Pharmaceutical product for administration in treatment, control and / or prevention of pain

Abstract

Pharmaceutical products for administration in the treatment, control and / or prevention of pain. The proposed invention relates to a medicament, and in particular to a pharmaceutical product for administration in the treatment, control and prevention of pain using the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Ph-Gly-NH2), and in particular to a pharmaceutical product based on the tetrapeptide, which can be used in the treatment, control and prevention of acute or chronic pain, in particular for the treatment of pain, in particular for the treatment of pain. In particular acute or chronic pain in cancer patients and in post-operative early stages after various surgical interventions. Proposed is a pharmaceutical product for administration in the treatment, control and prevention of pain, in which the mode of administration of the pharmaceutical product comprises administration of tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Ph-Gly-NH2) at a single dose of 2 mg to 7 mg at an administration interval of 4 hours or longer, with a daily dose of no more than 42 mg, and a pharmaceutical product for administration in the treatment, control and prevention of pain, in which the mode of administration of the pharmaceutical product comprises administration of tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Ph-Gly-NH2). The duration of the pain treatment course is at most 96 days, and the treatment course can be repeated multiple times.

Description

Technical Field

[0001] The proposed group of inventions relates to medicines, and in particular to pharmaceutical products for administration in the treatment, control and prevention of pain using the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2), and especially to pharmaceutical products based on the tetrapeptide, which can be used for acute or chronic pain, in particular in cancer patients and in the early postoperative period after various surgical interventions. Background Art

[0002] Acute and chronic pain is one of the most intolerable and psychologically taxing manifestations of disease, including cancer, and in the immediate postoperative period following a variety of surgical interventions. The high prevalence of pain requires a constant search and selection of new treatment options for its prevention or relief.

[0003] The current pharmacological spectrum of analgesics includes multiple groups of drugs: opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), combination products, corticosteroids, anticonvulsants, etc. However, the search for new analgesics and treatment methods based on their application remains an important issue because known analgesics have many serious disadvantages. Opioids are known to be associated with a high risk of drug dependence in patients with chronic pain and have a wide range of adverse events (AEs), including nausea, drowsiness, cognitive decline, fatigue, increased risk of balance disorders (risk of falls), immunosuppression, etc. Unlike opioids, other products (such as NSAIDs, corticosteroids, and anticonvulsants) are not associated with a high risk of drug dependence or AEs, but their analgesic effects are not always sufficient, especially in cancer patients.

[0004] The development of peptide-based analgesic methods is an area of ​​particular interest in the search for new methods for pain treatment, prevention and control. In particular, many publications describe the high analgesic activity of the tetrapeptides H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-Sar-OH (JPS58213743 (A), published on December 12, 1983, and JPS6054400 (A), published on March 28, 1985).

[0005] A method for the prevention and / or treatment of acute or chronic pain, which comprises administering a drug based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH in an amount of 0.5 to 10 mg / dose (patent RU2622980), was chosen as a prototype of the proposed invention.

[0006] The prototype method specifies a wide range of single doses: 0.5 to 10 mg / dose; this range, according to the full description of the patent, was determined "on the basis of extrapolated data ... for humans" from the results obtained in the following studies: studies of the effects of the tetrapeptides H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH "on behavioral responses in animals", high-dose toxicity studies in the open field test, and tests of balance on a horizontal rod (Example 8 of patent RU 2622980). However, no large-scale clinical trials were conducted. Example 9 of patent RU 2622980 contains details of the administration of these tetrapeptides to only six patients; in addition, "the prototype of the drug is used in cases where it is indicated that the patient is treated with an analgesic of the morphine group (stage 3 according to the WHO system), but for one reason or another, the drug is not available. When conventional morphine drugs appear, treatment with the experimental drug prototype is interrupted." Of the six patients, five had stage IV cancer (pancreatic cancer, colon cancer, breast cancer) in different parts of the body, and one had a vertebral fracture. Products based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or the tetrapeptide H-Tyr-D-Arg-Phe-Sar-OH were administered by subcutaneous injection twice daily at a dosage of 0.7 to 3 mg (usually for 4 to 5 days, when the clinic did not have morphine prescribed for analgesia for some reason). The analgesic effect (according to the description of patent RU 2622980) was manifested as pain relief within 10 to 15 minutes after administration, and the analgesic effect lasted for 4 to 10 hours.

