Cancer treatment and prevention of metastasis

 

(57) Abstract:

The invention relates to medicine, in particular to cancer, and for the treatment of cancer and prevention of its metastases. For this patient in the first phase of treatment to a direct injection into the tumor anti-cancer drug and hyaluronic acid MM less than the 750,000 daltons. In the second stage, the patient is administered systemically drug of the same acid in combination with a drug selected from the group spit, chemotherapeutic agent, in particular antioxidant. The steps are repeated to achieve clinical effect. The method provides a reduction in activity of the tumor process. 5 C.p. f-crystals.

The invention relates to cancer therapy and prevention of metastasis in cancer patients. This invention also relates to pharmaceutical compositions and dosage quantities suitable for such treatment and for prevention. In one application the present invention relates to the treatment of breast cancer and prevention of metastasis in patients with breast cancer.

Conventional treatment of breast cancer involves a mastectomy, surgical removal of the breast tissue. The method can vary from simple beats the th chain of lymph nodes, lying under the breast chest muscles surrounding the axillary lymph nodes.

When detected early, cancer of the breast is now considered an acceptable treatment, preserving the breast. So, as an alternative method of treatment is currently recommended removal of the tumor site in combination with resection of the axillary lymph nodes and radiation therapy. However, still there is considerable debate around what extremely minimum treatment necessary to achieve adequate local suppression. This is true for all types of cancer. Therefore, when considering treatment choose a way that will eliminate cancer defeat and eliminate the recurrence in the form of metastases, for example, in the breast or other organs and tissues.

In published application WO 91/04058 provides a new method of treatment of cancer along with other diseases, which consists in the introduction of metered quantities of pharmaceutical compositions containing an effective amount of spit, vitamin C, anti-cancer agents, along with other drugs and therapies, together with derivatives of hyaluronic acid, for example a hyaluronan is ka weighing 70 kg On page 27, line 35, the document States that the doses can be administered intravenously, intraarterially, intraperitoneally, vnutriplevralno and directly into the tumor by injection through a needle introduced under ultrasound or computed tomographic (CT) control.

If V11 presented on pages 42 and 43, described the treatment of solid cancer of the breast with a palpable supraclavicular and axillary lymph nodes. Treatment consisted of combined application of hyaluronic acid and/or its salts in addition to conventional chemotherapy used systemically by injection into the tumor, and introducing into the pleural cavity" (page 45, lines 3-5).

The paper also investigated system the introduction of the combination of hyaluronic acid and/or its salts with spit (nonsteroidal anti-inflammatory drugs), ascorbic acid (vitamin C), anti-cancer drugs along with other drugs.

Publication WO/CA93/00061 for the local treatment of skin diseases and conditions, and it describes the study of the local application of certain measured quantities, we offer pharmaceutical compositions. Using a local application of the matter of leather, get into the lymphatic system (page 31, line 35). During their stay in the skin, in particular in the epidermis, the drugs to treat the disease or pathological condition of the skin form of hyaluronic acid (for example, of sodium hyaluronate having a molecular weight less than the 750,000 daltons), delivering drugs into the skin. When applying spit inhibited the synthesis of prostaglandin, unblocking macrophages and cells - natural killer cells (from page 26, line 27, to page 27, line 35), thus providing the possibility of macrophages and natural killer cells to fight the disease or pathological condition.

Although destruction/elimination of malignant tumors and all available cancer is the ultimate goal, it cannot be done without considering the impact on metastasis. It is necessary to prevent metastasis and recurrence of cancer, particularly metastatic disease in vulnerable organs such as the liver.

In the past the treatment was not given sufficient attention and care effect metastasis (metastasis). Everything was focused on the destruction and elimination of the tumor. Thus, assigned or undertaken in the past, the treatment is taglandin in the tissue (which inhibited the ability of macrophages and cells natural killer cells to perform their function - destruction of cancer cells and the destruction of the tumor). So instead of being destroyed, the cancer cells are released from the tumor and was able to circulate through the body and settle in the more vulnerable areas (such as the liver or lungs - a certain way of metastasis.

Therefore, an object of the present invention is a new method of treating cancer, which one finds particular application in the treatment of breast cancer.

Another object of the present invention is to reduce the risk of metastasis with this method of treatment.

Another object of the present invention is to reduce the risk of recurrence of the disease, for example, breast cancer.

Another object of the present invention are pharmaceutical compositions and dosage amount of the pharmaceutical compositions suitable for use in such methods of treatment.

Additional and other objects of the invention will be clear to experts in this field from the following summary of the invention and detailed description of the implementation options.

Suddenly the th cancer), which not only causes a sharp reduction in the size and the disappearance of malignant tumors (such as breast cancer), but also unexpectedly reduces the risk of metastasis.

