Method for treatment of arthrosis deformans with elastase

A method is disclosed for treating a subject suffering from arthrosis deformans which comprises administering to said subject a therapeutically effective amount of a composition comprising elastase and a pharmacologically acceptable carrier. Particularly excellent results were obtained using this method for the treatment of gonarthrosis deformans.

This invention relates to a method and pharmaceutical composition for the 
treatment of arthrosis deformans containing elastase as an effective 
ingredient. 
Arthrosis deformans, also known as arthritis deformans, is a desease which 
does not accompany inflammation. The chief lesion thereof or effect is the 
degeneration of articular cartilage, accompanied by changes such as bone 
enlargement and bone fibrillation. The mechanism of the development of 
arthrosis deformans has not yet been elucidated in many respects, but 
because the development of this disease advances with the age of the 
patient, the metabolic disturbance of articular cartilage is thought to be 
an important factor. Namely, the amount of the matrix substances of 
cartilage, such as proteoglycans, is decreased, and at the same time, 
granules of mucopolysaccharides or proteins are liberated, which cause 
thinning of the articular cartilage and separation of collagen. 
Consequently, the cartilage assumes the form of an asbestos-like fiber, 
the surface of the articular cartilage becomes frayed in a manner similar 
to fine villi, and fibrillation of the cartilage occurs. Such changes 
occur more frequently in load-bearing joints, such as knee joints and hip 
joints. Accordingly, the aged often suffer from dysbasia due to 
gonarthralgia. The repair of degenerated articular cartilage is extremely 
difficult, so that at present, only symptomatic treatment is carried out 
on patients suffering from arthrosis deformans for the purpose of 
relieving pain. 
The present invention is directed to compositions for treating arthrosis 
deformans, and particularly compositions for palliating or clearing up 
arthralgia, which is a clinical characteristic of arthrosis deformans. As 
a result, it was found that the enzyme elastase achieves these objects. 
It is an object of this invention to provide a method for palliating or 
providing a remission from arthrosis deformans, and particularly for 
exerting an analgesic effect on arthralgia caused by arthrosis deformans. 
Elastase is an enzyme which specifically decomposes elastin, a 
water-insoluble scleroprotein. Elastase is industrially produced by 
extraction from swine pancreas. Porcine elastase has the following 
characteristics. First, porcine elastase has a molecular weight of 25,900, 
a value determined from the amino acid sequence of the primary structure 
of the elastase molecule, an isoelectric point of pH 9.5.+-.0.5, and a 
sedimentation coefficient S.sub.20,w of 2.6. As to activity, the porcine 
elastase molecule contains serine and histidine in its active center and 
has the property of specifically decomposing the synthetic substrates 
N-.alpha.-benzoyl-L-alanine methyl ester and 
acetyl-L-trialanine-p-nitroanilide, in addition to elastin. According to 
results obtained from measurements made using N-.alpha.-benzoyl-L-alanine 
methyl ester as a substrate, the optimal activation pH for elastase is 
from 8 to 10, particularly about 8.8. The activity of elastase is 
inhibited by NaCl, KCl, (NH.sub.4).sub.2 SO.sub.4, NaCN, CuSO.sub.4, and 
some N-.alpha.-benzoylcarboxy derivatives. 
As to biochemical properties, elastase has been confirmed to have a 
.beta.-lipoproteinase activity and a lipoprotein lipase activity, and it 
exerts a normalizing effect on the disturbance of lipid metabolism in the 
serum and tissues. Accordingly, in clinical applications, elastase has 
been used to ameliorate serum lipid anomalies associated with hyperlipemia 
and arteriosclerosis. Furthermore, elastase maintains and promotes the 
elasticity and dilatability of arterial walls. In other words, it 
functions to remove denatured elastin from arterial walls and to promote 
formation of fresh elastin, and in addition, hinders deposition of fat on 
the denatured elastin and thereby hinders development of atherosclerosis. 
The following literature references describe clinical applications of 
elastase: 
(1) Kazuo Ogawa, Yasuhiro Gosato: Morphological Study on 
Anti-atherosclerotic Action of Elastase, Nichi Ro Ishi, 10, 277-292 
(1973). 
