WO2009150278A1 - Composition pharmaceutique de melphalan - Google Patents

Composition pharmaceutique de melphalan Download PDF

Info

Publication number
WO2009150278A1
WO2009150278A1 PCT/ES2009/070212 ES2009070212W WO2009150278A1 WO 2009150278 A1 WO2009150278 A1 WO 2009150278A1 ES 2009070212 W ES2009070212 W ES 2009070212W WO 2009150278 A1 WO2009150278 A1 WO 2009150278A1
Authority
WO
WIPO (PCT)
Prior art keywords
melphalan
pharmaceutical composition
acid
concentration
formulation
Prior art date
Application number
PCT/ES2009/070212
Other languages
English (en)
Spanish (es)
Inventor
José Lucio NUÑEZ
José Bernardo ITURRASPE
Alberto Marchi
Original Assignee
Capital, Business Y Gestión De Finanzas, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Capital, Business Y Gestión De Finanzas, S.L. filed Critical Capital, Business Y Gestión De Finanzas, S.L.
Publication of WO2009150278A1 publication Critical patent/WO2009150278A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of pharmaceutical formulations of poorly soluble active ingredients.
  • it refers to injectable formulations of alkylating agents suitable for parenteral infusion processes in cancer chemotherapy.
  • Patent application WO 200801671 1 discloses a composition comprising a derivative of a salt of pyrimidixincarboxylic acid (lithium orotate) and melphalan which is intended reduce the levels of cytotoxic drugs, such as melphalan, in non-cancerous tissues by means of the derivatization of said drug in a lithium orotate salt.
  • US 6310039 discloses a formation of a transferrin, albumin or PEG conjugate, with at least one thiol group (-SH) attached to an anti-neoplastic drug (melphalan), showing a tumor inhibitory effectiveness at least equal to or greater than Ia of the compound only.
  • US patent application 20050214310 discloses a method of producing a melphalan prodrug, which can then be activated by an antibody-enzyme conjugate, wherein said antibody has specificity for a surface epitope of the tumor cell.
  • US 7135547 discloses a melphalan-linked glycosaminoglycan conjugate by means of a linker which has recognition sites for proteases.
  • New formulations is RU 2060031, in which a formulation comprising melphalan, polyvinylpyrrolidone, ascorbic acid, glutamic acid, hydrochloric acid and D-mannitol is disclosed. Tests of new injectable formulations using cyclodextrin derivatives have also been carried out, as disclosed in the paper entitled "New injectable melphalan formulations utilizing (SBE) 7m- ⁇ -CD or HP- ⁇ -CD '(Int Journal of Pharma VoI 189, Issue 2, 5 Nov 1999, Pages 227-234).
  • melphalan is marketed in the form of 2 mg tablets of base melphalan, or as lyophilized melphalan hydrochloride, together with a restorative solution, under the Alkeran® brand, as described in US Pat. No. 4,997,651 of Poole et al.
  • the first formulation that was commercialized of Alkeran® sterile injectable melphalan powder consisted of three components, and was reconstituted in two stages, just before its application.
  • the three components of the system consisted of a vial with melphalan base, in powder form, a vial containing an acidified alcohol (HCI) and a solvent vial composed of a phosphate and propylene glycol buffer diluent.
  • HCI acidified alcohol
  • solvent vial composed of a phosphate and propylene glycol buffer diluent.
  • the melphalan powder was dissolved in the acidified alcohol, stirring until its complete dissolution and then the melphalan concentration was diluted by the addition of buffer diluent phosphate and propylene glycol.
  • This three component system and the two stage reconstitution process was an awkward procedure.
  • the melphalan dissolved slowly and sometimes did not completely.
  • injectable lyophilized Alkeran® corresponds to that described in US Patent 4997651 of Poole et al.
  • This second commercial formulation of injectable Alkeran® consists of two components and partially overcomes the disadvantages of the first three component formulation.
  • the current formulation comprises lyophilized melphalan hydrochloride and polyvinylpyrrolidone (PVP), and a diluent comprising a mixture of sodium citrate, water, propylene glycol and ethanol.
  • PVP polyvinylpyrrolidone
  • Alkeran® injection is presented as a lyophilized melphalan hydrochloride formulation, equivalent to 50 mg of base melphalan and 20 mg of polyvinylpyrrolidone, which is reconstituted in a diluent consisting of 0.2 mg of sodium citrate, 6.0 ml of propylene glycol, 0.52 ml of 96% ethanol and water for injection in sufficient quantity to obtain 10 ml.
  • the Alkeran® to be infused must be diluted to no more than 0.45 mg / ml in Normal Saline Solution (SSN) of 0.9% w / v CINa and infused for 15 minutes (and before 60 minutes of being reconstituted according to your leaflet).
