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Патент USA US3072545

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United States Patent
Patented Jan. 8, 1963
dextrin, dextrose and‘ likeisubstances normally employed
Irving Inuer?eld, 20 Knickerbocker Road, Tena?y, NJ.
in pharmacological practice. '
I prefer to include with the excipients that are used,
N0 Drawing. Filed Nov. 4, 1958, Ser. No. 771,740
2 Claims. (Cl. 167-—73)
and as part of the carrier for the protease, a water-solu
this was accomplished through the intramuscular injec
laurate, mannitan, dulcitol, dextrose, soluble starch, dex
ble, stabilizing and solubilizing agent. The one which
I now prefer is “Carbowax,” a solid polyethylene glycol
This invention relates to chemotherapy and aims to
having a molecular weight within the range of about
provide a new method of introducing a therapeutically
1500 to about 4000. I have found that this substance
active proteolytic substance into the body through muco
augments the stability of my composition and causes it
sal tissue (buccally).
10 to dissolve readily when it is administered. Other water
It is frequently desirable in the treatment of various
'soluble, stabilizing and solubilizing agents that may be
physical disorders to increase the proteolytic enzyme con~
employed’ are a gum, such as karaya, tragacanth, agar,
tent and activity at the site of the disorder. This can be
gum arabic, Indian gum, cherry gum and plum gum; a
done through the introduction into the systemic circula
carbohydrate and derivatives thereof such as sorbitol,
tion of a proteolytic substance. Prior to my invention, 15 sorbitol laurate, sorbose, sorbitan, mannitol, mannitol
tion of a ?uid preparation containing a protease. Such
a preparation was made by suspending the desired quan
tity of a protease in an oil such as sesame oil or by in
trin, levulose, inositol, arabinose and beta lactose; and
methyl cellulose, gelatin and sodium chloride.
The protease that I employ as the active ingredient in
corporating the protease in physiological saline. The 20 the practice of my invention may be of animal, plant,
administration of a protease through intramuscular in
bacterial or fungal origin. Exemplary thereof are tryp
jection is subject to serious disadvantages. It is painful,
sin, pepsin, chymotrypsin, papain, bromelin, ?cin, pro
requires a visit to or attendance by a physician for each
tease recovered from a culture broth of Bacillus subtilis,
treatment, and, when an aqueous material such as physi
protease recovered from a culture broth of Aspergillus
ological saline is employed, it is necessary to prepare a
niger and protease recovered from a culture broth of
fresh batch just before injection as deterioration and loss
Trichophyton gypseam.
of efficacy of a protease in the presence of water is rapid.
The quantity of protease constituting an effective dos
I have made the surprising discovery that a safe but
age unit will vary according to the particular protease
effective quantity of a therapeutically active proteolytic
selected and the purity thereof, and ranges from about
substance can be easily introduced into systemic circula 30 0.5 to 15.0 mgs. per dosage unit, the amountselected in
tion by a patient personally without undue discomfort.
any given case being measured preferably in terms of
This may be accomplished by incorporating a dosage
proteolytic activity. Such activity can be readily deter
quantity of a protease in a pharmaceutically acceptable
mined according to the method described in D. G. Evans,
carrier that can be readily introduced into the mouth and
“Gelatinolytic Enzymes,” Journal of General Micro
held in the buccal cavity Where the therapeutically active
biology, vol. 1, page 378, 1948. Since trypsin is obtain
proteolytic substance will gradually penetrate the buccal
able in crystalline form, it can be used as the yardstick
mucosa and thus be introduced into the patient’s circula
against which the proteolytic activities of the other pro
tory system. Preferably, such a carrier consists of, or in
teases are measured. Thus, when so measured, while
cludes, a water-soluble, stabilizing and solubilizing agent.
the protease obtained from‘ a culture broth of Bacillus
Such administration may be safely continued at fairly
subtillis shows about the same order of proteolytic ac
frequent intervals so that the desired proteolytic enzyme
tivity as trypsin, the proteolytic activity of papain is about
content of the patients bloodstream may be maintained
half'the proteolytic activity of the same amount by weight
over a substantial period of time.
of trypsin. The degree of proteolytic activity per dosage
The proteases that can be employed to introduce a 45 unit that I prefer to employ in the practice of my inven
therapeutically active proteolytic substance into the sys
tion is that falling within the range of proteolytic activity
exhibited by 2.5 to 5 mgm. of trypsin.
under normal conditions, penetrate mucous membrane.
In order that my invention will be fully available to
However, when they are held in contact with such mem—
those skilled in the art, speci?c preparations illustrating
brane in the presence of body ?uid such as saliva, a 50 the practice thereof are described brie?y:
therapeutically active proteolytic. substance will enter the
Example I
bloodstream through this route. I believe this to be due
‘ temic circulation as a result of my invention will not,
to the fact that the molecules of the proteolytic materials
in question are too large to penetrate the intercellular
thoroughly admixed and the admixture thus produced is
space or pores in normal mucous membrane.
tableted. '
However, 55
protease in the presence of body ?uid is evidently adapt
ed to act so as to increase the permeability or porosity
of mucous membrane sufliciently to permit penetration
of therapeutically active enzymic material into the body.
5 mgm. trypsin and 100 mgm. “carbowax 4000” are
Example ll
5 mgm. trypsin and 100 mgm. beta lactose are thor
oughly admixed and the admixture thus produced is
Protease, while subject to rapid deterioration in an 60 tableted.
aqueous medium, is stable in dry form. For convenience
This application is a continuation-in-part of my pend
in dispensing and administration, the protease used in the
ing application, Serial No. 520,165, ?led July 5, 1955,
practice of my invention can be enclosed in an ordinary
now abandoned. My said application, Serial No.
520,165, is in turn a continuation-in-part of my applica
such protease in a tablet which can be readily introduced 65 tion, Serial No. 463,328, ?led October 19, 1954, and my
into the mouth and held in the buccal pouch until dis
application, Serial No. 485,594, ?led February 1, 1955,
solved in the saliva present and penetration of the buccal
which were copending therewith and each of which is
mucosa by the therapeutically active enzymic substance
now abandoned.
has been accomplished. Ordinary tableting procedure
WhatIclaim is:
can be followed, using excipients such as starch, soluble 70 1. The method of introducing a therapeutically active
starch, lactose, magnesium oxide, magnesium carbonate,
enzymic material into the systemic circulation of a sub
gelatin type of capsule. However, I prefer to incorporate
magnesium hydroxide, aluminum hydroxide, galactose,
ject which comprises placing a dosage quantity of a
protease in contact with mucous membrane and maintain
ing the protease in contact With said membrane in the
presence of body ?uid until said therapeutically active
enzymic material is absorbed by said subject.
U.S. Dispensatory, 24th ed., 1947, pp. 816-818.
Lesser: Drug & Cosmetic Ind., 71: 2, pp. 178, 179,
6 250-254.
Inner?eld et a1.: Jour. Clin. Invest, 31: 12, pp. 1049
1055, December 1952.
mgrn. of a protease as the essential active constituent
which consists in placement and retention thereof
Jour. Clin. Endocrinology, 8: 10, pp. 884-886, Oc
tober 1948.
2. A method for the administration of a chemothera
peutic composition containing from 0.5 mgm. to 15.0
References Cited in the tile of this patent
Sandberg ____________ __ Oct. 31, 1950
Inner?eld ____________ __ Jan. 30, 1962
Taylor et a1.: J.A.M.A. 155: 4, pp. 347-351, May 22,
Hardy et a1.: Surg., Gyn. & Obstet., 100: 1, pp. 91-96,
January 1955.
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