FR2505656A1 - THERAPEUTIC COMPOSITION BASED ON ACTIVE AND / OR C CHONDROITI SULFATE - Google Patents

Abstract

THIS INVENTION RELATES TO A THERAPEUTIC COMPOSITION TO AVOID OR REDUCE THE RISK OF REJECTION OR FAILURE OF THE TRANSPLANT OR IMPLANT, DURING TRANSPLANTATION OR IMPLANTATION IN THE BODY OF TISSUE OR ORGANS FROM THE SAME HUMAN OR ANIMAL OR OF A DIFFERENT HUMAN OR ANIMAL, OR INANIMATE PROSTHESES OR ORTHOPEDIC DEVICES, OR SURGICAL INSTRUMENTS, ETC., CHARACTERIZED IN THAT IT CONTAINS AS ACTIVE INGREDIENT OF CHONDROITINE SULFATE A OR ACTIVE CHONDROITINE SULFATE C OR THEIR MIXTURE, IN A FORM SUITABLE FOR INTRAVENOUS OR INTRAPERITONEAL INJECTION OR FOR DIRECT APPLICATION TO PERITONEAL STRUCTURES OR FOR COATING OF THE TRANSPLANT OR IMPLANT.

Description

The use of chondroitin sulfate "ac-

  tif "A and C, and mixtures of these drugs is fine

  known in the treatment of various cardiovascular disorders-

  and as a preventive therapy for these

  These drugs, including their production process, are described in U.S. Patents Nos. 3,895,106 and No. 3,895,107.

  production of these drugs is described in the application

  Patent Application No. 82,045 of the United States of America

  October 5, 1979 and No. 118 211 of February 4, 1980.

  We have now discovered that "active" chondroltin sulfate A, chondroitin sulfate

  "active" C, and their mixtures have therapeutic applications

  remarkable and very different canics It has been in-

  stated in the literature that in many cases organ or tissue transplants are susceptible

  rejection by the human recipient This problem is also

  present to some degree with inanimate implants such as dental implants, hip prostheses, intraocular implants, heart valves, etc. It is generally assumed that

  transplant rejection is associated with the system

  immune system of the body and / or physiological processes

  or surgical processes The immune system recognizes

  the transplanted tissue is born as foreign and produces antibodies which attack the foreign object to the recipient

  human These surgical and physiological failures

  which may be associated with mechanical damage

  tissue nick, clotting with decreased blood flow, etc. We have tried various ways to reduce

  or eliminate the rejection or failure problem.

  It has been found that "active" chondroitin sulfate A, "active" chondroitin sulfate C, or

  mixtures of these drugs seemed to reduce noticeably-

  the tendency of the human body to reject transplants

  and increase acceptance of implants.

  Rejection of implants is due to others

  factors including direct mechanical damage to tissues

  adjacent, devascularization of the tissues resulting in a poor supply of oxygen, rejection by the tissues of the foreign body is due to a direct lack of adhesion of the adjacent cells, a lack of strength

  clean electrostatic or poor regeneration

tion of tissues.

  The coating of foreign bodies and / or the

  treatment of the recipient with pre-

  sente invention reduce rejection and can lead to better acceptance of the implant by surrounding tissue. Development is believed to represent

  significant progress in this area of Therapeuti-

  than. Coating of surgical instruments reduces tissue damage from contact with instruments. Likewise, coating of catheters

  or implanted needles reduces mechanical damage

  contiguous endothelial cells of the vas canal

  cular. This development is believed to represent

  significant progress in this area of therapy

than.

  In short, the present invention provides a

  a process which comprises the administration of an effective amount

  effective "active" chondroitin sulphate A, "active" chorin 3 roîtin sulphate C or mixtures thereof

  human beings just before, during and / or after trans-

  planting or implanting in the body of tissues or organs from the same human or animal, or from different humans or animals, and inanimate prosthetic or orthopedic devices, instruments

  surgical, -etc, to reduce rejection or de-

transplant or implant bankruptcy.

