Use of arginine in the preparation of a medicament for the prevention and treatment of the side effe

专利摘要:
The present invention relates to the use of arginine in the prevention and treatment of side effects associated with extravascular outflow of a medicament administered by the intravenous route, and more particularly to injectable formulations for intravenous use comprising the same.
公开号:KR20030045066A
申请号:KR10-2003-7003557
申请日:2001-09-07
公开日:2003-06-09
发明作者:무제티로레나；마르티니알레산드로；부치조반니；콜롬보파올로
申请人:파마시아 이탈리아 에스.피.에이.；
IPC主号:

专利说明:

Use of arginine in the preparation of a medicament for the prevention and treatment of the side effects associated with the intravenous administration of pharmaceuticals}
[1] The present invention relates to the use of arginine in the prevention and treatment of side effects associated with intravenous administration of several medicaments, and more particularly to their injectable formulations.
[2] In the treatment, it is known that several agents administered via the intravenous route can, at least potentially, cause vascular damage at the site of injection and ulcer injury of surrounding tissue upon extravascular outflow.
[3] During vascular administration, extravascular outflow is usually observed by fluid outflow of blood, a solution injected through the intravenous route, or a mixture of both, from a blood vessel or lymphatic vessel in perivascular tissue.
[4] Out-of-vascular outflow may occur incidentally at several locations, for example, by missed positioning of the needle inside the vein during intravenous administration of the medicament with the resulting leakage of the drug solution into the perivascular tissue. Can be.
[5] Alternatively, the vein may leak out if the vein is too small for, for example, the rate of administration and / or the volume of the injected solution, or has already been damaged by prior administration or trauma of the medicament.
[6] Particularly painful ulcers may be induced by extravasation of some agents administered by the intravenous route, and in some cases, proliferation may be induced requiring surgical removal of the associated tissue.
[7] Extravasation phenomena associated with intravenous administration of the drug, in particular for cytotoxic antitumor agents used in chemotherapy, are described in Proc. Annu. Meet. Am. Soc. Clin. Oncol. 13: A1627, 1994; Seminars in Oncology, 27 (3): 347-61, 2000 Jun; Drug Safety, 12 (4): 245-255, 1995 Apr .; Nuritinga: An electronic journal of nursing ISSN 1440-1541 http://www.healthsci.utas.edu.au/nursing/nuritinga/vo12/stoios.html.
[8] In addition to the above chemotherapeutic agents, other classes of drugs administered by the intravenous route, synthetic or natural sources, can affect this kind of damaging action when contacted with perivascular tissue after extravasation.
[9] It is called, for example, antibiotics, antifungal and also sedative drugs.
[10] More generally, compounds that can cause ulcer damage after extravasation include, for example, antitumor agents such as tubulin antagonists, alkylating agents, antibiotics, antimetabolic agents, isomerase inhibitors, angiogenesis inhibitors and platinum derivatives. do. In addition, the above side effects can also occur by using, for example, antiviral or vascular inhibitors and other agents such as benzodiazepines.
[11] In this regard, examples of specific compounds that can cause ulcer damage by extravasation include, for example, amsacrine, vincristine, vinblastine, vinorelbine, vindesine, gemcitabine, etoposide, dhaka. Vazine, streptozosin, daunorubicin, idarubicin, epirubicin, doxorubicin, alkycycline (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyl-daunorubicin Internal Code: PNU 159548), plicamycin, penicillin, vancomycin, chloramphenicol, bleomycin, mitomycin, actinomycin D, paclitaxel, docetaxel, Sugen SU-5416, Sugen SU-6668, amphotericin B Cisplatin, carboplatin, ifosfamide; Fluorouracil, mechlorethamine, mustin, carmustine, esturamustine, irinotecan, topotecan, epinephrine, norepinephrine, dopamine and dobutamine.
[12] There is no enhanced efficacy and specific efficacy for the prevention and treatment of such injuries / ulcers that can progress from the point of clinical field of vision to necrosis of the relevant tissue in the most severe cases and in the absence of suitable treatment.
[13] Some possible treatments include the reduction of local toxicity of some of the most common agents that show impairment after extravasation, for example, topical administration of dimethylsulfoxide in the case of anthracycline or mitomycin extravasation. Seminars in Oncology , 27 (3): 347-61, 2000 Jun.], Topical injection of hyaluronic acid degrading enzymes for alkaloids [Proc. Annu. Meet. Am. Chem. Soc. Clin. Oncol., 13: A1627, 1994] or topical injections of sodium thiosulfate for Mechlorethamine (Drug Safety, 12 (4): 245-255, 1995 Apr.) are not known in the art at all.
