Composition for treating prostate cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and represents method of treating prostate cancer, which includes introduction to patient of composition, which contains degarelix lyophilisate or its pharmaceutically acceptable salt and excipient, dissolved in solvent, in initial dose 200-300 mg of degarelix in concentration 20-80 mg of degarelix per ml of solvent with the following after 14-56 days after initial dose supporting dose 320-55 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, possibly with one or more than one following additional supporting dose 320-550 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, introduced with interval from 56 days to 112 days between each supporting dose.

EFFECT: invention provides long release of degarelix from obtained depot of medication without increase of occurrence of side effects.

11 cl, 1 ex, 2 dwg, 4 tbl

 

The present invention relates to compositions for the treatment of prostate cancer.

PRIOR art

Prostate cancer is the leading cause of mortality and morbidity in men in industrialized countries. The growth of most prostate cancers depends on testosterone, and modern medical approach to the treatment of prostate cancer in the later stages includes androgen deprivation. The problem consists in the reduction of serum testosterone (T) below castration level (T≤0.5 ng/ml). This can be achieved, for example, bilateral orchiectomy or administration of receptor agonists gonadotropin-releasing hormone (GnRH).

Gonadotropin-releasing hormone (GnRH) is a natural hormone produced by the hypothalamus and interacting with receptors in the pituitary gland, stimulating the production of luteinizing hormone (LH). To reduce the production of LH were developed agonists of GnRH receptors (GnRH-R), such as leuprolide (lupron, Lupron) and gozlerin. The action of these agonists GnRH-R first stimulates the release of LH and only after long-term treatment leads to the desensitization of GnRH-R, so that production of LH stops, leading, ultimately, to suppress the production of testosterone by the testes. However, the initial stimulation of LH production agonist which leads to an initial increase in the production of male sex hormones. The duration of this phenomenon, known as "testosterone surge" ("testosterone surge or transient worsening of clinical manifestations" ("flare reaction"), can reach two to four weeks, and this phenomenon can stimulate prostate cancer; it can lead to worsening of current symptoms or appearance of new symptoms, such as spinal cord compression, bone pain and obstruction of the urethra. One method used to avoid this problem, represents the combined introduction of GnRH agonist-R antiandrogens, such as flutamide or bikalutamid what is known as complete androgen-deprivation therapy (total androgen ablation therapy (AAT). However, the use of anti-androgens is associated with serious side effects on the liver and gastrointestinal tract.

To overcome the "testosterone surge" or "transient worsening of clinical manifestations associated with GnRH agonists have been developed receptor antagonists of gonadotropin releasing hormone (GnRH-R). The GnRH antagonists competitive contact GnRH receptors, blocking them and lead to a rapid decrease in the allocation of LH and follicle-stimulating hormone (FSH), reducing by this, the production of testosterone without initial stimulation/splash. However, the peptide GnRH antagonists are often associated with the emergence of the histamine-releasing activity.

While in the application as agonists and antagonists of GnRH in the androgen-deprivation therapy for prostate cancer were obtained promising results, there are concerns about the relative safety of medicines available. For example, it was found that the GnRH antagonist Abarelix™ increases the risk of serious allergic reactions, including anaphylaxis with hypotension and fainting, and in some cases also were found to decrease its effectiveness in the treatment process. Indeed, Abarelix™ (Plenaxis™ in the USA) has been approved, but only for selected patients with advanced prostate cancer, and was eventually withdrawn from the market in 2005 for commercial reasons, probably related to these problems. In particular, it was suggested that certain types of androgen-deprivation therapy can lead to undesirable effects on the health of the cardiovascular system (see Yannucci et al. (2006) J. of Urology 176:520-525; and Etzioni et al. (1999) J. Natl. Cane. Inst 91:1033).

The authors of the present invention has developed a GnRH antagonist third generation degarelix, for the treatment of prostate cancer. Degarelix is a synthetic Decapeptide GnRH antagonist. Long-term evaluation in a multicenter randomized trial demonstrated that degarelix effect the veins and good move, no signs of systemic allergic reactions (see Koechling, et al., "Effect of various GnRH antagonists on histamine release from human skin"; Poster, 8th Int. Symp. GnRH Analogues in Cancer & Human Rep.; subm. European J. Pharm., March 2009). Application for registration certificate/application for registration of a new medicinal composition for monthly injection was submitted to the Management under the control over products and medicines (FDA) and European Agency for the evaluation of medical products (EMEA) on February 27, 2008, the Registration certificate was received from the FDA on December 24, 2008, and from EMEA February 27, 2009

However, there is a need for a treatment that provides long-term (for example, for periods of 1 year or more) to maintain the level of serum testosterone below 0.5 ng/ml while minimizing needs introduction (and, therefore, reduce the need, for example, the monthly visits of the patient to the hospital).

The inventors have found that to maintain the level of serum testosterone below 0.5 ng/ml (i.e., prevent testosterone surge) for a long period, it is necessary the introduction of degarelix with maintaining average minimum concentration (degarelix) in the plasma of more than 9-10 ng/ml, more preferably 11 or 12, or 13 ng/ml (see Fig.1). Pre-existing compositions (for example, the composition for monthly is doing) does not prevent testosterone surge during periods of duration of 3 months. However, a simple increase of dose is ineffective because of the risk of side effects and also due to the fact that the magnitude of the dose may become uncontrollable.

Degarelix get in powder form (acetate degarelix), which is dissolved with obtaining a solution for subcutaneous injection. It is dissolved in water for injection ("WFI") or, depending on the dose and concentration of degarelix, in the solution of mannitol (e.g., 2.5% or 5%) to maintain isotonicity.

In aqueous media at concentrations of 5 mg/ml or more acetate degarelix shows dependent on the nucleation fibrillazione that gives a substance the ability to form a gel depot in vivo injection. Accordingly, upon contact with body tissues, such as plasma, degarelix spontaneously forms a gel depot. Then there is a prolonged release of degarelix from the depot through diffusion.

The mechanism fibrillazione degarelix depends on nucleation, and for this reason the properties of the depot associated primarily with the concentration of degarelix.

