Endermic medicament with a gel base

A novel endermic medicament having a consistency of a gel is proposed which is formulated, as a gel base, with non-ionic water-soluble cellulose ether, e.g., methyl cellulose and hydroxypropyl methyl cellulose, modified with a modification agent containing, in the molecule, an alkyl group having 6 to 26 carbon atoms and a functional group having reactivity with the hydroxyl group in the cellulose ether, e.g., stearyl glycidyl ether, decyl glycidyl ether and cetyl epoxide. The endermic medicament formulated with the modified cellulose ether is stable by virtue of the very little interaction between the active ingredients and the gel base and also can exhibit high percutaneous absorptivity of the active ingredients through the human skin.

BACKGROUND OF THE INVENTION 
The present invention relates to an endermic medicament, i.e. a medicament 
for external application, with a gel base or carrier which is stable and 
has little interaction with the therapeutically effective ingredients 
contained in the medicament. 
Several types of base materials for endermic medicaments are known 
including those for oil-base ointments, those for emulsions and those for 
water-soluble medicaments. As a trend in recent years, water-soluble 
medicaments having a gel-like consistency are highlighted by virtue of the 
high transparency to give a feeling of cleanness to the patients, good 
spreadability on the human skin, excellent percutaneous absorptivity of 
the therapeutically effective ingredients contained therein, easiness of 
removal by washing with water and other features. Several types of the gel 
base for such a water-soluble medicaments are already known and available 
on the market including carboxyvinyl polymers exhibiting excellent effects 
of thickening and gelation. 
The above mentioned carboxyvinyl polymer is indeed an excellent gel base 
having high transparency to formulate an endermic medicament capable of 
giving satisfactory feeling of use to the patients. The polymer, however, 
has several problems caused by the fact that the polymer is basically a 
polymeric electrolyte. 
The first problem in the polymer of this type is the possible interaction 
thereof with the therapeutically effective ingredients contained in the 
medicament due to the presence of the carboxyl groups in the polymer. When 
a gelled medicament with a basic compound as the effective ingredient is 
prepared with a carboxyvinyl polymer as the gel base, for example, a salt 
is sometimes formed between the effective ingredient and the polymeric 
base resulting in eventual coloration or formation of precipitates and 
decrease in the releasability of the effective ingredient for percutaneous 
absorption. On the other hand, furthermore, the gel medicament can be 
highly thickened only by the combined use of a basic compound for 
neutralization while some of basic compounds may have reactivity with the 
effective ingredient to cause coloration or precipitation. When the 
effective ingredient is ionic in the form of a salt, in addition, 
extensive and time-consuming investigations must be undertaken for each of 
the effective ingredients on the types and amounts of the basic compound 
for neutralization in order to obtain optimum consistency of the 
particular gel medicament sometimes leading to a conclusion that the 
amount of the basic compound for neutralization must be very large. Such a 
large amount of a basic compound of course has a detrimental effect 
against the healthy condition of the human skin to which the gel 
medicament is applied. Thus, carboxyvinyl polymers are under strict 
limitations as a gel base of endermic medicaments in respect of the 
formulation of the effective ingredients. 
SUMMARY OF THE INVENTION 
The present invention accordingly has an object to provide an endermic 
medicament having a consistency of a gel capable of giving an excellent 
feeling of use to the patients by being formulated with a novel and unique 
gel base which is stable exhibiting little interaction with the 
therapeutically effective ingredients contained in the medicament and 
capable of imparting a gel-like consistency to the medicament even without 
use of any basic compound for neutralization. 
Thus, the endermic medicament having a consistency of a gel provided by the 
present invention comprises, as a blend: 
(a) a non-ionic water-soluble cellulose ether modified with a modification 
agent containing, in the molecule, an alkyl group having 6 to 26 carbon 
atoms and a functional group having reactivity with the hydroxyl group in 
the cellulose ether as a base; and 
(b) a therapeutically active ingredient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As is described above, the most characteristic feature of the invention 
consists in the use of a unique cellulose derivative as the base of the 
medicament. This cellulose derivative, which has never been used as a 
medicament base, is stable and capable of giving very pleasant feeling of 
use to the patients treated with the medicament and has little reactivity 
with almost all kinds of therapeutically active chemical compounds. 
