Chemically stable compositions of 4-hydroxy-tamoxifen

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxsifen which contains 4-hydroxy-tamoxifen in an alcohol water solution where amount of spirit is 35-99.9 wt % of the composition weight, and about 45%-55%, about 46%-54%, about 47%-53%, about 48%-52%, about 49%-51% or about 50% of said 4-hydroxy-tamoxifen is found as an isomer Z and remained amount of said 4-hydroxy-tamoxifen is in the form of isomer E. There is also disclosed method for preparing a pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxifen.

EFFECT: preparation of the pharmaceutical composition which contains an equilibrium ratio of isomers E and Z of 4-hydroxy-tamoxifen.

13 cl, 9 dwg, 4 tbl, 6 ex

 

The present invention relates to chemically stable compositions of isomers of 4-hydroxy-tamoxifen (4-OHT), the active metabolite of the drug tamoxifen.

Tamoxifen acts on estrogen receptors throughout the body and, as agonist and antagonist, causes a wide range of systemic effects. It is frequently prescribed against breast cancer because it blocks the effects of estrogen in breast tissue, slowing down or stopping as a consequence, the growth of existing cancer cells and preventing the development of a new cancer. Because of its wide spectrum of action tamoxifen causes significant side effects that increase the risk of endometrial cancer, endometrial hyperplasia and polyps, deep vein thrombosis, pulmonary embolism, changes in the levels of liver enzymes and toxic to eyes, including cataracts. Moreover, patients who are treated with tamoxifen, complain of hot flashes, vaginal discharge, depression, amenorrhea, and nausea.

Because of the shortcomings of tamoxifen, a number of researchers in the field of cancer suggested the substitution of 4-hydroxy-tamoxifen as treatment for breast cancer. 4-hydroxy-tamoxifen acts as a selective modulator of estrogen receptor (IMRE) (SERM), which shows Dane-specificity in relation to sensitive to estrogen tissues. In breast tissue it acts as an the agonist of estrogen. Studies have shown that 4-hydroxy tamoxifen may regulate the transcriptional activity related to the estrogen receptors, which may contribute to its tone-specific activity. In vitro 4-hydroxytamoxifen shows greater efficacy than tamoxifen, as measured by affinity binding to the estrogen receptor, or ER, and the affinity of binding to estrogen receptors, similar to that of estradiol (Robertson et al., 1982; Kuiper et al., 1997).

These studies support the use of 4-hydroxy-tamoxifen for treatment of breast cancer. In vitro studies 4-hydroxy-tamoxifen inhibits the growth of normal cells and breast cancer cells (Nomura, 1985; Malet, 1988, 2002; Charlier, 1995). In addition, when the transdermal delivery of 4-hydroxy-tamoxifen exerts antitumor effect on tumor breast cancer man, grown subcutaneously in mice (US patent No. 5904930). People have limited experiments have shown that the designated percutaneous 4-hydroxy tamoxifen may be concentrated in local tumours of the breast with a very small distribution system (Mauvais-Jarvis, 1986). 4-Hydroxy-tamoxifen and gives hope for the treatment of mastalgia, excessive scarring and gyno and to reduce the density of the breast.

In the chemical structure of 4-hydroxy-tamoxifen, or 1-[4-(2-N-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenylbut-1-ene, who voina bond between two carbon atoms gives rise to two stereoisomeric forms. Unlike tamoxifen 4-hydroxy-tamoxifen no two phenyl groups, and there are probably four different groups that are posted on different sides from alkinoos group. Therefore, the terminology CIS-TRANS just not perfectly applicable to the isomers of 4-hydroxy-tamoxifen. Instead, just apply denote E from the German entgegen", meaning against (opposite) and Z from the German zusammen, meaning together (see figure 1 and 2). Both isomers of 4-hydroxy-tamoxifen biologically active, but the Z isomer is more active biologically than the isomer E (patent US 6172263).

In the solid state mixture of isomers of 4-hydroxy-tamoxifen very stable. In solution, however, is the isomerization between form Z and E. Malet et al. observed that the spontaneous isomerization of Z - E-4-hydroxy-tamoxifen occurs at the time of 24-48 hours, but quickly stabilizes at a ratio of Z/E is equal to 70/30 as in the mother solution and culture medium or cultured cells and irrespective of temperature (-20°C, 4°C or 37°C). Cm. Malet et al. (2002). Katzenellenbogen et al. further showed that the isomers of hydroxy-tamoxifen, the original pure 99%undergo dependent on time and temperature isomerization, so after 2 days in the medium for tissue culture at 37°C. they were isomaltulose within 20%. This isomerization occurs more slowly at 4°C than at 37°C and its speed m which should be reduced by various antioxidants. Cm. Katzenellenbogen et al. (1985). According to Sigma, supplier 4-hydroxy-tamoxifen, the process of interconversion E-Z 4-hydroxy-tamoxifen contribute solvents with a low dielectric constant light during the incubation in culture medium.

The isomerization process can potentially affect the activity of the pharmaceutical composition comprising 4-hydroxy-tamoxifen as an active ingredient. Therefore, in order to meet international pharmaceutical legal requirements, there is a need for chemically stable compositions of 4-hydroxy-tamoxifen. "Sustainable" pharmaceutical composition is such, whose qualitative and quantitative composition, including physical, chemical and biological characteristics are not significantly change over time in certain conditions of temperature and humidity, for example, within 3 years at 25°C/60% RH, 1 year at 30°C/65% relative humidity and/or 6 months at 40°C./75% relative humidity. "Significant change" refers to the qualitative and/or quantitative differences, which may affect the strength, effectiveness or security of the pharmaceutical composition.

To provide stable compositions with 4-hydroxy-tamoxifen would be useful for a more complete understanding of the process of isomerization of 4-hydroxy-tamoxifen

Disclosure of inventions

The authors of the present invention discovered that the isomerization of 4-hydroxy-tamoxifen in the solution reaches equilibrium when the ratio of the isomers (Z:E approximately 1:1. Moreover, they discovered that as soon as this equilibrium ratio is achieved, it remains constant.

In accordance with this discovery the present invention includes pharmaceutical compositions of 4-hydroxy-tamoxifen as an active agent, where approximately 50% of 4-hydroxy-tamoxifen exist in isomeric form Z and the remainder in isomeric form E. In some implementations of a pharmaceutical composition for percutaneous destination in the form of a gel, solution, or other pharmaceutical forms containing alcohol and water solvent.

In a separate example gelinas formulations of pharmaceutical compositions include:

a) from about 0.01% to 0.2% by weight 4-hydroxy-tamoxifen,

b) about 0.5% to 2.0% by weight isopropyl myristate,

C) from about 60% to 75% by weight of absolute alcohol,

g) from about 25% to 40% by weight aqueous solvent

d) from about 0.5% to 5% by weight zheleobrazuyuschee agent, where the percentage of components is weight relative to the weight of the composition.

In another aspect of the invention includes a method of treating or preventing wedge the economic conditions by assigning the patient, in her needy, pharmaceutical compositions comprising 4-hydroxy-tamoxifen as an active agent, where approximately 50% of 4-hydroxy tamoxifen is present in isomeric form Z and the remaining amount in the form of isomeric forms, that is, the Clinical condition under which applies this designation, include breast cancer, mastalgia, density of breast tissue, excessive scarring, and gynecomastia.

With the purposes of the prevention or treatment of pharmaceutical compositions can be assigned by any method that delivers 4-hydroxy-tamoxifen to cells bearing receptors of estrogens in vivo. Preferably, the appointment did percutaneous (topicaine) in order to avoid the effect (metabolism) of the first circle and associated metabolism of 4-hydroxy-tamoxifen in the liver. When percutaneous assignment 4-hydroxy-tamoxifen can be applied to any surface of the skin. Application (application) on the chest is preferred because when percutaneous assignment 4-hydroxy-tamoxifen tends to concentrate in the local subcutaneous tissues with estrogen receptors.