[0007] Since the therapeutic range of the tetrapeptide in the prototype method was selected by "extrapolating to humans" the results obtained from studying the effects of the tetrapeptide "on behavioral responses in animals" and no large-scale clinical trials were conducted, the safety and efficacy of the proposed range of single therapeutic doses (0.5 to 10 mg / dose) remain questionable. There is a lack of sufficient validation for the efficacy of the minimum dose (0.5 mg) of the specified range, the safety of the maximum dose (10 mg), and for the specific doses (0.7 mg, 1 mg, 1.5 mg, 3 mg) selected for clinical use in six patients. The prototype method also lacks details of the maximum daily dose of the tetrapeptide. There is also no information on the maximum duration of analgesia using the prototype method (as mentioned above, the clinical trials in the prototype method include details of the use of the drug in only six patients, and only for a short period of time during which the morphine prescribed for these patients was not available for any reason). In addition, the specific examples of the use of the drug in patients failed to specify which of the two tetrapeptides proposed in the prototype method (tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or tetrapeptide H-Tyr-D-Arg-Phe-Sar-OH) was used in each individual patient; therefore, one cannot be sure that the clinical efficacy of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 has been definitively confirmed.

[0008] Therefore, there is an urgent need to improve the efficacy and safety of analgesia with the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 by developing the optimal dose, regimen and course of treatment with the tetrapeptide on a more solid basis based on large-scale clinical trials.

[0009] It is also important to develop pharmaceutical products based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 for use as pharmaceutical products for the treatment and / or prevention and / or management of pain.

[0010] Patent RU 2622980, chosen as a prototype, describes a method for treating and / or preventing pain with an injectable product based on the tetrapeptides H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH and prepared in particular in solution dosage form. Claims 12 and 15 describe a liquid dosage form composition comprising specific excipients in specific ratios.

[0011] Claim 12 of the prototype describes a pharmaceutical composition comprising a tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH and excipients (e.g., buffers, fillers, stabilizers, and solvents), and specifies a range of possible content values ​​for each component. However, these content ranges of the components are still partially hypothetical because they are not confirmed by specific examples in the complete description of the patent. Specifically, the claims specify a range of 0.01 to 0.5 wt% of the tetrapeptide, while the embodiments only list a composition with a tetrapeptide content of 0.15 wt%. In addition, the patent specification lacks information on compositions with a tetrapeptide content (in mg) other than 1.5 mg (the tetrapeptide content in all liquid injectable compositions listed in the embodiments is 1.5 mg). Therefore, there is still an urgent need to develop drugs for the treatment, control, and / or prevention of pain. Summary of the invention

[0012] An object of the present invention is to improve the efficacy and safety of pharmaceutical products for the treatment and / or prevention and / or control of pain, in particular the treatment and / or prevention and / or control of pain in cancer patients and in the early postoperative period after various surgical interventions, by developing optimal doses, regimens and courses of treatment with the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2.

[0013] This object is solved by a medicinal product for administration in the treatment, control and / or prevention of pain according to claim 1. Advantageous modifications and developments are specified in the dependent claims.

[0014] The expression "the mode of administration comprises administration of the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)" means that the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) is administered to a patient in need thereof according to the mode of administration.

[0015] In one aspect of the invention, the object is solved by a pharmaceutical product for the treatment of pain, wherein the mode of administration of the pharmaceutical product comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in single doses of 2 mg to 7 mg at dosing intervals of 4 hours or more, the daily dose not exceeding 42 mg. The duration of the course of pain treatment is preferably up to 96 days, which can be repeated several times.