The above defined cellulose derivative as the component (a) in the 
inventive medicament is prepared from a non-ionic water-soluble cellulose 
ether including, for example, alkyl celluloses, hydroxyalkyl celluloses 
and hydroxyalkyl alkyl celluloses such as methyl cellulose, hydroxyethyl 
cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, 
hydroxypropyl methyl cellulose, hydroxyethyl ethyl cellulose and the like. 
The molecular weight of these cellulose ethers as the starting material is 
not particularly limitative. Usually, it is preferable for easy handling 
that the cellulose ether has an average molecular weight which is 
represented by the viscosity of a 2% by weight aqueous solution thereof in 
the range from 5 to 1,000,000 centipoise or, more preferably, from 200 to 
300,000 centipoise at 20.degree. C. When the molecular weight of the 
starting cellulose ether is too low, the cellulose derivative obtained 
from such a starting cellulose ether cannot impart a sufficiently high 
consistency to the medicament in a moderately controlled amount of 
addition. When the molecular weight of the starting cellulose ether is too 
high, on the other hand, such a cellulose ether is less reactive with the 
modification agent to give the modified cellulose ether suitable as the 
component (a). 
The modification agent to be reacted with the above mentioned starting 
cellulose ether is a compound containing an alkyl group having from 6 to 
26 carbon atoms and a functional group reactive with the hydroxyl group in 
the cellulose ether. When the starting cellulose ether is reacted with the 
modification agent, therefore, the cellulose ether is further substituted 
with pendant groups containing an alkyl group having 6 to 26 carbon atoms. 
Various kinds of modification agents can meet the purpose including acid 
chlorides, isocyanates and epoxides having the above defined long-chain 
alkyl group in the molecule. Particular examples thereof include stearyl 
chloride, cetyl chloride, stearyl isocyanate, lauryl isocyanate, stearyl 
epoxide, cetyl epoxide, tetracosyl epoxide, hexacosyl epoxide, stearyl 
glycidyl ether, decyl glycidyl ether, hexyl glycidyl ether and the like 
though not particularly limitative thereto. These modification agents are 
reactive with the hydroxyl group in the cellulose ether so that alkyl 
groups having 6 to 26 carbon atoms are introduced into the cellulose ether 
substituting for the hydroxyl groups by the modification reaction which 
can be performed according to a known procedure. 
The number of the substituent groups introduced by the above mentioned 
modification reaction, referred to as the modifier groups hereinafter, is 
selected depending on the solubility behavior thereof and the desired 
thickening effect exhibited when the modified cellulose ether is dissolved 
in the solvent used as the diluent of the gel medicament. Usually, the 
number of the modifier groups is in the range from about 0.01 to about 0.1 
per glucose unit of the cellulose ether. As a general guide principle, the 
number should better be relatively small when the solvent is water and 
relatively large when the solvent is a mixture of water and alcohol. 
The gel base of the inventive endermic medicament is prepared by dissolving 
the above obtained modified cellulose ether in a suitable solvent. The 
concentration of the cellulose derivative here is usually in the range 
from 0.1 to 20% by weight or, preferably, from 0.5 to 5% by weight 
depending on the type of the medicament. When the concentration thereof is 
too low, no sufficiently high consistency of the gel base can be obtained 
as a matter of course. When the concentration thereof is too large, on the 
other hand, the consistency of the medicament would be too high to be 
smoothly applied to and spread over the human skin so that no good feeling 
of use can be given to the patients forming a crusty layer after 
evaporation of the solvent. 
The solvent to dissolve the modified cellulose ether can be water or a 
mixture of water with a lower alcohol and/or a polyhydric alcohol miscible 
with water. The lower alcohol is exemplified by ethyl alcohol, n-propyl 
alcohol, isopropyl alcohol and the like and the polyhydric alcohol is 
exemplified by glycerin, propylene glycol, polyethylene glycol and the 
like. Besides the solvents, the inventive endermic medicament can contain 
various kinds of pharmacologically permissible known adjuvants according 
to need including absorption aids such as isopropyl myristate, diisopropyl 
adipate, benzyl alcohol and the like, antiseptics, perfumes and so on. 