A wide range of topical formulations suitable for carrying out the invention, but the water-alcohol solution and aqueous-alcoholic gels are preferred. The concentration of 4-hydroxy-tamoxifen in these formulations can vary, but the dose should ensure that the local concentration of 4-hydroxy-tamoxifen in the tissue, which effectively counteracts the effects resulting from the estrogen.

In another aspect of the present invention includes a kit for storage, which includes:

a) a pharmaceutical composition with 4-hydroxy-tamoxifen as an active agent, where approximately 50% of 4-hydroxy tamoxifen is present in the form of the Z isomer and the remaining amount in the form of isomer E,

b) a container, inside of which is contained in the pharmaceutical composition. In some implementations of this set container may be packing on a single dose or container for a few doses, such as a container with a metering pump.

In another aspect, the present invention relates to a method of manufacturing a composition comprising 4-hydroxy-tamoxifen as an active agent, where approximately 50% of 4-hydroxy tamoxifen is present in the form of the Z isomer and the remaining amount in the form of isomer E.

Brief description of drawings

Figure 1 illustrates the E and Z isomers of 4-hydroxy-tamoxifen.

Figure 2 illustrates the reversible isomerization of 4-hydroxy-tamoxifen.

Figure 3 illustrates the concentration ratio of the isomers (in percent) for firms Panchim, party 98RD10079 at 25°C.

Figure 4 illustrates the concentration ratio of the isomers (in percent) for firms Panchim, party 98RD10079 at 30°C.

Figure 5 illustrates the ratio of the concentrations of some the s (in percent) for firms Panchim, party 98RD10079 at 40°C.

6 illustrates the concentration ratio of the isomers (in percent) for the company ICI, party I 17 at 40°C.

Fig.7 illustrates the concentration ratio of the isomers (in percent) for solutions II-IV at 25°C.

Fig illustrates the concentration ratio of the isomers (in percent) for solutions II-IV at 30°C.

Fig.9 illustrates the concentration ratio of the isomers (in percent) for solutions II-IV at 40°C.

The implementation of the invention

The present invention is based on a completely surprising discovery that the isomerization of 4-hydroxy-tamoxifen in solution comes to equilibrium when the ratio of isomers (Z:E approximately 50:50 rather than 70:30, as was shown Malet et al. and that this equilibrium value once achieved, remains constant. The inventors further discovered that vzaimoprevrascheny isomers E and Z 4-hydroxy-tamoxifen (see figure 2) is a reversible reaction with an equilibrium constant K, defined by the following formula:

where [E] and [Z] is the equilibrium concentration of the respective isomers and kfand krare the rate constants of forward and reverse reactions, respectively. Speed forward and reverse reactions, therefore, are equal.

This understanding of the behavior of the isomers of 4-hydroxy-tamoxifen makes possible the development of chemically stable what's compositions, which contain approximately equal amounts of Z and E isomers of 4-hydroxy-tamoxifen. In such compositions, the isomerization occurring between form Z and E, did not significantly affect the strength, effectiveness or security of the composition.

Moreover, because of the severity of pharmaceutical plants (rules), especially in regard to stability during storage, is required to provide the products, the composition of which does not change with time. Therefore, a great advantage to provide formulations, the composition which is stable and thus reliably and accurately determined (specified).

The skilled person knows how to determine the relative amounts of isomers Z and E in this composition. For example, as shown in the examples below, it is possible to apply the technique of liquid chromatography high resolution (HPLC) to estimate the ratio of Z/e

As discussed earlier, in the art described composition ratio Z/E, the components of 70/30. Moreover, in the art it is believed that the Z isomer has a higher biological activity than its opposite that is So all together prior knowledge in the art, apparently, is directed to compositions enriched isomer Z.

On the contrary, the present invention is a composition comprising 4-hydroxy-tamoxifen since the ratio is receiving Z/E approximately 50/50, and methods for producing such compositions. This ratio is particularly suitable for appointment to the human subject, because it is essentially physiological equilibrium value in vitro, found in tissues (Mauvais-Jarvis P, et al., Cancer Research 1986, 46, 1521-1525).

The inventors have performed several experiments to explore achieve equilibrium between the isomers of 4-hydroxy-tamoxifen in various conditions of light, temperature, pH and humidity, as well as in different environments, with different concentrations of 4-hydroxy-tamoxifen and at different ratios of alcohol/water solvent. In short, they have prepared alcoholic solutions containing different concentrations of 4-hydroxy-tamoxifen at different ratios of isomers Z and E, then watched the isomerization occurring in these solutions over at different temperatures and pH values (see Examples below). To 6 months was achieved sustainable ratio (approximately 1:1) isomers Z and E in many conditions and observed a clear tendency in all conditions. The rate of attainment of equilibrium directly dependent on temperature, pH, content of the alcohol/water solvent, light and concentration of 4-hydroxy-tamoxifen. In all cases affected were only the rate of equilibration (see Examples below), but not the final ratio of isomers Z and E, which surprisingly save what remained fairly approximately 1:1.

From the point of view of chemical kinetics, the dielectric constant is recognized as one of the fundamental properties that affect solvolytic reaction rate. In this regard, there are publications that highlight the influence of water on the degradation of the molecules. For example, Sanyude et al. studied the effect of the ratio of the water-alcohol on the degradation of aspartame. They report that the rate of degradation of aspartame increases with decreasing dielectric constant of the solvent environment, i.e. reduce the concentration of water in the environment. On the contrary, the authors of the present invention found that the rate of isomerization of 4-hydroxy-tamoxifen increases with increasing dielectric constant of the solvent environment, i.e. when the concentration of water in the environment is growing.

In agreement with the findings of the inventors of the present invention includes pharmaceutical compositions that include 4-hydroxy-tamoxifen, where about 50% of 4-hydroxy tamoxifen is in the form of the Z isomer and the remaining amount of 4-hydroxy tamoxifen is in the form of isomer that is, In some realizations, about 45%-55%, about 46%-54%, about 47%to 53%, and 48%-52%, about 49%-51% or about 50% of 4-hydroxy tamoxifen is in the form of isomer Z. Preferably, about 49%-51% and more preferably about 50% of 4-hydroxy tamoxifen is in the form of isomer z Such content is set SOS is the right balance, and not in the production of pharmaceutical compositions.

The equilibrium ratio of isomers Z and E 4-hydroxy-tamoxifen can be obtained in pure alcohol composition or mixture of alcohol and water solvent by mixing known quantities of isomers or exposing the composition to conditions which accelerate equilibration, such as high temperature, high content of 4-hydroxy-tamoxifen, high water content of the solvent or UV light. The inventors have demonstrated that the molecular size of the alcohol (ethanol or isopropanol) does not affect the rate of isomerization.

The pharmaceutical compositions of the present invention can be produced in any formados capable of delivering 4-hydroxy-tamoxifen for estrogen receptor in vivo. Preferably, the compositions are for "percutaneous destination", a phrase that means any variant of delivery of the drug from the surface of the patient's skin through the stratum corneum, epidermis and layers of connective tissue in the microcirculation system. This is usually achieved by diffusion along the concentration gradient. Diffusion can occur via intracellular (intracellular) penetration (through the cells), extracellular (intercellular) penetration (between cells), respreading (transappendageal) penetration (through bolosan the e follicles (follicles), sweat and sebaceous glands), or any combination of them.

Percutaneous assignment 4-hydroxy-tamoxifen has several advantages. First, it avoids hepatic metabolism occurring after oral assignment (Mauvais-Jarvis et al., 1986). Secondly, percutaneous designation significantly reduces systemic exposure of drugs and the associated risk of non-specific activation of estrogen receptors throughout the body; this is because 4-hydroxy-tamoxifen delayed (absorbed) in the first place in the local tissues. In particular, when 4-hydroxy-tamoxifen percutaneous put on the chest, high concentrations accumulate in breast tissue, presumably due to the large number of estrogen receptors in them, without the formation of high concentration in plasma (Mauvais-Jarvis et al., supra).

