Pharmaceutical vehicle

Disclosed is a pharmaceutical vehicle comprising (a) a fatty acid glyceride having a melting point higher than 37.degree. C., (b) a water-soluble, low viscous and non-irritating organic substance having a particle size smaller than 28 mesh and a viscosity lower than 300 cps as measured with respect to a 2% aqueous solution, (c) an organic polymeric substance having a particle size smaller than 28 mesh, which is capable of being swollen on contact with water, and (d) a water-soluble surface active agent.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a pharmaceutical vehicle. More 
particularly, the present invention relates to a pharmaceutical vehicle 
excellent in the property of gradually releasing an active ingredient. 
2. Description of the Prior Art 
Various gradually releasing pharmaceutical compositions have been known, 
but most of them are used for oral administration and gradually releasing 
suppository compositions have hardly been known. 
Recently, various attempts have been made to cure tumors by applying 
suppositories containing effective carcinostatic ingredients to the 
rectum, the uterus cervix, the vagina, the urethra and the like to allow 
the effective ingredients to act on the affected parts for a long time. 
For example, for remedy of uterine cancer, the effective ingredient is 
applied to the affected part once a day. Furthermore, in case of cancer of 
the rectus, it is necessary to apply the effective ingredient once a day 
because evacuation is ordinarily made once a day. Thus, suppositories of 
carcinostatic agents are ordinarily applied once a day. Therefore, 
development of a pharmaceutical vehicle for such suppositories capable of 
releasing the effective ingredient in about 24 hours has been desired. 
Suppositories comprising a fatty acid glyceride as the vehicle are known. 
Since these suppositories are arranged so that the vehicle is molten by 
the body temperature to release the effective ingredient, a fatty acid 
glyceride having a melting point lower than the body temperature 
(37.degree. C.) is used as the vehicle. Therefore, in scores of minutes 
after application of these suppositories, the vehicle is molten and the 
effective ingredient is released in a relatively short time. In short, 
these suppositories have not a property of gradually releasing the 
effective ingradient. Furthermore, when the effective ingredient has to be 
included at a high concentration, the area around the affected part 
becomes inflamed. 
Suppositories comprising a carboxyvinyl polymer as the vehicle are known as 
gradually releasing suppositories. These suppositories, however, are 
defective in that the speed of releasing the effective ingredient is too 
low or the effective ingredient is not sufficiently released. 
SUMMARY OF THE INVENTION 
We made researches with a view to developing a pharmaceutical vehicle for a 
suppository, which can release an active ingredient uniformly over a 
period of several to about 24 hours and can release the active ingredient 
as completely as possible during this period. As a result, it was found 
that when a fatty acid glyceride having a melting period higher than 
37.degree. C., which has not been used for suppositories, is mixed with a 
water-soluble surface active agent, a water-soluble, low viscous and 
non-irritaing organic substance and a water-swelling polymeric compound 
and the resulting composition is used as a suppository vehicle, the 
above-mentioned object can be attained. Based on this finding, we have now 
completed the present invention. 
More specifically, in accordance with the present invention, there is 
provided a pharmaceutical vehicle comprising (a) a fatty acid glyceride 
having a melting point higher than 37.degree. C., (b) a water-soluble, low 
viscous and non-irritating organic substance having a particle size 
smaller than 28 mesh and a viscosity lower than 300 cps as measured with 
respect to a 2% aqueous solution, (c) an organic polymeric substance 
having a particle size smaller than 28 mesh, which is capable of being 
swollen on contact with water, and (d) a water-soluble surface active 
agent. 
This pharmaceutical vehicle of the present invention is characterized in 
that in Ringer's solution, the vehicle is gradually swollen with the lapse 
of time and is gradually cracked and disintegrated, and therefore, in a 
pharmaceutical composition comprising an effective ingredient incorporated 
in this vehicle, the effective ingredient can be gradually released 
uniformly and sufficiently over a period of several to about 24 hours. 