[14] As already reported, in the most unfavorable case where the above treatment does not affect the desired effect, the recurrence of plastic surgery remains the only possibility of treatment.
[15] For the purpose of minimizing the undesired effects associated with intravenous administration of a therapeutic agent, at least potentially to cause ulcer damage by extravasation, specific formulations, for example, have improved resistance compared to conventional formulations. Liposomal Anthracycline Formulations [Journal of Controlled Release, 53 (1-3): 275-9, 1998 Apr. 30 and the use of cyclodextrins in the preparation of formulations for the parenteral route (US Pat. No. 5,804,568, Applicant: Supergen Inc.) are known in the art.
[16] Nevertheless, it is known that significant changes in the pharmacokinetics of the therapeutic substance itself can usually be induced by the encapsulation of liposomes as well as by the inclusion / binding of various active elements with cyclodextrins.
[17] The inventors unexpectedly found that arginine [The Merck Index, XII Ed. No. 817] has been shown to be particularly effective in the prevention and treatment of side effects due to extravasation associated with intravenous administration of some agents.
[18] The use of basic amino acids, and more particularly arginine, in the preparation of intravenous formulations of estramustine is also reported in PCT WO 01/19372, filed under the applicant's own name.
[19] However, as described herein, arginine acts against a possible thrombophlebitis known to occur at the site of injection upon intravenous administration of esturamustine.
[20] Accordingly, the object of the present invention relates to the use of arginine and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and treatment of side effects associated with extravasation of a medicament administered by the intravenous route.
[21] According to a preferred embodiment of the present invention, arginine means the essential amino acid in optically active form L-arginine, optionally in the form of a pharmaceutically acceptable salt for parenteral administration.
[22] Pharmaceutically acceptable salts include, for example, acid addition salts with organic or inorganic acids, such as hydrochloric acid, glutamic acid and aspartic acid.
[23] Preferably, the invention relates to the use of arginine or arginine hydrochloride.
[24] In view of the stability and resistance to characterizing arginine and pharmaceutically acceptable salts thereof, the present invention is particularly useful in the treatment of intravenous administration of several medicaments for its ease of use and modification.
[25] According to a preferred embodiment of the present invention, arginine is intravenous of an agent having anticancer activity such as, for example, tubulin antagonists, alkylating agents, antibiotics, antiviral agents, antimetabolic agents, isomerase inhibitors, angiogenesis inhibitors and platinum derivatives It is particularly useful in the prevention and treatment of perivascular damage associated with administration.
[26] In this regard, anthracyclines and doxorubicin, epirubicin, idarubicin, daunorubicin, alkcyclines (4-demethoxy-3 ', used as single agents or as a combination with other conventional chemotherapeutic agents -Deamino-3'-aziridinyl-4'-methylsulfonyl-danorubicin; internal code: PNU 159548), taxanes such as paclitaxel and docetaxel; Esthramustine phosphate; Particular preference is given to using arginine in anticancer treatments including intravenous administration of Sugen SU-5416 and Sugen SU-6668.
[27] For the purposes of the present invention, arginine may be co-administered or sequentially administered for the administration of a medicament injected by the intravenous route.
[28] When co-administered, arginine may be present as a component of the formulation itself.
[29] Depending on the type of medicament used, as an example, arginine may be present in admixture with an active element in the form of an arginine salt with any other pharmaceutical excipient for parenteral use or as an additional component.
[30] A typical example of a formulation that, when administered by the intravenous route, can inhibit ulceration after a possible extravascular outflow of esturamustine phosphate is an esturamustine phosphate containing formulation as an arginine salt, as described in the Examples. .
[31] Alternatively, as mentioned above, arginine may be present as an additional ingredient in the active bovine containing solution injected intravenously. In such cases, for example, in therapy involving intravenous administration of estradiol phosphate, the active cow may be combined with a pharmaceutically acceptable salt such as N-methyl-glucamine, otherwise known as meglumine. It may consist of salts.
