CN1950079A - Pharmaceutical solution formulations containing 17-AAG - Google Patents

Abstract

A pharmaceutical solution formulation containing 17-AAG in an amount of up to 15 mg/mL dissolved in a vehicle comprises(i) a first component that is ethanol, in an amount of between about 40 and about 60 volume %; (ii) a second component that is a polyethoxylated castor oil, in an amount of between about 15 to about 50 volume %; and (iii) a third component that is selected from the group consisting of propylene glycol, PEG 300, PEG 400, glycerol, and combinations thereof, in an amount of between about 0 and about 35 volume %.

Description

The pharmaceutical solution formulations that contains 17-AAG

Invention field

The present invention relates to contain the pharmaceutical solution formulations of 17-allyl amino-17-de-methoxy geldanamycin (" 17-AAG "), and methods for making and using same.

Background of invention

Geldanamycin belongs to the natural product ansamycins, and its member's feature is that the position connects to form Macrocyclic lactams benzenoid form nuclear (benzoquinone or hydroquinone nuclear usually) between two.Except that geldanamycin, Ansamycin also comprises macbecins, herbimycin, TAN-420 and reblastatin.

Geldanamycin and derivant thereof are to study ansamycins the most widely.Though at first the understanding to geldanamycin is the result of screening antibiotic activity, the interest to it mainly is based on its cytotoxicity to tumor cell at present, and thus as the potentiality of cancer therapy drug.It is the inhibitor of HSP-90 (" Hsp90 "), and HSP-90 participates in folding, activate and assembling (" object albumen ") of multiple proteins, comprises the key protein that participates in signal transduction, cell cycle control and transcriptional regulatory.Geldanamycin is upset Hsp90-object protein-interacting with combining of Hsp90, stops object albumen correctly folding, and makes them be subject to the destruction of proteasome-mediation.Sudden change implicit in many cancers or the protein of overexpression: p53, Bcr-Abl kinases, Raf-1 kinases, Akt kinases, Npm-Alk kinases p185 are arranged in Hsp90 object albumen ^ErB2Stride film kinases, Cdk4, Cdk6, Weel (a kind of cell cycle dependant kinase), HER2/Neu (ErbB2) and hypoxia inducible factor-1 α (HIF-1 α).Yet the liver toxicity of geldanamycin and low bioavailability cause its stagnation in clinical practice.

But still interesting exploitation has geldanamycin sample biological activity but has mass spectral geldanamycin derivant of pharmaceutically more acceptable property or analog.With chemical constitution, 17 of geldanamycin have become the focal position of being paid close attention to that is used for synthetic geldanamycin derivant, because its methoxyl group is easy to be replaced by nucleophilic group, obtain that 17-replaces-approach of 17-de-methoxy geldanamycin. with providing convenienceAnd structure-activity relation (SAR) studies show that, can introduce various 17-substituent group on chemistry and the space and do not destroy anti-tumor activity.Referring to, Sasaki etc. for example, US 4,261, and 989 (1981); Schnur etc., US 5,932, and 566 (1999); Schnur etc., J.Med.Chem., 38,3806-3812 (1995); Schnur etc., J.Med.Chem., 38,3813-3820 (1995); With Santi etc., US 2003/0114450 A1 (2003); Its content is included into this paper as a reference.The SAR inference is by Hsp90 and geldanamycin derivant (17-DMAG, as described below) between co-structured (co-structure) of X-ray crystal of complex support, show that the 17-substituent group stretches out and enter solvent (Jez etc., Chemistry from binding pocket; Biology, 10,361-368 (2003)).Therefore, position 17 is to introduce the substituent group of accommodation property such as the site of being paid close attention to of solubilizing group.Know that the geldanamycin derivant that maximum 17-replaces is 17-AAG, be disclosed in Sasaki etc. first, quote the samely, carrying out clinical trial at present.The geldanamycin derivant that another kind of noticeable 17-replaces is 17-(2-dimethyl aminoethyl) amino-17-de-methoxy geldanamycin (" 17-DMAG ", Snader etc., 2004/0053909 A1 (2004)), is also carrying out clinical trial.

