JP3510311B2 - Organ preservative - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an organ preservative and a protective agent containing (±) -N, N'-propylenedinicotinamide (generic name: nicarbaben) as an active ingredient.

[0002]

2. Description of the Related Art It has been conventionally known that various drugs have organ-preserving or protecting effects (for example, Japanese Patent Publication No.
-502819, JP-A-62-267233, JP-A-64-20, JP-A-3-72423, JP-A-3-101621, and JP-A-5-434.
63, etc.).

In particular, in Japanese Unexamined Patent Publication (Kokai) No. 3-101621, N- (2-hydroxyethyl) nicotinic acid amide nitrate (generic name: nicorandil) having a hydroxyl radical scavenging action can be used as an organ preservative and protective agent. It is stated to that effect.

On the other hand, nicarabene is known to be useful as an antithrombotic agent, antiarteriosclerotic agent and vasospasm inhibitor (Japanese Patent Publication No. 61-55911), but it shows an organ-preserving action or a protective action. Has not been reported so far.

[0005]

Various drugs which have been conventionally known to have organ-preserving or protective effects are not sufficient in activity, and even if they have some activity, side effects of the drug itself. Many of them have problems in terms of stability and stability, and most of them have not been put into practical use as pharmaceuticals.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to solve these problems, surprisingly, Nikarabene has solved these problems and has an excellent organ preservation and protection effect. The present invention has been completed and the present invention has been completed.

[0007] Nicarabene, which is an active ingredient of the organ preservation and protective agent of the present invention, is a known compound, for example, Japanese Examined Patent Publication No.
It can be synthesized by the method described in 1-55911.

The organs for which the preservatives and protective agents of the present invention are used are all human and animal organs, such as human and animal hearts, kidneys, pancreas, lungs and livers. The agent of the present invention is used by adding it in a preservation solution or a perfusate in order to minimize the damage to the organ removed from the organ donor (donor) during the organ transplant surgery. be able to.
It can also be administered to transplant patients as an organ protective agent for suppressing or preventing rejection after organ transplant. Furthermore, when the preservative of the present invention is used, the excised organ can be preserved without deterioration, and the function of the organ can be maintained until after transplantation. When organs are to be removed and stored for the purpose of transplantation, it is effective to administer the nikaraben preparation of the present invention to a donor in advance and allow a certain amount of nikaraben to be present in the organ cells in advance.

When the agent of the present invention is used as an organ preservative and a protective agent, nicarabene may be added to the preservative or perfusate in its original form or in various solvents capable of uniformly dissolving or dispersing nicarabene. It can be added as a solution or suspension.

As the solvent for the above purpose, for example, alcohols such as ethanol, propylene glycol, glycerin and polyethylene glycol, water, physiological saline, triacetin and the like, and a mixture thereof at any ratio are preferable. These solutions and suspensions can be sterilized by appropriately performing treatments such as filtration through a bacteria-retaining filter, heat sterilization, blending of a bactericide or irradiation. Alternatively, an aseptic drug substance or a solid preparation may be produced, and the aseptic solvent may be added just before use.

When nicarabene is used as an organ protective agent for suppressing or preventing rejection after organ transplantation, it is orally or rectally, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, etc. , Parenterally, but preferably by oral or intravenous administration.

For oral administration, solid or liquid preparations can be prepared. Examples of solid preparations include tablets, pills, powders and granules. Such a solid preparation may be prepared by mixing the active ingredient, nikaraben, with at least one pharmaceutically acceptable carrier, for example, sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, carboxymethyl cellulose and the like. it can. The formulation operation is carried out by a conventional method, but additives for formulation other than the above, for example, lubricants such as calcium stearate, magnesium stearate and glycerin may be contained.

Liquid formulations for oral administration include, for example, emulsions, solutions, suspensions, syrups or xyls. In these formulations, generally used pharmaceutically acceptable carriers such as water or liquid paraffin, and oily bases such as coconut oil, fractionated coconut oil, soybean oil and corn oil can be used.