It was suggested that the release of degarelix from the depot consists of two phases: the rapid release immediately after the introduction, which is due to the high initial concentration levels in the plasma; and the slow release phase, which determines the concentration levels in plasma in the maintenance phase. the ri pharmacokinetic (PK) modeling degarelix these two different phases were described as two phases of the suction of the first order, controlling the release of the depots: for quick absorption, causing an initial rapid release, characterized by short period of poluvsasavania, and slow absorption, causing the observed long-term phase, which is characterized by a long period of poluvsasavania.

The area under the curve of concentration-time (AUC) associated with the dose and concentration of the injected solution. AUC increased with increasing dose, but by increasing the concentration of the injected solution is reduced AUC. Thus, the estimated absolute bioavailability of 43,4%, 40,0%, 31,1%, 27,4%, and 21.3% with the dose concentration of 10, 20, 30, 40 and 60 mg/ml, respectively; increasing the concentration leads to a reduction in the overall bioavailability. According to observations, the practical benefit of increasing concentrations is to reduce the volume of injection with an increase in the probability of compliance by the patient mode and regimens, and so forth.

The inventors have unexpectedly discovered that the introduction of degarelix in the high dose and high concentration, for example, as is used in the maintenance phase, is associated with a slower release characteristics of degarelix received from the depot (as well as the General reduction in the bioavailability of degarelix discussed below). This unexpected effect means that the introduction of the definition of the different doses of degarelix in certain high concentrations provides depot, releasing a sufficient amount of degarelix to provide the desired therapeutic effect (i.e., provide the necessary concentration in the plasma), but releasing it slowly, providing long-term maintenance of plasma concentrations at a therapeutically effective level (for example, for three months or more with sufficient initial dose). Increasing the concentration of degarelix means that the amount of injection can be controlled even at these higher doses with an unexpected advantage of the actual enhancement of long-term release.

SUMMARY of the INVENTION

The inventors have developed a composition for introduction of degarelix in the high dose and high concentrations, which, when introduced according to the invention, can provide a prolonged release of degarelix without the need for monthly injections.

Thus, in the first aspect according to the present invention proposed a composition comprising degarelix or its pharmaceutically acceptable salt (e.g. acetate) for the treatment of prostate cancer, containing the lyophilisate of degarelix and excipient (for example, co-lyophilisate (co-lyophilisate), for example, sugars, such as mannitol), dissolved in a solvent (for example, an aqueous solvent, for example, water), and BBO is ima the patient in a dose of 200-300 mg degarelix at a concentration of 20-80 mg degarelix per ml of solvent followed, through 14-56 days after the initial dose, a supporting dose 320-550 mg degarelix at a concentration of 50-80 mg degarelix per ml of solvent, and (possibly) one or more than one subsequent additional supporting dose 320-550 mg degarelix at a concentration of 50-80 mg degarelix per ml of solvent introduced with the interval from 56 days to 112 days between each supporting dose.

In one example, the composition is administered to the patient in a dose of 200-300 mg followed by a supporting dose 320-550 mg, administered one month, for example through 28 days after the initial dose, with one or more than one subsequent additional supporting dose 320-550 mg at intervals between dose three months (for example 84 days). The initial dose of degarelix may be, for example, 240 mg in a concentration of, for example, 40 mg of degarelix per ml of solvent.

Supporting or supporting each dose may be, for example, from 360 mg to 480 mg at a concentration of, for example, 60 mg of degarelix per ml of solvent.

Degarelix (or its pharmaceutically acceptable salt) is intended for administration in the form of a liquid solution in a solvent, for example an aqueous solvent such as water (e.g. WFI) or a solution of water and mannitol. The initial and maintenance doses can be designed for administration by injection. Support the th dose is preferably introduced in the form of two injections, each of which includes (essentially) half the maintenance dose. The composition may provide therapeutically active average minimum concentration of degarelix in the plasma (the plasma concentration of 9 ng/ml or more, preferably 10 ng/ml or more, such as 12 mg/ml or more, as measured by techniques well known in the art), for example, through 28 days after the initial dose, and can support this therapeutically active concentration within, for example, at least 365 days and/or during treatment. Here, the terms "treatment" and "during treatment" means the period of time during which impose a maintenance dose; thus, the maintenance of this therapeutically active concentrations during treatment" means therapeutically active concentration support at least until the introduction of the last maintenance dose. The composition may reduce the level of testosterone in the patient's serum to 0.5 ng/ml or less, for example, since 3 days, for example, starting with 7 days, for example, starting from 14 days, for example, starting 28 days after the initial dose, and can maintain the level of testosterone in serum 0.5 ng/ml or less, for example, at least 365 days and/or during treatment.

In studies it was found that mo is an effective initial dose of 240 mg (40 mg/ml). In studies of one-month schemes introduction it has been demonstrated that two (monthly) maintenance dose, 160 mg (40 mg/ml) and 80 mg (20 mg/ml) were effective indicators testosterone response 100% and 98%, respectively, with 28 days to 364 days. However, the dose is 240 mg, 160 mg or 80 mg will not provide testosterone suppression during 3 months after injection. Thus, when the initial dose of 240 mg (40 mg/ml) additional dose will be required earlier than 3 months (e.g., 28 days). Imitation of the "real" three-month schemes using a dose of 480 mg (i.e., the initial dose of 480 mg with additional doses of 3, 6 and 9 months) shows that the minimum RK-level (concentration degarelix) will be approximately 8 ng/ml, which is insufficient. I think that with the introduction of a 0 month and additional usage for 1 month to reach steady state is faster, and it (along with composition, dose and concentration) is important. The use of higher doses as the initial dose for a "real" 3-month depot is impossible due to concomitant need sufficient release in the initial phase/phase saturation for the ability of increasing concentrations of degarelix in the plasma and, at the same time, long enough release to make the Oia sufficiently high concentration of the stationary state for 3 months. The inventors have unexpectedly discovered that certain compositions can provide therapeutically active average concentration of degarelix plasma (minimum plasma concentration of 9 ng/ml or more), for example, through 28 days after the initial dose, and can support this therapeutically active concentration within, for example, at least 365 days and/or during treatment, without the need for monthly maintenance doses. More unexpectedly, a definite composition (when it is implemented this way) and the treatment proposed by the inventors, are not associated with a significant increased side effects associated with injection (compared to a dose of 240 mg degarelix at a concentration of 40 mg/ml). This is particularly important given the high dose (or concentration) of degarelix in particular(s) support(s) dose (doses).

