Canadian Patents Database / Patent 1179264 Summary

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(12) Patent: (11) CA 1179264
(21) Application Number: 389215
(54) English Title: CONDRANOL FOR TRANSPLANTS
(54) French Title: CANDRANOL UTILISE POUR PREVENIR LE REJET LORS DES TRANSPLANTATIONS
(52) Canadian Patent Classification (CPC):
  • 167/199
(51) International Patent Classification (IPC):
  • A61K 31/70 (2006.01)
  • A61K 6/00 (2006.01)
  • A61L 27/34 (2006.01)
  • A61L 29/08 (2006.01)
  • A61L 33/08 (2006.01)
(72) Inventors :
  • MORRISON, LESTER M. (United States of America)
(73) Owners :
  • BIOMED RESEARCH, INC. (Not Available)
(71) Applicants :
(74) Agent: SMART & BIGGAR
(74) Associate agent:
(45) Issued: 1984-12-11
(22) Filed Date: 1981-11-02
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
263,788 United States of America 1981-05-14

English Abstract



49-104
ABSTRACT OF THE INVENTION
A method which comprises the administration of an effective
amount of "active" chondroitin sulfate A, "active" chondroitin
sulfate C, or mixtures thereof to humans just prior to, during,
and/or following the transplantation or implantation into the
body of tissue or organs from the same or another human or animal,
or inanimate prosthetic and orthopedic devices, surgical instru-
ments and the like, to mitigate rejection or failure of the trans-
plant or implant.


Note: Claims are shown in the official language in which they were submitted.


THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A surgical implant or transplant coated with an amount of "active"
chondroitin sulfate A or "active" chondroitin sulfate C sufficient to
ameliorate rejection of the implant or transplant.


2. A coated surgical implant according to claim 1 which is an indwelling
catheter, needle, or I.V. tubing.


3. A coated surgical implant according to claim 1 which is a heart
valve.


4. A coated surgical implant according to claim 1 which is a tooth
prosthesis.


5. A coated surgical implant according to claim 1 which is a bone
prosthesis.


6. A coated surgical implant according to claim 1 which is an artificial
prosthesis.


7. A coated surgical implant according to claim 1 which is an
intraocular implant.


8. A coated surgical implant according to claim 1 which is a suture.



9. A coated surgical transplant according to claim 1 which is an
organ transplant.


10. A coated surgical transplant according to claim 1 which is a heart
transplant.


11. A coated surgical transplant according to claim 1 which is a kidney

12

transplant.


12. A coated surgical transplant according to claim 1 which is a lung
transplant.


13. A coated surgical transplant according to claim 1 which is a skin
transplant.


14. A coated surgical transplant according to claim 1 which is a
surgical graft.

13

Note: Descriptions are shown in the official language in which they were submitted.


B~CKGROUND OF THE INVENTION
The use of "active" chondroitin sulfate A and C~ and mixtures of these
drugs are known for use in the treatment of a variety of cardiovascular
diseases and as preventative therapy for these diseases. These drugs including
their method of production are described in Morrison United States Patent
No. 3,895,106 and 3,895,107 issued July 15, 1975.
It has now been discovered that "active" chondroitin sulfate A,
"active" chondroitin sulfate C, and mixtures thereof, have a unique and very
different therapeutic use. It has been reported in the literature in numerous
instances that organ Of tissue transplants are subject to rejection by the
human host. This problem is also present to a degree in relation to inanimate
implants such as tooth implants, hip prosthesis, intraocular implant, heart
valve, etc. It is generally believed that the transplant rejection phenomena is
; associated with the immune system of the body and/or physiologic processes or
surgical procedures. The immune system recogni~es the transplanted tissue as
foreign and produces antibodies which attack the object foreign to the human
host. Surgical failure and physiologic failure may be related to mechanical
tissue damage, clotting with decreased blood flow, etc. Various approaches have
been followed in attempting to diminish or eliminate the rejection or failure
problem.




