PT95230B - USING RAPAMICINE AND / OR ITS DERIVATIVES AND / OR ITS DERIVATIVES AND / OR PRE-PHARMACIES IN THE PRODUCTION OF PHARMACEUTICAL COMPOSITIONS FOR INHIBITING THE REJECTION OF TRANSPLANTS OF ORGAOS OR FABRICS IN MAMMALS. - Google Patents

Abstract

The invention relates to the process for the preparation of pharmaceutical compositions to prevent the rejection of organ or organic tissue transplants in a mammal which needs said transplant, comprising the mixing of at least [3S-[3R*(1R*, 3S*, 4S*)] 6S*, 7E*, 9S*, 10S*, 14R*, 15E*, 17E, 19E, 21R*, 23R*, 26S*, 27S*, 34BR*]]-9, 10, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 32, 33, 34, 34B-hexadeca- hydro-9,27-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo- hexyl)-1-methylethyl]-10, 21-dimethoxy-6,8, 12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-C][1,4]oxazacyclo- hentriacontino-1,5,11,28,29(4H,6H,31H)pentone (rapamycin), of the formula <IMAGE> and/or one of the derivatives thereof and/or pre-drugs thereof, if necessary with one or more other chemotherapeutic agents which also act as inhibitors of the rejection of organ and tissue transplants, with pharmaceutically acceptable vehicular and/or auxiliary substances, in a proportion preferably between 0.01 and 15% by weight of active ingredient. The scope of the invention also embraces a process to prevent the rejection of organ or tissue transplants in a mammal, which involves the administration to said mammal of a) a quantity of rapamycin, in combination with b) a quantity of one or more other chemotherapeutic agents in order to inhibit the rejection of the transplant, for example azathioprine, corticosteroids, cyclosporin and FK506, the combined quantities of a) and b) being effective for inhibition of transplant rejection and maintenance of this inhibition.

Description

Invention refers to the process for preparing pharmaceutical compositions to prevent trans rejection. organ or organic tissue transplantation in a mammal in need of said transplant, comprising a mixture of at least 23S- / 3R * {1R *> 38 * »43 * 17 63 *, TE *, 9S *, 1OS *, 14R *, 153 *, 17E »19E, 21R * 23R *, 2SS *, 27S *, 34BR * 7J7-9,10,12,13,14,21,22, 23,24,25,20,27,32 , 33,34,34B-bexadeca-hydro-9,27-dihydroxy ~ 3-22- (4-MdrGxi ~ 3-metGxycyl »hexyl) -X ~ m2tylethyl-10, 21-» -diraethoxy-6, 3,12,14,20 »2ó-hexamethyl-23,27-epoxy-3 ^T -pyridoJ%, 1-C7 / 7, 47oxaazacyclo-hentriacontine-1, 5,11,23,29 (4 ^T I» õH, 31H) -pentone (rapamycin) of the formula

and / or one of its derivatives and / or its pre-products, possibly with one or more other chemotherapeutic agents, also act as inhibitors of organ and tissue transplant rejection, with the pharmaceutically acceptable carrier and / or auxiliary substances in a proportion preferably comprised between 0.01 and 15% by weight of active ingredient. The scope of the invention also encompasses a process for preventing the rejection of organ or tissue transplants in a mammal comprising administration to the cytology.

tadc mammal of

a) a rapamycin amount, in combination with

b) an amount of one or more other chemotherapeutic agents to inhibit transplant rejection, for example asathioprine, corticosteroids, cyclosporine and PK50o », the combined amounts of a) and b) being effective in inhibiting transplant rejection and preserving that inhibition .

Technical Field of the Invention

This invention relates to processes for inhibiting organ or tissue transplant rejection in mammals.

More particularly, the invention relates to processes for inhibiting transplant rejection in mammals in a deficient state, comprising administering an amount of rapamycin capable of inhibiting transplant rejection.