The effectiveness of percutaneous drug prescribing depends on many factors, including the concentration of the drug, the surface area of application, time and duration of application, skin hydration, physico-chemical properties of drugs and the distribution of the drug between the dosage form and the skin. Pharmaceutical formulations intended for percutaneous application, take advantage of these factors to achieve optimal delivery. Such formulations often include amplifiers permeability, which improves dermal absorbed is e, lowering the resistance of the stratum corneum by reversible changes in its physico-chemical properties, changing the hydration of the stratum corneum by acting as a co-solvent or changing the organization of lipids and proteins in the intercellular spaces. Such amplifiers percutaneous absorption include surfactants, DMSO, alcohol, acetone, propylene glycol, polyethylene glycol, fatty acids or fatty alcohols and derivatives thereof, hydroxy acids, pyrrolidone, urea, essential oils and mixtures of the above. In addition to chemical enhancers physical methods may increase percutaneous absorption. For example, occlusal (sealed) bandages cause skin hydration. Other physical methods include iontophoresis or sonophoresis, which apply electric fields or high frequency ultrasound, respectively, to enhance the absorption of drugs that are poorly absorbed because of their size or ionic characteristics.

Many factors and methods related to percutaneous delivery of drugs discussed in Remington: The Science and practice of pharmacy, Alfonso R. Gennaro (Lippincott Williams & Wilkins, 2000) pp.836-58 and Percutaneous Absorption: Drugs, Cosmetics, mechanisms methodology, Bronaugh and Maibach (Marcel Dekker, 1999). As evidenced by these publications in the field of pharmacy can be controlled by various factors and ways to achieve effective percutaneous delivery.

<> For percutaneous destination 4-hydroxy-tamoxifen can be delivered in water-startowa solution, aqueous-alcoholic gel, ointment, cream, gel, emulsion (lotion, powder, oil or similar formulations.

In the preferred implementation of the invention, 4-hydroxy-tamoxifen involve alcohol formulations, preferably, aqueous-alcoholic gel. The number of 4-hydroxy-tamoxifen in such a gel may be in the range from approximately 0.001 to approximately 1.0 g of 4-hydroxy tamoxifen per 100 g of gel. Preferably, it is in the range from about 0.01 to about 0.2 g of 4-hydroxy tamoxifen per 100 g of gel. In such implementations, the 4-hydroxy tamoxifen may be about 0,01%, 0,02%, 0,03%, 0,04%, 0,05%, 0,06%, 0,07%, 0,08%, 0,09%, 0,10%, 0,11%, 0,12%, 0,13%, 0,14%, 0,15%, 0,16%, 0,17%, 0,18%, 0,19% or 0.20% by weight of the pharmaceutical composition.

Formulations of the invention with 4-hydroxy-tamoxifen, comprise one or more non-aqueous solvent, such as alcohol solvents. Such solvents should be capable of dissolution as 4-hydroxy-tamoxifen and any applicable amplifier permeability. They should also be low boiling point, preferably less than 100°C at atmospheric pressure, to allow rapid evaporation upon contact with skin. The preferred alcohol solvents are, this is ol and isopropanol. In particular, ethanol makes an effective contribution to the percutaneous absorption of 4-hydroxy-tamoxifen, as quickly evaporates upon contact with the skin. The amount of solvent in the form of absolute alcohol in the formulation of the invention is between 35% and 99.9%, preferably between 50% and 85%, more preferably between 60% and 75% by weight. Thus, the number of absolute (anhydrous) non-aqueous solvents in gelinas formulations may be about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74% or 75% by weight.

Formulations can also include an aqueous solvent, which allows you to dissolve any hydrophilic molecules in the formulation and promotes skin hydration. The aqueous solvent may also adjust the pH, preferably in the range of from about 4 to about 12, more preferably in the range of from about 6 to about 11, even more preferably in the range of from about 8 to about 10 and just preferably at approximately 9. As shown below, the pH and, therefore, the choice of buffer solution affects the rate of attainment of equilibrium between the isomers Z and E 4-hydroxy-tamoxifen. The final ratio of equilibrium, however, remains approximately equal to 1:1 regardless of the buffer.

Aqueous solvents include zaschelachivayuschie and basic buffer solutions, including the phosphate buffer solutions (for example, monobasic or dibasic sodium phosphate), citrate buffer solutions (for example, sodium citrate or potassium citrate) and just purified water. Phosphate buffer is preferred according to the invention. The amount of aqueous solvent, preferably, is between 0.1% and 65% by weight of the pharmaceutical composition, more preferably between 15% and 50% and even more preferably between 25% and 40%. Thus, the aqueous solvent may be about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%. When the formulation contains an aqueous solvent, the amount of absolute alcohol solvent in the formulation, preferably from about 60% to about 75%.

Formulations with 4-hydroxy-tamoxifen may also contain one or more amplifier percutaneous absorption. Preferred enhancers percutaneous absorption are esters of fatty acids. One highly preferred fatty acid ester as the amplifier absorption is isopropyl myristate. When isopropyl myristate used in the gel, the quantity may be in the range from about 0.1 to about 5.0 g per 100 g of gel. Preferably, the amount of isopropyl myristate is in the range of from about 0.5 to about 2.0 g per 100 g of gel. In such implementations, isopropyl myristate can make the Colo 0,5%, 0,6%, 0,7%, 0,8%, 0,9%, 1,0%, 1,1%, 1,2%, 1,3%, 1,4%, 1,5%, 1,6%, 1,7%, 1,8%, 1,9% or 2.0% by weight of the pharmaceutical composition.

Additionally, formulations with 4-hydroxy-tamoxifen can include one or more geleobrazuyuschie agent for increasing the viscosity of the formulations and/or to act as solubilizing agent. Depending on the nature zheleobrazuyuschee agent he may be from 0.1% to 20% by weight of the formulation, preferably between 0.5% and 10%, more preferably between 0.5% and 5%. Thus, the number zheleobrazuyuschee agent may be about 0,5%, 1,0%, 1,5%, 2,0%, 2,5%, 3,0%, 3,5%, 4,0%, 4,5% or 5%. The preferred geleobrazuyuschie agents include carbomer, derivatives of cellulose, poloxamer and poloxamine. In particular, geleobrazuyuschie agents are chitosan, dextran, pectins, natural gums and cellulose derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC), etc. One highly preferred geleobrazujushchim agent is hydroxypropyl cellulose.

When the formulation includes geleobrazuyuschie agent, in particular acrylic polymer without prior neutralization, it may primarily include a neutralizing agent. The ratio of neutralizing agent/geleobrazuyuschie agent is preferably between 10:1 and 0.1:1, more pre is respectfully between 7:1 and 0.5:1 and even more preferably between 4:1 and 1:1. Thus, the ratio of neutralizing agent/geleobrazuyuschie agent may be about

7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1 or 0.5:1. The neutralizing agent in the presence of the polymer should form a salt, soluble in the solvent. The neutralizing agent must also call the optimum swelling of the polymer chains when charge neutralization and the formation of salts of the polymers. Apply neutralizing agents include sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol, trolamine (triethanolamine) and tromethamine (TRIS buffer). Skilled in the art will be able to choose the neutralizing agent in accordance with the type zheleobrazuyuschee agent used in the formulation. As zheleobrazuyuschee agent used derivatives of cellulose, no neutralizing agents are not required.

Table 1 represents the composition of two vysokoproizvoditelnykh gennych formulations with 4-hydroxy-tamoxifen. All components are pharmaceutically acceptable substances.