[32] In addition to the above and in terms of safety characterizing arginine, arginine may be present as a salt in combination with the active ingredient and in formulations injected as additional ingredients.
[33] It is apparent to those skilled in the art that in the preparation of such formulations, at least one equivalent of arginine per equivalent of active ingredient is required. From the above facts, it can be similarly applied to formulations for intravenous use comprising active cattle in addition to estrasmustin phosphate and in any case that can cause ulceration after extravascular outflow.
[34] As mentioned above, arginine can also be added to active cattle by performing as described in the literature, for example, on solutions containing thiosulfate or hyaluronic acid which are used topically once an extravasation event is observed. It may also be administered separately.
[35] In such cases, physiologically injectable arginine solutions, optionally in combination with other pharmaceutically acceptable excipients, may be administered via topical injection near the area damaged by the previous intravenous administration of the medicament.
[36] During the preliminary clinical studies required for medicaments administered intravenously, there is an assessment of any local response in case of partial accidental administration of the medicament outside the blood vessel itself. For example, this study, conducted in accordance with the experimental model described below, can assess the stimulatory / histologic damage capacity of a medicament administered by the intravenous route once it has been extravasated. In general, although repeated toxicological studies may allow clinical and histological examination of the injection site to indicate local tolerance of the drug, it is desirable to conduct special studies anyway.
[37] In this regard, any results obtained in animal models are useful for understanding whether possible accidental extravasation in clinical use can lead to the above-mentioned inconvenience at the site of administration. For the purpose of minimizing the possible clinical situation, the model generally considered is administered around the vein of the rabbit ear (peripheral vein).
[38] As one example, a limited amount (0.3-0.5 ml) of the compound being tested is injected into the perivascular area; The site of inoculation is carefully examined for at least 1 week.
[39] In order to assess the possible changes to the injection site in the most accurate and possible objective manner, a “score” system is used.
[40] Of note is the possible appearance of erythema, inflammatory edema and necrosis, the presence of ulcers or scab lesions. In general, each animal controls itself and the opposite ear receives the vehicle, ie there is the same solution that does not contain active cattle.
[41] The highest concentration of compound tested is the maximum concentration for clinical practice.
[42] Typically, two animals are sacrificed: one is sacrificed during the acute phase after drug administration (48-72 hours), and the other is sacrificed at least one week after drug administration.
[43] In this way, histological examination of the entire injection site is performed.
[44] As described above, arginine may be in combination and / or combination with one or more active cows, or alternatively in formulations that are injected with the usual physiological excipients to prevent and treat damage to extravascular outflows. May exist.
[45] The above formulations are prepared according to conventional techniques used in the preparation of pharmaceutical forms for intravenous administration and may also be used, for example, in the presence of bulking agents (e.g. lactose or mannitol), pH buffers. And other pharmaceutically acceptable excipients for parenteral use such as antioxidants, preservatives, tension modifiers and the like.
[46] The following examples are understood to better illustrate the invention without placing any limitation on the invention.
[47] Example 1
[48] Preparation of Salts of Estramustine Phosphate with Arginine
[49] 300 mg of esturamustine phosphate is weighed in a beaker and dispersed in 5 ml of water with magnetic stirring. 101 mg of arginine base is added to an aqueous dispersion of active ingredient with stirring, and a few minutes later a clear solution is obtained.
[50] The solution thus prepared is then diluted with water until the final volume is 10 ml to reach a final concentration of 30 mg / ml esturamustine phosphate and 10.1 mg / ml arginine (1: 1 in molar ratio each).
[51] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[52] Example 2
[53] Preparation of Estramustine Phosphate Salts Using Arginine in Combination with Arginine