History of the Invention

Rejection and infectious complications resulting from immunosuppression treatments are the main causes of organ allograft failure in man, that is, an organ graft made between two genetically different individuals within the same species Home sapiens. In order to minimize the specific side effects of the three effective agents used in clinical practice, namely azathioprine, corticosteroids and cyclosporins, small doses of each are used in the "triple therapy" combination. Of the three agents currently used in this triple therapy, cyclosporine is the most powerful, but has an undesirable side effect of nephrotoxicity in man that can lead to

damage to the kidney structure. Dosages of increased cortieosteroid and anti-lymphocyte, polyclonal or monoclonal antibody compositions are used for the treatment of rejection attacks. Some studies have been carried out to investigate other potenially effective compounds for use as immunosuppressive agents and transplant rejection inhibitors, but to date none have been found to be useful in clinical practice due to their side effects, such as toxicity , lack of effectiveness or a combination of these factors.

Fungal product VK5OS has been reported to have immunosuppressive activity in anisals with organ grafts (Qeliiai, V., et al., Vranaplant. Proe ^, Vol. ΣΧ, nô. 1 Pages 203-214, 1983). Although the immunosuppression activity of VK5C5 has been confirmed, the toxicity in mammals such as rats, pigs and dogs, and in primates, for example baboons, was too severe to be tested and clinical (Collier, B. St 7., ot al., Transplant Proc., Vol. XX, V2.1, figs 225-228, 1983).

It will be useful to discover a compound that has iso-suppression activity that can be used to increase transplant acceptance in a recipient, but that does not give rise to serious toxic side effects typically associated with conventional immunosuppressive therapy, such as those described above.

Rapamycin is a lipophilic macrolide with certain structural similarities to FE50Ó, produced by Streetomyces hygroscopieus with antifungal and antifungal properties (Sehgal, 3.TT. et al., J. Antibiot., Vol. 23, Pages 727-732, 1975, hg. CP, et al., J. Antibiot., Vol. 37, pages 1231-1237, 1584).

Rapamycin has been reported to inhibit two experimental immunopathies, that is, experimental allergic encephalitis and

adjuvant arthritis, and the formation of humoral antibodies (IgV type) Cartel, H.V., et ul., Can. V. 'Physiol Pharmacol., 55: 48-51, 1S77). It has also recently been found that rapamycin inhibits the activation of murine 7 cells, apparently through a mechanism different from both the? V5C $ and the cyclosporine mechanism of action. It was discovered so much

P75O6 as cyclosporine act at an early stage of the immune response blocking the formation of 11-2. Rapamlcin, on the other hand, did not block the formation of IT.-2 but acted at a later stage of the immune response by inhibiting the response of the β line, P cells to growth-promoting lymphokines. (Staruch, E. J., et al., Ghe. Ffaseb tTournal, Vol. 3, V2. 3> abstraet ^ 3411, 1939). In addition, rapamycin was found to block the immunosuppressive effect of PV5G6 but not that of cyclosporin A (Dumont, P.J. et al., The PASUB Journal, Vol. 3, VS. 4, abstraet ^ 5256, 1989). There were teachings or suggestions in this register, however, that rapamycin could or should be used to effectively inhibit tissue or organ transplant rejection in mammals. In addition, these records do not reveal ?, nor do they warn that the tonic side effects associated with ^ VõOó, and other immunosuppressive agents, will not appear equally with the administration of rapamycin as a transplant rejection inhibitor. e® planting operations.

Objectives of the Invention

One of the aims of the invention is to reveal a process of increasing the acceptance of grafts (or inhibiting the rejection of organ or tissue transplants) and mammals by administering an effective compound of low toxicity.

Another objective of this invention is to reduce the toxicity of other conventional chiropractic agents t Λ. 'ί. .

ί · for inhibiting transplant rejection by combining its administration with an effective low toxicity compound.

These and other objects of the invention will become more apparent in the light of the detailed description which follows. Summary of the Invention The present inventor has discovered a process for inhibiting the rejection of organ or tissue transplants and to mammals in need of such treatment, which comprises administering to said mammal an amount of rapamycin in order to inhibit transplant rejection.

the present inventor has also discovered a process of inhibiting tissue or organ transplant rejection in mammals and the state of need of such treatment, which precedes the administration to said mammal (a) a quantity of rapamycin together with (b) an amount of one or more other wanted agents for inhibiting transplant rejection, the amounts of (a) and (b) being effective in inhibiting transplant rejection and maintaining transplant rejection.