Table 1
The composition gennych formulations with 4-hydroxy-tamoxifen
IngredientQuantity per 100 g gel
Gel with 20 mg 4-OHTGel with 57 mg of 4-OHT
4-hydroxy-tamoxifen0.02 g0,057 g
Absolute ethanol66.5 g66.5 g
Isopropyl myristate1 g1 g
Hydroxypropyl cellulose1.5 g1.5 g
Phosphate buffer (pH 7, dilution 1:4)q.s. 100 gq.s. 100 g

The pharmaceutical compositions of the invention can be assigned for the treatment of many clinical conditions, where applicable tamoxifen and 4-hydroxy-tamoxifen. For example, you can assign for the treatment of breast cancer (Mauvais-Jarvis et al., 1986, example 4), mastalgia (Fentiman 1986, 1988, 1989), a history of excessive scarring (Neither, 1998; Ni, 2002) or gynecomastia (Gruntmanis and Braunstein, 2001)). They also can be assigned to prevent breast cancer in patients with a high risk of developing the disease or to reduce the density of breast tissue, when this condition interferes with mammography (Atkinson, 1999; Brisson, 2000; Son, 1999). Cm. also provisional patent application US No. 60/433959 registered 18 December 2002; 60433958, registered on 18 December 2002 and 60/458963, registered April 1, 2003, each of which is included here by reference for a complete description of these applications.

Although the invention is not limited by any theory in particular, clinically significant side effects antiestrogenic agents have when they substitute estradiol in tissues that are not targets. As 4-hydroxy-tamoxifen and estradiol have similar affinity binding to estrogen receptors, they compete for binding to the receptor approximately equally, when the concentration of one compound approaches the concentration of the other. If the concentration of 4-hydroxy-tamoxifen exceeds the concentration of estradiol, the first will be preferably associated with the estrogen receptor and Vice versa. Through the local 4-hydroxy-tamoxifen, you can reach high concentrations in the target tissues without simultaneously increasing levels of 4-hydroxy-tamoxifen in the plasma to the level when there is significant systemic competition for receptors estradiol.

For women, the preferred dose of 4-hydroxy-tamoxifen, which lead to concentrations in plasma of less than about 80 PG/ml, or the average concentration of estradiol in normal women before menopause. A more preferred dose of 4-hydroxy-tamoxif is on, leading to concentrations in plasma of less than about 50 PG/ml For men preferred dose of 4-hydroxy-tamoxifen, which lead to concentrations in plasma of less than about 20 PG/ml, or the average concentration of estradiol in normal men. Daily dose that should be assigned to, you can initially estimated on the basis of the absorption coefficients of 4-hydroxy-tamoxifen, the desired concentration in breast tissue and plasma concentrations, which should not be exceeded. Of course, the initial dose can be optimized for each patient depending on individual responses.

When assigning percutaneous formulations against breast conditions (breast cancer) dose 4-hydroxy-tamoxifen order of 0.25-2.0 mg/chest/day should give the expected result, and the dose of about 0.5-1.0 mg/chest/day preferred. In some implementations, the dosage of 4-hydroxy tamoxifen is about 0.5, is 0.75 or 1.0 mg/chest/day.

For the treatment of excessive scarring dose of about 0.25 to 6 µg 4-hydroxy-tamoxifen/cm2/day should give the desired result, with the preferred dose is from about 0.25 to 3 g or more preferred dose is from 0.5 to 2.5 g/cm2/day. A dose of approximately 1.0 and 2.0 mg/cm2/day highly preferred for treating conditions of excessive scarring.

Pharmaceutical compositions the AI of the invention can be packaged in kits for storage. These kits comprise (a) a pharmaceutical composition, as described herein, and (b) the container, and a pharmaceutical composition contained within the container. The container can be Packed on a single dose, such as film packaging (bag or container for a few doses, such as a container with a metering pump. Preferably, the container is opaque.

In another aspect, the present invention relates to a method for producing a pharmaceutical composition comprising 4-hydroxy-tamoxifen. In particular, presents a method for the production of pharmaceutical compositions of the invention described above.

In one implementation of the present invention is directed to a method of obtaining a pharmaceutical composition, comprising the step of bringing the composition comprising 4-hydroxy-tamoxifen, in a state of equilibrium, where approximately 45%-55%, approximately 46%-54%, about 47%to 53%, approximately 48%-52%, approximately 49%-51% or approximately 50% mentioned 4-hydroxy-tamoxifen is in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is in the form of isomer E.

In another implementation of the present invention is a process comprising the steps:

(1) the provision of a certain number of 4-hydroxy-tamoxifen;

(2) providing at least one Napo the preserver;

(3) the Association referred to 4-hydroxy-tamoxifen and at least one of the above-mentioned filler, forming thus the composition;

(4) bringing said composition in the equilibrium state, where approximately 45%-55%, approximately 46%-54%, about 47%to 53%, approximately 48%-52%, approximately 49%-51% or approximately 50% mentioned 4-hydroxy-tamoxifen is in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is in the form of isomer E.

In one implementation of the above-mentioned step (1) includes the provision of a certain number of 4-hydroxy-tamoxifen in the form of the Z isomer and/or the provision of a certain number of 4-hydroxy-tamoxifen in the form of isomer that is, 4-hydroxy-tamoxifen you can provide, using different relative amounts of isomers E and z for Example, you can provide 4-hydroxy-tamoxifen in the form of only one isomer (for example, only E only or Z). It is also possible to provide both isomers in equal or different amounts.

Fillers known in the art. In one implementation of the invention, the above filler is chosen from the group comprising water, pharmaceutically acceptable aqueous buffers, amplifiers permeability, geleobrazuyuschie agents, oils, neutralizing agents and mixtures of the above. Various Khujand the exercise of, described above for the compositions of the invention (ingredients, their quantities, can be transferred to the methods of the invention. Experienced in this field would know how to act to provide the desired ingredients in desired quantities.

According to the invention, the above method includes bringing mentioned pharmaceutical compositions comprising 4-hydroxy-tamoxifen, in the state of equilibrium. The above equilibrium is usually a condition where the ratio of the isomers E/Z varies slightly with time because of the mentioned pharmaceutical composition has reached equilibrium. In the above-mentioned equilibrium approximately 45%-55%, approximately 46%-54%, about 47%to 53%, approximately 48%-52%, approximately 49%-51% or approximately 50% mentioned 4-hydroxy-tamoxifen is in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is in the form of isomer E.

The kinetics by which equilibrium is reached depends on various parameters such as the initial ratio of E/Z (i.e. the corresponding number of isomers E and Z, initially granted), the final pH of the composition, nature and the quantities of the ingredients of the composition, the dielectric constant of the composition, the temperature of the production, storage temperature and exposure to light (the duration is alnost, wave length (wave), ...)

An experienced person will know how to monitor the progress of the isomerization and how to choose the parameters in order to ensure that the actual attainment of the equilibrium state.

Examples of parameters include:

- temperature in the range of 25-40°C., for example 30-35°C during manufacturing and/or

- temperature in the range of 25-40°C., for example 30-35°C, during storage and/or

- storage of 0.5-6 months, for example, 1, 2, 3, 4, 5 or 6 months, and/or

- exposure to light, especially UV light, during production and/or

- exposure to light, especially UV light during storage and/or

- the final pH of the composition and/or

- the dielectric constant of the composition and/or

- the ratio of water/alcohol, for example, the ratio of water/ethanol in the composition and/or

- the original ratio of E/Z value 2/98, 60/40, 63/37, 70/30, 10/90, 0/100...

The method of the invention may also include the step of packing the aforementioned pharmaceutical composition in a container, for example, packaging for one dose or container on many doses with a metering pump.

Link to further illustrative examples will help to provide a more complete understanding of the invention.

Example 1

This example shows that the isomerization of 4-hydroxy-tamoxifen occurs in solution and that the isomerization eventually reaches equilibrium, at which about 50% of 4-hydroxy-tamoxifenanxiety in the form of isomer Z, and the remaining amount in the form of isomer E.