The concentration of the maintenance dose of degarelix or its pharmaceutically acceptable salt may be 50-80 mg degarelix per ml of solvent, for example 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73. 74, 75, 76, 77, 78, 79, 80 mg/ml, for example 55-65 mg/ml. the inventors have found that the introduction of maintenance doses of degarelix or its pharmaceutically acceptable salts (e.g. acetate) (obtained by dissolving the lyophilisate containing degarelix and excipio the t (for example, co-lyophilisate, for example, mannitol) in a solvent, for example, water), for example, 360 mg, and 480 mg at a concentration of, for example, 55-65 mg degarelix per ml of solvent, for example, 60 mg/ml, may be particularly effective. Introduction maintenance doses of degarelix or its pharmaceutically acceptable salts 480 mg at a concentration of 60 mg degarelix per ml of solvent at intervals of 84 days (3 months) (for example, starting with the first maintenance dose after 28 days (one month) after the initial dose) can provide effective suppression of testosterone (i.e., the rapid decline of testosterone to levels below 0.5 ng/ml and sustain below this level by preventing testosterone surge) for periods up to 1 year or more without a significant probability of adverse effects. No side effects particularly surprising given the high doses and two injections; suddenly no gain side effects associated with injection, compared with significantly lower monthly doses (input single injection).

In another aspect according to the present invention is proposed pharmaceutical product (for example, a drug for injection) containing the lyophilisate of degarelix or its pharmaceutically acceptable salts (e.g. acetate degarelix) and excipient (e.g., lyophilized, for example, mannitol), Rast is Genny in a solvent (for example, aqueous solvent, for example, water), where the concentration of degarelix is from 40 mg to 80 mg, preferably from 50 mg to 80 mg degarelix per ml of solvent. The concentration of degarelix or its pharmaceutically acceptable salt may be 50-80 mg degarelix per ml of solvent, for example 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62. 63, 64, 65, 66, 67, 68, 69, 70, 71. 72, 73, 74, 75, 76, 77, 78, 79, 80 mg/ml, for example 55-65 mg/ml Number of degarelix can range from 320 mg to 550 mg (for example, 350-490 mg; for example, 440-520 mg). The number of degarelix may be, for example, 240 mg, 360 mg or 480 mg Pharmaceutical drug can be administered, for example, by injection, for example, in the form of a single injection, preferably in the form of two injections, and so forth.

In another aspect according to the present invention proposed a set to obtain a composition containing the lyophilisate of degarelix or its pharmaceutically acceptable salts (e.g. acetate degarelix) and excipient (e.g., lyophilized, for example, sugars, such as mannitol), dissolved in a solvent (for example an aqueous solvent such as water), at a concentration of from 20 mg to 80 mg degarelix per ml of solvent that includes one or more than one container (e.g. bottle) with lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient and one or more than one container (e.g., FLAC is h, the pre-filled syringe with solvent, optionally with means for injection (e.g. injection), for example a syringe and/or secure with a needle, cannula, and so forth. The set may include., means for transferring (superior migration of the solvent from the container (containers) (for example, pre-filled syringe, vial) with the solvent in the container (s) (e.g., a vial) with degarelix, for example, the tool adapter, such as adapter. Perhaps the kit can also include a device to further improve or enhance the dissolution (e.g., mixer). The set can provide a solution having a concentration of degarelix 20-80 mg/ml, for example 50-80 mg/ml, for example 55-65 mg/ml, for example 56, 57, 58, 59, 60, 61, 62, 63, 64 mg/ml Number of degarelix can range from 220 mg to 550 mg degarelix, for example, from 320 mg to 550 mg (for example, 350-490 mg; for example, 440-520 mg). The number of degarelix may be, for example, 240 mg, 360 mg or 480 mg In one example, the kit can provide a solution containing 480 mg of degarelix at a concentration of 60 mg/ml, the Set can include, for example, two containers (e.g., bottle) to 240 mg degarelix and, for example, one container (vial) with a liquid (for example, 10 ml WFI). The specialist will be clear that the mixing of the contents of each vial containing degarelix, is for example, with 4.2 ml of WFI will provide 4 ml of a solution containing approximately 240 mg degarelix at a concentration of 60 mg/ml, and two bottles together will provide 8 ml maintenance dose for injection in the form of one or more preferably two injections. In another example, the kit may include two containers (e.g., bottle) to 240 mg degarelix (in the form of a lyophilisate with excipients) and, for example, two pre-filled syringes, each of which contains WFI (4,2 ml). The specialist will be clear that the mixing of the contents of the pre-filled syringe containing 4,2 ml WFI, with 240 mg of degarelix from one of the containers, will provide 4 ml (injection) containing approximately 240 mg degarelix at a concentration of about 60 mg/ml, and that two such syringe and container together will provide 8 ml maintenance dose (480 mg) for injection (in the form of two injections).

In another aspect according to the present invention, a method for treating prostate cancer, comprising the administration to a patient in need this, the compositions containing the lyophilisate of degarelix and excipient dissolved in the solvent, in a dose of 200-300 mg degarelix at a concentration of 20-80 mg degarelix per ml of solvent followed through 14-56 days after the initial dose, a supporting dose 320-550 mg degarelix the sa at a concentration of 50-80 mg degarelix per ml of solvent, (possibly) one or more than one subsequent additional supporting dose 320-550 mg degarelix at a concentration of 50-80 mg degarelix per ml of solvent introduced with the interval from 56 days to 112 days between each supporting dose.

Degarelix you can enter in a dose of 200-300 mg followed by a supporting dose 320-550 mg, administered over 28 days (one month) after the initial dose, with one or more than one subsequent additional supporting dose 320-550 mg at intervals between dose and 84 days (three months).