Furthermore, in the pharmaceutical vehicle of the present invention, the 
effective ingredient releasing time can be freely controlled within a 
range of from several hours to several days by adjusting the amounts of 
the respective components appropriately.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The pharmaceutical vehicle of the present invention comprises as 
indispensable components (a) a fatty acid glyceride having a melting point 
higher than 37.degree. C., (b) a water-soluble, low viscous and 
non-irritating organic substance having a particle size smaller than 28 
mesh and a viscosity lower than 300 cps as measured with respect to a 2% 
aqueous solution, (c) an organic polymeric substance having a particle 
size smaller than 28 mesh, which is capable of being swollen on contact 
with water, and (c) a water-soluble surface active agent. These 
indispensable components will now be described. 
As the fatty acid glyceride that is used in the present invention, there 
can be mentioned, for example, monoglycerides, diglycerides and 
triglycerides of vegetable fatty acids (usually, mixtures of fatty acids 
having the carbon atom number of 10 to 18) obtained from coconut oil, 
olive oil and the like, and mixtures of these glycerides. These glycerides 
should have a melting point higher than 37.degree. C., and it is preferred 
that the melting point be not higher than 42.degree. C. For example, a 
mixture of Witepsol.RTM. H15 (manufactured by Dynamic Nobel Chemicals Co. 
Ltd.) or Suppocire.RTM. AM (manufactured by Gattefosse Co., Ltd.) obtained 
from coconut oil and having a melting point of 34.6.degree. C. and 
Witepsol.RTM. E85 or Suppocire.RTM. DM having a melting point of 
42.degree. C. may be used. The fatty acid glyceride is used in an amount 
of 10 to 95% by weight, preferably 40 to 80% by weight, based on the total 
pharmaceutical vehicle. 
As the water-soluble, low viscous and non-irritating organic substance, 
there can be used, for example, amino acids, saccharides and low viscous, 
water-soluble polymeric substances. As the amino acid, there can be 
mentioned, for example, alanine, glycine, phenylalanine, leucine, 
isoleucine, valine, lysine, proline and serine. As the saccharide, there 
can be mentioned, for example, glucose, maltose, mannitol, fructose, 
galactose, lactose, dextrose, xylitol, sorbitol, mannose and sucrose. As 
the viscous, water-soluble polymeric substance, there can be mentioned, 
for example, polymeric substances derived from natural products, such as 
dextrin, dextran, xylan, carragheenin, mannan, an alginic acid ester or 
propylene glycol, soluble starch, gum arabic, tragacanth gum, 
.alpha.-cyclodextrin, .beta.-cyclodextrin, galactan and inulin. These 
substances are used for facilitating elution of the effective ingredient 
from the pharmaceutical vehicle. The water solubility of these substances 
is at least 5%, preferably 10 to 30%, and the viscosity is lower than 300 
cps as measured with respect to a 2% aqueous solution. The particle size 
of these substances is smaller than 28 mesh (Tyler standard), preferably 
smaller than 200 mesh. These substances may be used singly or in the form 
of a mixture of two or more of them. These substances are used in an 
amount of 5 to 80% by weight, preferably 10 to 50% by weight, based on the 
total pharmaceutical vehicle. 
As the organic polymeric substance capable of being swollen on contact with 
water, there can be mentioned, for example, carboxyvinyl polymers such as 
Carbopol.RTM. (manufactured by B. F. Goodrich Chemical Co., Ltd) and 
polyacrylic acid, metal salts thereof, such as sodium and calcium salts, 
polyethylene oxide, gelatin, chondroitin sulfate, amylose, 
microcrystalline cellulose, carboxymethyl cellulose, metal salts thereof 
such as sodium and calcium salts, methyl cellulose and hydroxypropylmethyl 
cellulose. Sodium polyacrylate is most preferred because it has a highest 
swelling capacity. These organic polymeric substances should have a 
particle size of smaller than 28 mesh (Tyler standard), preferably smaller 
than 200 mesh. These organic polymeric substances may be used singly or in 
the form of a mixture of two or more of them. If the ratio of a polymeric 
substance having a high water solubility, such as sodium (polyacrylate), 
is too high, release of the effective ingredient is remarkably retarded 
because of a high viscosity thereof. If the ratio of a polymeric substance 
low in the water solubility, such as microcrystalline cellulose, is 
increased, the disintegration speed of the vehicle becomes too high and 
the gradually releasing characteristic is lost. 