Preparation contains the restriction of the pharmaceutical preparation of geldanamycin chemical compound such as geldanamycin body and 17-AAG, especially for parenteral, is the water solublity of its extreme difference, for 17-AAG, only dissolves about 0.1 mg/ml under the neutral pH.(the 17-DMAG dissolubility with alkyl amino is higher).To addressing this problem, Tabibi etc., US 6,682, and 758B1 (2004) has described a kind of preparation that is used for water-insoluble medicine such as 17-AAG, comprises (a) medicine, (b) the water miscible organic solvent of medicine, (c) surfactant and (d) water.The mixable solvent of water can be dimethyl sulfoxine (DMSO), dimethyl formamide, ethanol, glycerol, propylene glycol or Polyethylene Glycol.Surfactant is phospholipid (especially lecithin) preferably.Another is interested openly to be Ulm etc., and WO 03/086381 (2003), and it has described a kind of method for preparing Ansamycin pharmaceutical preparation, and this method comprises that (a) provides the Ansamycin that is dissolved in the ethanol; (b) product with step (a) mixes with medium chain triglyceride, forms first mixture; (c) remove ethanol fully from first mixture; (d) with product and the emulsifying agent and the combination of stabilizers of step (c), to form second mixture; (e) emulsifying second mixture.But optional lyophilizing of emulsive second mixture and rehydration.In a concrete compositions, medium chain triglyceride comprises sad and/or caproic acid, and emulsifying agent comprises phosphatidylcholine, and stabilizing agent comprises sucrose.In addition, Ulm etc., WO 2004/082676 A1 (2004) have described a kind of pharmaceutical composition and have comprised Hsp90 inhibitor such as 17-AAG, emulsifying agent and comprise medium chain and the grease of long chain triglyceride.

Summary of the invention

On the one hand, the invention provides the improved 17-AAG pharmaceutical solutions that is applicable to intravenous administration.This preparation contains the concentration that is dissolved in the carrier 17-AAG up to 15 mg/ml, and carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG 300, PEG 400, glycerol and combination thereof, and content is about 0-35 volume %.Above-mentioned percentage ratio is based on the volume/volume percentage ratio of first, second and the 3rd component cumulative volume.The about 0 volume % of the lower limit of the 3rd component represents that it is an optional components; Promptly can not exist.

On the other hand, the invention provides the method that needs the patient of this medicine 17-AAG, said method comprising the steps of:

(a) provide and contain the concentration that is dissolved in the carrier pharmaceutical solution formulations up to the 17-AAG of 15 mg/ml, carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG 300, PEG 400, glycerol and combination thereof, and content is about 0-35 volume %.

(b) pharmaceutical solution formulations with step (a) is diluted in the water, and preparation contains the dilution preparation up to 3 mg/ml 17-AAG; With

(c) the preparation intravenous with dilution gives the patient.

In another embodiment, provide preparation to contain the method for the pharmaceutical solution formulations of 17-AAG, described method comprises:

(a) provide a certain amount of 17-AAG;

(b) with the 17-AAG and the combination of a certain amount of carrier of step (a), described carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG 300, PEG 400, glycerol and combination thereof, and content is about 0-35 volume %;

(c) mixture of whipping step (b) dissolves basically up to 17-AAG; With

(d) randomly filtration step (c) through stirred mixture, comprise the pharmaceutical solution formulations of 17-AAG with formation;

The amount of the middle carrier of the amount of 17-AAG and step (b) makes the concentration of 17-AAG in pharmaceutical solution formulations up to 15 mg/ml in the step (a).

Detailed Description Of The Invention

Pharmaceutical solution formulations of the present invention is stable, form the clarification purple solution, can be diluted in easily in the water for injection (" WFI "), comprise the preparation that dilutes up to the clarification that is applicable to intravenous injection of 3 mg/ml 17-AAG (preferred 0.2-3 mg/ml) with formation.The preparation of dilution can be stablized a period of time, at least 10 hours, is about 12-24 hour usually.Because stability and aseptic problem do not advise prolonging the storage life of diluting preparation.Do not recommend undiluted preparation administration.

Compare with the prior art preparation, pharmaceutical solution formulations of the present invention has many advantages.Its easily preparation and storing, before using, finally be diluted among the WFI, the step that does not need a plurality of solvents to add, remove and/or add again.It avoids using solvent such as DMSO, owing to its abnormal smells from the patient (or abnormal smells from the patient of its metabolite) causes patient's acceptance poor.Pharmaceutical solution formulations of the present invention allowed to send the 17-AAG of requirement in about 90 minutes of acceptable infusion time.