(2) Akira Osawa: About Anti-arteriosclerotic Action of Elastase (elastic 
fiber decomposing enzyme). Nichinai Kaishi, 59, 20-29 (1970). 
(3) Shuko Naito, Toshio Tono, Tsutomu Iwabuchi, Yoshie Ishimaru, Akihide 
Uesugi, Michio Ogasawara, Akimasa Omori, Masao Kase, Hitoshi Kimura, 
Yasushi Shichiri, Saburo Yokoyama: Study on Effect of Elastase on 
Improvement of Anomalies of Serum Lipid by Double-Blind Procedure. Igaku 
no Ayumi, 82, 848-859 (1972). 
(4) Toshio Tono: Treatment of Arteriosclerotic Diseases by Elastase. Rinsho 
to Kenkyu 53, 1798 (1976). 
(5) Motoharu Hasegawa, Ken Kawasaki, Chikao Arai et al, 
Anti-arteriosclerotic Effect of Elastase, Dohmyaku Kohka, vol. 8 (1980), 
No. 2, pages 271 to 286. 
(6) Balo, J. and Banga, I.: The Elastolytic Activity of Pancreatic 
Extracts. Biochem. J., 46, 384 (1950). 
As mentioned above, the chief effect of arthrosis deformans is the 
degeneration of articular cartilage. The articular cartilage naturally 
undergoes degeneration with aging from injury or normal use, and such 
degeneration is accelerated by secondary factors such as wounds and 
interruptions in blood circulation. The degeneration of cartilage is 
thought to result fundamentally from a metabolic disturbance. The 
cartilage tissue consists of chondrocytes and extracellular substances. 
The latter are called the matrix substances of cartilage and consist of 
mucoproteins, mucopolysaccharides and collagen fibers. In the early stages 
of degeneration due to arthrosis deformans, levels of normal metabolic 
substrates decrease, and mucopolysaccharides and proteinaceous substances 
separate from the cartilage in the form of granules. At the same time, the 
collagen fiber separates into a plurality of fibers and the cartilage is 
converted into a frayed fiber, resembling asbestos. It is also thought 
that hyaluronidase penetrates the surface of the injured cartilage, 
destroys the matrix substances and destroys the structure of the collagen 
fibers. In any case, it is widely believed that the causes of arthrosis 
deformans are associated with the disturbance of the metabolism of 
mucopolysaccharides and collagen. 
Accordingly, if elastase can inhibit the disruption of mucopolysaccharides 
or the proliferation of collagen within the articular cartilage which 
occur in arthrosis deformans, the repair of this arthrosis and the 
amelioration of the clinical symptoms thereof can be achieved. 
However, it was not previously known whether or not elastase had such 
effects. This invention has therefore achieved an important discovery in 
the field of treatment of arthrosis deformans and makes it possible to 
substantially completely clear up arthralgia in some cases, a result which 
has heretofore been thought difficult to achieve. 
The invention will now be described in detail. 
Arthrosis deformans is a chronic painful disease in which retrogressive 
degeneration of articular cartilage results from congenital or acquired 
articular deformation and destruction of the articular load-bearing 
regions of the cartilage and proliferous change in the load-free regions 
of the cartilage. This disease is typified by gonarthrosis deformans and 
coxarthrosis deformans, that is, arthritic inflammation of the knee joint 
and hip joint, respectively. Gonarthrosis deformans and coxarthrosis 
deformans are particularly common forms of arthrosis deformans. This 
invention exhibits particularly outstanding analgesic and therapeutic 
effects against gonarthrosis deformans. 
In this invention, elastase is preferably orally administered, absorbed by 
the intestinal wall and carried into the blood. In the blood, elastase 
combines with .alpha..sub.2 -macroglobulin and .alpha..sub.1 -antitrypsin, 
is distributed widely over all of the body tissues, is metabolized chiefly 
in the liver, and then is excreted into the urine. The concentration of 
elastase in the blood reaches a maximum 6 hours after administration. The 
area under the blood concentration curve, which represents the total 
amount of elastase absorbed by the blood, increases in proportion to the 
dosage. 