The concentration of support(their) dose (doses) degarelix or its pharmaceutically acceptable salt may be 50-80 mg/ml, for example 55-65 mg/ml

In another aspect according to the present invention proposed a set including: at least one container for receiving the initial dose, containing the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient, where the lyophilisate of degarelix or its pharmaceutically acceptable salt is present in amount in the range from 200 mg to 300 mg; at least one container for receiving maintenance doses containing lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient, where the lyophilisate of degarelix or its pharmaceutically acceptable salt is present in amount in the range of the region from 320 mg to 550 mg; and at least one container containing the solvent. In one example, the kit can provide a solution containing 480 mg of degarelix at a concentration of 60 mg/ml, the Set can include, for example, two containers (e.g., bottle) to 240 mg degarelix and, for example, one container (vial) with a liquid (for example, 6 ml or 10 ml WFI). The specialist will be clear that the mixing of the contents of each vial containing degarelix, for example, with 4.2 ml of WFI will provide 4 ml of a solution containing approximately 240 mg degarelix at a concentration of 60 mg/ml in the solvent, and two bottles together will provide 8 ml maintenance dose for injection in the form of one or more, preferably in the form of two injections.

In another example, the kit of the present invention includes: at least one first container containing the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient, where the lyophilisate of degarelix or its pharmaceutically acceptable salt is present in amount in the range from 320 mg to 550 mg; and at least one second container containing a solvent.

In another aspect according to the present invention, a method for obtaining the concentration of the initial dose and concentration maintenance dose for the treatment of prostate cancer in a patient in need thereof, VK is uchumi: merge the contents of the at least one container for receiving the initial dose, containing the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient with the contents of the at least one container containing the solvent, where the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in a solvent to achieve a concentration in the range from 20 mg to 80 mg degarelix per ml of solvent to obtain the concentration of the initial dose; the Union after the interval ranging from 14 to 56 days from receiving the initial dose, the contents of at least one container for receiving maintenance doses containing lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient, with the contents of the at least one second container containing a solvent, where the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in a solvent to achieve a concentration in the range from 50 mg to 80 mg degarelix per ml of solvent to obtain the concentration maintenance dose; and repeating at least once, merge content from the at least one container for receiving maintenance doses with the contents of the at least one container containing the solvent, obtaining concentration maintenance dose after an interval in the range from 56 to 112 days from the obyedinenie with obtaining the previous maintenance dose.

In another aspect of the invention, a method for obtaining a composition for the treatment of prostate cancer, including merge the contents of the at least one first container containing the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient with the contents of the at least one second container containing a solvent, where the lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in a solvent to achieve a concentration in the range from 50 mg to 80 mg degarelix per ml of solvent to obtain the concentration of the maintenance dose.

Regarding the concentration maintenance dose, method of production can provide a solution having a concentration of degarelix 50-80 mg/ml, for example 55-65 mg/ml, for example 56, 57, 58, 59, 60, 61, 62, 63 or 64 mg degarelix per ml of solvent, or any intermediate value. Dose degarelix may be in the range from 320 mg to 550 mg (for example, from 350 mg to 520 mg, for example, from 440 mg 490 mg). Dose degarelix may be, for example, 240 mg (initial dose), 360 mg (maintenance dose) or 480 mg (maintenance dose).

DETAILED description of the INVENTION

A brief description of graphic materials

In Fig.1 shows a graphical representation of the index of treatment effectiveness (proportion of patients with browsemaster ≤ 0.5 ng/ml) against the concentration of degarelix in plasma.

In Fig.2 shows a graphical representation of the levels of average minimum concentration of degarelix in the plasma testosterone response after a three-month regimen of administration. Annual testosterone response in studies CS15 (240 mg) and CS18 (360/480 mg) according to the evaluation using the method of Kaplan-Meier. Dose (mg):240,360,480.

Definition

The terms "initial dose" and "dose" are used here interchangeably. The term "plasma concentration" means "minimum. concentration in plasma".

One month of treatment in most cases and when used as described in this application the results of clinical trials review, and is defined as 28 days. Essentially, two months relate to 56 days, three months belong to 84 days, four months belong to 112 days and so on.

The term "prostate cancer" refers to any cancer of the prostate, in which cells of the prostate mutate and multiply uncontrollably. The term "prostate cancer" includes prostate cancer at an early stage, localized prostate cancer, prostate cancer at a late stage, locally advanced prostate cancer (PR is which cancer cells spread (metastasize) from the prostate to other parts of the body, mainly the bones and lymph nodes).

Degarelix and related pharmaceutical compositions.

Degarelix is an effective antagonist of GnRH, representing Decapeptide-analogue of GnRH (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) containing p-ureidopenicillin in positions 5 and 6 (Jiang et al. (2001) J. Med. Chem. 44:453-67). It is indicated for the treatment of patients with prostate cancer who have shown androgen deprivation (including patients with rising PSA levels after already held prostatectomy or radiation therapy).

Degarelix is a selective antagonist (blocker) of GnRH receptors, competitive and reversible binding to the GnRH receptors in the pituitary gland, fast slimming, through this, the release of gonadotropins and therefore of testosterone (T). Prostate cancer is sensitive to testosterone deprivation, which is the main principle of treatment hormonecontaining prostate cancer. Unlike GnRH agonists, GnRH receptor blockers do not lead to an increase in the luteinizing hormone (LH) and subsequent testosterone surge/stimulation of the tumor and possible symptomatic transient worsening of clinical symptoms after the start of treatment.

Active ingredient degarelix is a synthetic amide linear Dec the peptide, containing seven artificial amino acids, five of which are D-amino acids. The medicinal substance is an acetate salt, but active group of substances is degarelix in free base form. The acetate salt of degarelix is a white or yellowish amorphous powder (low density after lyophilization). The chemical name is a D-alanine N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-i.e. phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L-i.e. phenylalanyl-4-[(aminocarbonyl)amino]-D-i.e. phenylalanyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl. It has the empirical formula C82H103N18O16Cl and molecular weight 1632,3. Chemical structure degarelix was shown earlier (EP 1003774, US 5925730, US 6214798) and can be represented by the formula: AC-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2.