Such water-swelling organic substance is used in an amount of 0.1 to 10% by 
weight, preferably 0.2 to 2% by weight, based on the total pharmaceutical 
vehicle. 
As the water-soluble surface active agent, there can be mentioned, for 
example, polyoxyethylene sorbitan monooleate such as Tween.RTM. 80 
(manufactured by Nikko Chemical Co., Ltd.) and polyoxyethylene 
sorbitan-hydrogenated castor oil derivatives such as HCO.RTM. 60 
(manufactured by Nikko Chemical Co., Ltd.). The water-soluble surface 
active agent is used in an amount of 0.001 to 10% by weight, preferably 
0.05 to 5% by weight, based on the total pharmaceutical vehicle. 
Various pharmaceutical compositions differing in the speed of release the 
effective ingredient can be obtained by using the pharmaceutical vehicle 
of the present invention while appropriately adjusting the mixing ratios 
of the respective components. Especially, the release speed of the 
effective ingredient can easily be controlled by adjusting the mixing 
ratio of the water-soluble, low viscous and non-irritating organic 
substance. 
The preparation of the pharmaceutical vehicle of the present invention will 
now be described. 
The fatty acid glyceride having a melting point higher than 37.degree. C. 
is heated and molten, and the water-soluble, low viscous organic 
substance, the organic polymeric substance capable of being swollen on 
contact with water and the water-soluble surface active agent are 
incorporated in and kneaded with the melt of the fatty acid glyceride. 
The pharmaceutical vehicle of the present invention which is prepared 
according to the above process is especially suitable as a vehicle for a 
suppository, but it can also be used as a vehicle for a medicine for oral 
administration. A gradually releasing suppository or medicine for oral 
administration may be prepared by incorporating an effective ingredient 
into the pharmaceutical vehicle of the present invention, optionally with 
taste and smell correctives in case of the medicine for oral 
administration, and forming the resulting composition into an appropriate 
shape. 
Any of effective ingredients that should be formed into gradually releasing 
pharmaceutical compositions or that are preferably formed into gradually 
releasing pharmaceutical compositions can be used. For example, there can 
be mentioned antipyretic, analgesic and anti-inflammatory agents such as 
acetyl salicylate, aminopyrine, indomethacin, oxyphenbutazone, sulpyrine, 
pyrabital, sodium dichlorofenac and ibuprophene, antihistamics such as 
d-maleic acid chloropheniramine, triprolidine hydrochloride, promethazine, 
thonzylamine hydrochloride and clemastin fumarate, antibiotics such as 
penicillins, cephalosporins, tetracyclines, erythromycin, josamycin and 
spiramycin, carcinostatic agents such as bleomycins such as disclosed in 
U.S. Pat. Nos. 3,681,491, 3,846,400, Ger. Offen. No. 2828933, futraful, 
mitomycin and 5FU, local anesthetics such as procaine hydrochloride, 
T-Cain, dibucaine and lidocaine, anticeptic agents such as fradiomycin 
sulfate, gentamicin sulfate and sulfonamides, vitamins such as ascorbic 
acid, and hormones such as testosterone and progesterone. The amount of 
the effective ingredient differs depending on the kind of the effective 
ingredient. For example, hormones are incorporated in amounts of 0.0001%, 
vitamins are incorporated in amounts of about 50% and bleomycins are 
incorporated in amounts of 0.25 to 3%, based on the pharmaceutical vehicle 
of the present invention. 
Pharmaceutical compositions formed by using the pharmaceutical vehicle of 
the present invention may be formed into gradually releasing suppositories 
having a shape suitable for the part to be applied, for example, a 
tablet-like shape, a pellet-like shape, a spindle-like shape, a 
pencil-like shape or a spherical shape. Further, these pharmaceutical 
compositions may be formed into gradually releasing drugs suitable for 
oral administration according to customary techniques adopted in the art 
of pharmaceutics. Moreover, these gradually releasing pharmaceutical 
compositions may be used in combination with instantaneously releasing 
pharmaceutical compositions. 