  • SSN Normal Saline Solution
  • the stainless steel condenser of industrial freeze dryers is not inert to acid hydrochloric.
  • the corrosive vapors that are generated during the filling of the vials are also a serious problem for the air ducts. All this hinders the process or makes the necessary equipment for the production of lyophilisate extremely expensive.
  • Alkeran® Another particularly inconvenient factor in the formulation of Alkeran® is the presence of propylene glycol, since according to the World Health Organization (WHO) this alcohol has an acceptable daily dose of 25 mg / kg.
  • WHO World Health Organization
  • 100 to 240 mg / m 2 are used in high doses of melphalan for neuroblastoma, with bone marrow transplantation, as a single dose, or in a total regimen that can be divided into three consecutive days.
  • Propylene glycol is a colorless and odorless liquid, which is commonly used as a solvent for many intravenous drugs, such as trimethoprim-sulfamethoxazole, diazepam, digoxin, esmolol, hydralazine, lorazepam, multivitamins, nitroglycerin, phenytoin, and phenobarbital.
  • the kidney eliminates almost 50% of propylene glycol and the rest is metabolized in the liver, becoming acetone, lactic acid or pyruvic acid.
  • Melphalan is indicated for the treatment of neoplasms of the blood, such as multiple myeloma in which case the indicated dose is 16 mg / m 2 , which is accompanied by 54 mg / kg of propylene glycol per day, that is, twice the dose Daily accepted by the WHO.
  • He Melfalano produces a tumor lysis syndrome affecting renal function, which is why patients should be medicated with allopurinol or urate oxidase.
  • Propylene glycol has two important toxicities, hepatic and renal. Therefore, renal toxicity in this type of patients would be dangerously potentiated by that of propylene glycol.
  • the elimination of propylene glycol would avoid the additional renal toxicity to the tumor lysis syndrome, described in the product leaflets.
  • the toxicity related to allergic-anaphylactic type phenomena such as bronchospasm, hypotension, skin irritation, glottis edema, etc.
  • the present invention solves the aforementioned problems. That is to say, it provides a new formulation of liquid melphalan, preferably free of propylene glycol, which has advantages over previous formulations such as greater chemical stability of melphalan, lower toxicity and reduction of risks in handling by nurses.
  • this new formulation not requiring the lyophilization process, allows a production process that prevents the degradation of the active material caused in said operation and avoids the use of expensive equipment necessary to lyophilize acid solutions.
  • liquid melphalan pharmaceutical composition stable during its storage period, useful for preparing an injectable infusion, object of the present invention
  • composition of the invention comprises melphalan, in a concentration of between 5 and 250 mg / ml, preferably between 25 and 75 mg / ml, and acid, preferably an aqueous solution of acid in a concentration of between 1 N and 12N, preferably between
  • melphalan is selected from the group comprised of melfalano base, its salts, melfalano hydrochloride, racemic mixtures and derivatives of melfalano.
  • said pharmaceutical composition of melphalan may contain a salt such as sodium chloride in a concentration of between 0.2 and 3% w / v.
  • the pharmaceutical formulation of melphalan comprises two separate liquid compositions that are previously mixed to be infused into parenteral infusion (ie prior to be injected into the patient), where the first liquid composition is the composition of the invention, and the second composition is a diluent composition, preferably free of propylene glycol.
  • Said diluent composition comprises, in a preferred version, an aqueous solution of a compound regulating acidity, ethanol and salt, where this salt is preferably sodium chloride in a concentration between 0.05M at 0.15M.
  • An alternative of said diluent composition of the invention comprises an aqueous solution of a base, which may be, among others, sodium hydroxide; ethanol; and optionally an acidity regulating compound, in a concentration between 0 and 0.3 M.
  • a base which may be, among others, sodium hydroxide; ethanol; and optionally an acidity regulating compound, in a concentration between 0 and 0.3 M.
  • This alternative diluent composition in a preferred version of the present invention, is incorporated into a sterile normal saline infusion container, prior to be injected into the patient It is understood as a container for infusion of sterile normal saline solution to the containers, already of glass, and to standard plastic bags, normally used for parenteral infusions containing normal saline solutions; These bags usually contain, 100, 250, 500 mi, etc.