  The object of the invention is to provide a new

calf mode of therapy.

  The invention also proposes to provide a new and improved therapy to tackle the problem of rejection, and to stimulate and promote acceptance by the human body of living and inanimate transplants or implants. More particularly, the present invention

  aims to provide a new important application

  drugs known as chond sulfate

  "active" droltine A, "active" chondroitin sulfate C and

  combinations of these drugs.

  As used herein, the terms "transplants" or "transplantation" refer to the

  transplant of tissue taken from the same person or from a person

  sounds different More specifically, it designates the o

  transplantation or application of part of the body tissue taken from another body or from another part of the body of the same person

  invention covers all of these processes and is par-

  particularly used in heart and kidney transplants,

  of lung and skin The term 'implant' or 'implant-

  "refers to the placement in the tissues of the

  body of a foreign substance, usually inanimate.

  A hip joint, a mechanical valve of the

  heart, surgical staples and an intra-lens

  ocular are examples The implantation of pig tissue in human beings for the reconstruction of a

  heart valve is also considered by the present

  the invention, either as an implant or as

  transplant The "implant" is not necessarily per-

  manent Thus, the term "implant" in the sense of this met-

  moire is more extensive than in the usual sense and-encompasses

  the use of drugs used to coat ins

  surgical instruments just before their temporary use in the human body An implanted catheter or needle can advantageously be coated with drugs just before placement on the patient. The same is true for IV tubes, sutures and even surgical instruments. coating or coating implants such as titanium rods used as bone and metal knee or hip joints is of considerable importance As used in this specification, the term device prosthesis "means

  any artificial substitute replacing a missing part

  te, for example teeth, hand, leg or an eye.

  Although she does not wish to bind herself by a

  any theory, the Applicant believes that the pre-

  sente invention improves the implantation of ina-

  nimés due to the fact that the drug has a

  negative electrical charge and the implants carry a charge

  Positive superficial age It is assumed that the drugs lead to neutralization of the positive charge or create a resultant negative charge which causes a

  less damage to contiguous cells or tissues.

  Another favorable factor is the lubrication properties of the drugs which seem to increase the compatibility of the implant with neighboring living tissues and prevent direct mechanical damage to the

  cells The lubricating properties of drugs

  by direct application to surfaces or structures

  intraperitoneal tures at the time of surgical processes

  gics of the abdomen can reduce the appearance of

post-operative energies.

  These and other objects of the invention

  will emerge from the detailed description which follows.

  The present invention applies to the trans-

  planting, from one human being to another, from one animal to a human being, of all organs and tissues including

  kidney, heart, lungs, skin, etc. It seems

  can also be useful in the case of fabric fixation

  known or organs, for example in cases requiring

  re-bonding of the cornea or retina.

  the drug can be administered in combination

  leading three to four days before transplantation and can advantageously be used for weeks, months or even years thereafter In any case, the drug is administered essentially simultaneously with transplantation The mode of administration is by aqueous solution for injection , orally,

  etc. Administration in the case of gold transplants-

  more important ganes is done intraperitoneally, intravenously, orally, or in the form of powder, ointment,

  eye drops, or aqueous solution The poso-

  logy is an effective quantity of the order of 0.1 to 10

grams or more per 24 hours.

  It is also beneficial to dive,

  fusing, coating or incubating the transplant or implant, i.e. the skin, heart, kidney or lung or

  artificial devices of synthesis with the medicin-

  just before the transplant or the implant in the

human body.

  In the case of inanimate implants for the eye

  or the joints, for example an intra-

  ocular, dental implant, knee implant, orthopedic plates or pins, prosthesis

  hip, inanimate transplant or implant can

  be coated with the medication just before mid-

  takes place in the human body, and periodically strengthened

  only by local applications or injections,

etc of the "active" drug.