Degarelix can be made for subcutaneous injection (as opposed to intravenously), usually in the abdomen, as described in more detail below. As with other medicines, administered by subcutaneous injection, the injection site can be changed periodically, adapting the treatment to reduce discomfort at the injection site. In General, injections should be made in areas that do not Bud is tons of pressure, for example, not near the belt or strap and not near the edges.

Introduction degarelix subcutaneous or intramuscular injection is effective, but daily injections usually are not preferable for the patient, and therefore, you can use depo-composition of degarelix described in more detail in WO 03/006049 and in published patent application U.S. No. 20050245455 and 20040038903. Briefly, subcutaneous administration of degarelix can be performed using depo-technology, where the release of the peptide comes from a gel depot for a period of time (usually from one to three months. Degarelix (and related peptides antagonists GnRH) has a high affinity receptor GnRH and much more soluble in water than other GnRH analogues. Degarelix and these are related with the GnRH antagonists are capable of forming a gel after subcutaneous injection, and this gel can act as a depot from which there is a release of the peptide over a period of several weeks or even months.

Thus, degarelix can be represented in the form of powder for dissolution in solvent) to obtain the solution for injection (such as subcutaneous injection, for example, with the formation of the depot, as described above). The powder can be presented in the form of a lyophilisate containing degarelix is (for example, in the form of acetate) and mannitol. A suitable solvent is water (e.g. water for injection, or WFI). The solvent can be represented in containers (e.g. bottles), for example, containing 6 ml of solvent. For example, degarelix can be represented in a bottle containing 120 mg of degarelix (acetate) dissolved in 3 ml of WFI, so that each ml of solution contains approximately 40 mg of degarelix; dissolution provides a 3 ml solution for injection contains approximately 120 mg of degarelix. Injection of two such solutions provides a starting dose of 240 mg degarelix at a concentration of 40 mg/ml In another example, degarelix can be represented in a bottle containing 240 mg of degarelix (acetate). After dissolved in approximately 4 ml of WFI each ml of solution contains approximately 60 mg of degarelix. Injection of two such solutions provides maintenance dose of approximately 480 mg degarelix at a concentration of 60 mg/ml In another example, degarelix can be represented in a bottle containing 180 mg of degarelix (acetate). After dissolved in approximately 3 ml WFI each ml of solution contains approximately 60 mg of degarelix. Injection of two such solutions provides maintenance dose of approximately 360 mg degarelix at a concentration of 60 mg/ml of the resulting solution, g is preset for injection, should appear as a clear liquid.

The scheme is the introduction of degarelix may include a starting dose of 240 mg, administered in the form of 2 injections of 3 ml of the composition of degarelix at a concentration of approximately 40 mg/ml, with subsequent dose 480 mg, administered in the form of two injections of 4 ml of the composition of degarelix at a concentration of about 60 mg/ml

After administration of the initial dose maintenance dose is administered with an interval in the range 14-56 days, such as 14 days, 28 days, 56 days, or any intermediate interval, and also, for example, with an interval of 28 days. Maintenance dose contains degarelix or its pharmaceutically acceptable salt, excipient and the solvent. Maintenance dose is in the range from 320 mg to 550 mg degarelix or its pharmaceutically acceptable salt, for example, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 550 mg, or any intermediate value, and also, for example, 360 mg or 480 mg degarelix or its pharmaceutically acceptable salt. The concentration of the maintenance dose of degarelix or its pharmaceutically acceptable salt is in the range from 50 mg/ml to 80 mg/ml, such as 50 mg/ml, 55 mg/ml, 60 mg/ml, 65 mg/ml, 70 mg/ml, 75 mg/ml, 80 mg/ml, or any intermediate value, and also, for example, 60 mg/ml degarelix or its pharmaceutically acceptable salt. In one example, the schema in which edenia degarelix may include, after administration of the initial dose, maintenance dose 360 mg or 480 mg degarelix or its pharmaceutically acceptable salt in the form of two injections of 4 ml at a concentration of about 60 mg/ml of solvent.

After the introduction of the first maintenance dose may be introduced additional maintenance dose with an interval in the range from 56 days to 112 days, such as 56 days 84 days 112 days, or any intermediate interval, and also, for example, 84 days. If necessary, you can continue the introduction of additional maintenance doses (doses) (for example, maintenance doses can be entered through 56-112 days after the previous maintenance dose). Additional supporting dose contains degarelix or its pharmaceutically acceptable salt, excipient and the solvent. Additional maintenance dose is in the range from 320 mg to 550 mg degarelix or its pharmaceutically acceptable salt, for example, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 550 mg, or any intermediate value, and also, for example, 360 mg or 480 mg degarelix or its pharmaceutically acceptable salt. The concentration of the additional maintenance doses of degarelix or its pharmaceutically acceptable salt is in the range from 50 mg/ml to 80 mg/ml, such as 50 mg/ml, 55 mg/ml, 60 mg/ml, 65 mg/ml, 70 mg/ml, 75 mg/ml, 80 mg/ml, or any p is omegaton value and also, for example, 60 mg/ml degarelix or its pharmaceutically acceptable salt.

Introduction and doses

Example 1 Clinical study

In the framework of this programme of development degarelix used a population pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation for better understanding of the RK and PD data and the relationship of these and other parameters. The results obtained in previous studies, showed that the average minimum concentration of degarelix plasma 7,34 ng/ml led to the achievement of serum levels of testosterone (T) ≤ 0.5 ng/ml in 96% of patients at 28 days, and the average plasma concentration of 4.54 ng/ml led to the fact that 83% of patients of the same group had T ≤ 0.5 ng/ml in 84 days. Due to the variability of the population believed that this average plasma concentration may not be sufficient to maintain long-term testosterone suppression in approximately 95% of patients. For this reason, it was suggested that the introduced dose should result in levels of average minimum concentration of degarelix serum >9 ng/ml or higher in studies 3 phase for a one-month scheme introduction.