In accordance with one aspect of the invention, the applicants have proposed a new method of treatment of cancer in humans, in particular malignant tumors, such as tumors of the breast or mammary glands, which includes the steps:

1) direct injection into the tumor non-toxic dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of anti-cancer drug and/or drug, suitable for use in the treatment of cancer (for example, from about 1 to about 2 mg of NovantroneTM(Mitoxantrone) or other chemotherapeutic agent (interferon or spit) and an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons) (for example, from about 10 to about 20 mg of sodium hyaluronate) in sterile water (the size of the tumor determines the amount that can be entered directly into the tumor), and

2) predicitve pharmaceutical composition, contains:

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons), for example, about 100-200 mg or more (due to the lack of toxicity and to reduce the side effects of any medicines (for example, spit), added together with him, if the amount of the form of hyaluronic acid exceeds about 200 mg per person weighing 70 kg);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, in effective non-toxic amount of from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol));

b) an effective non-toxic amount of a chemotherapeutic agent, as described above in paragraph (I) (anticancer drug or a drug suitable for the treatment of cancer, and so on),

and a combination thereof optionally together with

III) an antioxidant, such as vitamin C (with one implementation of the om 70 kg, adverse side effects of chemotherapy (spit: chemotherapeutic agent) is reduced, if not eliminated.

The frequency of treatment for malignant tumors usually can be from one (1) to four (4) times each month or more (as required). Regarding breast cancer, the frequency of direct injection into a malignant tumor in the breast pharmaceutical compositions specified above in subparagraph (1), and systemic (intravenous) injection of a metered amount of the pharmaceutical composition, containing:

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons), for example, about 100-200 mg or more drug introduced together with a number of forms of hyaluronic acid in excess of 200 mg per person weighing 70 kg (due to the lack of toxicity);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (available in prodad brand Voltarol)); and

b) an effective non-toxic amount of a chemotherapeutic agent, as described above in paragraph (I) (anticancer drug or a drug suitable for the treatment of cancer and so on), and combinations thereof optionally together with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C),

is from about (1) to three (3) times per month. (Form of hyaluronic acid, for example sodium hyaluronate, transports (causes transport) drugs and therapeutic agents in tumor tissue for its degradation and inhibits the synthesis of prostaglandin).

On the mammary gland, affected by a malignant tumor, may be affected by hyperthermia (heating to high temperatures). You can also assign other treatments. For example, as a warning, depending on the number entered spit and quantity of the introduced sodium hyaluronate may also be intravenously injected together with hyaluronate sodium drug that causes expression of the gastric mucosa, such as ranitidine.

In accordance with another aspect of the invention, the applicants have proposed a new method of cancer treatment, and this method includes the steps:

1) the system is amoxicilli number of drug suitable for the treatment of cancer, alone or preferably with an effective amount of the form of hyaluronic acid, such as hyaluronic acid or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons) (for example, from about 10 to about 20 mg of sodium hyaluronate) and

2) injection system preferably (preferably intravenously) a metered amount of the pharmaceutical composition, containing:

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons), for example, about 100-200 mg or more (due to the lack of toxicity);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol));

b) effectively is preferably together with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C).

The steps are repeated at a period of time at a selected interval, suitable for the patient.

Unexpectedly and in accordance with another aspect of the invention, in patients who regularly have introduced a metered quantity described above, during the term of their treatment, there was no metastatic effect (they had no metastases). Thus, there is a sudden significant decrease in the risk of metastasis.

Thus, in accordance with another aspect of the invention applicants propose a new method of treatment for reducing the risk for patients with cancer and with cancer metastases (risk reduction for these patients who are suffering from metastasis or suffering from metastatic effects), and specified method of treatment includes (preferably with another treatment, such as described above) system administration (preferably intravenous) a metered amount of the pharmaceutical composition containing

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its farmaci is n (for example 150000-225000 daltons), for example, about 100-200 mg or more (due to the lack of toxicity);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol)); and

b) an effective non-toxic dosage amount of a chemotherapeutic agent (anticancer agent or drug suitable for the treatment of cancer);

and combinations thereof, preferably with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C),

and this introduction continues with equal intervals (for example, 1 to 4 times per month) during the period of treatment prescribed for the patient for the treatment of cancer.