Formulations for oral administration include solid formulations such as those described above, eg, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,
Formulated as an enteric preparation by spraying a solution of an enteric substance such as polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer or methacrylic acid-methyl methacrylate copolymer in an organic solvent or water to form an enteric coating. You can also Enteric coated solid preparations such as powders and granules can be encapsulated.

The pharmaceutically acceptable carrier includes, if necessary, auxiliary agents, fragrances, stabilizers or preservatives which are usually used if necessary.

Liquid powder formulations may also be administered in capsules made of an absorbable material such as gelatin.

Solid preparations for rectal administration include suppositories containing nicarabene and manufactured by a method known per se.

The preparation for parenteral administration can be used as a sterile aqueous or non-aqueous solution, suspension or emulsion. Non-aqueous solutions or suspensions are pharmaceutically acceptable carriers with, for example, propyl glycol, polyethylene glycol or vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizing agents. These solutions, suspensions and emulsions can be sterilized by, for example, appropriately performing treatments such as filtration through a bacteria-retaining filter, addition of a bactericide or irradiation. In addition, a sterile solid preparation can be produced and used by dissolving it in sterile water or a sterile injectable solution immediately before use.

Examples of the dosage form for transdermal administration include ointments and the like. These are molded by a usual method.

When used as an organ protective agent of the present invention, the amount used varies depending on the type of organ, difference in simple preservation or perfusion preservation, and condition of transplanted organ, weight, etc.
Normal storage or perfusate concentration is 10 ^{-12 -10 -2} mg
It is used in the range of / ml, preferably in the range of 10 ^-5 to 10 ^-3 . When this drug is used as an organ protective agent for suppressing rejection after organ transplantation, it varies depending on the condition of the subject to be administered, age, sex, weight, administration route, etc. It can be administered in an amount of 100 mg / kg / day.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0022]

[Example] SD male rats (around 350 g) were anesthetized by intraperitoneal injection of pentobarbital 50 mg / kg, and a midline abdominal incision was made, followed by a catheter (0.26 m) in the right ureter.
1, 0.61 ml) was inserted. Next, heparin saline was injected from the vein, a catheter (22G) was inserted into the right renal artery, and then 10 ml of heparin saline was initially perfused. Immediately UW solution (Wisconsin University)
It was perfused with 20 ml and the kidney was removed. The excised kidney was immersed in a preservative solution containing UW solution and stored by cooling at 4 ° C for 48 hours. After storage, an isolated renal perfusion device (KN-8 manufactured by Natsume Seisakusho)
Isolated kidney perfusion (IPK = Isolat)
ed Perfused Kidney) was performed for 90 minutes. Perfusion and urine output were measured at 30 minute intervals. A part of perfusion rate and urine volume was used as data for biochemical examination. 2 experimental groups
In group I, after incision of the abdomen, 3 mg of nicarabene was intravenously injected into the rats, and 10 minutes later, 28 mg of nikaraben was added to UW solution /
The kidney was perfused with a perfusate containing 100 ml of the perfusate, and stored by cooling. In group II, saline was injected intravenously after abdominal incision, and after 10 minutes U
The kidney was perfused with the W solution and stored by cooling. The results are shown in Tables 1-5.

[0023]

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[0024]

INDUSTRIAL APPLICABILITY Nicarabene is extremely useful as an organ preservative and an organ protectant because it not only exhibits excellent organ preservation and protection effects but also has no particular side effects or stability problems.

Continuation of front page (56) Reference JP-A-3-279328 (JP, A) JP-A-3-81222 (JP, A) JP-A-56-75474 (JP, A) JP-A-60-61501 (JP , A) JP 62-67001 (JP, A) JP 3-101621 (JP, A) JP 55-76814 (JP, A) JP 61-502819 (JP, A) US Pat. (US, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A01N 1/02 A61K 31/455 CA (STN) CAOLD (STN) REGISTRY (STN) MEDLINE (STN)

Claims (2)

(57) [Claims] 1. An organ preservative containing (±) -N, N′-propylenedinicotinamide as an active ingredient. 2. Pre-organ transplant and viscera containing (±) -N, N'-propylenedinicotinamide as an active ingredient .
Protective agent of transplanted organs after the vessel transplantation.