The process for the preparation of the pharmaceutical vehicle of the 
present invention will now be described with reference to the following 
Examples. 
EXAMPLE 1 
A mixture of 26.1 g of Witepsol H15 and 39.2 g of Witepsol E85 was heated 
and molten at about 50.degree. C. A part of the melt was mixed and 
sufficiently kneaded with 30 g of powdered glycine passed through a 
200-mesh sieve, 0.5 g of sodium polyacrylate passed through a 250-mesh 
sieve and 2.5 g of Tween 80, and the kneaded mixture was combined with the 
remainder of the melt. The mixture was sufficiently and homogeneously 
blended and kneaded at a temperature maintained at about 50.degree. C. to 
form a pharmaceutical vehicle. 
EXAMPLE 2 
A mixture of 20.4 g of Suppocire AM and 35.6 g of Suppocire DM was heated 
and molten at about 50.degree. C., and a part of the melt was mixed and 
sufficiently kneaded with 20 g of mannitol passed through a 250-mesh 
sieve, 2.0 g of gelatin passed through a 200-mesh sieve and 2.0 g of a 
polyoxyethylene-hydrogenated castor oil derivative (HCO-60). The mixture 
was combined with the remainder of the melt, and the resulting mixture was 
sufficiently and homogeneously blended and kneaded to form a vehicle. 
The process for the preparation of pharmaceutical compositions by using the 
pharmaceutical vehicle of the present invention will now be described with 
reference to the following Examples. 
EXAMPLE 3 
To the whole amount of the vehicle prepared in Example 1 was added 1.7 g 
(activity factor of about 3 g) of powdery bleomycin hydrochloride while 
the vehicle was maintained at 50.degree. C., and after sufficient mixing, 
the temperature was lowered to 45.degree. C., and the mixture was placed 
in spindle-shaped molds so that 1 g of the mixture was packed in each mold 
and the mixture was cooled and solidified. Thus, there were obtained 
drugs, each containing bleomycin hydrochloride in an activity factor of 
about 30 mg. 
EXAMPLE 4 
A mixture of 26.1 g of Witepsol H15 and 39.2 g of Witepsol E85 was heated 
and molten at about 50.degree. C. A part of the molten mixture was mixed 
and sufficiently kneaded with 30 g of powdered glycine passed through a 
200-mesh sieve, 0.5 g of sodium polyacrylate passed through a 250 -mesh 
sieve, 2.5 g of Tween 80 and 2 g (activity factor of about 2 g) of 
3[(S)-1'-phenylethylamino]-propylaminobleomycin powder, and the mixture 
was combined with the remainder of the melt. The resulting mixture was 
sufficiently and homogeneously blended and kneaded while the mixture was 
maintained at about 50.degree. C. Then, the temperature was lowered to 
about 45.degree. C. and the mixture was placed in bullet-shaped molds so 
that 1.0 g of the mixture was packed in each mold. The mixture was cooled 
and solidified in these molds to obtain gradually releasing drugs, each 
containing the effective ingredient in an activity factor of about 20 mg. 
EXAMPLE 5 
A mixture of 20.4 g of Suppocire AM and 35.6 g of Suppocire DM was heated 
and molten at about 50.degree. C. A part of the melt was sufficiently and 
homogeneously glended and kneaded with 20 g of mannitol passed through a 
250-mesh sieve, 2.0 g of gelatin passed through a 200-mesh sieve, 2.0 g of 
a polyoxyethylene-hydrogenated castor oil derivative (HCO-60) and 20 g of 
erythromycin. Then, the temperature was lowered to about 45.degree. C., 
and the mixture was placed in spherical molds so that 1 g of the mixture 
was packed in each mold. The mixture was cooled and solidified in these 
molds to obtain gradually releasing drugs, each containing 200 mg of 
erythromycin. 
It will now be clarified that the pharmaceutical vehicle of the present 
invention has an appropriate speed of gradually releasing the effective 
ingredient and this release speed can be freely controlled, with reference 
to the following Experiment. 
