Kahalalide f

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to novel compositions and using kahalalide F, to a set containing the kahalalide F composition and to a reduced solution prepared from the kahalalide F composition. Combination of non-ionic surface-active substance and organic acid is suitable for using with a filling agent for preparing lyophilized formulation of kahalalide F.

EFFECT: improved preparing method.

10 cl, 7 ex

 

This invention relates to kahalalide F, peptide, isolated from herbivorous marine species of mollusk Elysia rufescens.

The premise of the INVENTIONS

Kahalalide F is an object of the European patent 610078. In the patent reported activity directed against cell cultures of human lung carcinoma A-549 and carcinoma human colon HT-29 in vitro.

More detailed information regarding kahalalide F can be found, for example, in the following publications:

The absolute stereochemistry of kahalalide F. Goetz, Gilles; Yoshida, Wesley Y.; Scheuer, Paul J. Dep. Chemistry, Univ. Hawaii, Honolulu, HI, USA. Tetrahedron (1999), 55 (25), 7739-7746.

[Erratum to document cited in CA131: 157974]. Tetrahedron (1999), 55(40), 11957.

Kahalalides: bioactive peptides from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp. Hamann, Mark T.; Otto, Clifton S.; Scheuer, Paul J.; Dunbar, D. Chuck. Department of Chemistry, University of Hawaii of Manoa, Honolulu, HI, USA. J. Org. Chem. (1996), 61 (19), 6594-6600.

[Erratum to document cited in CA125: 190997]. J. Org. Chem. (1998), 63 (14), 4856.

The marine environment: A resource for prototype antimalarial agents. El Sayed, Khalid A.; Dunbar, Charles D.; Goins, D. Keith; Cordova, Cindy R.; Perry, Tony L.; Wesson, Keena J.; Sanders, Sharon C.; Janus, Scott A.; Hamann, Mark T. the Development Center Natural Products, University of Mississippi, University, MS, USA. J. Nat. Toxins (1996), 5 (2), 261-285.

The antitumoral compound Kahalalide F acts on cell lysosomes. Garcia-Rocha, Mar; Bonay, Pedro; Avila, Jesus. 28049-Madrid, Spain. Cancer Lett. (Shannon, Irel.) (1996), 99 (1), 43-50.

Kahalalide F: a bioactive depsipeptide from the sacoglossan mollusk Elysia rufescens and the green alga Bryopsis sp. Hamann, Mark T.; Scheuer, Paul J. Dep. Chem., Univ. Hawaii, Honolulu, HI, USA. J. Am. Chem. Soc. (1993), (13), 525-6.

The INVENTION

The authors presented new songs and new applications kahalalide F.

PREFERRED OPTIONS.

The combination of non-ionic surfactants and organic acids suitable for use with a filler to obtain liofilizovannyh form kahalalide F, suitable for reconstitution. Reconstitution is preferably carried out using a mixture of emulsifying solubilizer, alcohol and water.

Liofilizovannye composition preferably contains mostly filler, namely, at least 90% or at least 95% filler. Examples of fillers are well known and include sucrose and mannitol. You can use other fillers.

Non-ionic surface-active agent in liofilizovannyh composition preferably is an ester of sorbitan, more preferably an ester of polyethylenimine, such as alkanoic of polyoxyethylenesorbitan, in particular monooleate of polyoxyethylenesorbitan, for example Polysorbate 80. The nonionic surfactant is usually a small % of the composition, such as from 0 to 5% of the composition, for example 2-3% of the composition.

Organic acid in liofilizovannyh composition is typically aliphatic acid, preferably hydroxycarboxylic acid, and more preferably in oxycarbonate acid, especially citric acid. Typically, the organic acid is a small % of the composition, such as from 0 to 5% of the composition, for example 2-3% of the composition.

The number kahalalide F in liofilizovannyh composition is usually less than 1% or often less than 0.1% of the mixture. A suitable amount is in the range from 50 to 200 μg, such as about 100 μg to 100 mg of the composition.

Emulsifying solubilizer for prerestore means, respectively, contains ester of polyethylene glycol, especially an ester of a fatty acid, more preferably oleate PEG, such as oleate PEG-35. Emulsifying the solubilizer is, respectively, from 0 to 10% prerestore funds, usually about 3-7%, for example about 5%. Alcohol is typically ethanol and is, correspondingly, from 0 to 10% prerestore funds, usually about 3-7%, for example about 5%. The rest of prerestore means is water, and the tool produces the recovered solution, suitable for intravenous injection.

For infusion kahalalide F suitable may be additional dilution of the recovered solution of 0.9% saline solution.

