MXPA00002516A - Anticancer compositions which can also be employed in. - Google Patents

Abstract

ANOTHER DISEASES ARISING IN TEGUMENTS AND MUCOUS The present invention discloses compositions which due to the synergism between their components they are quite efficient diminishing the percentage of the resistance appearance; its formulation employs substances known for their anticancer properties; these substances belong to four categories: 1.- differentiation inducers (which are substances that transform cancer cells into healthy cells), for instance: retinoic acid calcitriol and hydroquinone. 2. - apoptosis inducers (which are substances that induce the programmed death of cancer cells), such as fenretinide. 3. - cytostatic with high therapeutic index, such as 5- fluorouracil and metothrexate. 4. - steroid hormones with anticancer and ant-inflammatory role, such as hydrocortisone. With these compositions it is possible to make different types of: ointment (balm) spray, solutions, ovules and patches.

Description

ANTICANCEROS COMPOSITIONS THAT CAN ALSO BE USED IN OTHER DISEASES THAT ARE MANIFESTED ON TEGUMENTS AND MUCOUS Lie Jesús Hernández Alcocer, Mexican citizen born in the D.F on November 25, 1 42; with address in Rayo # 19 Col. Jardines del Pedregal and Dr. Gheorghe Ciustea, a Romanian citizen, born on January 1, 1929 in the department of Suceava, Sasca (Romania), which is identified with documents released by the Mexican Institute of Emigration and with Romanian passport. Both propose to homologate an invention called "Anticancer Composition that can also be used in other Diseases that are manifested on Teguments and Mucous".

TOPICAL APPLICATION OF ANTICANCEROS COMPOSITIONS THAT CAN ALSO BE USED IN OTHER DISEASES THAT ARE MANIFEST ON THE TEGUMENTS AND MUCOUS.

• ANALOGUE USES ON TEGUMENTS AND MUCOSA.

Some substances of the compositions made by the inventors are used in different types of ointments such as for example: 1. Efudíx, ointment with 5% 5-fluorouracyl; produced by ROCHE. It is used in keratosis, superficial basal cell epitheliomas and some precancerous conditions. (PLM 1997, page 822). 2. Airol, produced by ROCHE. Ointment with 0.05% retinoic acid, used as keratolytic, treatment of acne, precancerous lesions, etc. (PLM 1997, page 298). a) Eldopaque, 2 and 4% hydroquinone cream, produced by ICN. Used for the treatment of hyperchromia of the skin and for the reduction of melanin synthesis induced by ultraviolet rays. (PLM 1999, page 886). b) Eldoquin, 2 and 4% hydroquinone cream, produced by ICN. Used for the same purpose (PLM 1999, page 887). c) Bustillos White Cream, 4% hydroquinone cream, produced by Laboratorios Bustillos, used for depigmentation of teguments. (PLM 1999, page 688). a) Locoid, cream with 0.1% hydrocortisone butyrate, product by Sountofi Winthrop. Used in inflammatory dermatosis, and usually in local corticosteroid therapy. (PLM 1997, page 1209). b) Nutracort, cream with 1% hydrocortisone, produced by Laboratorio Galderma. Used for atopic dermatitis, eczema of feet and hands, neurodermatitis, lichen planus, etc. (PLM 1999, page 1564). c) Westcort, cream with .02% hydrocortisone valerate, produced by Bristos-Myers Squibb de México; It is used for allergic inflammatory dermatosis, photodermatitis, vulgar psoriasis, lichen planus, neurodermatitis and other types of dermatitis. (PLM 1999, pages 2274-2275).

• THE BASIS OF THE INVENTION In the compositions studied by the inventors different active substances are used, belonging to different classes of anticancer substances: 1) Differentiation Inductors such as retinoic acid (Cancer, Principies and Pracffce of Oncology, 5th Edition-1997, Authors Vincent T. De Vite Jr. and collaborators, Retinoids, p 483-485), calcitriol 1, 25 Dihydroxy vitoum D3 (Cancer, Principles and Practice of Oncoyogy, 5 Edition-1997, Authors Vincent T. De Vite Jr. and collaborators, page 487) and hydroquinone (Survival of Mice Recerving Melanoma Transplants is Promoted by Hydroquinone, Science vol. 2. 3.

