernel
oil, kaya oil (from Torreya nucifera S and Z) tung oil, kapok oil,
kuromoji oil (from Lindera umbellata), sasanqua oil (from Camellia
sasanqua), teaseed oil, perilla oil, cocoa butter, Isocacao MO-5
(registered by KAO-SOAP Com.Ltd.: Higher saturated fatty acid
triglyceride), cinnamon butter (from Cinnamomum japonicum S.EB.).
laurin butter, beef tallow, lard, wool fat, turtle oil, squalene,
etc.; materials obtainable by the modification of the fats and oils
mentioned above, by such procedures as hydrogenation,
interesterification, acetylation, fractional extraction, etc.;
mineral oils such as vaseline, paraffin, silicone oils, etc.;
esters of fatty acids having 6 to 30 carbon atoms with glycerol,
such as glyceryl palmitate, glyceryl laurate, glyceryl stearate,
glyceryl myristate, etc.; waxes such as esters of fatty acids
having 6 to 30 carbon atoms with alcohols having 2 to 8 carbon
atoms, e.g., isopropyl myristate, butyl stearate, diisopropyl
adipate, diethyl sebacate, etc.; higher fatty acids of 6 to 30
carbon atoms, e.g., stearic acid, oleic acid, etc.; and so forth.
These oily and fatty bases may be employed either singly or as
mixtures of two or more. Particularly preferred oily and fatty
bases are corn oil, cocoa butter, Isocacao MO-5 , interesterified
fats and oils (e.g., palmitic acid, stearic acid, etc.), artificial
suppository base (e.g., Witepsol (Dynamit Nobel
Aktiengesellschaft:Triglyceride of saturated vegitable fatty acids
with monoglycerides).
The amount of such oily and fatty bases to be employed is 0.5 to 15
times the weight relative to the penicillin compounds [I] to be
dispersed therein, and preferably 1 to 5 times on the same
basis.
The nonionic surfactants of this invention have an HLB value of 7
to 18, desirably 9 to 14. In such nonionic surfactants,
polyoxyethylene (hereinafter referred to as POE) higher alcohol
ether, wherein the higher alcohol has 8 to 18 carbon atoms, and of
which the average number of POE units (hereinafter referred to as
n) is 5 to 30, is exemplified by POE.cetyl ether(HLB= 8.8, n=7),
POE.cetyl ether(HLB=10.6, n=10), POE.cetyl ether(HLB=11.5, n=12),
POE.cetyl ether(HLB=12.8, n=15), POE.cetyl ether(HLB=13.6, n=17),
POE.cetyl ether(HLB= 14.1, n=20), POE.oleyl ether(HLB=8.9, n=8),
POE.oleyl ether(HLB=10.0, n=10), POE.oleyl ether(HLB=11.0, n=12),
POE.oleyl ether(HLB=11.6, n=15), POE.oleyl ether(HLB=13.6, n=20),
POE.oleyl ether(HLB=14.6, n=25), POE.stearyl ether(HLB=8.9, n=8),
POE.stearyl ether(HLB=10.6, n=11), POE.stearyl ether(HLB=12.2,
n=15), POE.stearyl ether(HLB=13.6, n=20), POE.stearyl
ether(HLB=14.5, n=20), POE.lauryl ether(HLB=8.6, n=5), POE.lauryl
ether(HLB=10.9, n=8), POE.lauryl ether(HLB=11.5, n=9), POE.lauryl
ether(HLB=12.1, n=10), POE.lauryl ether(HLB=13.0, n=12), POE.lauryl
ether(HLB=14.1, n=15), POE.lauryl ether(HLB=14.8, n=17), POE.lauryl
ether(HLB=15.5, n=20), POE.octyl ether(HLB=13.9, n=10), POE.octyl
ether(HLB=15.8, n=15), POE fatty acid ester, wherein the fatty acid
has 12 to 18 carbon atoms and whose n is 5 to 30, is exemplified by
POE.monostearate (HLB=10.6, n=10), POE.monostearate (HLB=13.0,
n=13), POE.monostearate(HLB=13.9, n=20), POE.monostearate(HLB=
15.9, n=30), POE.monostearate(HLB=15.2, n=25),
POE.monooleate(HLB=9.5, n=8), POE.monooleate(HLB=10.7, n=10),
POE.monooleate(HLB=10.7, n=10), POE.monooleate(HLB=13.6, n=15),
POE.monolaurate(HLB=12.6, n=10); POE sorbitan fatty acid ester,
wherein the fatty acid has 12 to 18 carbon atoms, whose n is 4, 5
or 20, is exemplified by POE.sorbitan monooleate (POE=10.0, n=5),
POE.sorbitan monolaurate(HLB=13.3, n=4), POE.sorbitan
monolaurate(HLB=16.7, n=20), POE.sorbitan monopalmitate(HLB=15.6,
n=20), POE.sorbitan monostearate(HLB=9.6, n=4), POE.sorbitan
monostearate(HLB=14.9, n=20), POE.sorbitan monooleate(HLB=10.0,
n=5), POE.sorbitan monooleate(HLB=15.0, n=20).