Detailed Description of the Invention

All Patents and Literature References are hereby incorporated by reference in their entirety.

The present invention describes a process for inhibiting the rejection of transplanted organs or tissues in mammals in need, comprising administering to said mammal an amount of rapamycin capable of inhibiting transplant rejection.

The present invention further discloses a process for inhibiting organ or tissue transplant rejection in mammals that need it? comprising administering to said mammal an amount of rapamycin effective to inhibit transplant rejection and to maintain inhibition of transplant rejection.

As used here, the term inhibition of organ or tee transplant rejection and the term maintenance of inhibition of transplant rejection referred to the increased acceptance of organ or tee transplant (or decreasing the likelihood of rejection of organ transplants). organ or tissue transplants) involving allografts, that is, transplantation of organs or teeidos from a donor to a recipient, both of the same species (intraspecific), such as Epaio sapiens.

Rapamycin is an antifungal antibiotic that is extracted from a streptomycete, for example Strsptomyces hygroscopiçus. The processes for the preparation of rapamycin are disclosed by Sehgal et al., In U.S. Patents Nos. 3,923,992 and 3 993 749- In addition, the processes for preparing rapamycin monoacyl and diacyl derivatives are disclosed by P.akhít, in American Patent MS. 4,316 325. In addition, Stella et al., In American Attorney T9. 4,650,803 disclose a water-soluble rapamycin prodrug, i.e., rapamycin derivatives which include the following prodrugs: glycinate prodrugs, propionate prodrugs and pyrrolidine-butyrate prodrugs.

The processes and compositions of the present invention include the use of natural and synthetic rapamycin, rapamycin prepared by genetic engineering, and all rapamycin derivatives and prodrugs, such as those described in U.S. Patents HSs. 3,929,992, 3,993,749; 4 316385, and 4 650 303 mentioned above, the content of which is incorporated herein by reference.

the present inventor found that the efficacy of rapamycin in inhibiting transplant rejection, for example, by depressing the mammalian immune system, was

recorded without the appearance of toxic side effects associated with conventional immunosuppressive agents, for example, azathioprine, corticosteroids and cyclosporine. Such toxic side effects include nephrotoxicity, severe leukopenia, thrombocytopenia, Cushing's syndrome and diabetes.

Rapamycin has been found to reduce or inhibit allograft rejection and; mammals, that is, the transplantation of organs or tissues from a donor to a recipient of the same species. Among such organs or transplanted tissues, and illustration, are the heart, liver, kidney, spleen, lung, small intestine, pancreas, skin, and bone mud, or a combination of any of the above.

As used here, the term quantity of transplant rejection inhibition caps ¹ *, refers to the rapamycin (or rapamycin) in conjunction with one or more other chemotherapeutic agents to inhibit rejection. which can be administered to inhibit transplant rejection in mammals and which maintains inhibition of transplant rejection without causing toxic side effects, for example, nephrotoxicity, renal failure, etc. Those skilled in the art will appreciate that dosages or amounts of a transplant rejection inhibiting compound that is administered to an individual. who will undergo, or has already undergone, an organ or tissue transplant will vary according to several factors, including individual characteristics, such as weight, age , and other factors, such as the type of organ or tissue transplanted or to be transplanted.

In one aspect of the present invention, the amount of tissue transplant rejection-inhibiting rapamycin comprises between about 0.5 mg / kg / day and the 50 mg / lg / day crown is preferably in the range between

about 1 to about 5 Eig / fg / day. Subsequent studies indicate that a dose, effective papafflicin therapy for inhibiting rejection comprises between. 0.01 to about 10 mg / kg / day, and preferably in the range of about 0.025 mg / 1 / day to about 5 mg / day / day. ^{í :!} The doses can be administered intermittently, for example, every other day or once every three days. When administered together with a guimiotherapeutic agent or salts to inhibit the rejection of transplanted organs or tissues, the effective therapeutic dose of rananiclna may even be lower & above indicated. In another aspect, the amount of rapamycin capable of inhibiting transplant rejection is administered over a period of from 1 to about 180 days, or eventually over a longer period of time if necessary. Those skilled in the art will recognize that compounds, drugs, agents and the like, for inhibiting transplant rejection, may be administered to a mammal, for example, a human, for an indefinite period of post-transplantation, in some cases throughout the individual's lifetime, provided that the individual is evidently tolerant to the compound, drug, agent, etc., reasonably well, without serious side effects.