Pag. 408. April, 1980. Walter Chawin, Alien H. Reed and all). 2) Apoptosis inducers, such as "Fenretidine". (GROWTH INHIBITION AND INDUCTION OF APOPTOSIS BY FENRET1NIDE 1N SMALL-CELL LUNG CANCER CELL UNE.) Kalemkerian GP, Slusher R., Romalingam S., Gadgeel S., Mabry M. Journ of the Nat. Canc. Inst. (USA). -87/22 (1674-1680), N- (4-HIDROXYPHENYL) RETINAMIDE INDUCES APOPTOSIS OF MALIGNANT HEMOPOETIC CELL UNES INCLUDING THOSE UNRESPONSIVE TO RETINOIC ACID. Delia D .; Lombardi L .; Pelicci P.G .; Grignani F. Et Al, Cancer Res. 1993; 53: Pag. 6036-6041, PREVENTION OF LOCAL RELAPSES AND NEW LOCALISATIONS OF ORAL LEUCOPLASKIAS WITH THE SYNTHETICS RETINOID FENRETINIDE (4HPR): PRELIMINARY RESULTS. Chiesa F. Tradaty N. Marazza M. Rossi N. Mariani L. Cleric M. Et al. Europ. J. Cancer 1992; 28 B: Page 97-102). 3) Cytostatics with high therapeutic index as 5 Flourouracilo and Metrotexate. (Cancer, Principles and Practice of Oncology, 5th Edition-1997, Authors Vincent T. De Vite Jr. and collaborators, 5 Flourouracilo, p.775-758, Metrotexate, pp. 432-436.) 4) Steroid hormones with paper anti-cancer and anti-inflammatory as hydrocortisone. (Cancer, Principles and Practice of Oncology, 5th Edition, 1997. Authors: Vincent T. De Vite Jr. and collaborators Prednisone (hydrocortisone) P. 2324-2325) These substances are synergistic with each other and in concentration used are easy to support on teguments and mucous membranes. All the active components are known products and very well studied from the medical point of view. This situation has allowed the inventors to avoid again experiments on animals, directly applying these compositions on human integuments and mucous membranes.

The concentration of the active components in the pharmaceutical preparations does not exceed 2% in the preparations used for teguments and does not exceed 0.2% in the preparations used for the mucous membranes and for the highly sensitive teguments. The substances belonging to the compositions are absorbed by the skin 1-2% and the mucous membranes up to 5% of the content. Because the concentration of the substances in pharmaceutical preparations is maximum 2%, the amount of active products that penetrate the blood is very small and have no harmful side effects on the body.

The pharmaceutical substances used each have the following pharmacological properties: > 5 Flourouracilo and Methotrexate have cytostatic activity and when they are used diluted they have a cell differentiation activity. > Retinoic Acid and Calcitriol are the most powerful cell differentiation agents known to date. > Fenretinide, acts as an Apoptotic Inductor. > Predmisona, acts as a coadjuvant in conventional cancer therapy. > Hydrocortisone, has a strong action free radicals and a cell differentiation action.

• MATERIAL AND METHOD The medicinal substances used are of pharmaceutical purity or purity P.A. (pro analysis). We present the components and physiological limits allowed in these compositions: 1) 5-Flourouracilo from 0.005 to 5,000 g. 2) Metrotexate from 0.001 to 2,000 g. 3) Retinoic acid from 0.001 to 2,000 g. 4) Fenretinide (N-4 Hydroxyphenyl retinamide) from 0.001 to 4,000 g. 5) Calcitriol from 0.00001 to 2,000 g. 6) Prednisone (hydrocortisone) or other steroid hormones from 0.001 to 2,500 g. 7) Hydroquinone from 0.005 to 10,000 g. 8) Cream from 99,996 to 70,000 g.

We present an example of an anticancer composition (cream or solution) for the skin that also serves in psoriasis: 1. 5-Flourouracilo 0.800 g. 2. Metrotexate 0.140 g. 3. Retinoic Acid 0.100 g. 4. Fenretinide (N-4 Hydroxy-phenyl retinamide) 0.120 g. 5. Calcitriol 0.00001 g. 6. Prednisone (hydrocortisone) 0.050 g. 7. Hydroquinone 0.800 g. 8. Cream or a non-toxic solvent 97.990 g.

Here is an example of the composition that we use with great success in the treatment of premalignant and malignant lesions of the cervix: 1) 5-Fluorouration 0.080 g. 2) Metrotexate 0.014 g. 3) Retinoic Acid 0.010 g. 4) Fenretinide 0.012 g. 5) Prednisone (hydrocortisone) 0.005 g. 6) Hydroquinone 0.080 g. 7) Cream or a non-toxic solvent 99.80 g.

Total lOO g. This composition has a total 0.2% active substance.

Many times these lesions on the cervix are produced especially by human papillomavirus and sometimes also by herpetic virus. The concentration of active substance in this cream needs to be 8-12 times smaller than the corresponding concentration for the skin, because of the high sensitivity of the cervical mucosa; You can also simplify the formula with 1 or 2 components. The simplification of the formula reduces efficiency little and for this a longer treatment time is needed.

Because some components can oxidize in the presence of air, the preparations must be kept tightly closed, for example: the creams are packed in metal tubes.

It is important to mention that cervical diseases involve hundreds of millions of women, a fact that determines that in many countries (Brazil, Mexico, Argentina, India, etc.); Cervical cancer is found, along with breast cancer in the first place of cancers in women. It is important to note that on the cervical lesions, these compositions in "optimal" concentration mentioned above produce a little burning. Healing (epithelialization) starts from the margin of the wound (from the wound) and develops towards the inside of the wound; When the healing is complete (when the injury is healed) the burning disappears. After one more week of using the composition, a colposcopic control is made that confirms the complete cure.