The relationship of the proportion of patients with castration levels of testosterone (T ≤ 0.5 ng/ml) and concentration of degarelix after 28 days is shown in Fig.1. This is based on Dan who's dated 1473 patients with prostate cancer in the clinical research division of the ROK-levels at intervals of 0-1, 1-2, 2-3 ng/ml and so on and applying the observed shares on the schedule against average points RK-intervals together with a smoothing line with 95% confidence interval (Cl). This shows that 97% of patients have a castration level of testosterone, provided that the concentration of degarelix remain above the threshold 9-10 ng/ml.

So, in a clinical study with a one-month scheme introduction it has been shown that the initial dose of 240 mg (40 mg/ml) was provided by the suppression of testosterone to castration levels (T ≤ 0.5 ng/ml) in 95% of patients within the first 28 days. Maintenance dose of degarelix 80 mg (20 mg/ml) was sufficient for a one-month study. The average minimum levels for maintenance doses of 80 mg (20 mg/ml) was approximately 12 ng/ml

Thus, in study after a one-month introduction degarelix it was found that the dose of 240 mg (40 mg/ml) was most effective the initial dose. Therefore, a starting dose of 240 mg (40 mg/ml) was also used for studies with a three-month scheme introduction. In studies with a one-month scheme of injection was demonstrated the effectiveness of two maintenance doses of 160 mg (40 mg/ml) and 80 mg (20 mg/ml), with indicators testosterone response 100% and 98%, respectively, with 28 days to 364 days. However, none of the doses studied in the study tomesen the th scheme introduction could not maintain testosterone suppression during 3 months after injection. The inventors have found that when the initial dose of 240 mg (40 mg/ml) additional dose will be required for approximately 28 days.

In phase-2 trial with a three-month scheme introduction investigated three different schemes. After the initial dose of 240 mg (40 mg/ml) extra dose of 240 mg was administered for 28 days and then at 3, 6 and 9 months, or 4, 7 and 10 months. In this study, maintenance dose of 240 mg was evaluated first in concentrations of 40 mg/ml and 60 mg/ml based on the results observed in various RK-profiles of different concentrations. Patients randomized in parallel to one of three groups with different three-month regimen of administration maintenance doses of degarelix:

240 mg (40 mg/ml) for 1, 3, 6, 9 months;

240 mg (60 mg/ml) for 1, 3, 6, 9 months;

240 mg (60 mg/ml) for 1, 4, 7,10 months.

None of these three regimens had no confidence interval lower limit, exceeding the mark of 80%; therefore, the main objective to demonstrate effectiveness in achieving and maintaining castration levels of testosterone within one year, at least 80% of the patients was not performed. The inventors have discovered; that the most important prognostic factor for time to testosterone levels >0.5 ng/ml were level is degarelix in the plasma during the treatment period. Thus, patients with lower levels of degarelix plasma is more likely to have the level of testosterone >0.5 ng/ml during the treatment period duration of one year. Analysis of monthly data on testosterone shows that on two visits after the introduction patients remains suppression, but there is a tendency to increase testosterone levels immediately before the next introduction of 3 months. Data of individual patients demonstrate the recovery suppression in most patients with elevated levels of testosterone after re-introduction; this applies to all three treatment groups. This is consistent with the observation that most patients first increase testosterone levels up to >0.5 ng/ml occurred three months after the previous introduction, during the minimum levels degarelix in the plasma. The average minimum levels of degarelix in the study were in the range of about 6.5 to 7.5 ng/ml That was significantly below the level of degarelix 9-10 ng/ml, which was considered necessary to maintain levels of testosterone ≤ 0.5 ng/ml for approximately 95% of patients, and pointed to the need for higher maintenance doses of degarelix.

Thus, the present study included an initial dose of degarelix 240 mg (40 mg/ml), followed by a more vysokopetrovsky doses degarelix, that is, alternative, 360 mg (60 mg/ml) or 480 mg (60 mg/ml), the latter was introduced on 1,4, 7 and 10 months.

Stage and duration of prostate cancer at inclusion in the study

In a recently conducted study included 133 patients (with the planned inclusion of 120 patients). Variables initial parameters of the disease for research 2 phases for the three-month schemes are presented in Table 1. Approximately 10% of patients who had localized cancer in their goals treatment was radical. Most patients had a rate of Gleason 7-10, and the majority of patients had normal activity measured on a scale of functional status ECOG (Eastern Cooperative Oncology Group, Eastern United group of oncologists). Also shows the average duration of prostate cancer (PCA) diagnosis.

Table 1
The original stage and duration of prostate cancer (phase 2, three-month scheme introduction)
Late selection of doses(CS18)
480 mg360 mg
(N=66)(N=67)
Stage PCA when enabledN=66N=67
Localized19(29%)26(39%)
Locally advanced22(33%)17(25%)
Metastatic16(24%)14(21%)
Classification not held9(14%)10(15%)
Radical treatmentN=66N=67
Yes6(9%)7(10%)
No60(91%)60(90%)
Staging PCA is not heldN=9N=10
Radical treatment4(44%)3(30%)
Figure GleasonN=66N=66
2-4 3(5%)8(12%)
5-624(36%)19(29%)
7-1039(59%)39(59%)
The duration of PCAN=64N=67
The mean (SD), years0,725(1,37)1,01(2,77)
Range(0,057-6,03)(0,063-20,3)
Scale functional status ECOGN=66N=67
Normal activity51(77%)49(73%)
Symptoms, ambulatory14(21%)15(22%)
Bed <50%1(2%)3(4%)
Bed >50%00
In bed 100%00
X - ray prostate cancer

The study was open, and the patients received a starting dose of 240 mg (40 mg/ml) at 0 month, followed by one treatment dose of degarelix of two things:

360 mg (60 mg/ml) for 1, 4, 7,10 months;

480 mg (60 mg/ml) for 1, 4, 7,10 months.