The therapeutically effective chemical compound compounded with the above 
described gel base to form the inventive endermic medicament can be any of 
substantially almost all kinds of pharmacological compounds including 
antibiotics, chemotherapeutic agents, vitamins, local anaesthetics, 
antihistamines, astringents, sulfas, antifungals, blood-circulation 
promotors, adrenocortical hormones and the like depending on the 
therapeutic purpose of the medicament. 
To summarize, the endermic medicament of the invention gives very pleasant 
and comfortable feeling of use to the patients and is free from 
limitations in the types of the therapeutically active chemicals by virtue 
of the inertness of the gel base as a nonionic water-soluble polymer 
different from conventional carboxyvinyl polymers with no risk of 
interaction to give versatility to the formulation of the medicament 
without causing problems in respect of stability. Conventional 
water-soluble cellulose ethers can of course be used as a gel base of a 
water-soluble endermic medicament although the desired thickening effect 
can be obtained by using a much larger amount thereof than the modified 
cellulose ether in the inventive medicament. Accordingly, the endermic 
medicaments prepared by using a conventional cellulose ether are not 
always quite satisfactory in respect of the feeling of stickiness or 
adhesiveness given to the patients treated therewith. On the contrary, the 
modified cellulose ether used in the inventive medicament can give a high 
thickening effect even when the amount thereof is greatly decreased as 
compared with conventional cellulose ethers and the gel medicament 
obtained by using the modified cellulose ether exhibits thixotropy 
contributing to the improvement of the feeling of use. 
In the following, the endermic medicament of the invention is described in 
more detail by way of examples although the scope of the invention is 
never limited thereby in any way. The description of the inventive 
medicament is preceded by the description of the synthetic procedures for 
the preparation of the modified cellulose ethers. The term of "parts" 
appearing in the following description refers to "parts by weight" in each 
occurrence. 
Synthetic Preparation 1 
Into 400 g of tert-butyl alcohol were dispersed 40 g of a hydroxypropyl 
methyl cellulose having a molecular weight corresponding to a viscosity of 
4200 centipoise of a 2% by weight aqueous solution thereof at 20.degree. 
C. (Metolose 60SH-4000, a product by Shin-Etsu Chemical Co.) and the 
dispersion was further admixed with 35 g of a 6% aqueous solution of 
sodium hydroxide and agitated for 2 hours at room temperature under an 
atmosphere of nitrogen. Further, 130 g of stearyl glycidyl ether (Epiol 
SK, a product by Nippon Oils and Fats Co.) were added to the reaction 
mixture which was agitated for additional 4 hours at 50.degree. C. After 
completion of the reaction, the reaction mixture was neutralized by adding 
acetic acid and cooled to room temperature followed by recovery of the 
solid material by filtration. The solid material thus obtained was washed 
with about 10 times by volume of hexane and acetone each twice and then 
washed with 100 times by volume of hot water at 95.degree. C. followed by 
drying to give a modified cellulose ether. 
The modified cellulose ether obtained in the above described manner gave a 
2% by weight aqueous solution having a viscosity of 150,000 centipoise at 
20.degree. C. as measured using a Brookfield viscometer. 
Synthetic Preparation 2 
Into 400 g of tert-butyl alcohol were dispersed 40 g of a methyl cellulose 
having a molecular weight corresponding to a viscosity of 4100 centipoise 
of a 2% by weight aqueous solution thereof at 20.degree. C. (Metolose 
SM-4000, a product by Shin-Etsu Chemical Co.) and the dispersion was 
further admixed with 35 g of a 6% aqueous solution of sodium hydroxide and 
agitated for 2 hours at room temperature under an atmosphere of nitrogen. 
Further, 75 g of stearyl glycidyl ether (Epiol SK, a product by Nippon 
Oils and Fats Co.) were added to the reaction mixture which was agitated 
for additional 4 hours at 50.degree. C. After completion of the reaction, 
the reaction mixture was neutralized by adding acetic acid and cooled to 
room temperature followed by recovery of the solid material by filtration. 
The solid material thus obtained was washed with about 10 times by volume 
of hexane and acetone each twice and then washed with 100 times by volume 
of hot water at 95.degree. C. followed by drying to give a modified 
cellulose ether. 
The modified cellulose ether obtained in the above described manner gave a 
2% by weight aqueous solution having a viscosity of 110,000 centipoise at 
20.degree. C. as measured using a Brookfield viscometer. 