This verification is very important for the regions (countries) where the medical network is less developed and the resources of the inhabitants are very low. The same compositions have a very strong sterilizing action on microbes, fungi, protozoa, also on microorganisms resistant to antibiotics. After the use of these compositions the cervix and the vagina are cleaned of infections. The application of a composition (for example: ointment) on the cervix can be done with an applicator that is used constantly or also with a swab.

The healing is done without scars (restitutio and integrum). Premalignant and malignant superficial lesions can be cured, cervical cancer (stage 0 and 1). Papanicolaou III cellular modifications are returned to Papanicolaou I.

In the treatment of cervix unlike surgical methods (with scalpel, laser or cryosurgery), the method that uses this composition has the advantage that it does not leave scars and that in most cases destroys the virus avoiding or decreasing the recidivism.

The pharmaceutical preparations that correspond to the composition for the skin is very useful in the treatment of psoriasis and until today is the best topical treatment to treat this condition. They can also be useful in other skin conditions: senile keratosis, Bowen's disease, lichen planus, different eczema, acute or chronic neurodermatitis, basal cell epithelioma, cutaneous lymphoma, cutaneous metastasis of breast cancer and many types of dermatitis.

The medico-social effects that the use of these preparations using the aforementioned compositions can bring can be very important for health in many overpopulated countries.

We present the case of two patients suffering from Cervix, which were cured using an ointment with this type of pharmaceutical composition: Patient S.O.C. of 43 years with diagnosis: "Low-grade pavement lesion, associated with Human Papilloma Virus (Ectropion of Cervix)". (Fig. 1).

After two weeks of treatment, a beneficial change is observed (Fig. 2). The treatment lasted 9 weeks. Today the patient is totally cured.

Patient R.M. G. 38 years old with Cervico Uterino and Papanicolaou class IV cancer, used the time of 3 months as an ointment as the example on page 5. After the treatment was cured obtaining the following results: Microscopic examination: Of two fragments of cervix; courts were taken for examination. Changes in the koilocytic type are seen in one of the fragments (Figure 3) without atypia (Figure 4) and the second fragment shows a cervical epithelium of normal characters (Figures 5 and 6). There are no other types of alterations.

Diagnosis: Cervix biopsy with flat condyloma changes without atypia. There is no evidence of neoplasia in the material examined.

Papanicolaou cervico vag. Td.

Surface cells 35% Intermediate cells 65% Parabasal cells 0% Basal cells 0% Endocervical cells some normal Endometrial cells no No neoplasic cells No viral alterations No cytolysis No estrogenic index 67 Scarce inflammatory reaction Bacterial flora Bacillus median amount Fungi no Trichomonas no Interpretation: Cytological study without alterations. Negative to cancer. Papanicolaou I.

Claims (5)

1. Complex composition that acts on cancers and different conditions of the teguments and mucous membranes, characterized by the following components and the following amounts: 5-Flourouracilo from 0.005 to 5,000 g. Metrotexate from 0.001 to 2,000 g. Retinoic acid from 0.001 to 2,000 g. Fenretinide (N-4 Hydroxyphenyl retinamide) from 0.001 to 4,000 g. Calcitriol from 0.00001 to 2,000 g. Prednisone (hydrocortisone) or other steroid hormones from 0.001 to 2,500 g. Hydroquinone from 0.005 to 10,000 g.

2. Complex composition in accordance with claim 1, which administered on the integuments and mucous membranes has an optimum efficiency. This composition is characterized because it contains: 1.-5-Flourouracilo 0.080 g. 2.-Metrotexate 0.014 g. 3.-Retinoic acid 0.010 g. 4.-Fenretinide (N-4 Hidroxyfenil retinamida) 0.012 g. 5.-Calcitriol 0.100 g. 6.-Prednisone (hydrocortisone) 0.005 g. /.- Hydroquinone 0.080 g.

3. Composition according to claims 1 and 2, characterized in that it uses inducers of differentiation (or maturation) of cancer cells (such as retinoic acid, calcitriol and hydroquinone).

4. Composition according to claims 1, 2 and 3 characterized by the fact that it uses inducers of apoptosis (genetically programmed death of cancer cells) such as: Fenretinide.

5. Composition according to claims 1, 2, 3, and 4 characterized by the fact that it uses the Cytostatics, the most efficient against cancer cells and the least aggressive for healthy tissues (such as Flourouracilo and Metrotexate). Composition according to claims 1, 2, 3, 4 and 5 characterized by the fact that it uses steroid hormones that have adjuvant anticancer properties (such as hydrocortisone). Use of the composition according to claim 1, characterized in that it is used in the preparation of a very efficient medicament for the treatment of psoriasis. Drug composition according to claims 1 and 2, characterized in that it can be pharmaceutically conditioned in different application forms such as: ointments, ovules, solutions, spray, patch. Medicament composition according to claims 1 and 2, characterized in that (when applied to highly sensitive mucosae and teguments) it is used at a concentration of 8-12 times lower than the optimum concentration used on the skin. Pharmaceutical composition characterized in that it contains the active products specified in claim 1 and a pharmaceutically acceptable carrier.