The initial dose was administered subcutaneously in the form of two injections of 120 mg (40 mg/ml). After 28 days have introduced a maintenance dose of 360 mg (at a concentration of 60 mg/ml, administered in the form of 2 injection 3 ml) or 480 mg (at a concentration of 60 mg/ml, administered in the form of 2 injections 4 ml), also in the form of two injections (240 mg each). Then with a three-month intervals administered maintenance doses, again in the form of two injections. Methods of dissolution and subsequent subcutaneous injection of degarelix with the formation of the depot is well known to the specialist and they are discussed above in this description. At each visit, serum testosterone, prostate-specific androgen and concentration degarelix in plasma was measured by techniques well known in the art.

The cumulative probability of maintaining testosterone response (T ≤ 0.5 ng/ml) with 28 days to 364 days are presented in Table 2 on the input dose. For higher doses of 480 mg (60 mg/ml) shows the response to treatment (in 93.3% remained castration levels of testosterone), numerically superior to the response to the scheme of injection with a dose of 360 mg (60 mg/ml) (89,0%). Although the and the lack of statistical significance, differences between the two treatment groups on the probability of encompassing the confidence interval of a valid measure of suppression in excess of the regulatory threshold of 90%, is significant: in the treatment group 480 mg of confidence probability of a valid measure of suppression in excess of 90% 79,9%, while for group treatment 360 mg it is only 39.7 per cent.

Table 2
The cumulative probability of testosterone ≤ 0.5 ng/ml from 28 days to 364 days - evaluation of the frequency response by Kaplan-Meier-analyzed group started to receive treatment (ITT) (CS18)
Degarelix 480/60 mgDegarelix 360/60 mgOnly
T>0,5
ng/ml
Cens%T>0,5
ng/ml
Cens%T>0,5
ng/ml
Cens%
N6667 133
with 28 days to46293,3%76089,0%1112292,8%
364 days
95% (CI)83,1;78,3;84,5;
97,4%94,6%95,0%
Ve is aatest cover (%) 79,9%39,7%
T>0.5 ng/ml number of patients with testosterone levels > 0.5 ng/ml
Cens is the number of censored observations up to 364 days inclusive
(%) - calculated probability of all levels of testosterone ≤ 0.5 ng/ml
95% confidence interval (Cl) in the treatment group was calculated double logarithmic transformation of a reliability function

Table 3 shows the proportion of patients with testosterone suppression (T ≤ 0.5 ng/ml) visits in the study.

For maintenance dose of degarelix 480 mg (60 mg/ml) was demonstrated long-term testosterone suppression in more than 95% of patients. When a maintenance dose of 360 mg (60 mg/ml) of long-term testosterone suppression was at least 90% of patients. The lowest values occur immediately before the re-introduction of 7 months (196 day, 90.6%) and 10 months (280 days, or 93.3%). In General, 125 of 127 patients (98%) showed reduced levels of those is tosterone below castration levels at 28 days.

In Fig.2 shows a graphical representation of the levels of average minimum concentration of degarelix in the plasma testosterone response after a three-month regimen of administration.

Table 3
The proportion of patients with testosterone ≤ 0.5 ng/ml, visits the analyzed group ITT (CS18)
Degarelix 480/60 mgDegarelix 360/60 mgOnly
Nn%Nn%Nn%
The analyzed group ITT6667133
Day
28626198,4%656498,5%12712598,4%
56616098,4%6464100%
84616098,4%6464100%
112605896,7%636196,8%
14 605998,3%6464100%
168585798,3%636298,4%
196595898,3%645890,6%
224585798,3%636298,4%
2525757100%626198,4%
2805554of 98.2%605693,3%
3085454100%6161100%
3365555100%605896,7%
364545296,3%605795,0%
N - number of patients
n - num the patients with testosterone ≤ 0.5 ng/ml
% = n/N×100

Table 4 shows the average percentage changes in the level of PSA in visits in the study. After 1 month there was a further decrease in PSA levels, and the average reduction was maintained during the study period (mean reduction 96-97%)

Adverse events

On the day of the termination of data collection 02 September 2008 133 patients with prostate cancer was introduced degarelix in a clinical study phase 2 with a three-month scheme is the introduction of the Example described above (CS18).

More frequent adverse events occurring during treatment were reported in more than 5% of patients in any treatment group in CS18, are the following (the percentage value is common to both groups with doses of 480 mg and 360 mg): tides (34%), pain at the injection site (17%), weight gain (11%), hypertension (8%), erythema at the injection site (7%), testicular atrophy (6%), asthenia (5%), arthralgia (5%), fatigue (5%), gynecomastia (5%), pyrexia (4%), decreased body weight (5%), fever (4%). There are reports of generalized hypersensitivity reactions of the immediate type when using previous GnRH antagonists. In this clinical study degarelix messages about immediate anaphylactic R is the shares was not.

In this clinical study focused on the evaluation of the hepatotoxic potential, and, starting from the date of termination of data collection, the data do not demonstrate any clinically significant abnormalities in the liver after treatment with degarelix.

In Example 1, the overall incidence of reactions at the injection site was 26%, and the total frequency of reactions at the injection was comparable for the two doses. The reaction at the injection site, which was reported most often was pain at the injection site (17%). Unexpectedly, these data are comparable with the results of a clinical study with a one-month scheme introduction using much smaller doses (for example, 240 mg) degarelix. The intensity of most of the reactions at the injection site was low or moderate (11% each), and 5% of patients reported severe reactions at the injection site. Six patients who reported severe reactions at the injection site, reported pain at the injection site as serious adverse events.

Conclusion

Thus, the inventors have found that the pharmacodynamic (PD) response to dose logically associated with pharmacokinetic (PK)/pharmacodynamic relationship to higher average minimum levels degarelix (at the end of treatment duration of one year or at the last available measurement) increased the doses of degarelix. The average minimum levels of degarelix in plasma is approximately 7 ng/ml, 10 ng/ml and 13 ng/ml at maintenance doses of 240 mg, 360 mg, and 480 mg, respectively. In addition, in patients receiving maintenance doses of 360 mg, and 480 mg, there were no significant differences in the frequency and nature of adverse events. On the basis of testosterone suppression and RC-results of initial and maintenance doses proposed here and defined below, are effective three-month scheme introduction.