  • Said aqueous solution of an acidity regulating compound is: a buffer solution selected from the group comprised of lactic acid / lactate, acetic acid / acetate, tartaric acid / tartrate, ascorbic acid / ascorbate, and monosodium / disodium phosphate; or is a solution of an acid salt selected from the group comprised of lactate, acetate, phosphate, tartrate and ascorbate. These salts can be, among others, sodium or potassium.
  • the present invention also provides a kit or set comprising said pharmaceutical composition of the invention, said diluent composition of the invention and a syringe, which can be pre-filled with the pharmaceutical composition of the invention.
  • the syringe can be pre-filled with the pharmaceutical composition of the invention and with the alternative diluent composition of the invention, and said syringe be double chamber.
  • These compositions in a preferred embodiment of the invention, are mixed in the normal saline solution of a sterile perfusion container, and then the formulation of the resulting invention is infused.
  • Another kit or set which provides the present invention, comprises two separate and sterile compartments that have the necessary means to mix the contents of both compartments aseptically prior to parenteral infusion, where one of said compartments contains the pharmaceutical composition of melphalan of the invention and the other compartment contains the diluent composition of the invention.
  • the present invention provides a method of preparing the pharmaceutical composition of the invention, characterized in that it comprises the steps of dissolving melphalan base or hydrochloride in hydrochloric acid between 3N and 8N in aqueous solution, sterilizing by filtration and preparing it as an injectable finished product.
  • the present invention provides a method of preparing the diluent composition of the invention comprising the steps of mixing an acidity regulating compound, sodium chloride, ethanol in water and sterilizing by filtration or by moist heat and preparing it as a solution diluent for infusion.
  • Figure 1 Evolution of melphalan concentration over time, for different temperatures, in HCI 3N (A) and HCI 6N (B).
  • FIG. 1 Evolution of the concentration of monohydroximelfalano (MHM) over time at various temperatures in 3N HCI (A) and 6N HCI (B).
  • a new pharmaceutical formulation of melphalan has been developed, which minimizes the chemical instability of said agent so that it is possible to prolong the time between the preparation of said formulation and the time it is infused in the patient
  • This new formulation in its preferred embodiment, does not have those effects Toxic caused by components present in the formulation available today in the market, and due to the simplicity of the dilution process of the formulation of the invention, the exposure of the health professional to said drug is reduced.
  • the present invention provides a pharmaceutical composition that can be stored for long periods.
  • This new pharmaceutical formulation comprises a new pharmaceutical composition of melphalan, liquid and stable, and a diluent composition.
  • this pharmaceutical formulation allows said melphalan to be introduced into the body of mammals, especially humans, in the absence of toxic components such as propylene glycol.
  • the pharmaceutical composition of melphalan main object of the present invention, comprises melphalan and acid.
  • Said acid is preferably hydrochloric acid.
  • said acid is in a concentration between 1 N and 12 N in aqueous solution; preferably in a concentration between 2N and 8N, more preferably between 5N and 7N. In the most preferred form of the invention said acid is in a concentration of 6N.
  • the water content of said pharmaceutical composition is necessary to prepare an aqueous acid solution in said concentrations, as is usual for a person skilled in the art.
  • a salt such as sodium chloride in a concentration of between 0.001 and 3% can optionally be added to said pharmaceutical composition.
  • an aqueous melphalan acid composition is achieved that provides the necessary chemical stability during its storage time, which depends on national health regulations but can be considered for two years.
  • This composition is so stable chemically the chromatographic purity of melphalan decreases only 2% maintained for 28 days at 60 Q C, temperature that would significantly affect the pharmaceutical formulations market.