[0016] This drug product has the following aspects:

[0017] Preferably, the pharmaceutical product is a medicinal product for administration to humans in the treatment, control and / or prevention of pain. According to a preferred embodiment, the mode of administration comprises administration for pain relief in cancer patients and in the early postoperative period after various surgical interventions.

[0018] Preferably, the mode of administration comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in the form of a solution for subcutaneous injection.

[0019] In a preferred embodiment, the mode of administration comprises administering the tetrapeptide while monitoring the severity of pain and / or the patient's response to the tetrapeptide, and increasing or decreasing the single dose and / or the number of daily doses and / or the dosing interval and / or the duration of the treatment course as needed. That is, the single dose and / or the number of daily doses and / or the dosing interval and / or the duration of the treatment course are increased or decreased as needed based on the monitoring of the severity of pain and / or the patient's response to the tetrapeptide.

[0020] Preferably, the mode of administration includes daily tetrapeptide injections or tetrapeptide injections with a break of one to several days depending on the severity of the pain.

[0021] In a preferred embodiment, the mode of administration includes determining the total duration of pain treatment by the patient's condition. In cancer patients, the duration of a single course of pain treatment can be up to 96 days or longer, and the course can be repeated multiple times; repetition of the course is recommended after a pause of at least 2 to 5 days between courses, wherein the number of repeated courses is determined by the patient's condition.

[0022] Preferably, the mode of administration comprises the total duration of treatment determined by the patient's condition. In patients with pain in the early postoperative period after various surgical interventions, the duration of pain treatment is preferably 1 to 10 days.

[0023] In a preferred embodiment, the mode of application comprises the use of a single dose of 4 mg to 7 mg of the tetrapeptide.

[0024] In a preferred embodiment, the mode of administration includes a suggested starting single dose of 4 mg of the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). The inventors have shown that the optimal composition for producing a drug product based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 contains a much higher level of the tetrapeptide than the 0.15 wt % (or 1.5 mg) described in RU 2622980, because as shown below, the suggested starting dose of 4 mg of the tetrapeptide is advantageous.

[0025] Preferably, the administration pattern includes increasing or decreasing the dose as needed according to a single dose increase or decrease of 25% to 50% relative to the previous value.

[0026] In a preferred embodiment, the mode of application comprises administering the tetrapeptide 2 to 3 times daily at a dose of 4 mg. The inventors have shown that the optimal composition for producing a pharmaceutical product based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 comprises a much higher level of the tetrapeptide than the 0.15 wt% (or 1.5 mg) disclosed in RU2622980, because as shown below, the optimal course of treatment for pain treatment, control and / or prevention (comprising administration of 4 mg of the tetrapeptide 2 to 3 times daily) is advantageous.

[0027] This object is also achieved by proposing a pharmaceutical product for the control of pain, wherein the mode of administration comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 mg to 7 mg, the daily dose not exceeding 42 mg, and with a dosing interval of 4 hours or more. The individual aspects of the pharmaceutical product are as outlined above for the treatment of pain or in the dependent claims, respectively.

[0028] This object is also achieved by proposing a pharmaceutical product for preventing the onset of pain, wherein the mode of administration comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 mg to 7 mg, the daily dose not exceeding 42 mg, and with a dosing interval of 4 hours or more. The individual aspects of the pharmaceutical product are as outlined above for the treatment of pain or in the dependent claims, respectively.

[0029] In a preferred embodiment, the drug product comprises tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) and excipients: sodium chloride, mannitol, glycine, sodium acetate trihydrate, acetic acid, and water in the following component ratios (wt %):

[0030]

[0031] The proposed pharmaceutical product is characterized by the following preferred embodiments:

[0032] Preferably, the drug product is characterized by the following component ratios, in wt %:

[0033]

[0034]

[0035] Preferably, the drug product is characterized by the following ratios of components, expressed in mg:

[0036]

[0037] Preferably, the drug product is characterized by the following ratios of components, mg:

[0038]

[0039] Preferably, the pharmaceutical product is in the form of a solution for subcutaneous injection or is prepared as a solution for subcutaneous injection. DETAILED DESCRIPTION

