阅读说明：本技术 包括双膦酸盐的用于预防或治疗慢性同种异体移植物能够障碍的组合物 (It is used to preventing or treating the composition that chronic allograft is capable of obstacle including diphosphonate ) 是由 金范锡 宋承桓 于 2018-04-13 设计创作，主要内容包括：本发明涉及用于预防或治疗慢性移植肾功能障碍的组合物,其包括用作骨质疏松症治疗剂的双膦酸盐。根据本发明,用于预防或治疗慢性移植肾功能障碍的含双膦酸盐组合物对预防和/或治疗慢性移植肾功能障碍(其中组织或器官移植手术后移植组织或器官的功能逐渐降低)是优异的,并因此有望显著提升移植手术后的长期存活率。(The present invention relates to the compositions for preventing or treating chronic transplant renal dysfunction comprising the diphosphonate as osteoporosis treatment agent.According to the present invention, for prevent or treat chronic transplant renal dysfunction containing bisphosphonate compositions to preventing and/or treatment chronic transplant renal dysfunction (function of wherein transplanting tissue or organ after tissue or organ transfer operation gradually decreases) is excellent, and be therefore expected to be obviously improved the long-term surviving rate after transfer operation.)

1. a kind of for preventing or treating the pharmaceutical composition of chronic allograft dysfunction comprising as activity Ingredient: diphosphonate.

2. pharmaceutical composition as described in claim 1, which is characterized in that the diphosphonate is for treating osteoporosis.

3. pharmaceutical composition as claimed in claim 2, which is characterized in that the diphosphonate be it is selected from the group below any one It is or a variety of: Risedronate (Risedronic Acid), ibandronate (ibandronic acid), etidronate (Etidronic Acid), A Lun phosphine Hydrochlorate (alendronic acid), Pamidronate (pamidronic acid), clodronate (Clodronate), Tiludronate (Tiludronic Acid), because How card phosphonate (because of card phosphonic acids), YM 529 (minodronic acid), olpadronate (olpadronic acid) and Neridronic Acid salt (stand Phosphonic acids).

4. pharmaceutical composition as described in claim 1, which is characterized in that the allograft dysfunction be by Caused by the transplanting of any tissue or organ selected from the group below: kidney, marrow, heart, cornea, intestines, liver, lung, pancreas and skin.

5. pharmaceutical composition as described in claim 1, which is characterized in that after described pharmaceutical composition improves transfer operation Long-term surviving.

6. pharmaceutical composition as described in claim 1, which is characterized in that described pharmaceutical composition is suspending agent, powder, particle Agent, tablet, sustained release preparation, injection, ointment or eye drops form.

7. a kind of for preventing or improving the food compositions of chronic allograft dysfunction comprising as activity Ingredient: diphosphonate.

8. food compositions as claimed in claim 7, which is characterized in that the diphosphonate is for treating osteoporosis.

9. food compositions as claimed in claim 8, which is characterized in that the diphosphonate be it is selected from the group below any one It is or a variety of: Risedronate (Risedronic Acid), ibandronate (ibandronic acid), etidronate (Etidronic Acid), A Lun phosphine Hydrochlorate (alendronic acid), Pamidronate (pamidronic acid), clodronate (Clodronate), Tiludronate (Tiludronic Acid), because How card phosphonate (because of card phosphonic acids), YM 529 (minodronic acid), olpadronate (olpadronic acid) and Neridronic Acid salt (stand Phosphonic acids).

10. food compositions as claimed in claim 7, which is characterized in that the graft function obstacle is by being selected from down Caused by the transplanting of any tissue or organ of group: kidney, marrow, heart, cornea, intestines, liver, lung, pancreas and skin.

11. food compositions as claimed in claim 7, which is characterized in that after the food compositions improve transfer operation Long-term surviving.

12. food compositions as claimed in claim 7, which is characterized in that the food compositions are capsule, tablet, particle Agent, powder agent or beverage form.

13. a kind of for preventing or treating the method for chronic allograft dysfunction, comprising: needed to having to treat Object apply pharmaceutical composition as described in claim 1 to 6 is any to prevention or treat chronic allograft The step of dysfunction.

14. method as claimed in claim 13, which is characterized in that described pharmaceutical composition is with daily 0.0001 to 50mg/kg Or 0.001 to 50mg/kg amount is administered to the object.

15. a kind of purposes of the pharmaceutical composition as described in claim 1 to 6 is any, chronic of the same race different for preventing or treating Body graft function obstacle.