  • This pharmaceutical composition of melphalan can be sterilized by filtration with polytetrafluoroethylene (Teflon®) or polyamide (Nylon®) membranes.
  • the pharmaceutical composition of the present invention does not show variation between the initial concentration and the final concentration of the melfalano Said pharmaceutical composition has a stability that allows storage at room temperature, suitable for zone IV (30 Q C and 65% RH) according to ICH standard.
  • the pharmaceutical formulation is liquid and suitable for parenteral infusions of melphalan and comprises said pharmaceutical composition formed by melphalan, water and acid and a diluent composition.
  • This formulation formed by two separate liquid compositions is previously prepared to be infused by mixing said compositions.
  • the pharmaceutical formulation of the present invention has a stability, after the hour of mixing the two compositions, superior to that of the current injectable Alkeran® formulation.
  • the new pharmaceutical formulation of melphalan presents as an additional advantage a method of preparing said injectable formulation, which reduces the chances of contamination of the nursing staff when preparing the infusion, eliminating the generation of spray during the reconstitution of the cytostatic
  • the new formulation absolutely avoids the inhalation and ingestion of melphalan by said professional, since the new formulation is liquid and does not comprise a component in solid or lyophilized state, as in the case of the injectable formulation that is currently marketed.
  • melphalane comprises melphalan base, racemic mixtures of melphalan, pure optical isomers, derivatives of melphalan, derivatives of phenylalanine mustard, Sarcolysin, L-PAM.
  • the diluent composition another object of the present invention, which is part of the pharmaceutical formulation of the invention, and that dilutes said pharmaceutical composition of Melphalan without altering its stability, is free of toxic components such as propylene glycol, in its preferred embodiment.
  • the diluent composition of the present invention comprises a neutralizing compound, salt and alcohol.
  • a pharmaceutical formulation ready to inject is obtained, with a pH between 3 and 7.
  • Said salt in the diluent composition is preferably sodium chloride, in a concentration of 0.05M to 0.15M, to give in the pharmaceutical formulation of the invention a concentration of between 8 and 13 mg / ml of sodium chloride, preferably between 9 and 12 mg / ml, more preferably 9 mg / ml.
  • Said neutralizing compound in the diluent composition can be a buffer solution (buffer) or a sodium or potassium salt, which, when mixed with the acid of said pharmaceutical composition of melphalan, acts by regulating the acidity.
  • This sodium or potassium salt is preferably selected from the group comprised of lactate, acetate, phosphate, tartrate and ascorbate.
  • Said buffer solution is selected from the set comprising a solution of an acid and its salt of an alkali metal.
  • Said buffer solution is selected from the set comprised of lactic acid / lactate, acetic acid / acetate, disodium / monosodium phosphate.
  • Said buffer solution has a concentration between 0.001 M and 0.2 M of said acid and between 0.01 M and 0.2 M of its alkali metal salt.
  • the alcohol present in the diluent composition of the invention is preferably ethanol.
  • said alcohol is in a concentration of between 0.5 and 10% w / w; preferably, in a concentration of between 1 and 2.5% w / w.
  • said diluent composition is essentially free of propylene glycol.
  • said diluent composition has a buffer (acetic-acetate or lactic-lactate or disodium phosphate); sodium chloride; and ethanol (1.8%).
  • a buffer acetic-acetate or lactic-lactate or disodium phosphate
  • sodium chloride sodium chloride
  • ethanol ethanol
  • said diluent composition has: an acidity regulating compound formed by an aqueous solution of sodium or potassium salt which can be acetate, lactate or disodium phosphate; sodium chloride in a concentration between 0.1 to 0.15 M; and ethanol (between 0.5 and 1.8% w / w).
  • an acidity regulating compound formed by an aqueous solution of sodium or potassium salt which can be acetate, lactate or disodium phosphate
  • sodium chloride in a concentration between 0.1 to 0.15 M
  • ethanol between 0.5 and 1.8% w / w
  • Said pharmaceutical formulation of the invention is obtained by diluting the pharmaceutical composition of the invention with the diluent composition of the invention, obtaining a ready-to-inject solution having a melphalan concentration of between 0.1 mg / ml and 0.5 mg / ml.