Applicants believe that the above treatments are successful because inhibited the synthesis of prostaglandin, reactivity thus macrophages and cells - natural killer cells to destroy the cancer is prevented or at least obstructed for neoangiogenesis (to the vitamin C (sodium ascorbate), and hyaluronic acid (for example, sodium hyaluronate) is excreted through the lymphatic system (according to the direct measurement, the concentration of hyaluronate (occurring in the body) is 10 times higher in lymph than in plasma). The authors also observed a prolonged effect after the introduction of a simple dose of the medication with the Ledger (form of hyaluronic acid, such as sodium hyaluronate), which is believed by the applicants, due to the fact that GK, injected, will pass through the lymphatic system. Therefore, you can anticipate improvements and lengthening effect in terms of immunosuppression, for example, when using cyclosporine. This was confirmed in some initial experiments using intestinal allografts, in which the intestine is grafted on arterial-venous leg, but all of her lymph vessels odseparowana. Thus, when the drug gets through the blood circulation, it should be in the lymphatic system, but lymphatic drainage, which is possible the output from the gut, no. Therefore, the drug remains in the grafts in the long term. In the original experimento authors one and two doses of cyclosporine in the Ledger provided indefinitely lapertosa and causes the transport of the drug, the drug is well tolerated and is released into the lymph nodes. Because the blood flow will also take, for example, gailbreath sodium, and therefore the drug, sodium hyaluronate and the drug will be delivered to the liver (hyaluronate sodium, carrying the drug in the tissue and liver cells). Thus, the two main plot emerging metastases is supplied, for example, sodium hyaluronate and drug (sodium, spit, anticancer drug), delivered to them, hyaluronate sodium, facilitating the transport of the drug into the tissue (lymph nodes and liver), which is required to prevent the development and/or metastasis of the cancer. Thus, sodium hyaluronate (and other forms of hyaluronic acid, including hyaluronic acid) may be injected systemically with the drug, and this introduction of the drug, together with the form of hyaluronic acid is delivered to the lymph nodes and liver. This introduction helps to reduce the risk of metastasis and, as the results of investigations of applicants, helps to suppress or even prevent the metastasis of the cancer, the treatment is conducted in humans. This introduction may also be used to treat cancer of the lymph system and liver, if they are diagnosed with cancer.

Therefore, in accordance with another aspect of the invention applicants propose new metered amount of the pharmaceutical compositions in the form for systemic administration (usually intravenous injection of the bag system for intravenous injection), and each such metered quantity includes

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000 - at 225,000 daltons), for example, about 100 to 200 mg or more (due to the lack of toxicity and reduce the side effects of the drug, administered together with the form of hyaluronic acid taken in excess of 200 mg per person weighing 70 kg);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, in effective non-toxic kolichestvo brand Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol)); and

b) an effective non-toxic amount of a chemotherapeutic agent (anticancer agent or a drug suitable for the treatment of cancer, and so on),

and combinations thereof, preferably with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C).

In accordance with another aspect of the invention applicants propose new metered amount of the pharmaceutical composition for injection (in the form suitable for injection), suitable for use, for example, with the above measured quantity, where the specified metered quantity placed in the container or bottle suitable for use for injection (e.g., a syringe), and contains an effective amount of anti-cancer drug and/or drug, suitable for use in the treatment of cancer (e.g. breast cancer, in the case of which the metered quantity is injected into each tumor of the breast) (for example, from about 1 to about 2 mg Mitoxantrone) and an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight of the Noi water.

Thus, the applicant proposed using the new metered amount of the pharmaceutical composition that includes

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000 - at 225,000 daltons), such as about 100 to 200 mg or more (due to the lack of toxicity);

II) an effective non-toxic amount of a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol)); and

b) an effective non-toxic amount of a chemotherapeutic agent (anticancer agent or a drug suitable for the treatment of cancer, and so on),

and combinations thereof, preferably with

III) an antioxidant, such as vitamin C (in one implementation - 25 g vitamin C)

a) treatment of cancer, the patient and

b) prevention metastasising amount of the pharmaceutical composition for injection (in a suitable form for injection), and the specified metered quantity placed in the container or vial for injection and contains an effective amount of anti-cancer drug and/or drug, suitable for use for the treatment of cancer (e.g. breast cancer, in the case of which the metered quantity is injected into each tumor of the breast) (for example, from about 1 to about 2 mg Mitoxantrone), and an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000 - at 225,000 daltons) (for example, from about 10 to about 20 mg of sodium hyaluronate), in sterile water; and

B) metered quantity, including

I) an effective amount of the form of hyaluronic acid (for example, hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000 - at 225,000 daltons), for example, about 100 to 200 mg or more (due to the lack of toxicity);

II) an effective non-toxic amount of a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, is adage under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol)); and

b) an effective non-toxic amount of a chemotherapeutic agent (anticancer agent or a drug suitable for the treatment of cancer);

and combinations thereof, preferably with

III) an antioxidant, such as vitamin C (in one implementation - 25 g vitamin C)

a) treatment of cancer in a patient,

b) prevention of metastasis in a patient suffering from cancer and/or

b) drug delivery to the lymphatic system and/or liver.