Rapamycin can be administered both orally and parenterally, for example »intramuscularly, intraperitoneally, subcutaneously or intravenously» to a mammalian individual.

The preferred route of administration is oral.

According to this invention »rapamycin can be administered in various pharmaceutical furnaces» including forms suitable for parenteral injections, such as sterile aqueous solutions or aqueous dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. In addition »rapamycin can be administered under the

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tablets, dragees, capsules and the like, for convenient oral administration. Rapamycin can be administered in a pharmaceutically acceptable or compatible carrier substance, which includes as a non-limiting example oils, for example, olive oil, alcohols, propylene glycol, and polyethylene glycol, and surfactants, such as the Chemophor EI (BASF), and polysorbate 80,

Another useful feature of the invention resides in the administration of raparicin together with other conventional drug therapies, such as triple therapy, azatriopine (available from Burroughs Wellcome Co., Research riangle lark, EC, under the trademark Imunoran), corticosteroids (available by TTpjofcn Company, Ealamazoo »p

ichigan, under the trademark Solu-íJedrol * j, cyclosporine and cyclosporine A (available from Sandoz Pharmaceuticals,

Past Hanover, Mew-Jersey, under the trademark Sandiaoune ^) 'and also EF5O5, available from Fujisawa xhsrraaceutieals Co., Itd, Osaka, Japan, under the trademark Pujiayoin?). Does it match? rapamycin with such conventional chemotherapeutic drugs or agents for inhibiting transplant rejection, the toxicity of the latter can be advantageously reduced by requiring smaller amounts of such drugs or toxic agents to inhibit transplant rejection in mammals, before or .after transplantation, and also maintain inhibition of transplant rejection.

Thus, the present invention discloses a process for inhibiting transplant rejection in mammals with this need, comprising administering to said mammal of (a) an amount of rapasiein, together with (b) an amount of one or more. other chemotherapeutic agents for inhibiting transplant rejection, the amounts of (a) and (b) being together effective for inhibiting transplant rejection and maintaining re11 inhibition ·

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rejection of transplants. It should be understood that the amounts of (a) or (b) alone may or may not be effective in inhibiting and maintaining transplant rejection. The combination of the two components (a) to (b) _t together, however, is effective in inhibiting and maintaining inhibition of transplant rejection.

Consequently, as used herein, such other "chemotherapeutic agents for inhibiting transplant rejection include, for example, azathioprine, corticosteroids, cyclosporine (and cyclosporine *,), poly- and monoclonal anti-lymphocyte antibodies (0K? 3) and PrbOtb or a combination of any of those mentioned.

The various characteristics of the invention described above, such as the type of organs or tissues that are transplanted, the effective amount for inhibiting transplant rejection and for maintaining inhibition of transplant rejection; the mode or route of administration,, and duration. of the treatment apply to the process of inhibiting the rejection of organ or tissue transplants by administering rapa micina together with or other chemotherapeutic points, to inhibit rejection le transplants, and maintaining inhibition of transplant rejection.

However, it should be understood that such other chemotherapeutic agents can be administered continuously or intermittently with rapamiein. In addition, the route of administration may differ from that used for rapamycin. This means that such other chemotherapeutic agents can be administered parenterally while rapamycin is being administered orally to the mammal.

• The present invention is described below in specific working examples, which are intended to illustrate the invention without limiting its scope.

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Rats: heterotopic allografts of the heart were performed, from a DA donor to PVO recipients. DA and PVC refer to specific mouse species. Rapasicin was administered intramuscularly in olive oil during the first 10 days of the postoperative period, except for Group 5 that only received the drug in the third to sixth days of the postoperative period. Graft survival was observed by daily palpation.