Preferably, carrier comprises the ethanol (first component) of the about 50 volume % of content, the GREMAPHOR GS32 (second component) of the about 20-30 volume of content % and the 3rd component propylene glycol of the about 20-30 volume of content %.

Propylene glycol can completely or partially be replaced by PEG 300 (300 mean molecule quantities gather (ethylene glycol)), PEG 400 (400 mean molecule quantities gather (ethylene glycol)), glycerol or its combination.

The ethanol USP level of preferably dewatering.Propylene glycol, PEG 300, PEG 400 or glycerol be the USP level preferably.

GREMAPHOR GS32 is as solubilizing agent/emulsifying agent of 17-AAG.Preferably, GREMAPHOR GS32 is the trade name Cremophor that BASF AG produces.Especially preferred is Cremophor EL, though also can use other level other Cremophor, for example Cremophor RH 60, Cremophor CO 40, Cremophor CO 410, Cremophor CO 455, Cremophor CO 60, Cremophor RH 40, Cremophor RH 410 and Cremophor WO 7.It will be understood by those skilled in the art that the preparation based on Cremophor needs carefully to use to a certain extent, because in some patients, occurred untoward reaction.

Though on pharmacopedics, used other Cremophor of various level as formulation auxiliary agents, up to now Cremophor as yet not with the Ansamycin coupling.In fact, Santi etc. do not advise using Cremophor in the Ansamycin preparation among US 2003/0114450 A1 (2003).In the mode of background, the exemplary of the preparation that contains Cremophor that relates to other medicines openly comprises: Brahm, and US 5,583, and 153 (1996); Gao etc., US6,121,313 (2000); Kuo etc., US 6,214,803 B1 (2001); Chen etc., US 6,555,558 B2 (2003); Xiang etc., US 6,653,319 B1 (2003); Whittle etc., US 2003/0021752 A1 (2003); Gao etc., US 2003/0044434 A1 (2003); Jiang etc., US 2003/0091639 A1 (2003); Hauer etc., US 2003/0104990 A1 (2003); Cai etc., US 2003/0114485 A1 (2003); Stanislaus, US 2003/0119909 A1 (2003); Naicker etc., US 2003/0171264 A1 (2003); Dong etc., US 2003/0198619 A1 (2003); Dong etc., US 2003/0232078 A1 (2003); Metcalfe etc., US 2004/0033243 A1 (2004); Namburi etc., US 2004/0052847A1 (2004); With Danishefsky etc., US 2004/0053910 A1 (2004).The content of above-mentioned document is included in this by reference.

In the preparation process of carrier, preferably merge first, second and the 3rd component with the order that hereinafter itemizes.That is, first component and second component are merged, and then the 3rd component is joined in first and second components of merging.

After the preparation carrier, can be prepared as follows pharmaceutical solution formulations: the 17-AAG that takes by weighing scheduled volume places suitable containers, adds the carrier of scheduled volume then.Then, stir 17-AAG and carrier up to the 17-AAG dissolving (preferably continue at least 6 hours, more preferably at least 10 hours, most preferably 12-14 hour or spend the night), filtration is preferably passed through 0.22 μ filter, so that pharmaceutical solution formulations of the present invention to be provided.Stirring can at room temperature or in the refrigerator be carried out.In case preparation preferably is stored in preparation in the refrigerator, preferred temperature is between-20 to 4 ℃.The brown glass test tube is used in suggestion or other suitable containers protects 17-AAG in order to avoid illumination.As mentioned above, the concentration of 17-AAG can be preferably the 2-15 mg/ml up to 15 mg/ml.

Carrier comprises first, second and the 3rd component, and expression also can comprise other composition.But, one preferred embodiment in, carrier is made of first, second and the 3rd component of above-mentioned relative quantity basically, and this just represents that carrier is limited to above-mentioned three kinds of components and those can not influence the basic feature of pharmaceutical solution formulations of the present invention and the component of new feature in fact.

Geldanamycin is well-known natural product, obtains by cultivating generation biological Ge Erde streptomyces hygroscopicus (Streptomyces hygroscopicus var.geldanus) NRRL 3602.As Sasaki etc., US4,261,989 (1981) is described, and by geldanamycin and allyl amine reaction, from the semi-synthetic preparation of geldanamycin 17-AAG, the content of the document is included in this by reference.