When the nonionic surfactant is used in the amount less than 0.01
time the weight relative to the oily and fatty bases being used,
the penicillin compounds [I] are hardly absorbed, while when the
amount of nonionic surfactant is more than 0.5 time the weight
relative to the oily and fatty bases being used, the penicillin
compounds [I] decompose gradually, and, therefore, the amount to be
used is 0.01 to 0.5 time the weight relative to the oily and fatty
bases, preferably, 0.01 to 0.3 time on the same bases.
The nonionic surfactants may be employed either singly or as a
mixture of two or more. Particularly preferred surfactants are, for
example, POE.higher alcohol ether and the mixture of POE.higher
alcohol ether and POE.fatty acid ester.
It is also possible to incorporate one or more of such additional
ingredients as metallic soaps, waxes, benzoic acid, polyethylene,
antioxidants, cellulose derivatives (for example ethyl-cellulose,
methyl-cellulose, carboxy-methyl-cellulose), preservatives, and the
like in a suitable amount.
The dosage forms which can be adopted in the practice of this
invention include suppositories which are solid at room temperature
but melt at body temperature, ointments or enema-type preparations.
These dosage forms may be achieved by procedures which are commonly
followed in the preparation of ointments, suppositories and the
like, by melting the oily and fatty bases and surfactant together
and evenly dispersing the fine-powdered penicillin compounds [I] in
the resulting melt. The preferred particle size of the penicillin
powder is within the range of 200.mu. 1.mu..
In a particularly preferred practice embodying the principle of
this invention, 6.67 to 200 parts of a powdery penicillin compound
[I] in the particle size range not more than 200.mu. and 1 to 50
parts of a nonionic surfactant with a HLB value of 7 to 18 are
uniformly dispersed together in 100 parts of oily and fatty bases
of solid or ointment in fused state and, if necessary, the
resultant composition is molded.
The dose unit of penicillin compound [I] in these preparations can
be adjusted from 500mg. to 5000mg. potency for human adults and
from 50mg. to 1500mg. potency for infants including neonates, and
these drugs are generally administered once or several times a
day.
TEST 1
Blood concentration and percent recovery in urine of
penicillins.
1. Test method:
Male, fasted rabbits, weighing about 3 kg. each, were used for
examining the rectal absorption and the intramuscular absorption of
the test drugs: The former examination was made by administering a
test drug in the form of suppository, namely the test drug was
inserted into the rectum and pushed about 3cm deep from the anus
with a glass rod, or in the form of ointment or enema type
preparation, namely the test drug was inserted about 3cm deep from
the anus with a small injection syringe. The latter examination was
made by injecting the test drug intramuscularly at the thigh of the
rabbits.
To determine the concentration of the penicillin compounds [I] in
blood, blood samples were taken from the heart at timed intervals
and the plasma samples were subjected to quantitative determination
by means of biological assay.
On the other hand, urine samples collected for six hours after
administration using a cannula were subjected to quantitative
determination of penicillin compounds [I] by the same method as
above. The urinary recoveries of penicillin compounds [I]
(unchanged form) were observed.
2. Drugs employed in the Test:
Dispersions of the penicillin compounds [I] in oily or fatty base
of this invention and at least one nonionic surfactant selected
from POE.higher alcohol ether, POE.fatty acid ester and
POE.sorbitan fatty acid ester (this invention: Test No. 1-12);
Dispersions of the penicillin compounds [I] in bases other than the
above oily or fatty base (control: Test No. 13-16); Dispersions of
penicillin compounds other than the above penicillin compounds [I]
in oily or fatty base of this invention and the above surfactant
(control: Test No. 17-18); Solution obtained by adding penicillin
compounds [I] to distilled water (control: Test No. 19).