Larger animals: based on initial toxicity studies, two experiments were considered adequate to test whether rapasicin had immunosuppressive activity, namely a short-term dosage in dogs undergoing kidney transplantation, and an indefinite dosage in pigs, which were also subjected to kidney transplantation.

Pigs: In pigs, an orthotopic renal transplantation model was used and culture of lymphocyte mixture ζϊ, ΣΕ »Ο) was performed to check & Mstoineompaílòilidade between donor and recipient. The average survival time for untreated controls is less than 10 days. Rapamycin was administered at a dose of 2 mg / Eg orally, daily, starting on the first day of the postoperative period.

results: Allograft Studies

Ducks:

For the rat, the allograft survival is shown in Table 1.

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; -ντ _Γ ·, Jv '.-- .. 11 J 57 * 70TA DE ΑΙ0 '· ’Π: 3ηΤ03 CARDÍAC03 T ΠΑ-03 C-group 1 ; ^T c. in Calendar of Sois dosage rats ? survival (days) 1 4 50: ng / kg x IGd 75 *, 33 *, 109 (x2) ? 4 10ag /! Cg x 10d 65, 77 »33, 100 3 4 2ng / fcg x IGd 53, 59 »59» 66 4 4 ImgAg x lOd 34, 45 »52, 55 5 4 E, 5mg / kg x lQd 19, 20, 20, 35 / * 5 10mg / 2: g Ú3-S 15 » 15, 19, 19 »21

ν, π. · Ravamicin was administered intramuscularly in olive oil.

(TJsaras-ss suspensions of 18 mg / ml and 10 mg / ml)

Species of mice used: 3A donors, TY- * recipients

-control rejection time (nsslO) - 7.4 days.

Explanation of Eabela 1: You will perform heterotopic cardiac allografts on the neck of rats, from DA donors to EWE recipients using the previously described surgical techniques (TTaron, 1., Acta, ãathol. Ricrgblol. Sancan. 79: 3.66, 1971). Rapamycin was dissolved in ascites in a maximum concentration of 15 mg / ml and was administered daily as an intramuscular injection, according to a dosing schedule ranging between 0.5 mg / ãg and 50 mg / kg for 10 consecutive days, and in the last group 10 mg / kg of ^S o 3 days 6s.

Graft survival was assessed by daily heart palpation.

Rapamiein prolonged graft survival for all doses tested. Although there was some loss of posture, however, it was not as pronounced as that observed when PA506 was administered to rats.

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Dogs

In dogs, dosages at all levels induced vasculitis and for doses above 0.25 mg / kg this led to manifestations so severe that the animals died before the end of the 28-day study. At higher dosages, vasculitis affected the gastrointestinal tract, also interestingly causing thrombocytopenia. Marked depletion of cells occurred in lymphoid tissue, particularly B cells. In the dog, toxicity due to vasculitis, which seems to have a particular predilection for the gastrointestinal tract, makes it possible to ascertain the immunosuppressive effects of the substance in this particular model. These species-specific reactions to rapamycin confirmed similar, unpublished observations by the inventor and his associates.

Pigs

Survival and cause of death are shown in Table 2, with current creatinine values.

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Allograft survival donates pigs receiving rapamycin at 2 mgAg / day orally in days, and current creatinine.

Explanation of Table 2i An orthotopic kidney transplantation with contralateral nephrectomy was performed in the pig, as previously described ÇOalne, R.T. et al., Brit. J. Surg., 59, 969-977 (1972). The donor and recipient pairs were obtained from a litter with different parents and the incompatibilities at the level of higher fististocompatibility complex (MHC) was confirmed by the reaction of the lymphocyte mixture (Bradley, BA, et al., Tis sue Antigene 4: 283-290, 1974) * Rapamiein was administered orally at 2 mg / kg / day dissolved in olive oil, at a concentration of 10 mg / ml.

In the case of pigs, one died of accelerated acute rejection and one died of technical failure. The remaining 8 animals recovered well and there was an initial weight loss of approximately 10%. Subsequently, around 502 days 5 animals developed anorexia, diarrhea and became so ill that it was decided that they should be killed.