In a particularly preferred embodiment, liofilizovannye composition contains 100 µg kahalalide F; 75 to 125 mg to 100 mg of a filler; 1-3 mg, basically about 2 mg, acids and 1-3 mg, basically 2 mg, non-ionic surfactants.

In addition, the preferred prerestore tool contains 2-7%, for example about 5%, emulsifying a solubilizer; 2-7%, for example about 5%, of alcohol, and the rest is water.

The invention also relates to kits comprising separate containers liofilizovannye composition and prerestore tool. Also presents methods of reconstitution.

This invention also relates to a method of treating any mammal, especially human, affected by a malignant tumor, which includes the introduction of the affected individual a therapeutically effective amount of a pharmaceutical composition obtained by the reconstitution liofilizovannyh compositions according to this invention. The invention, in particular, can be used to treat patients with refractory malignant tumors that do not respond positively to other treatments. In particular, compositions according to this invention can be used after attempts have been made to conduct another chemotherapy, which did not give results.

In one embodiment, for infusion is prepared recovered solution and administered over a 3-hour infusion at concentrations up to about 20 what does 25 mg/ml, usually up to 15 µg/ml. the Right equipment for infusion preferably includes glass, not a plastic container. The tube is preferably made of silicone.

Another aspect of this invention relates to new applications kahalalide F. In particular, the authors suggest its use against prostate cancer and, in particular, androgen-independent prostate cancer, breast cancer, colon cancer, lung cancer, ovarian cancer and for the treatment of neuroblastoma. Kahalalide F also shows activity against dedifferentiated and mesenchymal chondrosarcoma and osteosarcoma. For new applications, you can use the new pererestorani compositions presented in this invention, though other compositions.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or oral, local or parenteral administration, and they may contain purified connection or combination with any carrier or other pharmacologically active compounds. These compositions may be required in a sterile form for parenteral administration.

Introduction compounds or compositions according to this innovation is the invention can be accomplished in any suitable way, such as intravenous infusion, oral drugs, intraperitoneal and intravenous administration. The authors preferred to use the time of infusion up to 24 hours, more preferably 2-12 hours, with the most preferred time is 2-6 hours. Especially desirable short periods of time infusion, allowing treatment without having to stay in hospital overnight. However, you may require infusion for 12-24 hours and even longer. The infusion can be performed with suitable intervals, for example of 2-4 weeks. In the alternative Protocol dosing kahalalide F, for example, is administered about 1 hour for 5 consecutive days every 3 weeks. Can be developed for other protocols as options.

Pharmaceutical compositions containing the compounds according to the invention can be delivered using encapsulation in liposomes or nanospheres, in the compositions of extended release or other standard delivery methods.

The exact dose of the compounds will vary in accordance with the specific composition, method of application and the particular site, host and tumor, which is subjected to the treatment. Note should be taken of other factors, such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, the Combi is the situation of medicines, sensitivity to the reactions and the severity of the disease. The introduction can be performed continuously or periodically within the maximum tolerated dose.

The compounds and compositions according to this invention can be used with other drugs to provide a combination therapy. Other medicines can also be part of the same composition, or be provided as a separate composition for administration at the same time or at another time. The nature of the other drugs not specifically limited, and suitable candidates include

a) medicines with antimicrobial activity, especially funds, targeting elements of the cytoskeleton, including modulators of microtubules, such as taxonomie drugs (such as Taxol, paclitaxel, Taxotere, docetaxel), podophyllotoxin or Vinca alkaloids (vincristine, vinblastine);

b) antimetabolites drugs, such as 5-fluorouracil, cytarabine, gemcitabine, purine analogs, such as pentostatin, methotrexate;

c) alkylating agents such as nitrogen mustards such as cyclophosphamide or ifosfamide);

d) drug target is DNA, such as anthracycline drugs adriamycin, doxorubicin, headlight is orubicin or epirubicin;

e) drug target are topoisomerases such as etoposide;

f) hormones and agonists or antagonists hormones, such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leuprorelin, goserelin, cyproteron or octreotide;

g) of the medicinal product, the target of which is to signal transduction in tumor cells, including derivatives of antibodies, such as Herceptin;

h) alkylating drugs such as platinum drugs (cisplatin, carboplatin, oxaliplatin, paraplatin) or nitrosoanatabine;

i) drugs potentially affecting metastasis of tumours such as inhibitors of matrix metalloproteinases;

j) agents for gene therapy and antisense agents;

k) a therapeutic agent based on antibodies;

l) other bioactive compounds derived from marine organisms, especially didemnin, such as aplidine, or ecteinascidin, such as Et-743.