-- 2 --




1 We have found that "active" chondroitin sulfate A, "active"
2 chondroitin sulfate C, or admixtures of the drugs seems to signi-
3 ficantly reduce the tendency of the human body to reject trans-
4 plants and increase the acceptance of implants.
The rejection of implants is due to additional factors
6 including direct mechanical injury to adjacent tissues, devascu-
7 larization of tissues with resultant poor oxygen supply, tissue
8 unacceptance of the foreign body whether due to direct lack of
9 adherence of adjacent cells, lack of proper electrostatic forces,
or poor regeneration of tissues.
11 The coating of the foreign bodies and/or host treatment
12 with the drugs of this invention reduces rejection and may result
13 in better acceptance of the implant by the surrounding tissues.
14 It is believed that this development represents a signi-
ficant advance in this area of therapy.
16 The coating of surgical instruments will reduce direct
87 tissue damage resulting from contact with these instruments. Like-
wise, the coating of indwelling catheters or needles will reduce
19 mechanical damage to contiguous endothelial cells within the vascu-
O lar channel.
21 It is believed that this development represents a signi-


24 nt advance in this area of therapy.
2256




27
28


SU~ARY OF TIIE INV~NTION
Briefly, the present invention comprehends a method which comprises
the administration of an effective amount ot "active" chondroitin sulfate A,
"active" chondroitin sulfate C, or mixtures thereof to humans just prior to, dur-
ing, and/or following the transplantation or implantation into the body of
tissue or organs from the same or another human or animal, and inanimate pro-
sthetic and orthopedic devices, surgical instruments and the like, to mitigate
rejection or failure of the transplant or implant.
It is an object to provide a new mode of therapy.
It is also an object of my invention to provide a new and improved
therapy for combating the problem of rejection, and stimulating and promoting
acceptance of both living and inanimate transplants or implants on the human
body.
More particularly, it is an object of this invention to provide a
significant new mode or use of the drugs known as "active" chondroitin sulfate
A, "active" chondroitin sulfate C and combinations of these drugs.
As used herein, the term "transplant" or "transplantation" refers to
the grafting of tissue taken from the same or another person. More specifically,
it refers to the operation of transplanting or of applying to a part of the body
tissues taken from another body or from another part of the same body. This
invention covers the full ar-ay of such procedures and is particularly used in
heart, kidney, lung and skin transplants. The term "implant" or "implantation"
means the placement within the body tissues of a foreign, usually inanimate sub-
stance. A hip joint


ll~t3~,~4 ' ~
1 mechanical heart valve, surgica:L staples and intraocular lens are
2 examples. The implanting of pi~ tissue into humans for heart valve
3 reconstruction is also contemplated by this invention, whether re-
4 garded as an implant or a transplant. The "implant" need not be
permanent~ Thus, the term "implant" herein is broader than in the
6 conventional sense and includes the use of the drugs to coat surgi-
7 cal instruments just prior to their temporary use in the human body.
8 An indwelling catheter or needle can be beneficially coated with the
9 drugs prior to placement into the patient. Likewise, IV tubing,
sutures and even surfical instruments. The coating of implants
11 such as titanium rods to act as a bone, and mechanical metal knee
12 and hip joints is of considerable value. As used herein, a "pros-
13 thetic" device refers to any artificial substitute for a missing
14 part, as denture, hand, leg or eye.
While not bound by any theory, it is believed that the
16 present invention improves the implantation of inanimate devices by
17 virtue of the fact that the drug has a negative electrical charge
18 and the implants bear a positive surface charge. The hypothesis
19 is that the drugs lead to the neutralization of the positive charge
or create a resultant negative charge which provides for less
21 damage to contiguous cells or tissues. Another likely factor is
22 the lubricating properties of the drugs which seem to increase com-
231 patability of the implant with the surrounding living tissues and
241 prevents direct mechanical cell damage. The lubricating properties
of the drugs via direct application to intraperitoneal surfaces or
26 structures at the time of abdominal surgical procedures may reduce
27 the occurrence of post-operative adhesions.
28 These and other objects and advantages of this invention
29 will be apparent from the more detailed description which follows.


