Anti-cancer agents with benzophenanthridine structure and preparations containing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using benzophenanthridine alkaloid salts for preparing therapeutic agents for treating tumours, wherein the alkaloid salt is found in the form luteic, phosphatidic or hyaluronic acid, the benzophenanthridine alkaloid salt with phosphatidic acid or hyaluronic acid, and a based pharmaceutical composition for treating tumours.

EFFECT: what is shown is cytotoxic activity of the sanguinarine salts according to the invention at least twice increased in all studied tumour cell lines in relation to the chloride salt; it is suggested to be caused by higher absorption by the tumour cells.

12 cl, 8 ex

 

The present invention relates to the use of benzophenantridin alkaloids and their salts to obtain drugs for the treatment of tumors.

The invention also relates to new salts of the above-mentioned alkaloids containing compositions.

The level of technology

The first target for Oncology is the complete destruction of the tumor by any means, even if it causes serious side effects; the motto of primum non nocere ("first do no harm") is not used as a guide in the treatment of tumors, however, are preferably replaced by primum succerere ("hurry to help").

Cancer treatment usually involves radical surgery, targeted radiotherapy, including photodynamic therapy, large doses of drugs for chemotherapy, radiotherapy and treatment with cytokines (IL2) and monoclonal antibodies. Despite the large, ever-increasing the number of available treatments, the success rate from the point of view of recovery is still unsatisfactory, especially in the case of chemotherapy, because of the emergence of drug resistance.

In solid tumors chemotherapy quickly reduces the mass of the tumor, but not completely; because of the small number of extremely drug-resistant tumor cells can remain active and then to develop, often with fatal outcome. These cells have recently been called trunks the x tumor cells, which have significant potential for proliferation and adaptability. Mentioned cells constitute approximately 5% of the tumor mass and are resistant to all known at the moment tools of chemotherapy. The existence of tumor stem cells was first shown for myeloid leukemia (Bonnet D, Dick JE. Nature Medicine, 3, 730-737 (1997)) and subsequently installed for tumors of the breast and brain (Al-Hajj M, et al., Natl Acad. Sci., USA, 100. 3983-3988, 2003 Sing SK, et al., 432, 396-401, Nature 2004).

Recently, stem cells have been isolated from melanomas, tumors of the colon and lung slices (Ricci-Vitali, Nature 445, 111-115 (2007); D. Fang, Cancer Res., 65, 9328-9337 2005, 'eramo, Cell Death and Differentiation advance online publication, Nov 30. 2007 Doi: 10.1038/sj.cdd.4402283).

These cells, as mentioned above, are not controlled by conventional treatment and regenerate the tumor. Consequently, there is an urgent need for the development of compounds able to inhibit stem tumor cells, possibly through induction of apoptosis.

Description of the invention

At the moment it is known that benzophenantridin alkaloids, especially sanguinarine, chelerythrine, chelidonine and their salts luteomas, phosphatide or hyaluronic acids exert an antiproliferative effect on multidrug-resistant tumor stem cells in.

In particular, salt luteomas acid provide a strong cytotoxic effect against cancer to ATOC and the same strong antiangiogenic, anti-inflammatory and analgesic effect.

Thus, the first object of the invention relates to the use of benzophenantridin alkaloids and their salts to obtain drugs for the treatment of tumors.

A second object of the present invention provides a new salt benzophenantridin alkaloids and phosphatide or hyaluronic acid. Mentioned salts are particularly useful for targeting local or systemic injection.

In an additional aspect, the invention provides complexes benzophenantridin or isoquinoline alkaloids with human albumin in the form of nanoparticles and dispersions containing the above-mentioned complexes, which can be administered intravenously or orally. Nanoparticles selectively reach the tumor, where they exert cytotoxic and antiangiogenic effect of reducing the mass of the tumor. This drug is particularly useful for the treatment of solid tumors and more conventional forms of leukemia.

Phosphatidic acid contain residues of fatty acids, which may be the same or different, saturated or unsaturated unbranched chains containing 12-22 carbon atoms.

Preferred dipalmitoyl and distearoylphosphatidylcholine acid, which significantly increase oral and local bioavailability.

Particularly preferred salts of sanguinarine is with phosphatidic acid.

Salts according to the invention is able to induce apoptosis of tumor stem cells in submicromolar concentrations.

In vitro it was shown that salt sanguinarine and luteomas acid has a strong inhibitory effect against melanoma and stem cells of the colon at a concentration of 200 ng/ml. Her behavior towards other cancer stem cells is identical. These alkaloids can therefore be regarded as antitumor agents of a new generation, able to effectively treat tumors of the person. For tumors of the colon, liver, pancreas and cervix the most appropriate form is a salt with luteomas acid, dispersed in a suitable carrier, whereas for the treatment of skin tumors, such as melanoma, can successfully enter the salt of phosphatidic acid topically directly on the area affected by the tumor.