The preferred daily dosage of elastase according to this invention is, for 
example, 2,000 to 20,000 EL. U (elastase units) per patient suffering from 
arthrosis deformans. Elastase is continuously administered over a period 
of time of, for example, from 4 to 20 weeks, at such dosages. However, 
this invention is not limited to the above-mentioned dosage range, since 
the dosage may vary according to the needs of individuals patients. The 
acute toxicity of elastase is shown in the following table. Acute toxicity 
is measured in elastase units per kilogram body weight of the test animal. 
______________________________________ 
Acute Toxicity LD.sub.50 (EL. U/kg) 
Intra- Intra- 
Animal 
Sex Oral Subctaneous 
peritoneal 
veneous 
______________________________________ 
rat male &gt;150,000 &gt;75,000 6,380 6,380 
female &gt;150,000 &gt;75,000 5,850 6,380 
mouse male &gt;150,000 &gt;75,000 4,970 5,100 
female &gt;150,000 &gt;75,000 2,780 4,310 
______________________________________ 
Other toxicity values are shown by the following experiments. 
Subacute toxicity 
Elastase was orally administered to Wistar strain female and male rats at 
dosages of 750, 7,500 and 37,500 or 75,000 EL. U/kg/day for 4 weeks, and 
to female and male beagle dogs at dosages of 900 or 4,500 EL. U/kg/day for 
12 weeks. As a result, no noteworthy anomalous findings as to general 
physical condition, blood and urinary tests and morphological observations 
made visually and histologically were obtained for any of the rats and 
dogs. 
Chronic toxicity 
Elastase was orally administered to Wistar strain female and male rats at 
dosages of 2,250, 5,700, 11,250 or 22,500 EL. U/kg/day for 24 weeks. As a 
result, no anomalous findings as to general physical condition, blood and 
urinary tests, and visual and histological morphological observations were 
obtained for the rats tested. 
Teratogenicity 
Elastase was forcibly orally administered to pregnant mice and rats in the 
stage of organogenesis at dosages of 750, 7,500 or 75,000 EL. U/kg/day for 
6 consecutive days. As a result, death, hindrance to growth and 
teratogenesis of the embryos were not observed, and there was no effect 
upon the morphological and functional differentiation of the newborn 
animals. 
The pharmaceutical composition of this invention is generally orally 
administered. It is preferred to prepare the pharmaceutical composition of 
the invention as oral administrable, solid preparations, such as granules, 
tablets and capsules. The production of solid preparations can be carried 
out according to conventional methods using excipients commonly used in 
the art of pharmaceutical preparations. Accordingly, elastase granules are 
prepared by directly adding a binder to, for example, a mixture comprising 
elastase, lactose, starch and cellulose, or by adding a binder while 
spraying the foregoing mixture onto the binder as the binder moves along a 
fluidized bed. The thus-produced granules can be encapsulated to form 
capsules.

The effects of this invention are demonstrated by the clinical examples 
described below. 
CLINICAL EXAMPLES 
1. Subjects and procedures 
The subjects included 18 patients (men 6 cases, women 12 cases, ages 57 to 
88, average 70.9.+-.8.2 years old) that were diagnosed negative as to 
rheumatoid arthrosis and were clinically diagnosed as suffering from 
gonarthrosis deformans. These patients had underlying diseases as shown in 
Table 1. Thirteen patients displayed bilateral gonarthralgia and the other 
five patients displayed unilateral gonarthralgia. The distribution of the 
duration of gonarthralgia in the patients from the onset thereof was such 
that six cases fell into each of the periods of (1) three years or 
shorter, (2) four to five years, and (3) five years or longer. 
The effectiveness of elastase against gonarthrosis deformans was evaluated 
by administering capsules containing 1,800 EL.U elastase at a daily dosage 
of 3 capsules per day to each patient for 8 weeks, and investigating the 
severity of gonarthralgia before administration, 4 weeks after 
administration, and 8 weeks after administration. Curative effects were 
judged as "markedly effective" when the effects of gonarthralgia on motion 
were completely cleared up, as "effective" when the effects of 
gonarthralgia were palliated, as "ineffective" when there was no effect, 
and as "aggravated" when the effects of the gonarthralgia were made worse. 