3. Preparations of the drugs employed in the Test:
The ointment or enema type preparations (Test No. 1,2,5,6 and 10)
which are prepared by dispersing the penicillin compounds [I] in
the mixture of oily or fatty base and the nonionic surfactant; The
suppository type preparations (Test No. 3, 4, 7, 8, 9, 11 and 12)
which are prepared by dispensing evenly the dispersion of the
penicillin compounds [I] in the mixture of oily or fatty base and
the nonionic surfactant, melted at 40.degree.-45.degree.C, and
pouring into the container, and then solidifying with ice-water.
##SPC2##
It is apparant from Table 1 that compared with the cases (Test No.
13 to 16) in which bases other than the oily or fatty base of this
invention were employed, or the cases (Test No. 17 and 18) in which
penicillin compounds other than the penicillin compounds [I] of
this invention were employed, the use of the pharmaceutical
preparations of the penicillin compounds for rectal use (Test No. 1
to 12) comprising the penicillin compounds [I], the oily or fatty
base and the specific nonionic surfactant in specified proportions
achieve extremely high concentrations of the penicillins in blood,
at levels which are comparable to those attainable by the
intramuscular route (Test No. 19).
EXAMPLE 1
To 47 g. of olive oil is added 8g. of POE.laurylether(HLB= 11.5,
n=9), and the mixture is stirred. In the resultant solution is
dispersed 45 g. of fine-powdered disodium sulbenicillin, and 2.5 g.
aliquots of the dispersion are dispensed into 3 ml. plastics
containers tubes for rectal application.
EXAMPLE 2
To 50 g. of Isocacao MO-5 is added 20 g. of POE.monostearate(HLB=
13.0, n=13), and the mixture is melted at 45.degree.C. In this melt
is dispersed 30 g. of fine-powdered disodium sulbenicillin, and
1.33 g. aliquots of the dispersion are poured into plastic
containers for suppositories, then solidified with ice-water. The
procedure yields suppositories.
EXAMPLE 3
To 75 g. of cocoa butter is added a mixture of 6 g. of
POE.monostearate(HLB=13.7, n=15) and 4 g. of POE.cetylether(HLB=
8.8, n=7), which is melted at 45.degree.C. In this melt is
dispersed 15 g. of fine-powdered disodium carbenicillin, and 3 g.
aliquots of the dispersion are poured into plastic containers for
suppositories, then solidified with ice-water. The procedure yields
suppositories.
EXAMPLE 4
To 77 g. of squalene is added 3 g. of POE.lauryl ether(HLB= 8.6,
n=5), and the mixture is stirred. In this mixture is dispersed 20
g. of fine-powdered disodium sulbenicillin, and 2.5 g. aliquots of
the resulting dispersion are poured into 3 ml. plastic container
tubes for rectal application.
EXAMPLE 5
To 66.5 g. of Witepsol is added 3.5 g. of POE.monostearate(HLB=
13.9, n=20), and the mixture is fused at 45.degree.C. In this melt
is dispersed 30 g. of fine-powdered disodium sulbenicillin, and
1.33 g. aliquots of the dispersion are poured into plastic
containers, then solidified with cold water to obtain
suppositories.
EXAMPLE 6
At 45.degree.C, 26.7 g. of corn oil and 33.3 g. of Isocacao MO-5
are stirred together to obtain a solution. The solution is admixed
with 6.7 g. of POE.sorbitan monolaurate(HLB= 16.7, n=20) under
stirring. Then, 33.3 g. of fine-powdered dipotassium sulbenicillin
is dispensed therein, and 1.33 g. aliquots of the dispersion are
poured into 2 ml. plastic containers tubes for rectal application,
case being used to prevent settling.
EXAMPLE 7
To 50 g. of Witepsol are added 3 g. of POE.lauryl ether(HLB=13.0,
n=12) and 2 g. of POE.sorbitan monolaurate(HLB= 16.7, n=20), and
the mixture is melted at 40.degree.C. In this melt is dispersed 45
g. of fine-powdered disodium carbenicillin, and 2.3 g. aliquots of
the dispersion are poured into plastic containers, care being used
to prevent settling. The filled containers are solidified with
ice-water to obtain suppositories.
* * * * *