[0040] Unless otherwise specified, all technical and scientific terms used in this document have the meaning generally accepted by experts in the field to which the invention belongs. For any term with multiple definitions, the definitions described in this application shall apply. It should be noted that if a URL or similar address or identifier is cited as a reference, the specific identifier may vary significantly, and specific information in the Internet may appear or disappear, but equivalent information can be found online using a search engine. Reference to a specific part of the information is meant to indicate that the information is available and can be disseminated. The foregoing brief description of the present invention and the subsequent detailed description are for reference only, and should not limit any claimed object in any way. The use of the terms "it includes / includes", "includes / includes" and their synonyms should not be interpreted as restricting or limiting in any way. It should be noted that the methods and compositions described in the present invention are not limited to the specific methods, schemes, constructs and reagents described in this document, and may vary. It should also be mentioned that the terms used in this document are used only for the purpose of describing specific embodiments of the present invention, and should not limit the scope of the described methods and compositions, which are limited only by the attached claims of the present invention.

[0041] Clinical trials have been conducted involving the administration of the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) to patients via subcutaneous injection of the drug product Taphalgin.

[0042] The tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) is a highly specific μ1-opioid receptor agonist that shows little interaction with other opioid receptors (the interaction with the δ-receptor is 3 orders of magnitude weaker than that with the μ-opioid receptor, and no interaction with other receptors has been detected). Two subtypes of μ receptors have been identified: activation of the μ1 receptor leads to significant analgesia, while activation of the μ2 receptor leads to respiratory depression, cardiovascular system disorders (e.g., bradycardia) and intestinal motility inhibition. Therefore, the high specificity of the tetrapeptide in question for the μ1-opioid receptor ensures that there are no side effects typical of most opioid anesthetics. The tetrapeptide interacts with peripheral and central receptors, although it mainly works at the spinal cord level. After the tetrapeptide binds to the μ1 receptor, the G protein complex is released, which inhibits the release of neurotransmitters from cells by reducing the amount of cAMP produced, closing calcium channels and opening potassium channels, which particularly inhibits the transmission of pain signals in nociceptors. The tetrapeptides activate the analgesic system, disrupting the interneuronal transmission of pain signals at different levels of the CNS and altering the intensity of pain perception by acting on higher brain centers.

[0043] Taphalgin is a solution for subcutaneous injection, which contains the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) as an active ingredient and excipients including sodium acetate trihydrate, sodium chloride, mannitol, glycine, and water in the following component ratios:

[0044] Tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide: 0.4wt%,

[0045]

[0046] The content of the ingredients mentioned may vary within 15% to 20% of their respective values ​​specified above.

[0047] Taphalgin 4 mg / mL was used.

[0048] For the preparation of Taphalgin, the excipients are dissolved in water, then the peptide is dissolved in the resulting solution, which is sterilized, filtered and filled in ampoules or syringes.

[0049] A preliminary Phase I clinical trial was conducted in 39 healthy male volunteers to evaluate the safety, tolerability and pharmacokinetics of Taphalgin after subcutaneous administration. The study was conducted in the dose-increasing groups of each subsequent group (0.05mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg and 7mg). Starting from the lowest dose group, Taphalgin was administered once by subcutaneous injection. Each participant received only one dose. The dose escalation of each subsequent group was conducted only after a comprehensive evaluation of the incidence data of AE / serious AE (SAE), vital signs, electrocardiogram results, physical examination results and laboratory tests and dose-limiting toxicity (DLT) effects. If DLT is determined in a person receiving the research product in any group, the number of volunteers will have to be increased by three. If no volunteer in the extended group taking Taphalgin develops dose-limiting toxicity (i.e., if DLT is observed in 1 of 6 subjects), the dose escalation in the next group can continue. To evaluate the pharmacokinetics of Taphalgin, 22 blood samples were collected from each volunteer (before administration (0 hour), at 10, 20, 30 and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 96 and 120 hours after administration). The following parameters were calculated: area under the curve (AUC) during the follow-up period 0至t ), the area under the curve from dosing to infinity (AUC 0至∞ ), maximum concentration (C max ), time to reach maximum concentration (T max ), half-life (T 1 / 2 ), mean residence time (MRT) in plasma, and elimination rate constant (K el ) and distribution volume (V d). Taphalgin concentrations in plasma were determined by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS / MS) using a Triple Quad 4500 system (AB Sciex)