~ t~




DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is applicable to the transplantation, human-to-
-human, animal-to-human, of all organs and tissues including kidney, heart,
lungs, skin, etc. It also appears to be useful in cases of re-attachment of
tissues or organs such as in cases requiring the re-attachment of the cornea or
retina.
The drug can be administered beginning three to four days prior to the
transplantation or implant and can usefully be continued for weeks, months, or
even years thereafter. In any case, the drug would be administered essentially
concurrently with transplantation. The mode of administration is by injectible
aqueous solution, orally, or the like. The administration in the case of major
organ transplant is intra-peritoneally, intravenously or orally or powder, oint-
ment, eye drops, as an aqueous solution. The dosage would be an effective
amount on the order of 0.1 to 10 or more grams per 24 hour period.
It is also beneficial to soak, infuse, coat or incubate the transplant
or implant, that is, the skin, heart, kidney or lung or artificial, synethetic
devices with the drug just before transplantation or implant in the human recipi-
ent.
In the case of inanimate implants for the eye or joints such as intra-

ocular lens, tooth implant, knee implant, orthopedic plates or pins, hip pro-
sthesis, the inanimate transplant or implant, can be beneficially coated with
the drug just prior to placement in the hunlan body, and fortified periodically
by local applications or injections and the like of the "active" drug.
The soaking or coating procedures just described are usually

1~ 4
1 in addition to the more protracted systemic administration of the
2 drug earlier described hereinabove. The solution used to coat is
3 a 1 to 30% by weight of a physiologically compatible, normally
4 aqueous, solution of the drug. The drug can be applied to the eye
in drop form. The drugs can also be combined with conventional car-
6 riers to form a viscOIls ointment and coated onto a skin transplant
7 to mitigate rejection. The drugs used in the practice of this inven _
8 tion are prepared as follows:




EXA~IPLE 1
11
12 One hundred pounds of trimmed bovine trachea was chopped
13 into 1 inch square segments and added to about 50 gallons of de-
14 ionized water in a tank. The pH was adjusted to about 4.5 by addi-
tion of approximately 400 ml of glacial acetic acid. The resulting
16 suspension was agitated while the contents of the tank was raised
17 to about 50C. One and one-quarter pounds of pepsin was added
18 and the agitation continued for 30 minutes. Another 50 gallons
19 of de-ionized water was added to the tank and mild stirring con-
tinued for 12 hours at 50C until the trachealcartilage is freed
21 of connective tissue. The temperature of the suspension is then
22 raised to 80C and 2 fat layer formed on the top of the liquid.
23 The digestion liquor was drained off through a basket centrifuge
24 and discarded.
The remaining solids were twice washed with 50 gallons of
26 hot water (60-80C). A sodium hydroxide solution was prepared
27 by adding 1.5 lbs. of NaOH to 5 gallons of de-ionized water in a
28 tank. The twice washed solids were added to the sodium hydroxide

1 solution, and the volume adjusted with de-ionized water to 12 gal-
2 lons and the pH to 9-10. The contents of the tank was agitated
3 for 12 hours at 37C. The pH was then adjusted to 6.5 with
4 glacial acetic acid. The liquid was heated to boiling and then
5 permitted to cool. The liquid was filtered through a basket
6 centrifuge and the filtrate collected and retained. To the
7 retained filtrate was added 1.5 pounds of cetyl pyridinium chloride
8 followed by stirring for 30 minutes. The liquid was allowed to
9 stand for 16 hours. A precipitate form The supernatant was
10 decanted and the precipitate collected by continuous centrifugation
11 in a Sharples centrifuge. The collected precipitate was in 5
12 gallons of 0.5N sodium hydroxide. Ten gallons of methanol was
13 added and allowed to stand for 12 hours at room temperature. The
14 precipitate formed was again collected by continuous centrifuga-
tion and washed with 5 gallons of methanol. The precipitate was
16 dissolved in two gallons distilled water, the pH adjusted to 7.0
17 with glacial acetic acid and 1/4 pound of sodium chloride was
18 added, followed by stirring. Four gallons of methanol was added
19 and agitation was aarried out for 15 minutes. After standing
for 12 hours at room temperature, a precipitate had formed which
21 was collected by centrifugation. The precipitate was dried under
22 vacuum. Analysis showed the precipitate to be essentially CSA.
23 The material manifested a prolongation of plasma thrombus forma-
24 tion time 6 to 12 hours after administration in rabbits as des-
25 cribed by the Chandler loop method of over 80%.
26¦ A sterile solution suitable for intravenous injection or
27 local applicable is obtained by dissolving 125 mg. of the drug in 2.5
28 ml of USP sterile water for injection. If necessary,the solution canbe

.31. ~
1 finally sterilized by passing it through a sterilizing membrane fil-

2 ter. When donor human skin was soaked for five minutes in this sol-

3 ution and applied to an area of third degree burn, the rejection was

4 reduced.