Synthetic Preparation 3 
Into 400 g of tert-butyl alcohol were dispersed 40 g of the same methyl 
cellulose as used in Synthetic Preparation 2 described above and the 
dispersion was further admixed with 35 g of a 6% aqueous solution of 
sodium hydroxide and agitated for 2 hours at room temperature under an 
atmosphere of nitrogen. Further, 75 g of decyl glycidyl ether (Epiol L-41, 
a product by Nippon Oils and Fats Co.) were added to the reaction mixture 
which was agitated for additional 4 hours at 50.degree. C. After 
completion of the reaction, the reaction mixture was neutralized by adding 
acetic acid, cooled to room temperature and admixed with 800 g of hexane 
followed by recovery of the solid material by filtration. The solid 
material thus obtained was washed with about 10 times by volume of hexane 
and acetone each twice and then washed with 100 times by volume of hot 
water at 95.degree. C. followed by drying to give a modified cellulose 
ether. 
The modified cellulose ether obtained in the above described manner gave a 
2% by weight aqueous solution having a viscosity of 120,000 centipoise at 
20.degree. C. as measured using a Brookfield viscometer. 
Synthetic Preparation 4 
Into 400 g of tert-butyl alcohol were dispersed 40 g of a hydroxyethyl 
methyl cellulose having a molecular weight corresponding to a viscosity of 
3900 centipoise of a 2% by weight aqueous solution thereof at 20.degree. 
C. (SEB-04T, a product by Shin-Etsu Chemical Co.) and the dispersion was 
further admixed with 35 g of a 6% aqueous solution of sodium hydroxide and 
agitated for 2 hours at room temperature under an atmosphere of nitrogen. 
Further, 75 g of cetyl epoxide were added to the reaction mixture which 
was agitated for additional 4 hours at 50.degree. C. After completion of 
the reaction, the reaction mixture was neutralized by adding acetic acid, 
cooled to room temperature and admixed with 800 g of hexane followed by 
recovery of the solid material by filtration. The solid material thus 
obtained was washed with about 10 times by volume of hexane and acetone 
each twice and then washed with 100 times by volume of hot water at 
95.degree. C. followed by drying to give a modified cellulose ether. 
The modified cellulose ether obtained in the above described manner gave a 
2% by weight aqueous solution having a viscosity of 110,000 centipoise at 
20.degree. C. as measured using a Brookfield viscometer. 
EXAMPLE 1 
Four gel bases for endermic medicaments were prepared each by dissolving 
1.5 parts of one of the modified cellulose ethers obtained in the above 
described Synthetic Preparations 1 to 4 in a mixture of 82.5 parts of 
water and 16.0 parts of isopropyl alcohol. Each of the gel bases had 
adequate consistency suitable for application to and spreading over human 
skin and did not give unpleasant feeling when it was applied to and spread 
over the skin of testing panel members. 
EXAMPLE 2 
A gel medicament for external application was prepared from 1.0 part of 
tetracycline hydrochloride, 1.5 parts of the modified cellulose ether 
obtained in Synthetic Preparation 1, 81.5 parts of water and 16.0 parts of 
isopropyl alcohol. 
For comparison, another gel medicament for external application was 
prepared in the same formulation as above excepting replacement of 1.5 
parts of the modified cellulose ether with a combination of 0.75 part of a 
carboxyvinyl polymer (Carbopol 934, a product by Goodrich Co.) and 0.75 
part of triethanolamine. 
These gel medicaments were kept stored at room temperature to find that the 
first medicament according to the invention showed absolutely no changes 
in appearance even after 1 month of storage while formation of white 
precipitates was noted in the second medicament prepared for comparative 
purpose before long after preparation. 
EXAMPLE 3 
A gel medicament for external application was prepared in the same 
formulation as in Example 2 excepting replacement of 1.0 part of the 
tetracycline hydrochloride with the same amount of kanamycin sulfate and 
the modified cellulose ether obtained in Synthetic Preparation 1 with the 
same amount of the modified cellulose ether obtained in Synthetic 
Preparation 2. 
For comparison, another gel medicament for external application was 
prepared in the same formulation as above excepting replacement of 1.5 
parts of the modified cellulose ether with a combination of 0.75 part of a 
carboxyvinyl polymer (Carbopol 934, a product by Goodrich Co.) and 0.75 
part of triethanolamine. 