Applicants also proposed the use of

I) non-toxic dosage amount of a pharmaceutical composition for injection (in a suitable form for injection), and the specified metered quantity is in the container or vial for injection, and includes an effective amount of anti-cancer drug and/or drug, suitable for use for the treatment of cancer (e.g. breast cancer, in the case of which the metered quantity is injected into each tumor of the breast) (for example, from about 1 to about 2 mg Mitoxantrone), and an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts, predpochtitel the Colo 10 to about 20 mg of sodium hyaluronate), in sterile water; and

II) non-toxic dosage amount, including

1) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons), for example, about 100-200 mg or more (due to the lack of toxicity);

2) the drug is selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, commercially available under the brand name Voltarol)); and

b) a therapeutically effective non-toxic dosage amount of a chemotherapeutic agent (anticancer agent or a drug suitable for the treatment of cancer);

and a combination thereof, preferably with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C)

a) treatment of cancer in a patient,

b) prevention of metastasis in a patient suffering from cancer, and/or

C) delivery of the drug definition metered quantity of anti-cancer drug and/or drug suitable for use for the treatment of cancer (e.g. breast cancer, in the case of which the metered quantity is injected into each tumor of the breast) (for example, from about 1 to about 2 mg (Mitoxantrone), and an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons) (for example, from about 10 to about 20 mg of sodium hyaluronate), in sterile water; and

B) metered quantity, including

I) an effective amount of the form of hyaluronic acid, for example hyaluronic acid and/or its pharmaceutically acceptable salts, preferably of sodium hyaluronate having a molecular weight less than the 750,000 daltons (e.g., 150000-225000 daltons), for example, about 100-200 mg or more (due to the lack of toxicity);

II) a drug selected from the group including:

a) non-steroidal anti-inflammatory drug (spit), for example, from about 30 mg to about 100 mg (e.g., from 30 to 60 mg trometamina salt ketorolaco (commercially available under the trademark Toradol) and from 50 to 100 mg of diclofenac or diclofenac sodium (for example, immiteeritakse agent (for example, anti-cancer agent or a drug suitable for the treatment of cancer);

and combinations thereof, preferably with

III) an antioxidant, such as vitamin C (with a single implementation - 25 g vitamin C), for the manufacture of two pharmaceutical compositions, one of the components (A) and component (B), each for cancer treatment, prevention of metastasis and/or drug delivery to the lymphatic system and/or liver.

Suitable forms of sodium hyaluronate may include the fraction supplied by Hyal Pharmaceutical Corporation in 15 ml vials of sodium hyaluronate at a concentration of 20 mg/ml (300 mg/vial - party 2F3). Fraction of sodium hyaluronate is a 2% solution with a mean molecular weight of approximately at 225,000 daltons. Fraction also contains water in the required quantity, which was subjected to triple distillation and is sterile in accordance with the requirements of the U.S. Pharmacopeia for injectable formulations. Bottles of hyaluronic acid and/or its salts can be made of borosilicate glass type 1, closed butyl tubes, which do not react with the contents of the vial.

The fraction of hyaluronic acid and/or salts (for example sodium salt) and homologues, analogues, plot and its salts, may include hyaluronic acid and/or a salt thereof, having the following characteristics:

purified, essentially pyrogen-free fraction of hyaluronic acid obtained from a natural source, having at least one characteristic selected from the group (and preferably all specifications), including the following features:

I) a molecular weight in the region of 150,000 - at 225,000 daltons;

II) less than about 1.25% sulfated mucopolysaccharides on the basis of the total weight;

III) less than about 0.6% protein based on total weight;

IV) less than about M. D. iron by weight;

V) less than about 15 m., of lead by weight;

VI) less than 0.0025% glucosamine;

VII) less than 0.025% glucoronosyl acid;

VIII) less than 0.025% of N-acetylglucosamine;

IX) less than 0.0025% of the amino acids;

X) the ratio of UV attenuation at 257 nm, less than about 0,275;

XI) the ratio of UV attenuation at 280 nm of less than about 0.25;

XII) a pH in the range of 7.3 to 7.9.

Preferably, the hyaluronic acid is mixed with water, and the fraction of hyaluronic acid has an average molecular weight in the range of 150,000 - at 225,000. More preferably, the fraction of hyaluronic acid had extremely is harakteristiki:

I) less than about 1% sulfated mucopolysaccharides on the basis of the total weight;

II) less than about 0.4% protein based on total weight;

III) less than about 100 M. D. iron by weight;

IV) less than about 10 m., of lead by weight;

V) less 0,00166% glucosamine;

VI) less 0,0166% glucuronic acid;

VII) less 0,0166% N-acetylglucosamine;

VIII) less 0,00166% amino acid;

IX) the ratio of UV attenuation at 257 nm, less than about 0,23;

X) the ratio of UV attenuation at 280 nm of less than about 0,19; and

XII) a pH in the range of 7.5 to 7.7.