The 17-AAG that gives by pharmaceutical solution formulations of the present invention can be used for treating disease, such as but not limited to: excess proliferative disease, for example incidence cancer such as head, cervical region, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, pharynx, larynx, hypopharynx, salivary gland tumor and paraganglioma; Liver and biliary system cancer, especially hepatocarcinoma; Intestinal cancer, especially colorectal carcinoma; The treatment ovarian cancer; Minicell and nonsmall-cell lung cancer; Carcinosarcoma of breast, for example fibrosarcoma, malignant fibrohistiocytoma, embryonal rhabdomyosarcoma (rhabdomysocarcoma), leiomyosarcoma (leiomysosarcoma), neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma and alveolar soft part sarcoma; Central nervous system's neoplasm, the especially brain cancer; How outstanding gold (Hodgkin) lymphoma of lymphoma, lymph-plasma cell sample lymphoma, follicular lymphoma, mucosa associated lymphoid tissue lymphoma, mantle cell lymphoma, B-cellularity large celllymphoma, Burkitt ' s lymphoma and T-iuntercellular degeneration large celllymphoma.Clinically, size or reducing of quantity and/or the alleviating of related symptoms (being suitable for the place) of implementing methods described herein and using compositions described herein can cause cancer to be grown.On the pathology, implement methods described herein and use compositions described herein will produce related diseases effect of science, for example: anticancer is bred, and reduces the size of cancer or tumor, prevents from metastasis and suppress tumor vessel to take place.The method for the treatment of these diseases comprises the present composition that gives object treatment effective dose.Can repeat this method when needing.

By giving also can to treat the non-cancer disease that is characterized as cell hyperproliferation according to 17-AAG of the present invention.The illustrative example of these diseases includes but not limited to: atrophic gastritis, the inflammatory hemolytic anemia, transplant rejection, the inflammatory neutropenia, bullous pemphigoid, celiac disease, demyelinating neuropathy, dermatomyositis, inflammatory bowel (ulcerative colitis and Crohn ' s disease), multiple sclerosis, myocarditis, myositis, nasal polyp, chronic sinusitis, pemphigus vulgaris, primary glomerulonephritis, psoriasis, surgical adhesions, narrow or restenosis, scleritis, scleroderma, eczema (comprises atopic dermatitis, irritant dermatitis, allergic dermatitis), periodontal disease (being periodontitis), POLYCYSTIC KIDNEY DISEASE and type i diabetes.Other example comprises: vasculitis (for example, giant cell arteritis (temporal arteritis, Takayasu ' s arteritis), polyarteritis nodosa, allergic angiitis and granulomatosis (Churg-Strauss disease), the polyangitis overlap syndrome, hypersensitivity vasculitis (Henoch-Schonlein purpura), serum sickness, drug-induced vasculitis, infectious vasculitis, the hypertrophy vasculitis, the vasculitis that connective tissue disease is relevant, congenital defect of complement system related artery inflammation, Wegener ' s granulomatosis, Kawasaki ' s disease, central nervous system's vasculitis, Buerger ' s disease and systemic sclerosis); Gastroenteropathy (for example, pancreatitis, Crohn ' s disease, ulcerative colitis, proctitis ulcerosa, primary sclerosing cholangitis, any reason comprise the benign stricture (for example, bile duct, esophagus, duodenum, small intestinal or colon is narrow) that imaginary (ideopathic) causes; Respiratory tract disease (for example, the pneumoconiosis of asthma, hypersensitivity pneumonitis, asbestosis, silicatosis and other form, chronic bronchitis and chronic obstructive airway disease); Nose lacrimal passage disease (for example, all reasons comprise that imaginary (ideopathic) causes narrow); With pharynx drum (eustachean) pipe disease (for example, all reasons comprise imaginary cause narrow).