In order to eliminate psychological effects upon the measurements of 
effectiveness during the tests, the patients received the explanation that 
this drug was being administered as an antilipemic agent because it 
controls anomalies of blood lipid associated with arteriosclerosis, 
hypertension and other conditions, but the patients did not receive any 
explanation concerning its effectiveness against gonarthralgia. However, 
these patients had received and continued to receive during the test 
period antihypertensive agents, agents for improving cerebral circulation 
and other drugs for the treatment of their underlying diseases. However, 
the levels of these drugs in the patients' bodies remained unchanged from 
the day 8 weeks before the start of the test up to the last day of the 
test. During the tests, no patient received any other antiinflammatory, 
analgesic or steroid having the possible effect of palliation of 
arthralgia. 
2. Results 
(1) Effectiveness against gonarthralgia 
The results of the evaluations of the administration of elastase for the 
treatment of gonarthralgia in human patients are shown in Tables 2 and 3. 
As to the entire group of patients tested, there were no results of 
"aggravated" and only two results of "ineffective". The sixteen remaining 
patients showed distinct palliation or complete clearing of the 
gonarthralgia. Thus, the overall rate of improvement was 88.9%. 
With respect to the period of administration, after 4 weeks of 
administration of the elastase, 6 results (33.3%) were "markedly 
effective", 10 results (55.6%) were "effective" and 2 results (11.1%) were 
"ineffective". Eight results each of "markedly effective" and "effective" 
(44.48%) and no change in the two results of "ineffective" were observed 
after 8 weeks of administration of elastase to the same patients that were 
previously evaluated after 4 weeks. 
With respect to the effect of the duration of gonarthralgia from the onset 
thereof in the patient, there was one "ineffective" result in the 4 to 5 
year group and one such result in the 5 years or longer group. However, 
there was no distinct difference in the rate of improvement between the 
different groups, and in two cases wherein gonarthralgia which has been 
present for a long time (greater than 5 years), the gonarthralgia was 
completely cleared up. 
The patients who showed improvement perceived palliation or clearing of 
arthralgia at the beginning of the second week after the start of 
administration of elastase. When a comparison of effectiveness was made 
between the results after 4 weeks and the results after 8 weeks, results 
of "markedly effective" were somewhat higher after the 8 week period. 
However, no distinct difference in the rate of improvement was recognized. 
This indicates that the analgesic effect develops at a relatively early 
stage after the start of administration of elastase. 
TABLE 1 
__________________________________________________________________________ 
Details of Subject Diseases 
Duration of 
arthralgia 
No. 