The applicants also propose to use sodium hyaluronate produced and supplied by the company "Life CoreTMBiomedical Inc.", with the following specifications:

Specifications - Specification

Appearance - Particles from white to cream-coloured

Smell - Without noticeable odor

Medium viscosity

Molecular weight of <the 750,000 daltons

Stenogramma in the UV/visible spectrum, 190-820 nm Corresponds to the reference stenogramma

The optical density at 260 nm, a unit of the protected area. tight. - <0,25
Infrared stenogramma - Corresponds to the standard

As - 2

Cd - 5

Cr - 5

Co - 10

Cu - 10

Fe - 25

Pb - 10

Hg - 10

Ni - 5

Microbial biological cargo - Not observed

Endotoxin, E./mg NaHy - <0,07
Another form of sodium hyaluronate is sold under the name "Hyaluronan HA-M5070" company "Skymart Enterprises, Inc." and has the following characteristics:

Specification - test Results

N party HG1004

pH - 6,12

Chondroitin sulfate was Not detected

Protein - a 0.05%

Heavy metals, memorial plaques - Not more than 20

Arsenic, M. D. - No more than 2

Loss on drying, % - 2,07

The residue after combustion, % - 16.69 per

Internal viscosity, dl/S (XW: 679,000) - was 12.75

Nitrogen, % - 3,14

Analysis, % - 104,1

The number of bacteria /g - 80

E. coli - Negative

Mold and yeast, /g Not more than 50

Other forms of hyaluronic acid and/or its salts, analogs, homologues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid, you can choose other suppliers, such as suppliers identified in previously published papers in this area, provided that the selected form of hyaluronic acid is suitable for nikah the processes of its production and reception, you might find appropriate.

In U.S. patent 4141973 proposed fractions of hyaluronic acid (including sodium salt), with:

(a) the average molecular weight of more than 750,000 people, more preferably 1200000, i.e. limiting viscosity of more than 1400 cm3/g and preferably greater than 2000 cm3/,

b) the protein content of less than 0.5% by weight;

b) absorption of ultraviolet radiation of 1% solution of sodium hyaluronate, less than 3 at a wavelength of 257 nm and less than 2 at a wavelength of 280 nm;

d) a kinematic viscosity of 1% solution of sodium hyaluronate in the physiological buffer is greater than about 1000 cSt, preferably greater than 10,000 Centistokes;

d) the molar optical rotation of 0.1 - 0.2% solution of sodium hyaluronate in physiological buffer less -1110-3C - cm2/mol (disaccharide), measured at 220 nm;

e) the absence of significant cellular infiltration of the vitreous and anterior chamber, absence of light watery moisture, no haze or glow of the vitreous body and the absence of pathological changes in the cornea, lens, iris, retina and choroid ordinary night monkeys, when one milliliter of 1% is Mesa approximately half of the existing liquid vitreous body, moreover, these fractions of hyaluronic acid are

W) sterile and pyrogen-free and

C) panthenyl.

In the patent 1205031, published in "Canadian letters" (which is referenced U.S. patent 4141973 as the description of the prior art) refer to the fraction of hyaluronic acid having an average molecular weight from 50,000 to 100,000; 250,000 to 35,000 and from 500,000 to 730000, and discussed the processes of their production.

Further, the invention is illustrated with reference to the following data relating to persons suffering from cancer. Scheme dosed quantities obtained for each patient is fixed and denoted by the letter used to identify the patient. The chronology of the introduction of metered quantities in each diagram is given in reverse order with the dose, introduced the very first, at the end of the scheme, and the last dose at the beginning of the schema.

Patients treated

Example 1

The patient And the age of 42 years (female):

- breast cancer, occupying the whole breast, not previously treated;

- received treatment non-specific; anti-inflammatory drugs, sodium ascorbate, SC intravenously in combination with systemic therapy;

in 4 cases of tick-or metastasis;

dose see in the Diagram And listed at the end of the description (GK = sodium hyaluronate having a molecular weight less than the 750,000 daltons).

Example 2

The patient In the age of 60 years (female):

- local regional recurrence after resection;

- received treatment by direct injection of Novantrone/SC at a dose of 1 mg in combination with 10 kg SC in 4 different time;

- also received intravenous nonspecific anti-inflammatory drugs/GK;

a regression of its tumor reached 75% of its original size during 1,5 years;

- there were no metastases;

dose, see chart B, is given at the end of the description.

Example 3

Patient (female):

- received doses under the Scheme, provided at the end of the description, including direct injection into the tumor IN the breast, including direct injection and intravenous (in/in);

"surprisingly, the tumor disappeared without metastasis.