16. purposes as claimed in claim 15, which is characterized in that described pharmaceutical composition is with daily 0.0001 to 50mg/kg Or 0.001 to 50mg/kg amount is administered to the object needed with treatment.

17. the food compositions for preventing or improving chronic allograft dysfunction, comprising: making to have to improve needs The object wanted takes in the food compositions as described in claim 7 to 12 is any to prevent or improve chronic allograft The step of object dysfunction.

18. food compositions as claimed in claim 17, which is characterized in that with total food poidometer, the food compositions Diphosphonate containing 0.01 to 15 weight %.

19. food compositions as claimed in claim 17, which is characterized in that the food compositions contain is with every 100mL The diphosphonate that 0.02-10g, the preferably ratio of 0.3-1g are measured accordingly.

20. a kind of purposes of the food compositions as described in claim 7 to 12 is any, chronic of the same race different for preventing or improving Body graft function obstacle.

21. purposes as claimed in claim 20, which is characterized in that with total food poidometer, the food compositions contain The diphosphonate of 0.01 to 15 weight %.

22. purposes as claimed in claim 20, which is characterized in that it is 0.02- that the food compositions, which contain with every 100mL, The diphosphonate that 10g, the preferably ratio of 0.3-1g are measured accordingly.

Technical field

The present invention relates to the compositions for preventing or treating chronic allograft dysfunction comprising is used as The diphosphonate of the therapeutic agent of osteoporosis (osteoporosis).

Background technique

Continue three months or more kidney damages or the state of renal failure is referred to as chronic kidney disease.In such case Under, lasting haemodialysis or peritoneal dialysis are needed, and need kidney transplant to treat to it.In this organ transplant In the case where, due to the allograft dysfunction occurred after transfer operation, renal function often deteriorates again.It is of the same race different Body graft function obstacle is one of organ transplant rejection, may several months generation after the transfer.It is of the same race in generation In the case where allogeneic dysfunction, the deterioration of transplanted kidney, and therefore need to receive continuous peritoneal dialysis again Or haemodialysis.

This allograft dysfunction is broadly divided into acute allograft dysfunction and chronic same Kind allogeneic dysfunction (Ryan J.G et al., Med.Cli.N.Am. (2016) 100:487-503).Acute allogenic is different Body graft function obstacle occurs in after surgery 6 months and with such as hyperacute rejection, thrombosis, urine leakage (urine ) and the symptoms such as Ureteric Obstruction leak.For this purpose, largely the immunosuppressor such as application cortex hormone of aadrenaline have been used as controlling Treatment method.However, the rare a large amount of applications of chronic allograft dysfunction that postoperative several months to the several years slowly occurs Immunosuppressant treatment.Therefore, in the U.S., survival in 1 year is 96%, but the long-term surviving after kidney transplant sharply declines, 5 years Survival is 59% for 81% and survival in 10 years.However, the effective therapeutic agent developed thus is not enough (USRDS data, 2009).Accordingly Ground is developed and is desirable to significantly mention for the effective therapeutic or preventative medicament of chronic allograft dysfunction (Leonardo V.R. et al., Transplantation Rev. (2016) are published the long-term surviving rate of high kidney transplant patients In).

Detailed description of the invention

Technical problem

The present invention is finished to solve above-mentioned the problems of the prior art.It is an object of the present invention to provide one kind to be used for The pharmaceutical composition of prevention or treatment chronic allograft dysfunction comprising the two banks as active constituent Salt.

However, the technical issues of solving through the invention is not limited to the above problem, and those skilled in the art are under It states in description and is clearly understood that unmentioned other problems.

Solution to the problem

Hereinafter, various embodiments described herein is described with reference to the drawings.In the following description, in order to thorough Understand the present invention, elaborates various details, such as concrete configuration, composition, method etc..However, it is possible to none or Some embodiments are realized in the case where these multiple details or in combination with other known methods and configuration.In other feelings Under condition, without describing known method and technology of preparing in particular detail, in order to avoid unnecessarily make the present invention hard to understand.Whole In a specification, the specific spy described in conjunction with the embodiment is referred to the reference of " one embodiment " or " embodiment " Sign, configuration, composition or characteristic include in one or more embodiments of the present invention.Therefore, go out everywhere throughout the specification Existing the phrase " in one embodiment " or " embodiment " is not necessarily meant to refer to identical embodiment of the invention.In addition, In In one or more embodiments, specific feature, configuration, composition or characteristic can be combined in any suitable manner.

Unless being otherwise noted in specification, otherwise all scientific and technical terms used in specification have and the present invention The normally understood identical meanings of person of ordinary skill in the field.