  The immersion or coating that we just

  describe are usually performed in addition to the admin-

  delayed systemic administration of the drug being

  just described The solution used for the coating

  ment is an abnormally aqueous solution, physiologically compatible to 1 to 30% by weight of the drug The drug can be applied to the eye in the form of drops The drugs can also be combined with

  conventional supports to form a viscous ointment

  and be applied to a skin transplant to re-

  duire rejection The drugs used in the implementation of the present invention are prepared as follows:

EXAMPLE 1

  We cut 45.5 kg of beef trachea trimmed into sections of 6.45 cm 2 which are added to about 190 liters of deionized water contained in a container The p H is adjusted to about 4.5 by addition of about 400 ml of glacial acetic acid The resulting suspension is stirred while the contents of the container are brought to about 50 ° C. 0.567 kg of pepsin are added and stirring is continued for 30 minutes A further 190 liters are added of deionized water in the container and continue agitation gently for 12 hours at O'C until the tracheal cartilage is de-

  barred of connective tissue The temperature of the sus-

  pension is then brought to 80 C and a layer of fertilizer-

  is formed on the surface of the liquid The liquor of

  management flows through a basket centrifuge

and is thrown away.

  The remaining solids are washed

  twice with 190 liters of hot water (60-80 "C) One so-

  sodium hydroxide solution is prepared by addition

  from 0.680 kg of Na OH to 19 liters of deionized water

  naked in a container Solids washed twice are

  added to the sodium hydroxide solution, and the volume

  is adjusted to 45.5 liters with deionized water and the p H at 9-10 The contents of the container are stirred for 12 hours at 37 ° C. The p H is then adjusted to 6.5 with

  glacial acetic acid The liquid is heated to

  boiling, then allowed to cool The liquid is filtered

  in a basket centrifuge, the wire is collected

  trat et Onl le garde Add 0.680 kg of cetylpyridinium chloride to this filtrate, then stir for

  minutes The liquid is left to stand for 16 hours.

  A precipitate is formed.

  supernatant liquor and the precipitate is collected by cen-

  continuous trifugation in a Sharples centrifuge.

  The precipitate collected is dissolved in 19 liters of 0.5N sodium hydroxide. 38 liters of methanol are added and

  it is left to stand for 12 hours at the am-

  biante The precipitate formed is again collected by

  continuous centrifugation and washed with 19 liters of metha-

  nol It is dissolved in 7.56 liters of distilled water, the p H is adjusted to 7.0 with glacial acetic acid and

  0.113 kg of sodium chloride is added, followed by stirring.

  15 liters of methanol are added and the mixture is stirred for 15

  minutes 12 hour rest at room temperature

  biante, a precipitate is formed which is collected by cen-

  trifugation The precipitate is dried under vacuum Analysis reveals that the precipitate is essentially

  chondroitin A (CSA) The material manifests a prolonga-

  plasma thrombus formation 6 to 12 hours a-

  close administration to rabbits as described by the

  Chandler's loop method, more than 80%.

  A sterile solution suitable for injection

  intravenous or local application is obtained

  by dissolving 125 mg of the drug in 2.5 ml of sterile water

  the quality of Codex for injection Possibly, the solution can be finally sterilized by passage in a filter with sterilizing membrane When the skin of the human donor is immersed for 5 minutes in this

  solution and applied to the surface of a third burn

  sith degree, rejection is reduced.

  An ointment containing the drugs is

  prepared by adding from 1 to 30% by weight approximately of the

  drug to a vehicle or carrier that is normally

  viscous, for example petroleum jelly or is made vis-

  by adding emulsifiers or thickeners to water The vehicle or support generally consists of various mixtures of fats, waxes, animal oils or

  vegetable, and solid or liquid hydrocarbons.