Example 4

Patient G (female):

- received doses according to Scheme G, is given at the end of the description, including direct injection into the tumor IN the breast, including direct injection and intravenous (in/in);

- the patient has not succumbed to the disease.

Example 5

Patient D. - age 55 years (female):

in the last three years, there were no metastases of the tumor lesion in supraclavicular lymph nodes;

dose see in the Diagram, D, is given at the end of the description.

Example 6

Patients To the age of 73 years (female):

- carcinoma of the breast with metastases to the liver, about which 3 years were receiving treatment with intravenous anti-inflammatory drugs, SC, the sodium ascorbate in combination with intravenous (IV) chemotherapy;

the tumor has not increased, then began to grow, but in all this time of metastases was not (injection into the mammary gland was not received; although made of injection in the cervical lymph nodes on the left side);

she stopped treatment due to her age;

dose, see Diagram E, is given at the end of the description.

Example 7

Patient W age 56 years (female):

- carcinoma of the breast with metastases in nesluchajnye lymph nodes, the disease does not progessional for 4 years in the periodic treatment of intravenous anti-inflammatory drugs, sodium ascorbate and GK;

direct injection is not made;

dosed quantities, see the Diagram of W, is given at the end of the description.

Example 8

Ill>/BR>- received treatment weekly intravenous anti-inflammatory drugs, sodium ascorbate and GK;

the tumor has not progressed, did not give metastases, and in the end was awarded her some local growth;

treatment was discontinued because the patient was 81 years old, she was helpless and did not want to continue treatment;

she died from heart failure;

dosed quantities, see Scheme C, is given at the end of the description.

Example 9

The patient And the age of 64 years (male):

- prostate cancer, it was not observed any progression on the background of intravenous anti-inflammatory drugs, SC and the sodium ascorbate;

- dose see in the Diagram And listed at the end of the description.

Example 10

The patient - age 64 years (male):

- carcinoma of the colon and rectum with metastases to the liver, not progressing and not spreads within 2 years;

- received treatment from one to two times per week intravenous sodium ascorbate/ha and nonspecific anti-inflammatory drugs;

dosed quantities, see the Diagram To shown at the end of the description.

The following additional experimental data and the applied system introduction these patients nonspecific anti-inflammatory drugs, the sodium ascorbate and General Ledger. Only experimental treatment 63 patients, if possible, was made the most sparing surgery. Subject to the positive results of the analysis for estrogen receptors or progesterone patients were treated with agents that block the hormone. Only in some cases were oophorectomy. Applicants have used low-dose chemotherapy using methotrexate (100 mg/100 mg of ha in the first day) and 5-fluorouracil (5-FU) (350 - 500 mg/100 mg of ha on the second and third days), initially without CC, and later with SC injections.

In cases where the tumor was regarded as more aggressive, used a combination of four injections (see table 1).

Table 1

Treatment for breast cancer

1. Operation:

Modified radical mastectomy - 23 patient

Segmental resection and removal of lymph nodes - 40 patients

2. The impact on the hormonal status:

The purpose of the tamoxifen - 33/63 patients

Surgical oophorectomy - 3/63 patients

3. Chemotherapy:

The combination of ITC (mitoxantrone) + 5-FU (5-fluorouracil)

or

the combination of Novantrone, 5-FU,

of mitomycin C, MTC (MiTo tumor - c 1982 all patients.

6. Immunomodulation:

a) amplification of nonspecific immune response,

b) modification with inhibitors of prostaglandin E2 and the sodium ascorbate.

Exposure avoided. These patients were applied hyperthermia using microwave techniques to enhance the effects of drugs. Thus was achieved the survival for nine years in 90% of cases (see table 2).

Table 2

Cancer of the breast. Patients and survival

The number of patients - 63

Disease stage - I - 14 II - 49

Age - 27 to 75 years

the average age is 43 years

The number of survivors with cured cancer - 55

The average duration of survival in years - 8

The number of survivors with the presence of disease - 6

The number of deaths from the disease - 2

From these results it is evident that moderate doses of chemotherapy with the addition of nonspecific anti-inflammatory drugs and medications in Ledger has led to improved survival in the group of patients with high risk of relapse.

Alternative experimental treatment for local breast cancer in combination with or without systemic disease is aspenia. One patient was observed recurrence in both Breasts after irradiation; the other patient after irradiation when entering metastases in the bones of the skeleton. Held injection of mitoxantrone at a dose of 1 mg to 10 mg Ledger from 1 to 6 times as long as the tumor has not disappeared.

Additionally, we performed systemic chemotherapy in the General Ledger and hyperthermia. In cases of necessity, used drugs that block the hormone. Only thus subjected to treatment 10 patients. We all noted the overall effect in terms of backward development of local pathological process (see table 3).