As used herein, term " chronic allograft dysfunction " refers to the transfer operation in tissue or organ The function of the transplanting tissue or organ that occur afterwards gradually reduces, and when referring preferably to 6 months or longer after transfer operation Between the allograft dysfunction that generates.But the term is without being limited thereto, drastically reduces except non-functional.The tissue Or organ preferably can be kidney, marrow, heart, cornea, intestines, liver, lung, pancreas, skin etc., kidney is more highly preferred to.However, institute It states tissue or organ is without being limited thereto, as long as the tissue or organ are transplanting.

As used herein, term " diphosphonate (bisphosphonate) " refers to the analogue for pyrophosphate Compound, and the P-O-P- group of pyrophosphate is substituted by the stable P-C-P- group of enzyme.To on the C atom of P-C-P- group The substitution of hydrogen atom can prepare the diphosphonate with various structural elements and feature.Approval is for clinical known two banks Salt includes: YM 529 (minodronate), Alendronate (alendronate), etidronate (etidronate), clodronate (clodronate), Risedronate (risedronate), Tiludronate (tiludronate), ibandronate (ibandronate), because of card phosphonate (incadronate), YM 529, Ao Pa Phosphonate (olpadronate), Neridronic Acid salt (neridronate), EB-1053 etc., and such diphosphonate is total Therapeutic agent that is well known and being used as osteoporosis.

The present invention provides a kind of for preventing or treating the pharmaceutical composition of chronic allograft dysfunction, It includes the diphosphonate as active constituent.

In embodiments of the invention, the diphosphonate is preferably used for treatment osteoporosis, Yi Jigeng Preferably Risedronate (Risedronic Acid), ibandronate (ibandronic acid), etidronate (Etidronic Acid), A Lun phosphine Hydrochlorate (alendronic acid), Pamidronate (pamidronate) (pamidronic acid), clodronate (Clodronate), Tiludronate (Tiludronic Acid), because card phosphonate (because of card phosphonic acids), YM 529 (minodronic acid), olpadronate (olpadronic acid), how Vertical phosphonate (Neridronic Acid), EB-1053 or the like, and Risedronate (Risedronic Acid), ibandronate (her class's phosphine Acid), etidronate (Etidronic Acid), Alendronate (alendronic acid) and Pamidronate (pamidronic acid) be more highly preferred to. However, the diphosphonate is without being limited thereto, as long as the diphosphonate is for treating osteoporosis.

In another embodiment of the present invention, the allograft dysfunction is by selected from the group below Side effect caused by the transplanting of any tissue or organ: kidney, marrow, heart, cornea, intestines, liver, lung, pancreas, skin etc., and Allograft dysfunction refers to the reduction of the tissue or organ dysfunction transplanted after transfer operation.

In another embodiment of the present invention, described pharmaceutical composition improves after transfer operation 10 years or longer Long-term surviving and described pharmaceutical composition can be configured to diversified forms, including suspending agent, powder, granule, tablet, sustained release Preparation, injection, ointment, eye drops etc..

In the present invention, described pharmaceutical composition can with capsule, tablet, granule, injection, ointment, powder or The form of beverage is characterized and described pharmaceutical composition can be characterized by for the mankind.Described pharmaceutical composition can basis Conventional method is respectively configured to the oral preparation of such as powder, granule, capsule, tablet and aqueous suspension, external preparation, And suppository and aseptic injectable solution, and use.However, described pharmaceutical composition is without being limited thereto.Pharmaceutical composition of the invention is also It may include pharmaceutically acceptable carrier.As pharmaceutically acceptable carrier, adhesive, glidant, disintegrating agent, excipient, Solubilizer, dispersing agent, stabilizer, suspending agent, pigment, flavoring agent etc. can be used for being administered orally；Buffer, preservative, analgestic, Solubilizer, isotonic agent, stabilizer etc. can be used for injection mixture；Matrix, excipient, lubricant, preservative etc. can be used for Local application.The preparation of pharmaceutical composition of the invention can be by mixing it with pharmaceutically acceptable carrier as described above And it prepares in various ways.For example, for being administered orally, described pharmaceutical composition can be formulated into tablet, tablet (troches), the form of capsule, elixir (elixirs), suspending agent, syrup, eye disc (wafers) etc..It is described for injection Pharmaceutical composition can be formulated into the form of unit dose ampoule or multi-dose type.Optionally, described pharmaceutical composition can be matched Solvent, suspension, tablet, capsule, sustained release preparation etc. is made.