An ointment containing the drugs is prepared by adding
6 from about 1 to 30% by weight of the drug to a vehicle or carrier

7 which is normally viscous such as petroleum jelly or made viscous
8 by the addition of emulsifiers or thickeners to water~ The vehicle

9 or carrier are usually composed of various mixtures of fats, waxes,
animal and vegatable oils, and solid or liquid hydrocarbons.
11
12 EXAMPLE 2
13
14 One starting material for the preparation of active chon-
droitin sulfate A is bovine trachea. This material is obtained
16 from the slaughter houses as soon as possible after the animals
17 are slaughtered. It is then frozen until processed. In processing,
18 it is trimmed free of tissue and finely ground. This ground tis-
19 sue is defatted with five parts of acetone. Two extractions are
20 made to reduce the fat content to approximately 1 percent or less.
21 The defatted material is dried and re-ground. A 5 percent solution
22 of the latter is made up in a 0.lM calcium acetate buffer containing
2~ 1 percent papain plus 0.005 M cystein hydrochloride and 0.005 M
24 disodium versenate as enzyme activators. The entire-mixture is
25 maintained at 62C + 3C for 24 to 30 hours with gentle stirring.
26¦ Approximately 85 to 95 percent solubilization of the trachea is
271 obtained. This supernatant is decanted and is precipitated with
28 two volumes of acetone. The acetone supernatant is decanted.


~ 3~
1 The remaining precipitated material is dissolved in isotonic saline
2 to make a solution of 3-5 percent. To the latter is added a satur-
3 ated solution of potassium permanganate in 2 to 5 ml. portions
4 with constant stirring, adding each portion until the purple color
5 has been totally discharged. Depending on the various raw materials
6 started with, this may take anywhere from 50 to 200 ml. of potas-
7 sium permanganate solution per 6 lbs. of starting raw material.
8 When at the interval between addition and discharge, the color
9 becomes long (sic) (more than 5 minutes), no further permanganate
lO is added. The solution is then allowed to stand overnight to
11 permit flocculation of the manganese dioxide and completion of any
12 reactions. The manganese dioxide is removed either by centrigu-
13 gation or filtration through a coarse filter paper. The mangan-
14 ese dioxide cake is washed with additional isotonic saline. In
15 some cases the addition of a small amount of foma]dehyde or
16 methanol will cause flocculation of manganese dioxide which is
17 then precipitated with one volume of aceton~. The resultant oily
18 precipitate is collected by decantation, the solvent evaporated
19 or the cake dissolved in a minimum amount of water and the final
20 product obtained by lyophilization. It appears on paper chroma-
21 tography to be essentially pure chondroitin sulfate A. Analysis
22 of the product shows a typical chondroitin sulfate A infra-red
23 spectrophotometric absorption curve. Optical rotation determination
24 gives values of (a)D24= -24; nitrogen content, 3.3%.

26
271
28

1 EXAMPL~ 3




3 One starting material for the preparation of active
4 chondroitin sulfate C is shark cartilage. This material obtained
in dry form is ground and defatted with three to five parts
6 acetone. One extraction is usually sllfficient. This extracted
7 shark cartilage is then treated as indicated above for the dried
8 bovine trachea after the defatting stage.
9 The drugs prepared as in Example 2 and 3 are usePul in al~
of the procedures described hereinabove.
11 Having fully described the invention, it is intended that



13 it be limited only by the lawful scope of the appended claims.
14




18
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Admin Status

Title Date
Forecasted Issue Date 1984-12-11
(22) Filed 1981-11-02
(45) Issued 1984-12-11
Expired 2001-12-11

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1981-11-02
Current owners on record shown in alphabetical order.
Current Owners on Record
BIOMED RESEARCH, INC.
Past owners on record shown in alphabetical order.
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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Date
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Drawings 1993-12-17 1 7
Claims 1993-12-17 2 31
Abstract 1993-12-17 1 17
Cover Page 1993-12-17 1 13
Description 1993-12-17 10 371