Case 
Age 
Sex Underlying disease 
Arthralgia from onset 
Note 
__________________________________________________________________________ 
1 K. T. 
71 man cerebral infarction, diabetes 
left knee 3 years 
paresis on the right 
side 
2 Y. W. 
77 woman 
Parkinson's disease 
knee, bilateral 
&gt;5 
3 S. O. 
57 woman 
hypertension knee, bilateral 
5 
4 T. I. 
65 woman 
tension headache 
knee, bilateral 
4 stiffness in both hands 
for 
2 years 
5 Y. M. 
73 man polygenetic cerebral 
left knee, lumbago 
3 no motoric paralysis, 
mild 
infectionn dementia 
6 Y. S. 
67 woman 
hypertension knee, bilateral, 
3 so-called periarthritis 
numero- 
left shoulder scapularis in the left 
shoulder 
7 M. H. 
82 man cerebral infarction, asthma 
knee, bilateral, lumbago 
&gt;5 
8 K. U. 
68 woman 
hypertension knee, bilateral 
&gt;5 
9 M. S. 
69 woman 
hypertension knee, bilateral 
4 
10 M. T. 
58 woman 
hypertension knee, bilateral 
&gt;5 carpal tunnel syndrome 
11 K. K. 
80 woman 
hypertension, TIA 
knee, bilateral, lumbago 
&gt;5 
12 K. U. 
88 man cerebral infarction 
knee, bilateral 
5 no motoric paralysis 
13 T. U. 
81 woman 
hypertension knee, bilateral 
&gt;5 
14 K. H. 
75 woman 
hypertension knee, bilateral 
2 
15 F. Y. 
67 woman 
hypertension knee, bilateral 
4 carpal tunnel syndrome 
16 M. G. 
72 woman 
hypertension left knee 5 
17 Y. K. 
64 man hypertension left knee 3 
18 T. M. 
62 man hypertension, cerebral 
right knee 3 hyperreflexia in the 
right 
infarction tendon 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
Effect of Elastase Administration on Gonarthralgia 
Duration of 
gonarthralgia 
Effect on arthralgia 
No. 
Case 
from onset 
after 4 w. 
after 8 w. 
Side effect 
Miscellaneous 
__________________________________________________________________________ 
1 K. T. 
3 years 
+ + 
2 Y. W. 
&gt;5 + + 
3 S. O. 
5 + ++ transient 
epigastric 
discomfort 
4 T. I. 
4 ++ ++ morning stiffness in hands cleared, lumbago 
also 
cleared 
5 Y. M. 
3 ++ ++ 
6 Y. S. 
3 + + transient 
cinesalgia in the left shoulder not 
changed 
epigastric 
discomfort 
7 M. H. 
&gt;5 + + lumbago lasting 
8 K. U. 
&gt;5 ++ ++ 
9 M. S. 
4 + + transient 
administration discontinued after 2 w, and 
epigastric 
restarted because of worsened arthralgia 
discomfort 
10 M. T. 
&gt;5 + + carpal tunnel syndrome not changed 
11 K. K. 
&gt;5 + ++ lumbago lasting 
12 K. U. 
5 - - 
13 T. U. 
&gt;5 - - 
14 K. H. 
2 ++ ++ 
15 F. Y. 
4 + + carpal tunnel syndrome not changed, 
troubles in 
dancing eliminated 
16 M. G. 
5 ++ ++ 
17 Y. K. 
3 ++ ++ 
18 T. M. 
3 + + 
__________________________________________________________________________ 
++ markedly effective 
+ effective 
- ineffective 
TABLE 3 
__________________________________________________________________________ 
Rate of Effectiveness Analyzed from Duration of Gonarthralgia 
Duration of arthralgia 
3 years or shorter 4 to 5 years 5 years or longer 
Overall 
Effec- 
Term of administration 
tiveness 
4 w 8 w 4 w 8 w 4 w 8 w 4 w 8 
__________________________________________________________________________ 
w 
markedly 
3 3 2 3 1 2 6 8 
effective 
effective 
3 3 3 2 4 3 10 8 
in- 0 0 1 1 1 1 2 2 
effective 
ag- 0 0 0 0 0 0 0 0 
gravated 
rate of 
6/6 
100% 
6/6 
100% 
5/6 
83.3% 
5/6 
83.3% 
5/6 
83.3% 
5/6 
83.3% 
16/18 
88.9% 
16/18 
88.9% 
effec- 
tiveness 
__________________________________________________________________________ 
Several typical case histories of patients for whom "markedly effective" 
and "ineffective" results were obtained are given below. 
T.I. (Case 4, result--markedly effective, 65-year old woman) was a patient 
who had a vague pain in the occipital region and a stiff shoulder for 5 
years and consulted a physician, but had no distinct neurological local 
symptoms and was under observation for tension headaches. About 4 years 
ago, she began to complain of bilateral gonarthralgia which caused pain 
when she stood up from a sitting position or when she went up or down 
steps. Crepitation was present in the knee joints on both sides. Further, 
she had morning stiffness in the fingers of her hands for about 2 years. 
Administration of elastase at the above-mentioned dosage was started. After 
4 weeks, the cinesalgia in the knee joints was completely cleared up, and 
morning stiffness in the fingers also was cleared up. 