EXAMPLES of INVENTIONS

Experimental work, which explains the invention described in the following examples.

Example 1

Development of liofilizovannyh parenteral pharmaceutical composition kahalalide F, KF.

The aim of this study was to develop a stable parenteral compositions KF for IP is of use in early clinical trials.

Ways

The solubility and stability of the KF investigated depending on the concentrations of Polysorbate 80 (P80; 0.1 to 0.5% wt./about.) and citric acid monohydrate (CA; 5-15 mm), using the method of experimental design. Stability liofilizovannyh products KF containing crystalline (mannitol) or amorphous (sucrose) fillers, investigated at +50C and +300With in the dark. Liofilizovannye products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry. Conducted research extract after reconstitution of liofilizirovannogo product KP and further cultivation in the liquid for infusion, in order to choose the best filler for reconstitution.

Results

Found that the combination of P80 and CA is required to solubilize KF. Liofilizovannye products were much less stable with increasing concentrations of P80 and CA, the main impact of the concentration of P80. For further study chose a combination of 0.1% wt./about. P80 and 5 mm CA. Liofilizovannye products containing as filler sucrose were more stable compared with products containing mannitol. Determined the glass transition temperature of the product on the basis of sucrose, which amounted to +460C. Amorphous state of the product was confirmed by IR analysis. Rest the R, consisting of Cremophor EL, ethanol and water for injection (5/5/90% vol./about./about. CEW) kept KF in solution after reconstitution and further dilution with 0.9% NaCl (normal saline) up to 0.5 μg/ml

Conclusion

Presents a stable liofilizovannye composition containing 100 μg kahalalide F, 100 mg of sucrose, 2.1 mg CA and 2 mg P80, which must prerestart using a filler consisting of 5/5/90% vol./about./about. CEW, and further diluted using normal saline.

Example 2

Compatibility and stability kahalalide F in devices for infusion.

Kahalalide F prepared in pharmaceutical compositions in the form of liofilizovannyh products containing 50-150 μg of active substance per dose. Before intravenous (IV) the introduction of its pererastayut in a solution consisting of Cremophor EL, absolute ethanol and water for injection (CEW, 5/5/90% vol./about./about.) with further dilution in 0.9% wt./about. the sodium chloride for infusion. The aim of this study was to examine the compatibility and stability kahalalide F in various systems for infusion before starting clinical trials. Due to the presence of infusion solution of Cremophor EL was detected leaching of diethylhexylphthalate from vinyl vessels for infusion (PVC, Add-a-Flex®). Loss kahalalide F due to sorption on the contact surface is chestah shown in the case of containers for infusion, consisting of low density polyethylene (LD-PE, Miniflac®). The authors concluded that kahalalide F must be entered within 3-hour infusion at concentrations of 0.5 µg/ml to 14.7 µg/ml, using a set of reference consisting of a glass bottle and silicone tubes. 150 micrograms powder kahalalide F for infusion in a vial, reconstituted in 5/5/90% vol./about./about. CEW, stable in the original container at least 24 hours at room temperature (+20-25°C) and lighting conditions of the environment. Infusion solutions when stored in glass containers for infusion or at room temperature (+20-25°C, in darkness), or in the refrigerator (+2-8°C, in the dark) are stable at least within 5 days after preparation.

Example 3

Toxicological safety kahalalide F in vitro.

The authors assessed the potential toxicity kahalalide F - compounds derived from Hawaiian mollusk Ellysia rubefescens, which shows that he has a strong hemotoksicheskie action directed against tumor cells of prostate and breast cancer neu-1 (sverkhekspressiya Her2).

In the case of analysis of cytotoxicity in vitro CellTiter96 (MTS, Promega) kahalalide displays low toxicity against heart cells (H9c2 (2-1)or skeletal muscle (L8)(LD50=5 mm, 0.6 mm, respectively). In contrast to this is about kahalalide cytotoxic towards liver cells (AML-12) and kidney (NRX-52E) (LD 50=0,17 ám, 1.6 ám, respectively) and exhibits an intermediate toxic to stem myelogenous cells (FDC-P1, LD50=14 µm). The obtained data are in good agreement with data on toxicity in vivo.

The authors also found that the drug at high concentrations is neurotoxic used in the analysis system, and this correlates with data on animals, showing the presence of neurotoxicity above the maximum tolerated dose (MTD). Using fluorescent coloring on the viability (glycosilated ethidium and kaltsin, molecular probes) together with immunocytochemical, the authors determined that kahalalide at a concentration of ˜10 μm toxic to neurons of the Central nervous system (CNS) (positive neurofilaments), but spares astrocytes (positive for glial fibrillar acidic protein), and touch (expressing the substance P) and the motor (positive cholineacetyltransferase) neurons in the spinal cord.