[49] . In the final phase of the study, clinical and biochemical blood tests were also performed, and coagulation parameters were investigated. The total study duration for each volunteer did not exceed 14 days. The study showed that different doses of Taphalgin (0.05 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg and 7 mg) had good safety and tolerability when administered once to healthy volunteers. The highest dose reached by dose escalation was 7 mg, and no dose-limiting toxicity was recorded (AE severity was grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE)). In the investigator's evaluation, the tolerability of Taphalgin in all patients was described as "good" or "excellent". The most common AEs reported during the study (greater than 5% of the total number of AEs) were: asthenia (n=11; 28.20%), dry mouth (n=11; 28.20%), hypoesthesia (n=9; 23.08%), and head discomfort (n=9; 23.08). The observed AEs were mild, did not require treatment, and almost all resolved with full recovery.

[0050] The time to reach the maximum concentration of the drug after subcutaneous injection is an average of 30 minutes, indicating rapid absorption from subcutaneous adipose tissue. After a single administration, Taphalgin is actively distributed not only in the bloodstream, but also in peripheral tissues, as indicated by the distribution volume (average 24 to 39 L), which far exceeds the volume of circulating blood. Distribution is followed by a fairly rapid elimination phase: the half-life of the drug is 1.3 to 2.5 hours; therefore, it is completely eliminated from the systemic circulation in about 15 hours.

[0051] In general, similar elimination values ​​are typical for therapeutic peptides, of which Taphalgin is a representative. The average residence time of a drug molecule in humans is 3.03 ± 0.42 hours.

[0052] Phase II clinical trial evaluated the efficacy and safety of different doses of Taphalgin in cancer patients who are experiencing pain. In addition, the optimal dosing regimen was selected, and its pharmacokinetic parameters in the case of multiple administration were evaluated. Pain intensity was evaluated based on a numeric rating scale (NRS) from 0 to 10. The study was carried out in the following patients of both sexes: the age was 18 to 70 years old (including the end value), there was a cancer diagnosis record, and severe cancer pain was controlled by morphine during recruitment (NRS pain intensity score <3 during screening, morphine maximum daily dose 60mg IM, receiving stable dose or morphine for at least 7 days before screening), and life expectancy exceeded 1 month. Patients did not receive analgesics other than those specified in the scheme. Patients' physical activity scores on the Eastern Cooperative Oncology Group (ECOG) performance status scale were 0 to 3, i.e., they were active and able to move around (up and about), lasting more than 50% of the waking hour (level 2 on the ECOG scale), or were only able to take care of themselves to a limited extent, and more than 50% of the waking time was confined to a bed or chair (level 3 on the ECOG scale). The study was conducted in two stages. The total duration of the trial for each patient was 20 days or less. In stage 1 (duration: 10 days), the dose of Taphalgin was selected: each participant received an initial single dose (2, 3, 4, 5, 6 or 7 mg) of the drug randomized to them, followed by titration according to an established procedure. The number of doses depends on the pain intensity evaluated by the NRS scale for each individual patient. The parallel group design with different starting doses in each group was selected based on the fact that the Phase I clinical trial showed an acceptable safety profile of the different doses of Taphalgin studied in the trial. In stage 2, patients received Taphalgin (solution for subcutaneous injection at an individualized dose selected in stage 1; maximum single dose = 7 mg, maximum daily dose = 42 mg) or the comparator drug morphine (solution for intramuscular injection at an individualized dose selected prior to the start of stage 1).

[0053] In cases of breakthrough pain, morphine is used in the form of a 10 mg / 1 mL solution for injection.