[54] 300 mg of esturamustine phosphate is weighed in a beaker and dispersed in 5 ml of water with magnetic stirring. 202 mg of arginine base is added to the aqueous dispersion of the active ingredient with stirring, and a few minutes later a clear solution is obtained. The basic pH of the obtained solution becomes physiological value about 7.5 by slowly adding hydrochloric acid.
[55] The solution thus prepared is then diluted with water until the final volume reaches 10 ml to reach a final concentration of 30 mg / ml esturamustine phosphate and 10.1 mg / ml arginine (1: 2 each in molar ratio).
[56] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[57] Example 3
[58] Preparation of Estramustine Phosphate Salt Using N-Methyl-Glucamine in Combination with Arginine
[59] 300 mg of esturamustine phosphate is weighed in a beaker and dispersed in 5 ml of water with magnetic stirring. 120.8 mg of N-methyl-glucamine are added to the aqueous dispersion of the active ingredient with stirring, and a few minutes later a clear solution is obtained. The resulting solution is then added with stirring in an amount corresponding to 202 mg of arginine using a suitable mixture of arginine base and arginine hydrochloride to maintain a final pH as close as possible to physiological pH (about 7.5). The solution thus prepared is then diluted with water until the final volume is 10 ml to reach a final concentration of 30 mg / ml esturamustine phosphate and 20.2 mg / ml arginine (1: 2 each in molar ratio).
[60] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[61] Example 4
[62] The formulations described in the examples above are also prepared by dissolving the freeze dried formulation of the commercial Estracyt ^R containing 300 mg per virus of the active cow.
[63] Reconstitution of the formulation is carried out using 10 ml of a solution containing 20.2 mg / ml of arginine to reach a final concentration of 30 mg / ml esturamustine phosphate and 20.2 mg / ml of arginine (1: 2 each in molar ratio).
[64] Arginine solutions used to dissolve conventional lyophilic solutions are prepared by dissolving in a suitable amount of arginine base and hydrochloride in water such that the final concentration is 20.2 mg / ml and the pH is as close as possible to the physiological value (about 7.5).
[65] Example 5
[66] Preparation of Formulations Containing Doxorubicin and Arginine in a Molar Ratio of 1: 1
[67] 40 mg of doxorubicin hydrochloride and 12 mg of arginine are weighed into a 20 ml flask. The mixture is then dissolved in 15 ml of physiological solution (0.9 wt /% NaCl) by magnetic stirring. The HCl solution of pH 3 or less is added to the solution thus prepared. The solution thus prepared is then diluted with the above physiological solution until the final volume is 20 ml to reach a final concentration of 2 mg / ml doxorubicin and 0.6 mg / ml arginine (1: 1 molar ratio each).
[68] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[69] Example 6
[70] Preparation of Formulations Containing Doxorubicin and Arginine in a Molar Ratio of 1: 2
[71] A solution containing doxorubicin and arginine in a molar ratio of 1: 2, respectively, is prepared by performing similarly as described in Example 5 and using twice the amount of arginine, ie 24 mg of arginine per 40 mg of doxorubicin hydrochloride.
[72] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[73] Example 7
[74] Preparation of Formulations for Intravenous Use, Containing Sugen SU 5416 with Arginine in a Molar Ratio of 1: 1
[75] Dilute 10 ml of an aqueous NaCl solution (0.9 wt.% By volume) with 10 ml of water for the purpose of obtaining a solution of 0.45 wt.% By volume sodium chloride in a 20 ml graduated flask.
[76] Then 39.79 mg of arginine hydrochloride is simply shaken manually and dissolved into the obtained solution.
[77] The solvent solution thus prepared is used in a diluted solution of compound Sugen SU 5416 having the following composition:
[78] ingredientAmount in Formulation (Weight / Volume%) Sugen SU 54160.45 PEG 40045 Benzyl alcohol2 Cremophor EL31.5 Anhydrous ethanolVolume to sum to 1000
[79] To obtain a solution containing Sugen SU 5416 and arginine in a molar ratio of 1: 1, 1 part by weight of the active ingredient-containing formulation is diluted with 2 parts by weight of a solvent containing arginine.
[80] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.
[81] Example 8
[82] Preparation of an Intravenous Route Formulation Containing Sugen SU 5416 and Arginine in a Molar Ratio of 1: 2
[83] Performing similarly as described in Example 7, using 79.58 mg of arginine hydrochloride to obtain a solution containing Sugen SU 5416 and arginine in a molar ratio of 1: 2 each.
[84] A solution prepared as described above, filtered and suitably sterilized, is tested for local tolerance of the animal after extravasation.