17-AAG can be with other anticancer or cell toxicity medicament administering drug combinations, these anticancer or cell toxicity medicaments comprise: alkylating agent, angiogenesis inhibitor, antimetabolite, dna cleavage agent, DNA cross-linking agent, DNA intercalator, DNA minor groove binding, inhibitor of heat shock protein 90, histone deacetylase inhibitor, microtubule stabilizer, nucleoside (purine or pyrimidine) analog, protease inhibitor, topoisomerase (I or II) inhibitor, tyrosine kinase inhibitor.Concrete anticancer or cell toxicity medicament comprises: β-lapachol, 17-DMAG, bicalutamide, bleomycin, bleomycin, bortezomib (bortezomib), busulfan, calicheamycin, camptothecine, capecitabine, callistatin A, CC-1065, cisplatin, latent algin (cryptophycins), daunorubicin, discodermolide, docetaxel, doxorubicin, many card Mi Xing (duocarmycin), dynemycin A, Epothilones, etoposide, floxuridine, floxuridine, fludarabine, fluorouracil, gefitinib, geldanamycin, gemcitabine, hydroxyurea, imatinib, interferon, interleukin, irinotecan, leptomycin B, methotrexate, ametycin, oxaliplatin, paclitaxel, halitoxin (spongistatins), suberoylanilide hydroxamic acid (SAHA), plug is for group, hycamtin, Trichostatin A, vinblastine, vinblastine and vindesine.

Anticancer or the cell toxicity medicament of parallel administration can be a kinases inhibitor, comprising: quinazoline, especially 4-anilinoquinazoline, for example Iressa (AstraZeneca; N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-[3-(4-morpholinyl) propoxyl group]-4-quinazoline amine) and Tarceva (Roche/Genentech; N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine mono-hydrochloric salts); Phenyl amino-pyrimidine, for example Gleevec (Novartis; 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridine radicals)-2-pyrimidine radicals] amino]-phenyl] Benzoylamide); Pyrrolo--and pyrazolopyrimidine, for example BIBX 1382 (Boehringer Ingelheim; N8-(3-chloro-4-fluorophenyl)-N-2-(1-methyl-4-piperidyl)-pyrimido [5,4-d] pyrimidine-2, the 8-diamidogen); Indole and hydroxyindole, for example Semaxinib (Pharmacia; 3-[(3,5-dimethyl-1H-pyrroles-2-yl) methylene]-1,3-dihydro-2H-indol-2-one); The benzylidene Cyanoacetyl-Cyacetazid; Flavone, for example flavopiridol (Aventis; 2-(2-chlorphenyl)-5,7-dihydroxy-8-[(3S, 4R)-3-hydroxyl-1-methyl-4-piperidyl]-4H-1-.alpha.-5:6-benzopyran-4-ketone); Staurosporine, for example CEP-701 (Cephalon); Antibody, for example Herceptin (Genentech); And ribozyme, for example Angiozyme (Ribozyme Pharmaceuticals).

When using pharmaceutical solution formulations of the present invention, according to administration frequency, the dosage that gives 17-AAG be about the 4-4000 milligram/square metre.17-AAG preferred dosage scheme is weekly about 450 milligrams of/square metre (Banerji etc., Proc.Am.Soc.Clin.Oncol., 22,199 (2003, abstract 797), " the I clinical trial phase of heat shock protein 90 (HSP90) inhibitor 17-pi-allyl-17-de-methoxy geldanamycin (17AAG) that pharmacokinetics (PK)-pharmacodynamics (PD) instructs " (" A Pharmacokinetically (PK)-pharmacodynamically (PD) GuidedPhase I Trial of the Heat Shock Protein 90 (HSP90) Inhibitor 17-Allyl-17-demethoxygeldanamycin (17AAG) ").Perhaps, give about 308 milligrams/square metre of dose weekly.Referring to Goetz etc., Eur.J.Cancer, 38 (Supp.7), S54-S55 (2002), " 17-pi-allyl-amino-geldanamycin (17-AAG) is the I clinical trial phase among the cancer patient late " (" A phase I trial of 17-Allyl-Amino-Geldanamycin (17-AAG) in patients with advanced cancer ").Another kind of dosage is weekly twice, dosage 220-340 milligram/square metre (preferred 220 milligrams/square metre or 340 milligrams/square metre).Can be used for dose scheme with another kind of medicine such as docetaxel therapeutic alliance and be every giving this two kinds of medicines three weeks, the dosage of each administration 17-AAG improves and reaches 650 milligrams/square metre.

Will be further understood that enforcement of the present invention with reference to the following examples, these embodiment only are exemplary and not restrictive.