[0054] The comparator drug was selected because it is widely used in this type of patient and is based on the results of preclinical trials of Taphalgin, which proved the hypothesis that it is comparable to morphine in terms of the intensity of its analgesic effect. The primary efficacy endpoint is the rate of achieving adequate analgesia throughout the day. This effect is understood to be mandatory compliance with two criteria, namely achieving a daily average NRS pain intensity score of <3 and requiring no more than 2 injections of morphine (10 mg IM) for control of breakthrough pain within 10 days. The following secondary endpoints were also selected to determine the analgesic efficacy of Taphalgin:

[0055] Trends in daily mean NRS pain intensity scores (in points);

[0056] Hourly mean NRS pain intensity score between the first and second doses (at visit 10);

[0057] Trends in daily doses of additional analgesics used to control breakthrough pain (in mg);

[0058] Nighttime sleep quality (duration of nighttime sleep without pain disturbance) based on a Likert 3-point scale from the patient diary as follows: 1 = good sleep quality (6 to 8 hours), 2 = fair quality (4 to 6 hours), 3 = poor quality (less than 4 hours);

[0059] The frequency of drug dose increases;

[0060] · There is a general need for changes in treatment.

[0061] The patients were divided into 6 groups and received different initial doses of Taphalgin:

[0062] Group 1 (n=6): 2 mg; Group 2 (n=6): 3 mg; Group 3 (n=12): 4 mg; Group 4 (n=6): 5 mg; Group 5 (n=6): 6 mg; Group 6 (n=6): 7 mg. All groups had comparable demographics (p>0.05).

[0063] In stage 1, the analysis showed statistically significant differences in the daily mean NRS pain intensity scores between study days in the groups receiving 2 mg (p<0.00001), 3 mg (p<0.03681), 4 mg (p<0.00131), 6 mg (p<0.00497) and 7 mg (p<0.01788) doses of Taphalgin, indicating a favorable trend in pain severity and a reduction in pain intensity associated with the study drug in these groups. Comparative analysis of the daily mean NRS pain intensity scores from days 1 to 10 showed no significant differences between the study groups, indicating that even the lowest studied single dose of Taphalgin (2 mg) showed adequate efficacy, although the average daily dose within the subgroup on day 10 was 8.33 mg, while the average starting dose of morphine in this subgroup was 18.33 mg.

[0064] In Phase 2 of the study, no significant differences in NRS pain intensity scores between study days were found in the morphine group; thus, the within-group trend in pain perception was stable (p=0.88079). The trend in the daily average NRS pain intensity scores in the Taphalgin group also remained stable, i.e., the patients' pain perception was stable (p=0.46607). Thus, the product controlled pain intensity, as did morphine, as demonstrated by the between-group comparison, which showed that throughout Phase 2, the groups did not differ in pain intensity (p>0.05).

[0065] Table 1

[0066] Trends in daily mean Numeric Rating Scale (NRS) pain intensity scores during Phase 2 of the trial.

[0067] Dosing day Taphalgin morphine р 11 0.07±0.16 0.12±0.22 0.4392 12 0.18±0.34 0.30±0.38 0.5581 13 0.19±0.26 0.24±0.35 0.6814 14 0.16±0.25 0.24±0.35 0.5061 15 0.09±0.22 0.28±0.30 0.1252 16 0.14±0.19 0.17±0.21 0.3721 17 0.11±0.15 0.17±0.23 0.4656

[0068] Analysis of sleep quality showed improvement in patients treated with Taphalgin: by study days 9 to 10, 76% to 79% of patients had fair sleep quality and 20% to 23% had good sleep quality.