U.K. (Case 8, result--markedly effective, 68-year old woman) was a patient 
who had hypertension (blood pressure about 160 to 180/90 mm Hg) for about 
10 years and consulted a physician for the purpose of controlling her 
blood pressure. About 4 years ago, she began to complain of arthralgia in 
the knee on both sides which occurred when she stood up from a sitting 
position, when she started walking or when she would go up or down steps. 
She received drainage of joint fluid and intra-articular steroid 
injections as treatments for gonarthrosis deformans several times over the 
last 5 years. She had mild dilatation of the heart. Her knee joints both 
sides did not show redness but showed swelling and crepitation. 
Administration of elastase was begun as described above. After 4 weeks, the 
patient said that the pain in her knees had disappeared entirely, and she 
stopped complaining of having difficulty in standing up and of going up 
and down steps. As a drug used in combination with the elastase, 
trichlormethiazide at a dosage of 4 mg/day was used to treat her 
hypertension. 
M.G. (Case 16, result--markedly effective, 72-year old woman) consulted a 
physican for hypertension and a stiff shoulder as her main problems. She 
engaged in Japanese dancing, and she had a pain in the left knee for about 
5 years which has made it difficult for her to stand up from the sitting 
position in the formal manner, and when doing so she felt a strong pain in 
the left knee joint. No particular anomalies were present in the chest and 
the abdomen. Crepitation was present upon flexion of the left knee. 
Swelling of the joints was not very distinct. 
Administration of elastase was begun as described above. After 4 weeks, the 
pain in the left knee was completely cleared up, and this patient said 
that her problems with Japanese dancing had disappeared. 
T.U. (Case 13, result--ineffective, 81-year old woman) had hypertension for 
about 15 years and consulted a physician for the purpose of a precise 
examination. She had cinesalgia in the knees on both sides for about 15 
years, and she receive intra-articular steroid injections many times. When 
standing up or going up and down steps, she felt a distinct pain in her 
knee joints. Her gait was aided by a cane or a helper. Her knee joints 
showed swelling and distinct crepitation. An X-ray image of the knee 
joints showed that the joint gaps on both sides were narrowed, 
irregularities were present on the surface of the joint, and sclerosis of 
subcartilagious bone was present. In the periarticular region, distinct 
formation of osteophytes was observed and the joint on the whole had a 
destroyed appearance. 
Administration of elastase was begun as described above, but no improvement 
was recognized after either 4 weeks or 8 weeks of treatment with elastase. 
(2) Effectiveness against other types of arthralgia 
In the foregoing clinical examples, there were 3 cases in which the 
patients had gonarthralgia combined with lumbago probably resulting from 
lumbar vertebrae deformans. In one of these cases, Case 5, the lumbago 
also cleared up during the term of administration of the elastase. In Case 
6, the patient had cinesalgia in the left shoulder, that is, periarthritis 
humeroscapularies. No change in this condition was observed during the 
term of administration of elastase. In Cases 10 and 15, the patients 
frequently complained of anomalies of sensation, particularly in the 
second through the fourth fingers, but this symptom was not cleared up by 
the administration of elastase. In all of these cases, however, 
gonarthralgia was palliated or cleared up by the action of elastase. 
(3) Side effects 
Transient epigastric discomfort was observed as an anomalous side effect 
for some subjects during the term of administration of the elastase. In 
Cases 3, 6 and 9, the patients suffered from epigastric discomfort for 
several days one to two weeks after the administration of elastase began. 
In Cases 3 and 6, the epigastric discomfort then disappeared after 4 
weeks. In Case 9, the administration of elastase was discontinued at the 
beginning of the second week because of epigastric discomfort. However, 
because the pain in the patient's knee joints worsened when the 
administration of elastase was discontinued, the patient realized the 
palliative effect of the drug on gonarthralgia, and the administration of 
elastase was therefore restarted at the beginning of the third week, with 
consequent palliation of gonarthralgia. The administration of elastase was 
thus continued in this case and the epigastric discomfort cleared up after 
4 weeks. In none of the cases were nausea, vomiting, exanthema or the like 
observed. 