A. Obtaining solutions containing 4-hydroxy-tamoxifen

Water-alcohol solution containing 4-hydroxy-tamoxifen, get, based on the following formula:

4-hydroxy-tamoxifen0,057 g
isopropyl myristate1,000 g
klucel (hydroxypropyl cellulose)1,500 g
absolute ethanol66,500 g
phosphate buffer qsf100.0 g

In water-alcohol solutions phosphate buffer replaces Cluzel. The composition of the buffer is as follows:

KN2RHO40,8526 g
Na2HPO43,4826 g
Purified water1000 g

Prepare solutions containing five different concentrations(0,02%, 0,04%, 0,06%, 0,08% and 0.10%) 4-hydroxy-tamoxifen. The composition of each solution is given in the table below.

0,02%0,04%0,06%0,08%0,10%
4-OHT4-OHT4-OHT4-OHT4-OHT
4-OHT (g)0,016to 0.0320,0480,0640,080
Absolute ethanol (g)53,21053,21053,21053,21053,210
Myristate (g)0.800 to0.800 to0.800 to0.800 to0.800 to
Buffer qsf (g)80,00080,00080,00080,00080,000

For each of these concentrations prepare separate solutions containing Z-4-hydroxy-tamoxifen, or a mixture of Z - and E-4-hydroxy-tamoxifen. Tested 4-hydroxy-tamoxifen from three different post is Usikov:

- PANCHIM:4-OHT E+Z (party 98RD10079)
- PANCHIM4-OHT Z (party 7421)
- ICI4-OHT Z (part I 17)
- SIGMA4-OHT Z (party C).

Because there was only a small amount of Z-4-hydroxy-tamoxifen from SIGMA, prepared only 0,06% solution of this package (party). The solution was tested, as described below, only at 25°C and 40°C.

B. Conditions of the study

Each solution is divided into three parts in bottles brown glass 30 ml, then placed in an oven adjusted to 25°C, 30°C and 40°C.

The relative amounts of Z and E isomers of 4-hydroxy-tamoxifen determined at baseline and at time points corresponding 2 weeks, 1 month, 2 months, 3 months, 4 months and 5 months.

C. Analytical methods

to determine the relative quantities of each of the isomers of 4-hydroxy-tamoxifen used HPLC using a standard solution of 4-hydroxy-tamoxifen as a solution for comparison. Operating parameters for HPLC following:

column Beckman Ultrasphere ODS 250×4.6 mm 5 µm
the mobile phase60% 0.5% aqueous solution of triethylamine,
brought to a pH of 2.5 with 25%
hydrochloric acid
40% acetonitrile

the current velocity0.8 ml/min
wavelength245 nm
amount of application20 ál
time pass20 min

Before HPLC water-alcohol solutions were diluted with mobile phase to get concentration of 4-hydroxy-tamoxifen about 2.3 μg/ml

Initial concentrationTaken volumeThe mobile phase qsp
0,02%645 μl50 µl
0,04%325 ál50 µl
0,06% 215 ál50 µl
0,08%160 ál50 µl
0,10%130 ál50 µl

The order of elution as follows:

4-OHT E: the retention time of 13.3 min

4-OHT Z: the retention time of 15.0 min

The percentage of each isomer was calculated by the following formulas:

G. data Processing

The reversible isomerization reaction and achieved equilibrium are related by the following equations:

where

A0= initial concentration of the reagent

Aeq= concentration of the same reagent in the balance

A = concentration in time t

kf= the rate constant of the direct reaction

kr= rate constant for the reverse reaction

t = time, measured in months.

Graphas a function of time is plotted on a straight line with a slopeand crossing the y axis at 0.

D. Results

The tables below show the results of the study; to the point in time, equal to 6 months, many solutions have come to equilibrium with the ratio of the isomers Z and E approximately 1:1. The rate constant of co is prevrasheniya isomers directly depends on the temperature, and on the initial concentration of the pure Z isomer and the initial concentration of the mixture of isomers E/Z.

The contents of the individual isomers Z and E 4-hydroxy-tamoxifen in the range of total concentration of from 0.02% to 0.1% as a function of time are presented in figure 3, 4 and 5. A solution of 4-hydroxy-tamoxifen store at 25°C (figure 3), 30°C (figure 4) and 40°C (figure 5). The medicinal substance 4-hydroxy-tamoxifen, used to prepare the solution, has the original concentration ratio of isomers E and Z 63% and 37%, respectively (PANCHIM party 98RD10079).

With the change of the nominal concentration of 4-hydroxy-tamoxifen from 0.02% to 0.10% of the value of the rate constants for the reversible isomerization is increased linearly. Values of rate constants increase with temperature.

The same equilibrium the ratio of the size of about 1:1 is observed in the application of medicinal substances 4-hydroxy-tamoxifen, with an initial ratio of E/Z 2/98 (PANCHIM party 7421) and 0/100 (party ICI VH) (see Fig.6 for example). Packaging PANCHIM 7421 (the ratio of E/Z 2/98) and ICI VH (the ratio of E/Z 0/100) represent the rate constants are very close in value for each nominal concentration of 4-hydroxy-tamoxifen and at each investigated temperature. Surprisingly, the closer the source, the ratio of E/Z to 1:1, the higher is the rate constant for reaching equilibrium (see table 1).

Table 1
Rate constants
Packaging PANCHIM 98RD10079 (original ratio of E/Z: 62,5/37,5)
The rate constant (month-1for nominal concentrations of 4-hydroxy-tamoxifen
(Z+E) in solution (%)
0,020,040,060,080,10
25°C0,08640,25560,17690,21790,254
30°C0,11390,17260,23740,29320,3231
40°C0,21920,37610,47410,60260,8472

Packaging PANCHIM 7421 (original ratio of E/Z: 2/98)
The rate constant (month-1for nominal concentrations of 4-hydroxy-tamoxifen
(Z+E) in solution (%)
0,020,040,060,080,10
25°C0,02250,06370,08860,13520,1827
30°C0,04570,0864to 0.14870,19000,2568
40°C0,10970,22870,38770,53110,6300

ICI party VH (original ratio of E/Z: 0/100)
The rate constant (month-1for nominal concentrations of 4-hydroxy-tamoxifen
(Z+E) in solution (%)
0,020,040,06 0,080,10
25°C0,03470,04840,09160,14760,2169
30°C0,02540,08010,15630,27180,3103
40°C0,07220,23230,39240,50950,6960

Example 2

This example demonstrates the effect of isopropyl myristate, nature of present alcohol and the ratio of alcohol/phosphate buffer at isomerization of 4-hydroxy-tamoxifen. Apparently, the choice of a non-aqueous solvent (buffer or water) has no significant effect on the isomerization process. The amount of non-aqueous solvent is indirect proportional to the rate of isomerization, but the final equilibrium ratio of Z/E amount of nonaqueous solvent has no effect.

Solutions containing 0.06% of 4-hydroxy-tamoxifen, is prepared, as shown in the table below:

The solution is to compareSolution II/td> Solution IIISolution IV
4-OHT E+Z (g)0,0480,0480,0480,048
Myristate (g)0.800 to///
Alcohol (g)Absolute ethanol
53,210
Absolute ethanol
53,210
Isopropanol
53,210
Absolute ethanol
40,000
Buffer qs (g)80,00080,00080,00080,000

Solutions II, III and IV, described above, is prepared from packaging 4-hydroxy-tamoxifen PANCHIM party 98RD10079. The original ratio of E/Z 63%/37%.

Solution for comparison: Helena formulation without zheleobrazuyuschee agent Cluzel.

Solution II: solution for comparison without isopropylmyristate and containing ethanol.

Solution III: solution II, where the substituted ethanol isopropyl alcohol.

Solution IV: solution II, where the ratio of ethanol/buffer is 50/50 instead 66,5/33,5.