Table 3

Alternative experimental breast cancer treatment

Patients:

1. For several years, 10 patients received the experimental treatment:

With recurrence after surgery - 4

With relapse after radiotherapy - 1

The defeat of both Breasts - 5

2. 1 of 10 at diagnosis were distant metastases; all were affected axillary lymph nodes.

The results:

- 10 out of 10 the overall effect in terms of the response of the lesion and regional lymph nodes;

- 2 out of 10 (first patients) died due to systemic disease;

- 8 out of 10 is alive and well sense the percentage response was not excessive, although it was an initial increase of the area of the tumor. What was impressive is the return of the mammary gland to normal in some cases and only a small scar tissue, detected by mammography, in other patients.

This unique method of treatment. It seems that the drugs entered in the Ledger, almost exclusively operate on the tumor tissue and does not have a significant impact on normal tissue.

Because of the possibly large number of changes of measured quantities used in examples without deviating from the range of the invention, it is proposed that all material contained herein be interpreted as an illustration of the invention and not in a limiting sense. T T T T TA

1. A method of treating cancer in humans to prevent or reduce metastasis, including the introduction of an effective dosage amount of hyaluronic acid and/or its pharmaceutically acceptable salt having a molecular weight less than the 750,000 daltons, in combination with a chemotherapeutic agent, wherein said treatment consists of stage direct injection into the tumor non-toxic dosage amount of the pharmaceutical composition, adenia cancer, and a form of hyaluronic acid selected from the group comprising hyaluronic acid and/or its pharmaceutically acceptable salts and their combinations, in sterile water and stage system the introduction of a non-toxic dosage amount of a pharmaceutical composition containing an effective amount of the form of hyaluronic acid selected from the group comprising hyaluronic acid and its pharmaceutically acceptable salts, and the drug is selected from the group comprising non-steroidal anti-inflammatory drug (spit), chemotherapeutic agent, and, optionally, an antioxidant, and repeat these steps as often as may be necessary to prevent or reduce metastasis.

2. The method according to p. 1, characterized in that the composition for systemic injections preferably contains sodium hyaluronate having a molecular weight less than the 750,000 daltons.

3. The method according to p. 1, characterized in that the systemic injection of the pharmaceutical composition is combined with the introduction of antioxidants.

4. The method according to PP.1 to 3, characterized in that the frequency of treatment varies from one to four times each month or more.

5. The method according to PP.1 to 3, characterized in that the form of ablespoon on PP.1 - 5, characterized in that the system introduction is carried out by intravenous injection.

 

Same patents:
The invention relates to the field of medicine and for use in cosmetics for correcting facial flaws as wrinkles and folds, as well as to improve the shape and volume of the lips and prevent skin aging
The invention relates to the field of chemical technology and can be used in the production of hyaluronic acid for medical purposes

FIELD: medicine, surgery.

SUBSTANCE: one should apply a hemostatic film onto damaged spleen, moreover, as hemostatic material one should apply hyaluronic acid-based film (HA) being chemically associated with 5-aminosalicylic acid and impregnated with ferrum of the following total structural formula:

. Moreover, substitution degree of carboxylic groups with 5-aminosalicylic acid corresponds to 30-50% M. The innovation provides stimulation of fibroblastic activity and accelerated formation of granulations.

EFFECT: higher efficiency of therapy.

8 dwg

FIELD: medicine.

SUBSTANCE: method involves introducing single injection of 0.3-0.5 ml of 8% combined hydrogel solution of chytosan ascorbate of 94-98% deacetylization, molecular mass of 100-700 kDa containing 200 mg of hyaluronic acid in 1 l of solution, 2 g of chondroitin-sulfuric acid, 110-440 mg of kettle serum growth factor and 50 mg of heparin.

EFFECT: enhanced effectiveness in strengthening thin sclera in short time.

5 dwg

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent used in treatment inflammatory and degenerative joint diseases. Agent comprising hyaluronic acid and chondroitin sulfate can comprise also dimethylsulfoxide, sodium diclofenac, chlorhexidine bigluconate, cosmetic whey, medicinal comfrey roots extract and parabena extract. Also, invention relates to a method for treatment of inflammatory or degenerative joint diseases, and a device for delivery of the claimed agent to a site damaged by the disease. The claimed agent provides reducing treatment period, to enhance effectiveness of anti-inflammatory effect and to intensify regeneration of intra-articular fluid.

EFFECT: valuable medicinal properties of agent, improved treatment method.

13 cl, 8 ex

FIELD: medicine, cosmetology.

SUBSTANCE: one should carry out subepidermic implantation of aqueous hyaluronic acid solution at concentration ranged 0.9-1.1 weight% to be performed as linear injections by developing fibrous netting. The innovation suggested provides stable effect of skin rejuvenation due to developing reinforcing netting at applying certain concentration of hyaluronic acid in injectional composition.