These gel medicaments were kept stored at room temperature to find that the 
first medicament according to the invention showed absolutely no changes 
in appearance even after 1 month of storage while formation of white 
precipitates was noted in the second medicament prepared for comparative 
purpose before long after preparation. 
EXAMPLE 4 
Five gel medicaments for external application were prepared each from 0.1 
part of gentamycin sulfate, 2.0 parts of the modified cellulose ether 
obtained in Synthetic Preparation 1, 0.014 part of triisopropanolamine, 
77.82 parts of water and 16.0 parts of an organic solvent which was one of 
five different solvents including ethyl alcohol, isopropyl alcohol, 
glycerin, polyethylene glycol 400 and propylene glycol. 
For comparison, five more gel medicaments for external application were 
prepared each in the same formulation as above excepting replacement of 
the modified cellulose ether with the same amount of the same carboxyvinyl 
polymer as used in Example 2 for comparative purpose, increase of the 
amount of the triisopropanolamine to 1.4 parts and decrease of the amount 
of water to 76.43 parts. 
These ten gel medicaments prepared according to the invention and for 
comparative purpose were each subjected to the in vitro releasing test 
according to the procedure described below. 
Thus, a Franz-type permeation cell having a receptor cell of 30 ml capacity 
and an area for permeation of 10 cm.sup.2 was used and 0.5 g of the gel 
medicament was applied to and evenly spread over the donor-side surface of 
the partitioning membrane which was a membrane filter having a pore size 
of 0.45 .mu.m made from a mixed cellulose ether (a product by Millipore 
Co.). The amount of the genetamycin sulfate released into the receptor 
cell was quantitatively determined by the fluorescent post-column 
high-performance liquid chromatography after lapse of a length of time. 
The results obtained with the gel medicaments prepared according to the 
invention are shown in Table 1 below in .mu.g. Absolutely no release could 
be found of the gentamycin sulfate when the gel medicament applied to the 
membrane surface was prepared using the carboxyvinyl polymer as the gel 
base while the releasability of the active ingredient was good in each of 
the inventive medicaments although the rate of release was dependent on 
the kind of the solvent to some extent as is shown in the table. 
EXAMPLE 5 
A gel medicament for external application was prepared from 1.0 part of 
croconazole hydrochloride, 2.0 parts of the modified cellulose ether 
obtained in Synthetic Preparation 1, 0.6 part of triisopropanolamine, 48.5 
parts of water, 31.5 parts of propylene glycol and 16.4 parts of isopropyl 
alcohol. 
An in vivo percutaneous absorption test of the thus prepared endermic 
medicament was undertaken using rats as the test animals in the procedure 
described below. As a control, the same percutaneous absorption test was 
undetaken with a commercial product of an endermic medicament having a 
similar consistency and containing croconazole hydrochloride in the same 
concentration as above (Pilzcin Gel, a product by Shionogi & Co.). 
TABLE 1 
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Solvent Time, hours 
Amount released, .mu.g 
______________________________________ 
Ethyl alcohol 
1 312 
2 370 
6 434 
Isopropyl alcohol 
1 357 
2 458 
4 492 
Glycerin 0.5 156 
1 253 
2 321 
Polyethylene glycol 
0.5 260 
400 1 351 
2 404 
Propylene glycol 
0.5 222 
1 285 
2 367 
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Thus, a 0.3 g portion of the gel medicament was applied to and spread over 
the shaved abdominal skin of a male rat of the Wister strain and the 
medicament was recovered after 4 hours by washing with ethyl alcohol. 
Separately, the abdominal skin of the rat after removal of the gel 
medicament was taken by resection. The amounts of the croconazole 
hydrochloride in the ethyl alcohol washing and in the resected abdominal 
skin were determined by the high-performance liquid chromatography to give 
the results shown in Table 2 below. 
TABLE 2 
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Recovery, %, in 
Amount, .mu.g, re- 
washing tained in the skin 
______________________________________ 
Inventive medi- 
92.5 22.6 
cament 
Commercial 98.3 8.3 
medicament 
______________________________________ 
The results shown in Table 2 clearly indicate that the percutaneous 
absorptivity of the therapeutically effective ingredient is much higher in 
the inventive endermic medicament than in the commercial medicament of the 
similar type.