Meanwhile as being suitable for preparing the carrier of preparation, the example of diluent or excipient, lactose, glucose, sugarcane can be used Sugar, D-sorbite, mannitol, xylitol, antierythrite, maltitol, starch, Arabic gum, alginates, gelatin, calcium phosphate, Calcium silicates, cellulose, methyl, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, hydroxy benzenes Propyl formate, talcum powder, magnesium stearate, mineral oil etc..In addition, may also include filler, anticoagulant, lubricant, wetting agent, Aromatic, emulsifier, preservative etc..

The administration method of pharmaceutical composition of the invention includes but is not limited to: oral, intravenous, intramuscular, intra-arterial, marrow In interior, dura mater, heart is interior, transdermal, subcutaneous, peritonaeum is interior, intranasal, enteron aisle, local, sublingual or anal route.Oral or parenterally Application is preferred.As used herein, term " parenterally " includes: subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intracapsular (intrabursal), (intrasternal) in breastbone, dura mater be interior, intralesional and intracranial injection or infusion techniques.Of the invention Pharmaceutical composition can also be used for rectal administration in the form of suppository.

Pharmaceutical composition of the invention can be changed, the work including certain compound used based on various factors Property, the age of patient, weight, general health, gender, diet, administration time, administration method, discharge rate, pharmaceutical composition The severity of object and the specified disease that be prevented or treat.The dosage of pharmaceutical composition can according to the situation of patient, weight, The severity of disease, the form of drug, administration method and duration and change, and can be appropriate by those skilled in the art Ground selection.Described pharmaceutical composition can be applied with daily 0.0001 to 50mg/kg or 0.001 to 50mg/kg amount.It can be one day Once or more than a day apply secondaryly.Dosage is not intended to limit the scope of the present invention.Medicine as described in the present invention Compositions can be configured to the form of pill, sugar coated tablet, capsule, liquid, gel, syrup, slurries or suspension.

In addition, the present invention provides a kind of for preventing or treating the food group of chronic allograft dysfunction Close object comprising the diphosphonate as active constituent.

In embodiments of the invention, it is preferable that the diphosphonate is for treating osteoporosis, Yi Jigeng The preferably described diphosphonate be it is selected from the group below any one or more: Risedronate (Risedronic Acid), ibandronate (ibandronic acid), etidronate (Etidronic Acid), Alendronate (alendronic acid), Pamidronate (pamidronic acid), chlorine Phosphonate (Clodronate), Tiludronate (Tiludronic Acid), because of card phosphonate (because of card phosphonic acids), YM 529 (minot phosphine Acid), olpadronate (olpadronic acid) and Neridronic Acid salt (Neridronic Acid), EB-1053 etc..However, the diphosphonate is not It is limited to this, as long as the diphosphonate is for treating osteoporosis.

In yet another embodiment of the present invention, the allograft dysfunction is by selected from the group below Side effect caused by the transplanting of any tissue or organ: kidney, marrow, heart, cornea, intestines, liver, lung, pancreas, skin etc., and Allograft dysfunction refers to the reduction of the tissue or organ dysfunction transplanted after transfer operation.

In yet another embodiment of the present invention, the food compositions improve the long-term surviving after transfer operation, And capsule, tablet, granule, powder, beverage can be formulated as etc..

In the present invention, the food compositions can be used in various foods, for example, beverage, chewing gum, tea, Vitamin complex, healthy replenishers etc., and can be with pill, powder, granule, the shape for being transfused agent, tablet, capsule or beverage Formula uses.Here, for the amount of the diphosphonate in food or beverage, in the case where food compositions of the invention, usually Diphosphonate can be added with the amount of 0.01 to 15 weight % of food total weight, and in the case where healthy beverage composition In, it can be according to 0.02~10g of 100mL, and the amount of ratio of preferably 0.3~1g is added.

Food compositions of the invention may also include the food additives of this field routine, such as flavoring agent, condiment, coloring Agent, filler and stabilizer.In food compositions as described in the present invention, other than making diphosphonate as main component, The ingredient of addition is not particularly limited, and the food compositions may include as traditional food various flavoring agents or Natural carbohydrate etc. is used as supplementary element.The example of natural carbohydrate includes: including such as glucose and fructose Monosaccharide, the disaccharides of maltose and sucrose, dextrin and cyclodextrin polysaccharide etc. conventional sugar, and including xylitol, The sugar alcohol of D-sorbite and antierythrite etc..In addition to above-mentioned flavoring agent, as flavoring agent, it may be advantageous to use natural flavouring (thaumatin, qualities of stevia extract (such as content rebaudioside-A and glycyrrhizin)) and synthetic flavorings (saccharin, A Siba Sweet tea etc.).The ratio of natural carbohydrate is usually every 100mL composition of the invention about 1 to 20g, preferably about 5 to 12g.