  • the pharmaceutical formulation of melphalan of the present invention in an alternative embodiment, comprises the pharmaceutical composition of the present invention and the alternative diluent composition of the present invention.
  • Said alternative diluent composition of the present invention consists in the solution of a base, for example sodium hydroxide; ethanol; and optionally an acidity regulating compound, as described in example 10.
  • This alternative allows, for example, to add a small volume (10 ml, for example) of said sterile alternative diluent composition (which may contain a minimum proportion of lactate of sodium, or sodium acetate, or disodium phosphate, or sodium ascorbate or sodium tartrate, or mixtures thereof, to obtain an adequate infusion pH) to 250 ml of normal saline (SSN), homogenize, then add 50 mg of the pharmaceutical composition of melphalan of the invention, to obtain an infusion solution of 0.225 mg / ml of melphalan.
  • a small volume (10 ml, for example) of said sterile alternative diluent composition which may contain a minimum proportion of lactate of sodium, or sodium acetate, or disodium phosphate, or sodium ascorbate or sodium tartrate, or mixtures thereof, to obtain an adequate infusion pH
  • SSN normal saline
  • This new formulation of melphalan without propylene glycol in an alternative embodiment, can be presented in a two-chamber syringe or in two separate syringes.
  • the pharmaceutical formulation, object of the present invention has a chemical stability far superior to the currently available injectable Alkeran® formulation. This stability is evident from tests of stability of the injectable formulation Alkeran® and the pharmaceutical formulation of the present invention, both with an initial concentration of melphalan 0.45 mg / ml to 20 Q C where 72 minutes After initiating the test, the injectable Alkeran® formulation presents a decrease in melphalan purity of 10.82% and an increase of 6.77% in the concentration of monohydroxyelphalan, while the formulation of the present invention shows an average decrease in The melphalan purity of only 6.19% and an average increase of 2.92% in the concentration of monohydroxyelfalane (The average corresponds to the values of examples 9.3, 9.4 and 9.5).
  • the present invention also provides a kit or set of elements that allows the use of the pharmaceutical composition of the invention in a safe manner, reducing the risks of contamination of the medicament and the nursing staff and facilitating the operation of administering the medication.
  • said kit comprises a syringe, which can be filled, which contains the pharmaceutical composition of melphalan of the present invention and a container container of the diluent composition of the invention.
  • said kit comprises two separate and sterile compartments containing, one the pharmaceutical composition of melphalan of the invention and the other the diluent composition of the invention. These container containers have the necessary means to achieve the mixing of both compositions aseptically.
  • Another preferred form of the invention is constituted by a kit that has a double chamber syringe containing in a first chamber the pharmaceutical composition of the invention, separated from the second chamber containing the alternative diluent composition of the invention. When these two chambers are injected into a perfusion bag with sterile SSN, they form the formulation of the present invention.
  • HPLC results were obtained according to Pharmaeuropa, VoI 19, N Q 2, April 2007, pag. 318-21.
  • the melphalan solution was fractionated in 6N HCI in 48 vials, placing 1 ml of solution in each one. 14 vials were placed in a refrigerator at 2-8 Q C, 12 vials in an oven at 25 Q C and 12 vials in an oven at 40 Q C.
  • solution A was prepared from 523.9 mg of melphalan (Lot: D-Mel-120-07) and then dissolved, without difficulty, at room temperature (TA) in 6N HCI, and filtered by 0.45 um Nylon filter, with a Darling plastic syringe of
  • HPLC determines its chromatographic purity of 97.98% with 0.40% monohydroximelfalano. After 17 hours at RT a new HPLC test was performed without observing variations in its purity.
  • the pharmaceutical formulation of the invention was prepared as follows: Pharmaceutical composition of melphalan: 50 mg of base melphalan was dissolved in 1 ml of 6 N aqueous hydrochloric acid solution. This composition is introduced into a syringe.
  • Diluent composition in a bag or bottle of 1 10 ml of aqueous solution containing 0.06 M sodium acetate, 0.006 M acetic acid, a concentration of 0.08 M sodium chloride and 1.8% ethanol p / p.