As in example 1, with the isomerization each solution watch tip is of time. The drawings below show the results.

Replacement of ethanol isopropyl alcohol and remove isopropyl myristate not have a significant impact on reversible kinetics of 4-hydroxy-tamoxifen.

Increasing the concentration of aqueous solvent (buffer) from 33.5% to 50% leads to a significant increase in the rate constant at 25°C and 30°C. the Difference is less pronounced at 40°C. the Increase in the concentration of the buffer leads to an increase in the dielectric constant of the mixture and thus facilitates the polarization of hydroxyl groups and, therefore, the conjugation of double bonds alkinoos group 4-hydroxy-tamoxifen. The same phenomenon is observed when replacing the buffer with water. It is important to note the role of pH of buffer solution to the kinetics of the reversible isomerization of 4-hydroxy-tamoxifen.

Example 3

This example demonstrates the effects of extreme temperature on the isomerization of 4-hydroxy-tamoxifen. Very high temperatures accelerate the process of equilibration, while very low temperatures it slow. This example also shows that the amount of aqueous solvent contained in the mixture affects the rate of isomerization, as noted in example 2.

Prepare two solutions containing 0.06% of Z-4-hydroxy-tamoxifen, the solution V and the solution VI. The solution V contains 4-hydroxy-tamoxifen in pure ethanol. Solution VI contains 4-is hydroxy-tamoxifen in the mixture to 66.3% water and 33.7% ethanol. For the degree of isomerization occurred in each solution, see through one week at -20°C, 25°C and 60°C. the Results are shown in the table below. After a week there is no isomerization at -20°C and 25°C, while the beginning of isomerization is observed at 60°C. In the light of the results published Malet et al., surprisingly, the isomerization is not detected in the solutions V and VI after a week of storage at -20°C and 25°C.

Table 2
The influence of extreme temperature and alcohol content on the isomerization
-20°CThe solution VSolution VI
Time 0%S00
%Z100100
1 week%S00
%Z100100
25°CThe solution VSolution VI
Time 0%S00
%Z100100
1 week%S00
%Z100100
60°CThe solution VSolution VI
Time 0%S00
%Z100100
1 week%S19,050,6
%Z81,049,4

Example 4

This example shows the action of the light on the isomerization of 4-hydroxy-tamoxifen. For the degree of isomerization that occurs in each solution containing 0.06% of 4-hydroxy-tamoxifen, with an initial ratio of E/Z 98/2 (in a mixture of 66% water and 34% of ethanol), see for two hours at room temperature and at two wavelengths in the UV: 380 nm and 254 nm. The results are shown in table 3 below.

UV light accelerates the achievement of equilibrium; indeed, in 5 minutes you can observe the process of isomerization at room temperature. At 254 nm isomerization is faster than 380 nm. Besides at 254 nm phenomenon isomerization combined with destruction (degradation) of the two isomers to impurities, called approx. 1 and approx. 2, which are derived from phenanthrene. Thus, the equilibrium ratio of isomers E/Z, achieved under UV light, different from 1:1.

Example 5

This example shows the effect of pH on the isomerization of 4-hydroxy-tamoxifen. The amount of isomerization that occurs in solutions containing 0.06% of 4-hydroxy-tamoxifen, with an initial ratio of E/Z 100/0 and 37/63, see for 2 months at 40°C. 4-Hydroxy-tamoxifen dissolved in a mixture of 66.5% in absolute ethanol, 32,4% or phosphate (pH from 2 to 8), or carbonate (pH 10) buffer and 1% isopropyl myristate. The results are shown in table 4 below.

Table 4
The effect of pH on the isomerization at 40°C
a similar ratio of E/Z 100/0Time 0Day 8Day 15Month 1Month 2Month 3
Buffer pH 2,2The final pH 4%S0,029,045,947,448,047,7
%Z100,071,054,152,652,052,3
Buffer pH 4The final pH 6%S0,012,534,343,248,148,5
%Z100,087,5 65,756,851,951,5
Buffer pH 6The final pH 7%S0,02,99,616,631,340,8
%Z100,0to 97.190,4of 83.468,659,2
Buffer pH 8The final pH 9%S0,03,4the 11.620,636,444,1
%Z100,096,688,479,463,655,9
Buffer pH 10The final pH 12%S0,048,3 48,848,848,848,9
%Z100,051,751,251,251,251,1
The original ratio of E/Z 37/63Time 0Day 8Day 15Month 1Month 2Month 3
Buffer pH 2,2The final pH 4%S62,952,548,548,248,048,0
%Z37,147,551,551,852,052,0
Buffer pH 4The final pH 6%S62,956,8 51,049,449,048,5
%Z37,143,249,050,651,051,5
Buffer pH 6The final pH 7%S62,561,158,055,852,050,4
%Z37,538,942,044,248,049,6
Buffer pH 8The final pH 9%S62,760,656,954,250,8to 49.9
%Z37,339,4to 43.145,849,250,
Buffer pH 10The final pH 12%S63,448,549,049,048,849,0
%Z36,651,551,051,051,251,0

Low and high pH values speed up the process of equilibration. The closer the pH to neutral (7,0), the slower equilibrium is reached. However, pH, apparently, has no significant effect on the equilibrium ratio of isomers E/Z of about 1:1.

Example 6. Methods of obtaining pharmaceutical compositions of 4-hydroxy-tamoxifen, under the equilibrium of the isomer ratio of about 1:1

The following examples illustrate the methods of the invention. These methods mainly lead to stable compositions of 4-hydroxy-tamoxifen, with the ratio of the isomers (E:Z is about 1:1

Method:

(1) 0.06 g of 4-hydroxy-tamoxifen, containing both isomers E and Z at the level of 60/40, respectively, mixed with 66.5 g of absolute ethanol and stirred until complete dissolution at room temperature is e;

(2) then add 1.0 g of isopropyl myristate and stirred;

(3) add to 32.4 g of aqueous phosphate buffer and mixed with solution (final pH about 9);

(4) finally, the solution is transferred into a bottle of opaque glass and then stored at 25°C/60% relative humidity for 6 months.

Method B:

(1) 0.08 g of 4-hydroxy-tamoxifen, containing both isomers E and Z at the level of 60/40, respectively, is mixed with a 53.2 g of absolute ethanol and stirred until complete dissolution at room temperature;

(2) then add 0.8 g of isopropyl myristate and stirred;

(3) to the solution was added with 25.9 g of aqueous phosphate buffer to achieve a final pH 9);

(4) finally, the solution is transferred into a bottle of opaque glass and then stored at 40°C./75% relative humidity for 2 months.

Method:

(1) 0.08 g of 4-hydroxy-tamoxifen, containing both isomers E and Z-level 0/100, respectively, is mixed with a 53.2 g of absolute ethanol and stirred until complete dissolution at room temperature;

(2) then add 0.8 g of isopropyl myristate and stirred;

(3) to the solution was added with 25.9 g of aqueous phosphate buffer to achieve a final pH 9);

(4) finally, the solution is enclosed in a bottle of opaque glass and then stored at 40°C/75% consider Inoi humidity for 6 months.

Method G:

(1) 0.06 g of 4-hydroxy-tamoxifen, containing both isomers E and Z at the level of 60/40, respectively, mixed with 66.5 g of absolute ethanol and stirred until complete dissolution at room temperature;

(2) add to 32.4 g of aqueous carbonate buffer and mixed with solution (final pH about 12);

(3) finally, the solution is transferred into a bottle of opaque glass and then stored at 40°C for 15 days.

References (cited publication)

Each of the following publications are included here fully by reference.

Atkinson, C., R.Warren, S.A.Bingham, and N.E. Day, Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen, Cancer Epidemiology, biomarkers are & Prevention, 8: 863-66 (1999).