In addition to the above ingredients, food compositions of the invention may also include that various nutrients, vitamin, minerals (electricity Solve matter), synthesis condiment and condiment, colorant and the filler (cheese, chocolate etc.) of natural condiment, pectic acid and its Salt, alginic acid and its salt, protective colloid thickener, pH adjusting agent, stabilizer, preservative, glycerol, ethyl alcohol, are used for organic acid Carbonic acid agent in soda etc..These ingredients can be used alone or be applied in combination.Although the ratio of this kind of additive is not It is critically important, but the ratio is generally selected from the range of every 100 parts by weight composition 0 of the invention to about 20 parts by weight.

In addition, the present invention provides a kind of for preventing or treating the method for chronic allograft dysfunction, Including the pharmaceutical composition as described in claim 1 to 6 is any being applied to the object that there is treatment to need to prevention or treatment The step of chronic allograft dysfunction.

In embodiments of the invention, described pharmaceutical composition is in the method with daily 0.0001 to 50mg/kg Or 0.001 to 50mg/kg amount is administered to object.

In addition, the purposes for the pharmaceutical composition that the present invention provides a kind of as described in claim 1 to 6, for preventing or Treat chronic allograft dysfunction.

In one embodiment, described pharmaceutical composition is with daily 0.0001 to 50mg/kg or 0.001 to 50mg/kg's Amount is administered to the object needed with treatment.

In addition, the present invention provides a kind of for preventing or improving the food group of chronic allograft dysfunction Object is closed, takes in the food compositions as described in claim 7 to 12 is any with the object for improving needs including making to prevent Or the step of improving chronic allograft dysfunction.

In embodiments of the invention, with total food poidometer, the food compositions contain 0.01 to 15 weight % Diphosphonate.In another embodiment of the present invention, it is 0.02-10g that the food composition, which contains with every 100mL, It is preferred that the diphosphonate that the ratio of 0.3-1g is measured accordingly.

In addition, the purposes for the food compositions that the present invention provides a kind of as described in claim 7 to 12, for preventing or Improve chronic allograft dysfunction.

In embodiments of the invention, with total food poidometer, the food compositions contain 0.01 to 15 weight % Diphosphonate.In another embodiment of the present invention, it is 0.02-10g that the food compositions, which contain with every 100mL, It is preferred that the diphosphonate of the ratio corresponding amount of 0.3-1g.

Advantageous effect of the invention

According to the present invention, for preventing or treating the combination containing diphosphonate of chronic allograft dysfunction Object is chronic of the same race different caused by gradually decreasing to the function by the transplanting tissue or organ that occur after tissue or organ transfer operation Body graft function obstacle has excellent preventative and/or therapeutic effect, and is therefore expected to after being obviously improved transfer operation Long-term surviving.

Brief Description Of Drawings

Fig. 1 shows that identifying being averaged for entire diphosphonate (bispho) experimental group according to an embodiment of the present invention deposits Motility rate (~300 months) result obtained.

Fig. 2 shows that the long-term surviving rate for identifying Alendronate administration group according to an embodiment of the present invention is obtained Result.

Fig. 3 shows that the long-term surviving rate for identifying etidronate administration group according to an embodiment of the present invention is obtained Result.

Fig. 4 shows that the long-term surviving rate for identifying Pamidronate administration group according to an embodiment of the present invention is obtained Result.

Fig. 5 shows that the long-term surviving rate for identifying Risedronate administration group according to an embodiment of the present invention is obtained Result.

Fig. 6 is shown identifies etidronate administration group, ibandronate administration group according to an embodiment of the present invention With the average viability result obtained of Pamidronate administration group.

Implement preferred plan of the invention

The present invention relates to the compositions for preventing or treating chronic allograft dysfunction comprising is used as The diphosphonate of the therapeutic agent of osteoporosis.According to the present invention, for preventing or treating chronic allograft function The composition containing diphosphonate of obstacle to by occur after tissue or organ transfer operation transplanting tissue or organ function by Chronic allograft dysfunction caused by gradually reducing has excellent preventative and/or therapeutic effect, and therefore It is expected to be obviously improved the long-term surviving after transfer operation.

The form to carry out an invention

Details of the invention will be further described by embodiment below.These embodiments are only used for being more fully described The present invention, and it is obvious to the skilled person that purport according to the present invention, the scope of the present invention is not It is limited to these embodiments.