1. A method of treating prostate cancer, comprising the administration to a patient a composition comprising a lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in the solvent, in a dose of 200-300 mg degarelix at a concentration of 20-80 mg degarelix per ml of solvent followed through 14-56 days after the initial dose, a supporting dose 320-550 mg degarelix at a concentration of 50-80 mg degarelix per ml of solvent, possibly with one or more than one subsequent additional supporting dose 320-550 mg degarelix at a concentration of 50-80 mg degarelix per ml of solvent, input interval from 56 days to 112 days between each supporting dose.

2. The method according to p. 1, where the composition contains a lyophilisate of degarelix or its pharmaceutically acceptable salts and mannitol, RAS is voennyi in the solvent.

3. The method according to p. 1, where the solvent is a water.

4. The method according to p. 1, wherein the composition is administered in a dose of 200-300 mg degarelix followed through 28 days after the initial dose, a supporting dose 320-550 mg degarelix, one or more than one subsequent additional supporting dose 320-550 mg degarelix intervals between dose and 84 days.

5. The method according to p. 1, where the concentration of the initial dose is 40 mg degarelix per ml of solvent.

6. The method according to p. 1, where the concentration of support(their) dose (dose) is 55-65 mg degarelix per ml of solvent.

7. The method according to p. 1, where the concentration of the maintenance dose is 60 mg degarelix per ml of solvent.

8. The method according to p. 1, where the initial dose of degarelix is 240 mg

9. The method according to any of paragraphs. 1-8, where the maintenance dose is 360 mg or 480 mg

10. A method of treating prostate cancer, comprising the administration to a patient a composition comprising a lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in the solvent, in a dose of 240 mg degarelix at a concentration of 40 mg degarelix per ml of solvent, followed, after 28 days after the initial dose, supporting a dose of 480 mg of degarelix at a concentration of 60 mg degarelix per ml of solvent, the capacity of one or more than one subsequent additional supporting dose of 480 mg of degarelix at a concentration of 60 mg degarelix per ml of solvent, with an interval between each supporting a dose of 84 days.

11. A method of treating prostate cancer, comprising the administration to a patient a composition comprising a lyophilisate of degarelix or its pharmaceutically acceptable salt and excipient dissolved in the solvent, in a dose of 240 mg degarelix at a concentration of 40 mg degarelix per ml of solvent, followed, after 28 days after the initial dose, supporting a dose of 360 mg degarelix at a concentration of 60 mg degarelix per ml of solvent, possibly with one or more than one subsequent additional supporting dose of 360 mg degarelix when the concentration of the dose of 60 mg degarelix per ml of solvent, with an interval between each supporting a dose of 84 days.



 

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25 cl, 9 tbl, 14 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to pharmacology and describes a histidine-free pharmaceutical composition containing high-purity factor VIII; arginine and saccharose, a surfactant for the prevention or at least the inhibition of a surface adsorption of factor VIII; 0.5 to 10 mM calcium chloride for the specific stabilisation of factor VIII, and sodium citrate or maleic acid as a pH buffer.

EFFECT: invention provides the protective function for preserve high-yield factor VIII over the whole cycle of pharmaceutical processing, long storage and end recovery and administration into the patient.

18 cl, 16 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to traumatology and orthopaedics, enabling preparing a biologically active preparation of autoblood for enhancing neogenesis processes. The presented technique involves sampling whole blood, centrifuging, selecting a middle layer of plasma so that to avoid the erythrocyte ingress. The centrifuged platelet concentrate is frozen in a cold room at temperature below minus 1 C°, dried for at least three minutes within the temperature range of 2 C° to 52 C°; the lyophilisate is sterilised before use.

EFFECT: technique of platelet-rich plasma lyophilisation enables preserving the TGF PDGF VEGF factor viability min 1,5 months from the moment of blood sampling.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, pharmaceutics and medicine, more specifically to a new generation of high-stable dosage forms prepared with using the process of sublimation in a specific mode with a composition containing no stabilising agents reducing the width of therapeutic action of finished dosage form substantially. The invention concerns the pharmaceutical composition for injections and infusions containing 3-oxy- and methylpyridine derivatives and pharmaceutically acceptable salts thereof as an active ingredient, sodium chloride or potassium chloride as an additive agent, in the form a lyophilisate. The process involves the sublimation followed by the vacuum dewatering for at least 64 hours.

EFFECT: pharmaceutical composition possesses high stability for the whole shelf-life as opposed to all known pharmaceutical formulations of these compounds; it preserves pharmacological activity and enables dissolving the composition immediately before use and reducing a risk of the negative effect of the thermal sterilisation of aqueous solutions.

2 cl, 7 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine. A pharmaceutical formulation for the treating diseases associated with endothelial dysfunction contains an active ingredient presented by a methyl pyridine derivative - 1.0-6.0 wt %; purine - 10.0-80.0 wt % and additive agents - the rest. The active substance is presented by compounds of a group: 3 -(N,N-dimethyl carbamoyloxy)-2-ethyl-6-methylpyridinium succinate, 3-methylpyridinium succinate, 2-ethyl-6-methyl-3-hydroxypyridinium hydrochloride, 6-trichloromethyl-2-chloropyridine (nitrapyrin), 2-ethyl-6-methyl-3-hydroxypyridine succinate. Purine is presented by inosine, adenosine, hypoxanthine. The pharmaceutical formulation may be presented in the form of injections, lyophilisate, solid capsules, tablets and suppositories.

EFFECT: formulation according to the invention provides creating the stable drug dosage form which considerably exceeds the existing analogues in pharmacodynamics activity on the endothelial dysfunction and toxicological properties.

4 cl, 4 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a gel biologically active composition for topical application containing chitosan hydrochloride in an amount of 10-20 wt %, an organic acid in an amount of 1-10 wt %, distilled water - the rest. The above organic acid is specified in acetic, ascorbic, glycolic, lactic, citric or succinic acids.

EFFECT: providing a lower toxicity and a wider spectrum of biological action of the composition ensured by the synergetic effect of a reaction of chitosan hydrochloride and the organic acid.

11 ex, 11 tbl, 2 dwg

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