EXAMPLE 2

  A starting material for the preparation of "active" chondroitin sulfate A is beef trachea This material is obtained from slaughterhouses as soon as possible after the slaughter of animals On

  then freeze it until processing.

  ment, it is trimmed to get rid of the tissues and it is finely ground This ground tissue is degreased with 5 parts of acetone Two extractions are carried out to reduce the fat content to about 1 percent or less The degreased material is dried and ground

  again We prepare a solution at 5 percent of this-

  the material in 0.1 M calcium acetate buffer containing 1 percent papain plus 0.005 M cysteine hydrochloride and 0.005 M disodium versenate as enzyme activators The whole mixture is

  maintained at 62 C + 3 C for 24 to 30 hours with stirring

  moderate tion Solubilization of approximately 95% of the trachea is obtained This supernatant liquor is

  isolated by decantation and is precipitated with two vo-

  lumes of acetone The supernatant acetone liquor is separated by decantation The remaining precipitated material is dissolved in an isotonic saline solution to obtain a solution of 3 to 5 percent A saturated solution of permanganate is added to the latter

  potassium in 2 to 5 ml portions with constant stirring

  aunt, adding each serving until the

  their purple has completely disappeared According to the various

  starting raw materials, it may be necessary to use

  use 50 to 200 ml of permanganate solution

  potassium for 2.72 kg of starting raw material

  that in the interval between the addition and the dis-

  appearance ', the color is slow to disappear (more than 5

  nutes), no more permanganate is added.

  then rest the solution for 16 hours to

  put a flocculation of the manganese dioxide and the a-

  manganese dioxide is removed by centrifugation or filtration using a coarse filter paper The manganese dioxide cake

  washed with additional isotonic saline

  In some cases, the addition of a small amount of formaldehyde or methanol causes a

  flocculation of manganese dioxide which is then pre-

  precipitated with a volume of acetone The resulting oily precipitate is collected by decantation, the solvent is evaporated or the cake is dissolved in an amount

  minimum of water, and the final product is obtained by lyo-

  philisation It appears by chromatography on the pa-

  pier it is Ytine A chondro sulphate

  partially pure Analysis of the product reveals a curve

  typical spectrophotometric absorption in the infrared

  red corresponding to chondroitin sulfate A The determination of the rotary power gives values of

(a) D = -24; nitrogen content, 3.3%.

EXAMPLE 3

  A starting material for the preparation of "active" chondroitin sulfate It is shark cartilage This material obtained in dry form is ground and degreased with 3 to 5 parts of acetone An extraction is generally sufficient This extracted shark cartilage is then treated as shown above for

  beef trachea dried after the degreasing step -

  ge. The drugs prepared as in Examples 2 and 3 are useful in all processes

described above.

Claims (6)

  1 Therapeutic composition to avoid or reduce the risk of rejection or failure of the transplant or implant, during transplantation or implantation in the body of tissues or organs from the same human or animal or from a human being or of a different animal, or of prostheses or inanimate orthopedic devices, or of surgical instruments, etc., characterized in that it contains, as active ingredient, active chondroitin sulfate A or active chondroitin sulfate C or their mixtures under one   form suitable for intravenous injection or-   intraperitoneally or for direct application to struc-   peritoneal or transplant coating or the implant.   2 Composition according to claim 1, ca-   characterized in that it is presented in a form   suitable for intravenous injection.   3 Composition according to claim 1, characterized in that it is presented in a form suitable for intraperitoneal injection or   direct application to peritoneal structures.   4 Composition according to claim 1, ca-   characterized in that it is presented in a form   suitable for coating trans-lant or   ir Lr Dlant just before placement in the re- human dreamer.   Composition according to Claim 1, characterized in that it is used in the form of a sterile solution.   6 Composition according to claim 1, ca-   characterized in that it is used in the form of an aqueous solution.   il 7 Composition according to claim 1, characterized in that it is used under the form of an ointment.   8 Implant or transplant coated with a colposi- tion according to claim 1.