  • the formulation of the invention is prepared by injecting the pharmaceutical composition of melphalan that is in the syringe into the bag containing the diluent composition, to achieve a melphalan formulation of 0.45 mg / ml, ready for infusion.
  • This formulation has three times less organic solvent than the Alkeran® formulation.
  • Example 6 Test of solubility and stability of the pharmaceutical formulation a) 25 g of the diluent composition of example 3 are weighed and 0.25 ml of solution A of example 2 is added with micropipette with 1 ml tip, in this way it is obtained The pharmaceutical formulation of the invention in a concentration of 0.5 mg / ml of melphalan. No precipitate formation is observed. This formulation has a pH 2.02 at 23 QC . The solution does not change after 18 hours. A chromatographic purity of 96.65% melphalan is determined by HPLC, with 2.37% monohydroximelfalane (after 72 min of reconstitution).
  • a solution of 0.45 mg / ml is prepared from the reconstituted: 1 vol of the reconstituted in Example 7.1 is diluted in 10 vol of freshly prepared SSN (pH 5.54 to 24.8 Q C) and a solution is obtained 0.45 mg / ml solution. The 0.45 mg / ml solution is injected into an equipment of HPLC at different times.
  • the solution of 0.225 mg / ml is injected by HPLC, where after 7 minutes of preparation it has a chromatographic purity of 94.58% of melphalan, with 2.35% of monohydroximelfalano; at 36 minutes it has a chromatographic purity of 89.48% melphalan, with 6.61% monohydroxyelfalane and after 72 minutes it has a chromatographic purity of 84.52% with 10.29% monohydroximelfalano.
  • the kit of the present invention was manufactured with a pre-filled syringe of a total volume of 1 ml containing the pharmaceutical composition of the invention, in a concentration of 50 mg / ml of melphalan in an aqueous solution of 6N hydrochloric acid and by On the other hand, a vial was prepared to infuse with 10 ml of diluent composition of the present invention, made with an aqueous solution containing 0.06 M of sodium acetate, 0.006 M of acetic acid, a concentration of sodium chloride 0, 08 M and 1.8% w / w ethanol. When mixing said compositions, the pharmaceutical formulation of the present invention is obtained, at a concentration of 0.45 mg / ml, ready to be infused. In this way, less transfer manipulation is achieved than if a 5 mg / ml solution is prepared and then 0.45 mg / ml is diluted.
  • a batch of the pharmaceutical composition of melphalan of the invention of 50 mg of base melphalan in 1 ml of 6 N hydrochloric acid solution at 20 Q C was prepared with a batch G-Mel-126-07 of base melphalan.
  • One sample was diluted to 1 mg / ml in Methanol, its purity was analyzed by HPLC and 99.21% was obtained, with 0.15% monohydroximelfalano.
  • An alternative diluent composition of the invention was prepared as follows: 100 ml of absolute ethanol was poured into a 200 ml flask, to which 50 ml of distilled water was added, then 46.4 ml of solution was added of 2.5 N sodium hydroxide, homogenized and brought to volume with distilled water.
  • Example 11 An aqueous alkaline solution, as a sterile diluent, was prepared to dilute the SSN (9 mg / ml), which for every 35 ml of solution contains 0.2 g of sodium citrate dihydrate,
  • Example 12 35 ml of the sterile diluent previously used in the application example 1 1 was used to basify 75 ml of an SSN and generate 10 ml of a hypotonic saline solution of 6.14 mg of NaCl / ml, which was used to dilute 1.0 ml of the pharmaceutical composition of Melfalano Hydrochloride of the invention, which has the equivalent 50 mg of base melphalan for each ml of 6 N hydrochloric acid solution, and a solution of 0.45 mg / ml is obtained of melphalan in SSN of physicochemical characteristics similar to example 1 1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique de melphalan utilisée pour préparer une perfusion injectable, stable au stockage, caractérisée en ce qu'elle comprend du melphalan et un acide, de préférence une solution aqueuse d'acide chlorhydrique. L'invention concerne une préparation pharmaceutique de melphalan comprenant deux compositions liquides séparées qui sont mélangées avant d'être injectées par perfusion parentérale, la première composition liquide étant ladite composition pharmaceutique de melphalan et la seconde composition liquide étant une composition de diluant. L'invention concerne également une trousse ou un ensemble comprenant ladite composition pharmaceutique, ladite composition de diluant et une seringue pré-remplie.
PCT/ES2009/070212 2008-06-10 2009-06-08 Composition pharmaceutique de melphalan WO2009150278A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ARP080102465A AR066943A1 (es) 2008-06-10 2008-06-10 Una composicion farmaceutica de melfalano
ARP080102465 2008-06-10