Complexes with albumin suitable for the introduction using Loco-regional injection at a dose much lower than the toxic dose, and over very long periods; the selectivity to stem tumor cells compared with normal cells and a strong antiangiogenic effect leads to a rapid reduction and possible elimination of the tumor.

More suitable for oral and topical introduction is salt sanguinarine, luteo the Oh of the acid. It is shown that the said salt is especially effective in the treatment of oropharyngeal cavity, head and neck tumors, melanoma and tumors of the cervix, to a greater extent than the alkaloids that are not associated with the acid, plus it affects any viruses associated with cancer.

Also useful salts of hyaluronic acid, increasing the intake of alkaloid cell and allowing it to destroy the tumor.

The preparations obtained in the course of well known processes such as described in "Remington''s Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA, together with suitable excipients.

The examples below illustrate details of the invention.

Example I to Obtain salt luteomas acid and sanguinarine

3,68 g of sanguinarine chloride dissolved in 100 ml of ethanol, while stirring, 3.6 g of luteolata potassium, the mixture react for 3 hours the Formed potassium chloride is filtered off and the solution concentrated to a small volume. Obtain 5.6 g of salt.

Example II to Obtain salts of sanguinarine and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol)

3.7 g of sanguinarine chloride dissolved in 50 ml of methanol; this solution with stirring, 7.5 g of sodium salt of 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol)-1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol), and the mixture is left for 2 hours under stirring. The resulting solution was diluted with equal about what yamam of methylene chloride and the mixture is left for 0.5 hour with stirring. Precipitated sodium chloride is filtered off and the filtrate is concentrated until dry under vacuum at a temperature not exceeding 35C. Receive 10 g of brown solid substance having a melting point of 70C.

Example III - Receiving albumin nanoparticles with chelerythrine

1 g of chelerythrine dissolved in 15 ml of dioxane at room temperature and added to a solution of 5 g of human albumin in 300 ml of saline solution. The mixture is left under stirring in a sterile atmosphere for 4 h the Resulting opaque solution was exposed to ultrasound for 1 minute. The physical appearance and color of the suspension changes. The solution is dried by sublimation without the addition of excipients.

Example IV

In accordance with the procedures of example III get the solution of chelerythrine and dried by sublimation under sterile conditions in a container, which contains 10 mg of chelerythrine after the process is complete.

The lyophilisate is used in Loco-regional treatment of tumors of the oropharyngeal cavity.

Example V - Anagramania chewable tablets for the treatment of head and neck tumors

Luteal sanguinarine10,00 mg
Soy lecithin30,00 mg
Anhydrous whether the traditional acid 10,00 mg
Lactose240,00 mg
Mannitol550,00 mg
The methylcellulose40,00 mg
Palmitostearate50,00 mg
Berry flavor40,00 mg
Ammonium glycyrrhizinate0.5 mg
Talc10,00 mg

Example VI - Soft gelatin capsules for the treatment of tumors of the cervix

Sanguinarine lutein10,00 mg
Soy lecithin50,00 mg
Beeswax50,00 mg
Ammonium glycyrrhizinate10,00 mg
Vegetable oil in sufficient quantity to800,00 mg

Example VII - Soft gelatin capsules for the treatment of tumors of the cervix

Sanguinarine lutein10,00 mg
Soy lecithin50,00 mg
Beeswax50,00 mg
Sodium succinyl-glycyrrhetic10,00 mg
Vegetable oil in sufficient quantity to800,00 mg

Example VIII - Emulsion oil-in-water salts fosfatidinozitol acid and sanguinarine for the local treatment of melanoma

Salt dipalmitoylphosphatidyl acid and sanguinarine0.40 g
Propylene glycol10,00 g
Isopropylmyristate5,00 g
Cetyl alcohol5,00 g
Polysorbate 803.00 g
Carbomer0.40 g
Methyl parahydroxybenzoate0.10 g
Sodium propyl parahydroxybenzoate 0.05 g
Purified water in sufficient quantity to100 g

1. The use of salts benzophenantridin alkaloids to obtain drugs for the treatment of tumors, where the alkaloid is in salt form luteomas, hyaluronic or phosphatidic acid.

2. The use according to claim 1, where benzophenantridin alkaloids selected from sanguinarine, chelerythrine, chelidonine.

3. The use according to claim 2, where the alkaloid is chelerythrine.

4. The use according to claim 1 of luteolata sanguinarine.

5. The use according to claim 1 salts of sanguinarine and phosphatidic acid.

6. Salt benzophenantridin alkaloids with phosphatidic acid or hyaluronic acid.

7. Salt according to claim 6 with phosphatidic acid.

8. Salt according to claim 7, where phosphatidic acid is dipalmitoyl or distearoylphosphatidylcholine acid.

9. Salt according to claim 7 or 8, where benzophenantridin alkaloid is a sanguinarine.

10. Salt according to claim 7 or 8 as antimelanoma tools.

11. Sol according to claim 9 as antimelanoma tools.

12. Pharmaceutical composition for the treatment of tumors containing salt p-11 as an active ingredient.



 

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