The authors concluded that kahalalide F is a promising drug for the treatment of prostate cancer because of its neurotoxicity is relatively moderate at or below the MTD. In addition, preliminary data show that kahalalide F can manifest itself as an ideal drug for the ecene neuroblastoma subject to availability for delivery due to its selectivity with respect to the neurons of the Central nervous system.

Example 4

Selective antitumor activity kahalalide F.

Kahalalide F is a lysosomal poison that has selectivity in vitro against gormononezawisimy prostate tumors, tumor cells of the breast neu+ (sverkhekspressiya Her2) and for neuroblastoma. Advanced MoA includes the inhibition of erbB2 and blocking EGF receptor, and inhibition of gene expression of TGF. Preclinical models in vivo confirmed the selectivity and sensitivity gormonzavisimykh tumors of the prostate (PC-3 and DU-145) at MTD for rodents 300 µg/kg of body weight. Antiproliferative in vitro studies show equivalent IC50activity in some prostate tumors (0,27 micron PC-3; 0.25 μm DU-145; to 0.73 µm T-10, is 0.24 μm DHM and to 0.19 μm RB), but no activity against sensitive to hormones LnCAP. Other studies show the election, but a little weaker IC50activity against tumor cells of the breast neu+ (2.5 µm SK-BR-3: 2 μm BT-474) and the line of neuroblastoma cells (1 μm BE(2) (C). Research exposure in vitro suggest that the impact KF does not depend on the mode. In most cases, the minimum exposure time for 1 hour as effective as exposure in 48 hours. Moreover, immediate and delayed cytotoxic effects have the same pharmacodynamics and will not increase icehouse with increasing duration of treatment.

In the near future will begin phase 1 clinical trials, including the scheme of introduction of five days per week, for the estimation of KF as a potential chemotherapeutic agents against solid tumors.

Example 5

Analysis of the effects of kahalalide F (PM92102)against samples of human tumors taken directly from patients.

In vitro studies showed the presence of activity of KF, which causes swelling of the cells and ultimately death (Garcia-Rocha, et al., Can Letters 99: 43-50). In this study, fresh samples of human tumors was treated with KF to determine its activity, using analysis based on the cloning of human cancers. One hundred and four specimens of tumor patients was treated with KF in the conditions of continuous exposure for 14 days at concentrations of 0.01, 0.1 and 1.0 μm. Samples were incubated in the system cloning with 2-layer soft agar at 37°C and were removed on day 14 for counting colonies. Colonies formed in the treated cups, compared with the number of colonies formed in untreated control cups, and calculated the percentage of colonies that survive at each concentration. Cup a positive control contained cellular poison orthovanadate sodium (200 mg/ml). Among these samples, approximately 30% can be assessed with appropriate negative and positive control is I. Responses in vitro (inhibitory response detected in 50% survival) was observed in 16% (5/31), 19% (6/31) and 81% (25/31) of the samples at concentrations of 0.01, 0.1 and 1.0 μm, respectively. There had been a positive relationship between concentration and response to KF, with more significant response (81%) was observed at the highest tested concentration (1,0>0,1>0,01). Significant responses were observed in samples of breast cancer (100%), colon cancer (75%), non-small cell lung cancer (100%) and ovarian cancer (91%). KF is a promising antitumor agent, which reacts with a wide range of tumors.

Example 6

Phase I and pharmacokinetic study kahalalide F in patients with advanced androgen-refractory prostate cancer. KF shows antitumor activity both in vitro and in vivo in various models of solid tumors, including breast cancer, colon cancer, non-small cell lung cancer and in particular prostate cancer. At the present time on the basis of selectivity KF spend his further development as a potential anti-cancer remedies for cases of androgen-independent prostate tumors.

PURPOSE: this clinical phase I and pharmacokinetic (PK) study study the PK profiles of toxicity and antitumor activity of KF.

METHODS: KF impose a one-hour intravenous in which usii for five consecutive days every three weeks to patients with advanced or metastatic androgen-refractory prostate cancer. Based on the values of MTD determined in mice chose the initial dose is 20 mg/m2/day, which is equivalent to a total dose of 100 mg/m2. PK-characteristics KF was determined in plasma during the first year. The bioanalysis KF performed the LC-MS/MS. During the study, each patient was also evaluated levels of LDH, AF and especially PSA to determine the activity of KF.