Brisson, J., .Brisson, G.Cote, E.Maunsell, S.Berube, and J.Robert, Tamoxifen and mammographic breast densities. Cancer Epidemiology, biomarkers are & Prevention, 9: 911-15 (2000).

Bronaugh and Maibach, Percutaneous Absorption: Drugs, Cosmetics, Mechanisms Methodology, Marcel Dekker 1999.

Charlier, C., A.Chariot, N.Antoine, M.P.Merville, J.Gielen, V.Castronovo, Tamoxifen and its active metabolite inhibit growth of estrogen receptor-negative MDA-MB-435 cells, 49(3): 351-8 (1995).

Fentiman, I.S., Tamoxifen and mastalgia. An emerging indication, Drugs 32: 477-80 (1986).

Fentiman, I.S., M.Caleffi, H.Hamed, and M.A.Chaudary, Dosage and duration of tamoxifen treatment for mastalgia: a controlled trial, British Journal of Surgery 75: 845-46 (1988).

Fentiman, I.S., M.Caleffi, H.Hamed, and M.A.Chaudary, Studies of tamoxifen in women with mastalgia, British Journal of Clinical Practice, Supplement 68, 43(11): 34-36 (1989)).

Gruntmanis, U. and G.D.Braunstein, Treatment of gynecomastia, Curr. Opin. Investig. Drugs, 2:643-649 (2001).

Hu, D., M.A.Hughes, G.W.Cherry, Topical tamoxifen - a potential therapeutc regimen in treating excessive dermal scarring? Br. J. Plast. Surg., 50(6): 462-9 (1998).

Neither, D., X.Zhu, M.Xu, B.Chen, A.H.Margaret, W.C.George, The inhibitory effect of tamoxifen on human dermal fibroblast-populated collagen lattices, Zhonghua Zheng Xing Wai Ke Za Zhi, (18(3): 160-2 (2002).

Katzenellenbogen, J.A., K.E.Carlson, B.S.Katzenellenbogen, Facile geometric isomerization of phenolic non-steroidal estrogens and antiestrogens: limitations to the interpretation of experiments characterizing the activity of individual isomers, J. Steroid Biochem, 22(5): 589-96 (1985).

Kuiper, G.G.J.M., .Carlsson, .Grandien, E.Enmark, J.Heggblad, S.Nilsson, J.Gustafsson, Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology, 138: 863-870 (1997).

Malet S., A.Compel, P.Spritzer, N Bricourt, NH Yaneva, I.Mowszowicz, F.Kutten and P Mauvais Jarvis, Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Research, 48: 7193-7199 (1988).

Malet, C., P.Spritzer, .Cumins, D.Guillaumin, P.Mauvais-Jarvis, F.Kuttenn, Effect of 4-hydroxytamoxifen isomers on growth and ultrastructural aspects of normal human breast epithelial (HBE) cells in culture, J. Steroid Biochem. & Mol. Bio., 82: 289-96 (2002).

Mauvais-Jarvis, P., N.Baudot, D.Castaigne, P.Banzet, and F.Kuttenn, Trans-4-hydroxytamoxifen concentration and metabolism after percutaneous local administration to human breast. Cancer Research, 46: 1521-1525 (1986).

Nomura, Y., H.Tashiro, F.Takaeko, Effects of antiestrogens and medroxyprogesterone acetate on the clonogenic growth of tamoxifen-sensitive and resistant human breast cancer cells, Jpn. J. Cancer Chemotherapy, 12(4): 844-50 (1985).

Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, Lippincott Williams & Wilkins, 2000, pp.836-858.

Robertson and Katzenellenbogen, J. Org. Chem., 47: 2387 (1982).

Robertson, D.W., J.A.Katzenellenbogen, D.J. Long, E.A. and Rorke B.S.Katzenellenbogen, antiestrogens Tamoxifen. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen, J. Steroid Biochemistry, 16(1): 1-13 (1982).

Son, H.J., and K.K.Oh, Significance of follow-up mammography in estimating the effect of tamoxifen in breast cancer patient who have undergone surgery, American Journal of Roentgenology, 173: 905-909 (1999).

The US patent No. 5904930.

The US patent No. 6172263.

Patent application US No. 60/433958.

Patent application US No. 60/433959.

Patent application US 60/458963.

1. Pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxifen, which includes 4-hydroxy-tamoxifen in aqueous-alcoholic solution, where the amount of alcohol is 35-99,9 wt.%, by weight of the composition and about 45-55%, about 46 to 54%, about 47-53%, about 48-52%, about 49-51% or about 50% mentioned 4-hydroxy-tamoxifen is present in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is present in the form of isomer E.

2. The pharmaceutical composition according to claim 1, in which about 48-52% mentioned 4-hydroxy-tamoxifen is present in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is present in the form of isomer E.

3. The pharmaceutical composition according to claim 1, in which about 50% mentioned 4-hydroxy-tamoxifen is present in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is present in the form of isomer E.

4. The pharmaceutical composition according to claim 1, which further includes the amplifier constant.

5. The pharmaceutical composition according to claim 4, in which the amplifier permeability includes at least one fatty acid ester.

6. The pharmaceutical composition according to claim 1, which Zap is published in the packaging for a single dose or in a container on many doses fitted with a metering pump.

7. A method of obtaining a pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxifen, comprising the steps:
(1) provision of 0.001 to 1.0% by weight of the composition 4-hydroxy-tamoxifen;
(2) providing a water-alcohol solution, where the amount of alcohol is 35-99,9 wt.%, by weight of the composition;
(3) the Association referred to 4-hydroxy-tamoxifen with a water-alcohol solution with the formation of the composition, in which approximately 45-55%, about 46 to 54%, about 47-53%, approximately 48-52%, about 49-51% or approximately 50% mentioned 4-hydroxy-tamoxifen is in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is in the form of isomer E.

8. The method of obtaining pharmaceutical compositions of 4-hydroxy-tamoxifen for intradermal injection, comprising the step of bringing an aqueous-alcohol solution containing 4-hydroxy-tamoxifen, in the equilibrium state, and the method includes:
(1) provision of 0.001 to 1.0% by weight of the composition 4-hydroxy-tamoxifen;
(2) providing a water-alcohol solution, where the amount of alcohol is 35-99,9 wt.%, by weight of the composition;
(3) the Association referred to 4-hydroxy-tamoxifen with a water-alcohol solution with the formation of the composition, in which approximately 45-55%, about 46 to 54%, AP is sustained fashion 47-53%, approximately 48-52%, about 49-51% or approximately 50% mentioned 4-hydroxy-tamoxifen is in the form of the Z isomer and the remainder of the amount referred to 4-hydroxy tamoxifen is in the form of isomer E.

9. The method according to claim 7 or 8 where the above-mentioned pharmaceutical composition is in equilibrium includes approximately 48-52%, for example, approximately 50% mentioned 4-hydroxy-tamoxifen in the form of the Z isomer and the remaining amount mentioned 4-hydroxy-tamoxifen in the form of isomer E.

10. The method according to claim 7 or 8, where step (1) includes the provision of a certain number of 4-hydroxy-tamoxifen in the form of isomer Z and, if necessary, provides a certain amount of 4-hydroxy-tamoxifen in the form of isomer E.

11. The method according to claim 7 or 8 where the above-mentioned pharmaceutical composition comprises an amplifier permeability, in particular, the aforementioned pharmaceutical composition include, at a minimum, ether fatty acids.

12. The method according to claim 7 or 8, further comprising the step:
(4) packs mentioned pharmaceutical composition is packaged in a single dose or in a container on a lot of doses, fitted with a metering pump.

13. The pharmaceutical composition obtained by the method according to claims 7-12.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to four defined crystalline polymorphous forms of the monohydrate of a compound A having the following chemical composition:

.

Compound A. These four polymorphous forms, denoted here as forms I, II, III and IV, exhibit CXC chemokine receptor ligand activity.