Conclusions 
The following results were obtained by the foregoing clinical examples 
wherein elastase was administered for 8 weeks to 18 patients suffering 
from gonarthrosis deformans and attendant gonarthralgia: 
(1) Four weeks after administration, in 6 out of the 18 cases, the elastase 
administrations showed such a marked effectiveness that the arthralgia was 
completely cleared up, and in 10 of the 18 cases, arthralgia was 
considerably palliated so that these cases were judged as results of 
"effective". Two cases were judged as results of "ineffective". No cases 
were found wherein "aggravated" was the result. 
(2) Eight weeks after the administration of elastase began, 8 out of the 18 
cases obtained "markedly effective" results, 8 cases were judged as 
"effective" results, 2 cases were judged as "ineffective" and no cases 
were judged as "aggravated". The overall rate of improvement was 88.9%, 
which is very high. The rate of "markedly effective" was 44.4%, the rate 
of "effective" was 44.4%, the rate of "ineffective" was 11.1%, and the 
rate of "aggravated" was 0%. 
(3) In 3 cases (16.7%), epigastric discomfort was observed as a side 
effect, but the administration of elastase was not discontinued in any of 
these cases. 
The above results strongly suggest that elastase is extremely effective 
against arthralgia in gonarthrosis deformans. It is particularly 
noteworthy that an excellent analgesic action can be obtained at an early 
stage of the term of administration of elastase. 
It is believed that elastase has a decomposing action not only upon elastin 
but also upon mucopolysaccharides. Therefore, it can be assumed that 
elastase has an effect upon anomalies of mucopolysaccharides or collagen 
which underlie arthrosis deformans. However, with respect to the analgesic 
effect of elastase shown in the clinical examples, it is difficult to 
interpret this as anything other than repair of the matrix structure of 
the cartilage. This is suggested because the analgesic effect is obtained 
at an extremely early stage of treatment, but it is difficult to 
understand, in cases of advanced arthrosis deformans where the condition 
has been present for a long time, how the knee cartilage can be repaired 
by short-term administration of elastase. 
In any event, the effectiveness of the pharmaceutical composition of this 
invention against arthrosis deformans is powerfully indicated by the fact 
that, when the composition containing elastase of this invention was 
administered to patients without informing them of the relation between 
this composition and gonarthralgia, persistent gonarthralgia was 
considerably palliated or completely cleared up during the term of 
administration for most of the patients. 
The present invention will now be described in further detail with 
reference to the following examples of pharmaceutical compositions 
according to the invention. 
EXAMPLE 1 
100 g of elastase (85 EL. U/mg) together with 400 g of sucrose fatty acid 
ester were mildly triturated to form a uniform powder. To this powder were 
added 500 g of spray-dried lactose, 495 g of crystalline cellulose and 300 
g of CMC calcium, and the mixture was agitated. Then, 5 g of calcium 
stearate was added to the mixture through an 80-mesh sieve and uniformly 
mixed therein, and the resulting mixture was formed into tablets each 
weighing 180 mg. These tablets were used as a therapeutic drug for the 
treatment of arthrosis deformans. 
EXAMPLE 2 
The following amounts of the ingredients described below were used in this 
example: 
______________________________________ 
Nomparel 2.5 kg 
HPC-L 0.5 kg 
elastase (85 EL. U/mg) 0.6 kg 
sucrose fatty acid ester 
1.5 kg 
cornstarch 2.7 kg 
HP-55 1.95 kg 
acetyl monoglyceride 0.25 kg 
ethanol q.s. 
______________________________________ 
A centrifugal fluid coater was charged with the Nomparel. While an 
ethanolic solution of HPC-L was being sprayed therein, a mixed powder of 
elastase, sucrose fatty acid ester and cornstarch was also dispersed 
therein, and the resulting mixture was granulated. The produced granules 
were spray-coated with an ethanoloc solution of acetyl monoglyceride and 
HP-55 by means of the above apparatus to produce enteric granules. These 
granules were used as a therapeutic drug for treatment of arthrosis 
deformans. Nomparel is a mixture of sucrose and cornstarch, HPC-L is 
hydroxypropylcellulose and HP-55 is hydroxypropylmethylcellulose 
phthalate.