Publications (1)

Publication Number Publication Date
WO2009150278A1 true WO2009150278A1 (fr) 2009-12-17

Family

ID=41136247

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2009/070212 WO2009150278A1 (fr) 2008-06-10 2009-06-08 Composition pharmaceutique de melphalan

Country Status (2)

Country Link
AR (1) AR066943A1 (fr)
WO (1) WO2009150278A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004438A1 (fr) 2010-07-05 2012-01-12 Capital, Business Y Gestión De Finanzas, S.L. Préparation pharmaceutique injectable de melphalane
CN102458114A (zh) * 2009-05-29 2012-05-16 锡德克斯药物公司 包含环糊精衍生物的可注射美法仑组合物及其制备和使用方法
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4997651A (en) * 1987-11-19 1991-03-05 Poole Stephen W Pharmaceutical formulations
WO2003072082A1 (fr) * 2002-02-22 2003-09-04 Schering Corporation Formulations pharmaceutiques d'agents anti-neoplastiques, notamment la temozolomide et procedes de fabrication et d'utilisation associes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4997651A (en) * 1987-11-19 1991-03-05 Poole Stephen W Pharmaceutical formulations
FI924668A (fi) * 1987-11-19 1992-10-15 Wellcome Found Foerfarande foer framstaellning av vaesentligen ren melfalanhydroklorid
WO2003072082A1 (fr) * 2002-02-22 2003-09-04 Schering Corporation Formulations pharmaceutiques d'agents anti-neoplastiques, notamment la temozolomide et procedes de fabrication et d'utilisation associes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Derwent World Patents Index; AN 1989-152759 *
STOUT, S. A. ET AL.: "The hydrolysis of L-phenylalanine mustard (melphalan)", INTERNATIONAL JOURNAL OF PHARMAEUTICS, vol. 24, 1985, pages 193 - 208 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102458114A (zh) * 2009-05-29 2012-05-16 锡德克斯药物公司 包含环糊精衍生物的可注射美法仑组合物及其制备和使用方法
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
US10940128B2 (en) 2009-05-29 2021-03-09 Cydex Pharmaceuticals, Inc. Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same
US11020363B2 (en) 2009-05-29 2021-06-01 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
WO2012004438A1 (fr) 2010-07-05 2012-01-12 Capital, Business Y Gestión De Finanzas, S.L. Préparation pharmaceutique injectable de melphalane

Also Published As

Publication number Publication date
AR066943A1 (es) 2009-09-23

Similar Documents

Publication Publication Date Title
ES2784629T3 (es) Composiciones farmacéuticas inyectables estables que comprenden 2-hidroxipropil-beta-ciclodextrina y alfaxalona
ES2567716T3 (es) Formulaciones que contienen amiodarona y sulfoalquil éter ciclodextrina
ES2223549T3 (es) Formulacion que contiene moxifloxacino y sal comun.
CN108135980B (zh) 在非质子极性溶剂中制备稳定的胰高血糖素治疗制剂的方法
MXPA02011003A (es) Composiciones farmaceuticas estables de ion metalico-lipido, en polvo, para el suministro de farmacos y metodos de uso.
EP1439830B1 (fr) Composition pharmaceutique d'acide propionique 2-(4-isobutylphenyle)
ES2898425T3 (es) Composición acuosa que comprende dantroleno
KR101777587B1 (ko) 주사가능한 이부프로펜 제제
ES2791349T3 (es) Formulación acuosa que comprende paracetamol e ibuprofeno
WO2012004438A1 (fr) Préparation pharmaceutique injectable de melphalane
MXPA02010740A (es) Composicion farmaceutica similar al gel para la administracion subcutanea que comprende acidos bisfosfonicos o sus sales.
ES2731526T3 (es) Solución farmacéutica de Pemetrexed
WO2007095722A1 (fr) Formules de doxorubicine pour applications anticancéreuses
JP2023093518A (ja) 沈殿抵抗性低分子薬物製剤
ES2843723T3 (es) Formulaciones farmacéuticas inyectables de lefamulina
EP1848419B1 (fr) Preparations injectables de diclofenac et sels acceptables sur le plan pharmaceutique de celui-ci
ES2866981T3 (es) Disolución de levodopa para infusión
WO2009150278A1 (fr) Composition pharmaceutique de melphalan
ES2198424T3 (es) Soluciones inyectables listas para el empleo que contienen doxorrubicina.
Singh et al. Design and development of sustained release injectable in situ gel of cytarabine
DK2262493T3 (en) METHODS OF TREATMENT WITH prolonged continuous infusion of Belinostat
KR20090040299A (ko) 특별히 표적화된 국소 투여를 위한 주사용 약제학적 조성물
ES2759621T3 (es) Formulación farmacéutica que contiene curcumina
ES2794093T3 (es) Formulación parenteral de esmolol
US20200338082A1 (en) Formulations, systems, and methods for therapeutic treatment

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09761835

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM1205A DATED 28-03-2011)

122 Ep: pct application non-entry in european phase

Ref document number: 09761835

Country of ref document: EP

Kind code of ref document: A1