EFFECT: invention relates to a pharmaceutical composition based on said compounds, to use thereof for treating different diseases and to methods for synthesising the said polymorphous forms.

58 cl, 2 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and can be used for treatment of pulmonary cancer. Essence of invention lies in the fact that before initiation of treatment an extracorporeal ray treatment of 300 ml of patient's blood in red diapason range with λ=0.67 mcm in continuous-wave mode during 3 minutes at maximum radiant power 17 mlW, radiation level w=3.06 J/cm2 is conducted. Then irradiated blood is incubated with cytostatic in therapeutic dose during 40 minutes at T=37°C, whereafter the irradiated blood with cytostatic is inserted to patient intravenously by drop infusion. During course of treatment three or four such procedures are conducted at three days interval, in total one or two courses of treatment at three weeks interval are conducted.

EFFECT: use of this invention enables to transfer patients with tumors of stage three or four into resectable condition by means of stimulating involution and regress of neoplastic deposits from lymphonodus at neoadjuvant therapy delivery of photo- modified autoblood.

2 ex

FIELD: medicine.

SUBSTANCE: group of invention concerns medicine, namely to oncology and can be used in prostate cancer treatment. The methods of the invention imply administration of a composition containing therapeutically effective quantities of supercritical extracts of rosemary, curcuma, marjoram and ginger, as well as therapeutically effective quantities of water-alcoholic extracts of holy basil, ginger, curcuma, Scutellaria baicalensis, rosemary, green tea, Polygonum cuspidatum, Coptis chinensis Franchet and barberries.

EFFECT: inhibition of prostate cancer cell growth due to the effect of COX-2 composition without any significant side-effects.

36 cl, 1 tbl, 5 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.

EFFECT: increased output of the product under mild conditions.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)- ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine in crystalline form, having a powder X-ray diffraction pattern with peaks at diffraction angles (2θ) 15.7±0.1, 17.3±0.1 and 19.7±0.1. The invention also relates to a pharmaceutical composition, to methods of treating cancer in mammals, as well as to a method of treating abnormal cell growth in mammals in need of such treatment.

EFFECT: obtaining an novel biologically active compound having the said inhibitory activity.

12 cl, 1 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: aqueous pharmaceutical composition containing: a) 0.005-10 wt % of one or more water-soluble pharmaceutically active components or their pharmaceutically acceptable salts; b) 0.01 to 10 wt % of hydroxypropylmethylcellulose with viscosity 2500 to 5500 sP (mPa*s); and c) a buffer for maintaining a pH level of a pharmaceutical composition within 5 to 7, can be prepared by a method which involves: i) dissolution of said components in water to form an aqueous solution, and ii) filtering of the aqueous solution prepared at the stage i), through a filter of pore size ≥ 1 micron and ≤10 micron.

EFFECT: compositions prepared by said method are able to exhibit improved mucoadhesive ability and stability.

13 cl, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, food industry and veterinary medicine, specifically to methods for obtaining stable water-soluble medicines enriched with biologically active substances from natural objects. Natural hydrophobic associates of biologically active substances are converted into stable hydrophobic complex with a specially selected combination of surface active molecule substances (SAMS), which is easily solved in water.

EFFECT: method allows of creating highly concentrated water or water-soluble medicines (ointments, ready tablet forms) with water insoluble compounds used as biologically active substances, or of obtaining complex medicines enriched with added components though hydrophobic and/or water phase, which increases their biological efficiency and bioavailability.

19 cl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medical agents and concerns a remedy in the form of an injection precursor product for obtaining liquid injectable composition, containing as agent for prevention and/or treatment of neurodegenerative diseases, nervous disorders or diseases requiring nerves regeneration the effective quantity of (2R)-2-propyloctane acid or salt thereof, and 1-5 equivalents of the basic ion of metal as per 1 equivalent of (2R)-2-propyloctane acid or salt thereof, metal salt selected from phosphoric acid metal salt, carbonic acid metal salt, and sulfurous acid metal salt and may optionally contain metal hydroxide as the source(s) of the basic metal ion.

EFFECT: development of the remedy which is resistant to pH fluctuations and does not grow turbid at solution.

21 cl, 3 dwg, 21 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and concerns liquid water pharmaceutical compositions containing factor VII polypeptides and a stabilising agent, a method for producing and applying such compositions as well as a container for such a composition and application of such composition for treatment of factor VII dependent syndrome.

EFFECT: invention ensures production of liquid water pharmaceutical composition containing factor VII polypeptide with decreased formation of chemical and/or physical degradation products, such as products of fermentative degradation or autocatalysis.

24 cl, 8 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: method for prevention and treatment of the patients with Alzheimer's disease implies application of preparation "Semax 1% nasal drops" in a daily dosage 18-20 mg introduced 3 drops into each nasal passage 6-7 times a day.

EFFECT: improved clinical effectiveness.

4 ex, 1 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine, namely to pharmaceutical solution of meloxicam for parenteral introduction in therapeutically effective quantity for treatment of rheumatoid arthritis, osteoarthritis, arthrosis, inflammatory and degenerative diseases of joints, which are accompanied with pain syndrome, which contains meloxicam and pharmaceutically acceptable excipients and auxiliary substances, which differs by the fact that it additionally contains glycine, with quantitative ratio of meloxicam and glycine 0.05-0.2 wt %: 0.05-0.1 wt % respectively.

EFFECT: high efficiency with higher safety with respect to development of gastro-intestinal side effects, high stability during storage.

11 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: for prevention and treatment of diseases of cardiovascular and/or nervous system, arterial hypertension claimed is original composition of ethylmethylhydroxypyridine succinate, succinic acid and ethylenediaminetetraacetic acid disodium salt in form of solution for injections, which additionally contains pyridoxin or its pharmaceutically acceptable salt and povidon.

EFFECT: high stability, convenience in application and high therapeutic efficiency in prevention and treatment of diseases of cardiovascular and nervous system and arterial hypertension.

14 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to composition in form of solution, which contains17-AAG in amount up to 15 mg/ml, dissolved in carrier, which contains (i) first component, representing ethanol, in amount approximately from 40 to approximately 60 vol. %; (ii) second component, representing polyetoxylated castor oil, in amount approximately from 15 to approximately 50% vol. %; and (iii) third component, selected from group consisting of propylene glycol, "ПЭГ" 300, "ПЭГ" 400, glycerin and their combinations, in amount approximately from 20 to approximately 30 vol. %.

EFFECT: stable pharmaceutical composition in form of solution, which, when diluted with injection water, is suitable for intravenous introduction.

24 cl, 5 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to composition of dexibuprofen syrup, including dexibuprophene ((S)-ibuprophene) with average particle size from 10 to 300 mcm as active ingredient, which does not contain glycerin and has viscosity from 500 to 300 cP and pH from 3.0 to 6.0.

EFFECT: increased safety, constant efficiency and improved taste.

6 cl, 34 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: aqueous pharmaceutical preparation contains therapeutically effective amount of Cetuximab or EMD 72000, or one of the appropriate murine, humanised or chimeric analogues of an antibody, a buffer of pH 5.2 to 6.0, amino acid chosen from the group containing L-arginin, glycine and L-methionine, and a surface-active substance chosen from the group containing polyethylene sorbitan fatty acid ester and polyoxyethylene-polyoxypropylene copolymer provided that it does not contain sugar.

EFFECT: offered aqueous preparation high temperatures, and can be used for treatment of tumours.

10 cl, 5 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly to gynaecology, and covers therapy of vaginal infections. The offered method of vaginal infection treatment involves the stages of cleaning and cooling of a woman's perineum by applying a wet substratum containing a coolant and the stage of treatment by introduction of an active antimycotic component into vagina.

EFFECT: due to application of said cleaning and cooling compositions in combination with the antimycotic component, the method provides faster relief of pain, burning, itching and discomfort sensations associated with the vaginal infections.

16 cl, 1 ex

Up!