Embodiment 1

Present embodiment has been described the preparation of the carrier that uses in the preparation of the present invention, and carrier comprises 50 volume % ethanol, 20 volume %Cremophor EL and 30 volume % propylene glycol.(394.5g) (BASF Aktiengesellschaft, 200mL 210g) mix with Cremophor EL for USP, 500mL with dewatered ethanol.Above-mentioned two kinds of components are mixed with after forming uniform liquid, and the adding propylene glycol (USP, 300mL, 310.8g).Compositions is mixed to evenly once more, filters, obtain 1 elevator carrier by 0.22 μ filter.

Embodiment 2

According to the conventional method of embodiment 1, use 450mL (355.1g) ethanol, 280mL (294g) Cremophor EL and 270mL (279.5g) propylene glycol, prepare the carrier of another batch 1L.Obtain comprising the carrier of 45 volume % ethanol, 28 volume %Cremophor EL and 27 volume % propylene glycol.

Embodiment 3

According to the conventional method of embodiment 1, use 500mL (394.5g) ethanol, 150-500mL (157.5-525g) Cremophor EL and 0-350mL propylene glycol, prepare the carrier of another crowd of 1L.Obtain comprising the carrier of 50 volume % ethanol, 15-50 volume %Cremophor EL and 0-35 volume % propylene glycol.

Embodiment 4

Present embodiment has been described and has been used the carrier of the foregoing description preparation to prepare pharmaceutical solution formulations of the present invention.Accurately take by weighing 17-AAG (1.0g) with analytical balance and place clean glass container.(95mL) joins in the container with carrier, stirs to dissolve fully up to 17-AAG.With remaining carrier the solution final volume is adjusted to 100.0mL.Then, solution is filtered by 0.22 μ filter to guarantee aseptic and to be stored under 4 ℃.

Embodiment 5

Pharmaceutical solution formulations of the present invention stable as follows.Two groups of sample formulation according to embodiment 1 are stored in respectively under 5 ℃ (" sample A ") and 25 ℃ (" sample B ").Get the aliquot of each sample at the 0th day, the 17th day and the 23rd day and be diluted to final theoretical concentration 400 μ g/mL 17-AAG.Measure purity and the concentration of 17-AAG in each aliquot with reversed-phase HPLC.The result is shown in Table A:

Table A-17-AAG stability of formulation
				Sample	Natural law	17-AAG *
Concentration (μ g/mL)	Purity (%)
		A(5℃) B(25℃)	0 17 23 0 17 23			10.53 10.97 10.39 10.53 10.88 10.19	97.62 96.93 96.89 97.62 96.28 96.10

^*Relating to is the meansigma methods of four samples

The long-time stability data of preparation of the present invention are shown in table B:

Condition of storage	Time (moon)	Purity (%)
			-20±5℃	0	98.4
1	98.9
		2		98.9
3	98.7
		6		98.5
9	98.1
		12		98.2
5±3℃	0				98.4
		1	98.9
	2			98.8

	3	98.7
			6	97.4
	9	96.7
			12	95.9
	25 ± 3 ℃ of 60 ± 5% relative humidity	0			98.4
1			96.9
		2		95.7
3			93.9
		6		87.1
9			77.5
		12		71.9

The above results shows, even preparation of the present invention at room temperature stores (storing though be recommended in the refrigerator), is stable at least three weeks or longer time.

Above-mentioned detailed description of the present invention comprises briefly or exclusively relates to the paragraph of concrete part of the present invention or aspect.Should understand this is that special characteristic can be relevant with a described more than paragraph for clear and convenient, and content described herein comprises all the suitable information combination in the different paragraphs.Similarly, though each chart described herein and the concrete embodiment of the present invention of explanation expression, should understand, when concrete feature is described in the content of concrete chart or embodiment, to a certain extent, these features also can be used in the content of other chart or embodiment, with the further feature combination, or in whole summary of the invention.

All documents that this description is quoted are included into this paper as a reference.

Claims (27)

1. pharmaceutical solution formulations, described preparation comprise the concentration that is dissolved in the carrier 17-AAG up to 15 mg/ml, and described carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG300, PEG 400, glycerol and combination thereof, and content is about 0-35 volume %.

2. pharmaceutical solution formulations as claimed in claim 1 is characterized in that, described second component is Cremophor EL.

3. pharmaceutical solution formulations as claimed in claim 1 is characterized in that, described the 3rd component is a propylene glycol.