Histological examination of these animals revealed that they suffered from interstitial pneumonia, probably due to over-immunosuppression, and this was the reason why they became ill. In addition, renal histology showed no evident rejection, except for a minimal degree in an animal that did not receive the substance for 4 days. Histological examination of the colon in these animals revealed mucosal and submucosal edema but did not reveal vasculitis or ulceration. Therefore, this fact was probably a side effect of the systemic effects of pneumonitis. The remaining 3 animals remained alive, and the dosage was completed as shown in Table 3.

Discussion

Rapamiein showed an immunosuppressive and non-toxic effect in the rat up to the dose of 0.5 mgAg despite the compound being more effective at higher doses.

In the pigs, the results of toxicity studies revealed that the substance was tolerated at a dose of 1 m? Ag with the animals in both cases gaining weight. Histological examination showed colitis, but neither vasculitis nor suggestion was observed. Rapamycin was effective as an immunosuppressive agent, but after about 50 days of continuous dosing at 2 mgΑδ »50 / animals developed interstitial pneumonitis due to over-immunosuppression, and these animals were killed. However, no animal showed any sign of colon ulceration or vasculitis. Consequently, in future studies, controlling blood levels of the substance will be beneficial.

In conclusion, rapamycin is a very effective immunosuppressive agent that can be used to inhibit organ transplant rejection in mammals.

Claims (25)