EXPERIMENT 
(1) Preparation of Samples: 
Bleomycin hydrochloride was incorporated as the effective ingredient in an 
activity factor of 30 mg into a vehicle prepared in the same manner as 
described in Example 1 according to a recipe shown in Table 1, and the 
total amount was adjusted to 1000 mg. The mixture was molded into spindles 
having a bottom diameter of 10 mm and a height of 16 mm. Thus, there were 
prepared samples E to M according to the present invention and comparative 
samples A to D, as indicated in Table 1. 
TABLE 1 
__________________________________________________________________________ 
Fatty Acid Glyceride 
Melting 
Lowly Viscous 
Water-Swelling 
Water-Soluble 
Witepsol.RTM. H15 (a) 
Witepsol.RTM. E85 (a) 
Point Water-Soluble 
Polymeric 
Surface Active 
Recipe 
or Suppocire.RTM. AM (b) 
or Suppocire.RTM. DM (b) 
(.degree.C.) 
Substance 
Substance 
Agent 
__________________________________________________________________________ 
A a. 100.0 -- 34.6 -- -- -- 
B a. 80.0 a. 20.0 36.6 -- -- -- 
C a. 70.0 a. 30.0 37.8 -- -- -- 
D a. 60.0 a. 40.1 38.8 -- -- -- 
E a. 38.1 a. 16.4 37.8 glycine PANA* Tween 80 
40 2.0 3.5 
F a. 36.6 a. 24.4 38.8 mannitol CMC-Ca** Tween 80 
35 1.5 2.5 
G a. 26.8 a. 40.2 40.5 glycine PANA Tween 80 
30 0.5 2.5 
H a. 45.9 a. 30.6 38.8 maltose gelatin HCO 60 
20 1.5 2.0 
I a. 45.9 a 30.6 38.8 glycine PANA Tween 80 
20 1.0 2.5 
J b. 23.1 b. 53.9 41.6 alanine PANA Tween 80 
20 0.5 2.5 
K b. 30.4 b. 45.6 40.5 dextrin gelatin Tween 80 
20 2.0 2.0 
L b. 31.4 b. 47.1 40.5 mannitol PANA Tween 80 
20 0.5 1.0 
M b. 48.9 b. 32.6 38.8 glycine microcry-stalline 
HCO 60 
15 cellulose 
3.0 
0.5 
__________________________________________________________________________ 
Note 
*PANA: sodium polyacrylate 
**CMC-Ca: calcium carboxymethyl cellulose 
(2) Test Procedures: 
In a test tube having a diameter of 17 mm was charged 10 ml of Ringer's 
solution (Japanese Pharmacopoeia). Twelve test tubes were used for each 
sample. The test tubes were dipped in a thermostat tank maintained at 
37.degree. C. and one gradually releasing drug sample prepared above, 
which was wrapped with gauze, was dipped in Ringer's solution in the first 
test tube and the test tube was allowed to stand still. Then, at intervals 
of 2 hours, samples were charged in the fresh test tubes successively. At 
predetermined intervals, the amount of bleomycin hydrochloride being 
related in Ringer's solution was determined by measuring the absorbance at 
a wave length of 292.5 nm. 
(3) Results: 
The obtained results are shown in FIG. 1. From these results, it will 
readily be understood that in comparative samples A and B formed by using 
the fatty acid glyceride having a melting point lower than 37.degree. C., 
about 50% of the effective ingredient is released within 30 minutes from 
the start of the experiment and in comparative samples C and D formed by 
using only the fatty acid glyceride having a melting point higher than 
37.degree. C., only 17% (in sample C) or 7% (sample D) of the effective 
ingredient is released even after 24 hours from the start of the 
experiment. In contrast, as will be apparent from the results shown in 
FIG. 1, when the pharmaceutical vehicle of the present invention is used, 
the effective ingredient is ordinarily dissolved out substantially 
completely in about 24 hours (see samples F, G and H) and this released 
time can be controlled within a range of from about 10 hours (see sample 
E) to a time longer than 24 hours (samples I to M). Thus, it will readily 
be understood that the release speed of the effective ingredient can be 
freely controlled by appropriately adjusting the mixing ratios of the 
components of the pharmaceutical vehicle of the present invention.