4. pharmaceutical solution formulations as claimed in claim 1 is characterized in that, described carrier comprises first component that content is about 45-50 volume %, and content is about second component of 20-30 volume % and the 3rd component that content is about 20-30 volume %.

5. pharmaceutical solution formulations as claimed in claim 4 is characterized in that, described second component is Cremophor EL, and described the 3rd component is a propylene glycol.

6. pharmaceutical solution formulations as claimed in claim 1 is characterized in that, described carrier comprises about 50 volume % ethanol, about 20 volume %Cremophor EL and about 30 volume % propylene glycol.

7. pharmaceutical solution formulations as claimed in claim 4 is characterized in that, described carrier comprises about 45 volume % ethanol, about 28 volume %Cremophor EL and about 27 volume % propylene glycol.

8. pharmaceutical solution formulations as claimed in claim 1 is characterized in that, does not have described the 3rd component.

9. method that needs the patient 17-AAG of this medicine said method comprising the steps of:

(a) provide and contain the concentration that is dissolved in the carrier pharmaceutical solution formulations up to the 17-AAG of 15 mg/ml, described carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG 300, PEG400, glycerol and combination thereof, and content is about 0-35 volume %.

(b) pharmaceutical solution formulations with step (a) is diluted in the water, and the dilute solution that contains up to 3 mg/ml 17-AAG is provided; With

(c) just the dilute solution intravenous of step (b) gives the patient.

10. method as claimed in claim 9 is characterized in that, described second component is Cremophor EL.

11. method as claimed in claim 9 is characterized in that, described the 3rd component is a propylene glycol.

12. method as claimed in claim 9 is characterized in that, described carrier comprises first component that content is about 45-50 volume %, and content is about second component of 20-30 volume % and the 3rd component that content is about 20-30 volume %.

13. method as claimed in claim 12 is characterized in that, described second component is CremophorEL, and described the 3rd component is Cremophor EL.

14. method as claimed in claim 9 is characterized in that, described carrier comprises about 50 volume % ethanol, about 20 volume %Cremophor EL and about 30 volume % propylene glycol.

15. method as claimed in claim 9 is characterized in that, described carrier comprises about 45 volume % ethanol, about 28 volume %Cremophor EL and about 27 volume % propylene glycol.

16. method as claimed in claim 9 is characterized in that, does not have described the 3rd component.

17. method as claimed in claim 9 is characterized in that, described 17-AAG with about 4-4000 milligram/square metre amount give.

18. method as claimed in claim 9 is characterized in that, described 17-AAG gives with about about weekly 450 milligrams/square metre amount.

19. method as claimed in claim 9 is characterized in that, described 17-AAG gives with about about weekly 308 milligrams/square metre amount.

20. a method for preparing the pharmaceutical solution formulations that contains 17-AAG said method comprising the steps of:

(a) in container, provide a certain amount of 17-AAG;

(b) with the 17-AAG and the combination of a certain amount of carrier of step (a), described carrier comprises (i) first component ethanol, and content is about 40-60 volume %; (ii) the second component GREMAPHOR GS32 is about 15-50 volume %; (iii) the 3rd component is selected from propylene glycol, PEG 300, PEG 400, glycerol and combination thereof, and content is about 0-35 volume %;

(c) mixture of whipping step (c) dissolves basically up to 17-AAG; With

(d) mixture after being mixed of filtration step (c) randomly comprises the pharmaceutical solution formulations of 17-AAG with formation;

The amount of the middle carrier of the amount of 17-AAG and step (b) makes the concentration of 17-AAG in pharmaceutical solution formulations up to 15 mg/ml in the step (a).

21. method as claimed in claim 20 is characterized in that, described second component is CremophorEL.

22. method as claimed in claim 20 is characterized in that, described the 3rd component is a propylene glycol.

23. method as claimed in claim 20 is characterized in that, described carrier comprises first component that content is about 45-50 volume %, and content is about second component of 20-30 volume % and the 3rd component that content is about 20-30 volume %.

24. method as claimed in claim 23 is characterized in that, described second component is CremophorEL, and described the 3rd component is Cremophor EL.

25. about 20 volume %Cremophor EL and about 30 volume % propylene glycol.

26. method as claimed in claim 20 is characterized in that, described carrier comprises about 45 volume % ethanol, about 28 volume %Cremophor EL and about 27 volume % propylene glycol.

27. method as claimed in claim 20 is characterized in that, does not have described the 3rd component.