权利要求:
Claims (19)
[1" claim-type="Currently amended] Use of arginine and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of side effects associated with extravasation of a medicament administered by the intravenous route.
[2" claim-type="Currently amended] 2. Use according to claim 1, wherein the arginine is in the form of an arginine salt or as a hydrochloride salt.
[3" claim-type="Currently amended] Use according to claim 1, wherein the medicament administered by the intravenous route is an anti-tumor agent.
[4" claim-type="Currently amended] The tubulin antagonist, alkylating agent, antibiotic, antiviral agent, antimetabolic agent, isomerase inhibitor, angiogenesis according to claim 3, wherein the antitumor agent is used alone or as a combination or combination with other conventional chemotherapy agents. Use selected from the group consisting of inhibitors and platinum derivatives.
[5" claim-type="Currently amended] The doxorubicin, epirubicin, idarubicin, daunorubicin, alkcycline (4-deme according to claim 3, wherein the antitumor agent is used as a single agent or as a combination or combination with other conventional chemotherapeutic agents. Oxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyl-daunorubicin; internal code: PNU 159548), paclitaxel, docetaxel, esturamustine phosphate, Sugen SU-5416 and Sugen SU- 6668, and a pharmaceutically acceptable salt thereof.
[6" claim-type="Currently amended] 6. The use according to claim 5, wherein the antitumor agent is estramustine phosphate, doxorubicin or Sugen SU 5416, and a pharmaceutically acceptable salt thereof.
[7" claim-type="Currently amended] Use of a composition for intravenous administration comprising an antitumor agent and arginine in the manufacture of an anticancer agent for preventing and treating side effects associated with extravasation of the antitumor agent.
[8" claim-type="Currently amended] 8. Use according to claim 7, wherein the antitumor agent is selected from the group consisting of doxorubicin, Sugen SU 5416, esturamustine phosphate and pharmaceutically acceptable salts thereof.
[9" claim-type="Currently amended] 8. Use according to claim 7, wherein the arginine is in the form of an arginine salt or as a pharmaceutically acceptable salt thereof.
[10" claim-type="Currently amended] 8. Use according to claim 7, wherein the antitumor agent is in the form of arginine salt.
[11" claim-type="Currently amended] Intravenous formulation of anti-tumor agent (i) and
A product or kit for use in anticancer therapy for preventing and treating side effects associated with extravasation of an antitumor agent, comprising a parenteral formulation of arginine or a pharmaceutically acceptable salt thereof (ii).
[12" claim-type="Currently amended] Of the side effects associated with the extravasation of the antitumor agent administered by the intravenous route, including administering the antitumor agent and arginine to a mammal in need of prevention and treatment of the side effects associated with the extravasation of the antitumor agent. Prevention and treatment method.
[13" claim-type="Currently amended] The method of claim 12, wherein the arginine is in the form of an arginine salt or as a pharmaceutically acceptable salt thereof.
[14" claim-type="Currently amended] 13. The tubulin antagonist, alkylating agent, antibiotic, antiviral agent, antimetabolic agent, isomerase inhibitor, angiogenesis according to claim 12, wherein the antitumor agent is used alone or as a combination or combination with other conventional chemotherapy agents. The method is selected from the group consisting of inhibitors and platinum derivatives.
[15" claim-type="Currently amended] 15. The doxorubicin, epirubicin, idarubicin, daunorubicin, alkcycline (4-deme according to claim 14, wherein the antitumor agent is used as a single agent or as a combination or combination with other conventional chemotherapeutic agents. Oxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyl-daunorubicin; internal code: PNU 159548), paclitaxel, docetaxel, esturamustine phosphate, Sugen SU-5416 and Sugen SU- 6668, and a pharmaceutically acceptable salt thereof.
[16" claim-type="Currently amended] The method of claim 15, wherein the anti-tumor agent is estramustine phosphate, doxorubicin or Sugen SU 5416, and a pharmaceutically acceptable salt thereof.
[17" claim-type="Currently amended] The method of claim 12, wherein the antitumor agent is in the form of an arginine salt.
[18" claim-type="Currently amended] The method of claim 12, wherein the mammal is a human in need of preventing and treating side effects associated with extravasation of the antitumor agent.
[19" claim-type="Currently amended] Doxorubicin, epirubicin, idarubicin, daunorubicin, alkcycline (4), used as arginine or pharmaceutically acceptable salts thereof, and as a single agent or in combination with other conventional chemotherapeutic agents -Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyl-daunorubicin; internal code: PNU 159548), paclitaxel, docetaxel, Sugen SU-5416 and Sugen SU-6668, and A formulation for intravenous administration comprising an anti-tumor agent selected from the group consisting of pharmaceutically acceptable salts thereof.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-09-12|Priority to ITMI2000A001984

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2000-09-12|Priority to IT2000MI001984A

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2001-09-07|Application filed by 파마시아 이탈리아 에스.피.에이.

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2001-09-07|Priority to PCT/EP2001/010398

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2003-06-09|Publication of KR20030045066A

优先权:

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申请号 | 申请日 | 专利标题

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ITMI2000A001984|2000-09-12|

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IT2000MI001984A|IT1318689B1|2000-09-12|2000-09-12|Use of arginine in the preparation of a medicament for lapreparazione and treatment of side effects associated with|

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PCT/EP2001/010398|WO2002022134A1|2000-09-12|2001-09-07|Use of arginine in the preparation of a medicament for the prevention and treatment of the side effects associated with the intravenous administration of pharmaceuticals|