EFFECT: higher efficiency.

2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition and a method for it preparing. The composition comprising effective doses of hyaluronic acid, glycyrrhetinic acid as active components and polyvinylpyrrolidone is used in treatment of morbid inflammatory and ulcerous states of moisture epithelial surfaces, such as mucosa inflammation and Behchet's syndrome. The composition shows favorable effect due to its moistening action.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

6 cl, 3 ex

FIELD: medicine, in particular, ophthalmology.

SUBSTANCE: invention relates to prophylaxis of myopia progressing. Biopolymer in amount of 1 ml is administered through cannula in Tenon's space to posterior eye pole, wherein said biopolymer represents 2 % chitosan ascorbate hydrogel solution having deacetilation ratio of 94-98 %, molecular mass of 100-700 kD, containing per 1 l of solution 200 mg of hyaluronic acid, 2g of chondroitin sulfuric acid, 110-440 mug of cattle serum growth factor, and 50 g of heparin.

EFFECT: effective prophylaxis of myopia progressing; due to improved blood circulation in posterior eye pole and building up of sclera tissue followed by biodegradation of biopolymer.

1 tbl, 1 ex

FIELD: veterinary medicine.

SUBSTANCE: method involves exposing tendon and its sheath injury zone to laser radiation of pulse succession frequency equal to 512 Hz, power of 16 W for 6 min on the background of single intravenous Hyonate dose containing 40 mg of sodium hyalurate as active agent.

EFFECT: enhanced effectiveness of treatment; accelerated treatment course.

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves a single administration of 1.0 ml of 2% combined hydrogel solution of chitosan ascorbate with deacetylation degree 94-98% and molecular mass 100-700 kDa into Tenon's space wherein this solution comprises 200 mg of hyaluronic acid, 2 g of chondroitinsulfuric acid, 110-440 mcg of cattle serum factor and 50 mg of heparin in 1 l of the solution. Method provides revascularization of the eye posterior pole based on resorption and substitution of hydrogen by the own connective tissue enriched with newly formed vessels of capillary type and activation of perivasal chorioepiscleral anastomosis. Invention can be used in treatment of the central atherosclerotic chorioretinopathy.

EFFECT: improved method of treatment.

1 tbl, 1 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention proposes a preparation used in healing wounds and for prevention sticking a bandage to wound. The preparation comprises hyaluronic acid sodium or potassium salt of molecular mass from 200000 to 2500000 Da, iodine, potassium iodide and water. The preparation is made in form of sterile aqueous solution or gel. The preparation possesses high effectiveness in infected and chronic wounds.

EFFECT: enhanced effectiveness of preparation.

4 cl, 16 dwg, 11 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves administration of chitosan sponge with square up to 2 cm2 into sub-Tenon's space wherein chitosan sponge shows the deacetylation degree 98%, its molecular mass is 1000 kDa and it comprises 2.8 x 10-9 g of hyaluronic acid, 27.8 x 10-8 g of chondroitinsulfuric acid, 3.06 x 10-11 g of cattle serum growth factor and 7 x 10-9 g of heparin per 1 mm2 of chitosan sponge. Method provides stabilizing visual function, to improving vision and expanding vision field based on enhancing sensitivity of optic nerve as result of blood stream enhancing. Invention can be used in treatment of progressing glaucoma with non-stabilizing functions.

EFFECT: improved method of treatment.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves applying surgical intervention and antitumor therapy. After having removed a part or the whole lung, mediastinum is opened by cutting out horseshoe-shaped or rectangular flap of mediastinal pleura and carrying out lymphodissection. Then, hemostatic sponge is placed in mediastinum. The sponge is impregnated with antitumor chemotherapeutical preparations in intraoperative mode. Pleura is sutured above the sponge. Another hemostatic sponge impregnated with cytostatic preparations in intraoperative mode is attached to visceral pleura of interlobular sulcus.

EFFECT: prolonged chemotherapeutical preparations delivery to malignant neoplasm foci or subclinical metastases.

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: after keeping during pharmaceutically acceptable period oxaliplatinum is placed in transparent, colorless and residue-free solution at concentration of, at least, 7 mg/ml, and a solvent contains sufficient quantity of, at least, one hydroxylated derivative chosen among of 1.2-propandiol, glycerol, maltite, saccharose and inositol. The innovation describes the way to obtain such a preparation. The preparation is stable during pharmaceutically acceptable period of time, that is it remains transparent, colorless and free of any residue within the range of 2-30 C that could be available during its transportation, storage and/or any handling.

EFFECT: higher efficiency of application.

14 cl, 6 ex, 4 tbl

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).

EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

Up!