1 ~. - Process for the preparation of pharmaceutical compositions containing, as active substance, at least 23S- / 3M1B *> 3S *, 4S * 27 6S *, 7B *, 9S *, IOS *, 14R *, 15E *, 1? B, 19E 21R * 23R «, 26S *, 27S *, 34BR * 7_7-9,10,12,13,14,21,22,23,24,25,25, 27,32,33,34,34B- hexadeca-hydro-9,27-dihydroxy-3- / §- (4-hydroxy-3-methoxycyclohexyl) -1-methylethyl7-10,21-dimethoxy-S, 8, 12.14.20.26- hexamethyl-23,27-epoxy-3H-pyrion / 2,1,1-c7jT, £ 7sxaazacyclo-hentriacontine-1 »5,11,28,29 C4H, 6H» 31R) -pentone (rapamycin) and / or one of its derivatives and / or drugs for inhibiting organ or tissue transplant rejection in mammals, characterized by the fact that at least an effective amount is mixed to inhibit organ or tissue transplant rejection in mammals, / 3S - / 3R * (1R *, 3S *, 4S * 17 OS *, 71 *, 9S *, 1OS *, 14R *, 15S *, 17S, 19S, 21R *, 23R *, 2ÓS *, 27S *, 34BR * 7J7 9,10,12,13,14,21,22,23,24,25,26,27, 32,33,34,34B-hexadeca-hydro-9,27-di-hydroxy-3- / 2- (4-hydroxy) -3-flethoxycyclohexyl) -X-methylethyl7 ~ 1,0,21-dimethoxy-o, 8,12,14, 20.26-hexamethyl-23,27 ~ epoxy-3H-pyrido / 2,1-C7 / T, 47oxaazacyclo-hentriacontine-1,5,11,28,29 (4H, 6H, 31H) -pentone (rapamycin) of the formula e / or one of the rapamycin derivatives and / or the prodrugs, with a pharmaceutically acceptable carrier and / or diluent, in a weight ratio of about 0.01 to 15 parts by weight of rapamycin to about 99, 99 to 85 parts by weight of auxiliary ingredients, preferably between 0.1 to 10 parts by weight of rapamycin to 99.9 to 90 parts by weight of auxiliary ingredients, and said mixture will be given the form of presentation corresponding to the intended route of administration . 2?. Process according to claim 1, characterized in that one or more other chemotherapeutic agents which inhibit organ or tissue transplant rejection are used in mixture with rapamycin. 3®. Process according to claim 2, characterized in that said chiropractic agent is chosen from the group consisting of azathioprine, cortieosteroids, cyclosporine, BX50Õ and their combinations. 4 ^g . Process according to one of Claims 1 to 3, characterized in that said pharmaceutical composition is provided with a form of presentation suitable for oral administration. 5®. Process according to claim 4, characterized in that said pharmaceutical composition is given in the form of tablets, sachets, capsules or the like. 6®. Process according to any one of claims 1 to 3, characterized in that the said pharmaceutical composition is given a form of presentation suitable for parenteral administration. 7. The process of claim 6 wherein said pharmaceutical composition is in the form of a sterile injectable aqueous solution or dispersion or of a sterile powder for the preparation of injectable solutions or dispersions. 83 »- Process to inhibit the rejection of transplants of an organ or tissue in a mammal in need of such treatment, characterized by the fact that it comprises the administration to that mammal of an amount of rapamycin that inhibits transplant rejection. 93. The method according to claim 8, characterized in that it comprises the administration of an amount of rapamycin which inhibits transplant rejection, preferably within the range of about 0.5 to about 50 mg Ag of body weight. per day. 10 ^g . Process according to claim 9, characterized in that said amount is between about 1 and about 5 mgAf of body weight per day. 113. The method of claim 8, characterized in that it comprises administering an amount of rapamycin that inhibits transplant rejection, preferably between about 0.01 and about 10 mg / kg of body weight per day. . 123. The method of claim 8 or 11, characterized in that said amount is between about 0.025 and about 5 mg Ag at body weight per day. * ff ff / Ϊ · '' ’íl. 13®. Process according to claim 8, characterized in that the administration of the amount of rapamycin that inhibits transplant rejection takes place over a period of time between 1 and 180 days. Process according to claim 8, characterized in that said rapamycin is administered to the mammal orally. 15 ^? ·. Process according to claim 1, characterized in that the aforementioned rapamycin is administered to the mammal parenterally * 16 ^a . Process according to claim 1, characterized in that it comprises administering to a mammal an amount of rapamycin effective to inhibit transplant rejection and to maintain inhibition of transplant rejection over time. 17®. Process according to claim 16, characterized in that an effective daily dose of rapamycin between 0.5 to 50 mgAg / day is administered. 18®. Process according to claim 17, characterized in that said daily dose is comprised between 1 to 5 mg / kg / day. 19®. Process according to claim 16, characterized in that a daily dose of rapamycin is administered that inhibits transplant rejection in the range between 0.01 and 10 mg / kg / day. 20®. Process according to claim 19, characterized in that the said daily dose is in the range between 0.025 and 5 mg / kg / day, 21 ?. Process according to claim 16, characterized in that said effective daily dose of rapamycin is administered over a period of time from 1 to 180 days. 225. The method of claim 16, wherein the said daily dose of rapamycin is administered to the mammal orally. 23 ?. Process according to claim 16, characterized in that said daily dose of rapamycin is administered to the mammal parenterally. 24 ?. Process according to claims 8 to 23, characterized in that it comprises the administration to the mammal of a) an amount of rapamycin in combination one b) an amount of one or more other chemotherapeutic agents to inhibit transplant rejection, the amounts of a) and b) being administered effective for inhibiting transplant rejection and for preserving that inhibition. 255. The method of claim 24, wherein said chemotherapeutic agent is chosen from the group consisting of azetioprine, corticosteroids, cyclosporine, PK506 and combinations thereof. 26 ’. Process according to claim 25, characterized in that the said effective amount of pamycin is between about 0.5 and about 50 mg / kff / day. 27 ^§ . Process according to claim 25, characterized in that said amount of rapamycin is between 1 and 5 mg / kg / day » 28 ?. Process according to claim 24, characterized in that an amount of rapamycin inhibiting transplant rejection ranging from 0.01 to 10 mg / kg / day is administered. 29 ^. Process according to claim 28, characterized in that the said amount is between 0.025 and 5 mg / kg / day. 30 ?. Process according to claim 24, characterized in that said rapamycin and chemotherapeutic agent or agents are administered to the mammal over a period of time from 1 to 130 days. 31 ?. Process according to claim 24, characterized in that said rapamycin is administered to the mammal orally. 32 ?. Process according to claim 24, characterized in that the said rapamiein is administered to the mammal parenterally.