RESULTS AND DISCUSSION

Currently registered 7 patients. The average age of patients was 66 years (limits 54-75). One patient in each level was introduced 20, 40, 80 and 160 µg/m2/day. As a result of increased transaminases 4 patients were injected current dose level of 320 mg/m2/day. The first patient in this study was re-introduced, the dose at the same level. The observed adverse effects were a quickly reversible moderate headache, fatigue, pain and local swelling. The only related drug toxicity up to the present time was rapidly reversible increase in CTC - ASAT level 3 severity, which took place at 320 mg/m2/day. PK studies revealed a linear relationship between dose and AUC throughout the dose limits. Total plasma clearance was 267 ml/min (± 115), and the end of the half-life of intravenous KF in these patients was the 0,46 hour (± 0,13). The maximum concentration in plasma, which was achieved at the level of the current dose (35-50 ng/ml), potentially active against prostate cancer in the count of clonogenic analysis of tumors (activity starting with 15 ng/ml). Still a good move mode. One patient revealed a significant decrease in the PSA level ( > 50%)associated with clinical improvement (decrease in pain). Two other patients experienced a small decrease in PSA, a decrease continues after two cycles. The maximum tolerated dose has not yet been achieved and the investigation continues.

Example 7

Kahalalide F is cytotoxic towards dedifferentiation and the mesenchymal chondrosarcoma, CHSA, and osteosarcoma, OSA, and also to the cells of hepatocellular carcinoma and carcinoma of the prostate. Kahalalide F is not inhibited cell growth CHSA and OSA significantly and had the ability to induce cytotoxic activity even when exposed to cells within a short period of time, like 10 minutes.

1. Composition kahalalide F to treat any mammal, affected by a malignant tumor, in particular person, containing liofilizovannye mixture kahalalide F, up to 5% non-ionic surfactants, up to 5% organic acid and at least 90% filler.

2. Set containing composition according to claim 1, the cat is who added the solution for reconstitution, together with instructions on dilution of the solution for reconstitution, consisting of a mixture of emulsifying a solubilizer, alcohol and water.

3. The recovered solution prepared from a composition according to claim 1 or set 2.

4. The recovered solution according to claim 3, prepared in the reconstitution using the solution for reconstitution, consisting of a mixture of emulsifying a solubilizer, alcohol and water.

5. Diluted recovered solution containing the recovered solution according to claim 3 or 4, prepared by dilution with 0.9% saline to a concentration suitable for infusion kahalalide F.

6. The use of a composition according to claim 1 as a drug for the treatment of malignant tumors.

7. The use of a composition according to claim 1 as a drug for the treatment of prostate cancer, breast cancer, colon cancer, lung cancer, ovarian cancer, for the treatment of neuroblastoma or protivodifteriynuyu or mesenchymal chondrosarcoma or osteosarcoma.

8. The use according to claim 6, whereby the composition according to claim 1 is administered by infusion for about 1 h for 5 consecutive days every 3 weeks.

9. The use according to claim 7, whereby the composition according to claim 1 is administered by infusion for about 1 h for 5 following the Rog consecutive days every 3 weeks.

10. The use according to any one of p-9, according to which a composition according to claim 1 is administered for refractory patients.



 

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35 cl, 11 tbl, 7 ex

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction

The invention relates to the field of medicine and relates to a stable form of anti-cancer drug containing paclitaxel, and how it is received by dissolving crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or mixtures thereof, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, optionally filtering the resulting solution, freezing and removal of the solvent by sublimation under reduced pressure at low temperature, and optional separation of dose in terms providing sterility

The invention relates to pharmaceutical industry

FIELD: organic chemistry, chemistry of peptides.

SUBSTANCE: invention proposes derivative of kahalalide F that is not a mixture of isomers known as kahalalide F wherein a derivative has structure comprising a cyclic moiety and by-side chain and prepared from the formula (I): . This derivative differs from the formula (I) by one or more of the following features: 1-2 amino acids that are not identical with that's as amino acids in the structural formula (I); absence of one or two amino acids in by-side chain of the structural formula (I); 1-10 additional methylene groups in acyl group of the by-side chain of the structural formula (I); 1-5 methylene groups that are absent in acyl group of the by-side chain of the structural formula (I); 1-3 substitutes added to acyl group of the by-side chain of the structural formula (I); 5-methyl-substitute that is absent in acyl group of the by-side chain, and absence of acyl group of the by-side chain.

EFFECT: new structure of compound.

12 cl, 5 tbl, 60 ex

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