[0069] Prior to the start of the study, all patients participating in Phase 1 of the trial were taking morphine at a personalized dose that ensured adequate pain relief. At baseline, the mean stable daily dose of this product for all Taphalgin dose subgroups was 20.31 mg; 14 (33.33%) patients were at a dose of 10 mg; 18 (42.86%) patients were at a dose of 20 mg; 6 (14.29%) patients were at a daily dose of 30 mg; 3 (7.14%) patients were at a daily dose of 40 mg; and 1 (2.38%) patient received morphine at a dose of 60 mg. The Taphalgin dose was adjusted in Phase 1 until a daily dose that ensured adequate pain relief was reached. The mean daily dose of the drug at visit 10 was 8.25 mg in the combined subgroup, 8.33 mg in dose subgroup 2, 6.80 mg in dose subgroup 3, 10.10 mg in dose subgroup 4, 7.25 mg in dose subgroup 5, 8.80 mg in dose subgroup 6, and 6.00 mg in dose subgroup 7. Thus, the individualized daily doses of morphine and Taphalgin for each patient evaluated in the study could be compared. In phase 1 of the study, patients received a stable dose of the drug on day 6 or 7, on average. The mean daily dose for days 7 to 10 was included in the analysis and compared with the pre-determined morphine dose for each patient. In general, the mean daily dose of Taphalgin was 1 / 3 of the morphine dose for the same patient.

[0070] Table 2 below shows the results of the adverse event (AE) investigations.

[0071] Table 2

[0072] Number of adverse events (AEs) reported during Phase 2 of the study, N (% of the total number of AEs in the corresponding group)

[0073]

[0074]

[0075] Notes: 1. There were a total of 32 patients in both groups, 16 in each group. 2. SAE = serious adverse event.

[0076] In the second phase of the study, 30 SAEs were reported in 10 of the 32 patients (31.25%). The analysis of the incidence of AEs in the Taphalgin group and the morphine group in the second phase of the study is shown in Table 2. The safety profile was shown to be significantly more favorable in the Taphalgin group than in the morphine group: the incidence of AEs in the morphine group was 50.0%, with 27 AEs reported in 8 patients, and 1 SAE was reported in 1 patient in the morphine group. The incidence of AEs in the Taphalgin group was only 12.5%, with 3 AEs reported in 2 patients in this group. The comparative analysis of AEs showed significant differences between the groups (p=0.022). At the same time, there were no significant between-group differences in the severity of AEs, the causal relationship between AEs and treatment, or the AE outcomes.

[0077] In addition, the trend of opioid-related disorders was evaluated in patients switched from morphine to Taphalgin; it showed that the incidence of opioid-related disorders decreased throughout the 10 days of dose titration: although its incidence was 59.52% (25 / 42) at baseline, it decreased to 14.29% (6 / 42) at the end of 10 days of Taphalgin treatment. Therefore, far from causing opioid-related AEs, Taphalgin helped to reduce these AEs in patients already receiving morphine.

[0078] These data show the considerable clinical efficacy of Taphalgin. Throughout the study, the use of this product allowed the maintenance of sufficient analgesia that had been achieved by intramuscular injection of morphine. Data on the frequency of administration show that even in the low-dose range (2 to 4 mg) with a favorable safety profile, the drug can control tumor-related pain for 8 to 12 hours. However, in order to achieve sufficient pain control, the dose of Taphalgin must be selected based on the specific situation, because the pathogenesis of pain, the intensity of pain perception and the severity of pain are subject to individual differences. Although the clinically effective dose is 2 mg, additional doses up to 7 mg are well tolerated and are not related to dose-limiting toxicity. The maximum daily dose of Taphalgin must not exceed 42 mg. The drug must be administered with a dosing interval of no less than 4 hours.

[0079] None of the patients receiving Taphalgin experienced sedation associated with decreased alertness and concentration. Sleepiness, memory and attention deficits are typical AEs that occur with the use of opioids and significantly affect patients' quality of life and ability to work.

[0080] Another important factor is that, unlike opioids, Taphalgin does not depress the respiratory center: patients receiving this product did not show dyspnea, which was observed in the morphine group.

[0081] Therefore, these studies suggest that the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) should be administered for pain in single doses of 2 to 7 mg and daily doses not exceeding 42 mg with dosing intervals of 4 hours or longer.

[0082] The recommended initial dose is 4 mg. The dose and dosing diversity are then individualized, taking into account pain severity and response to treatment. If a single dose must be raised, this should be done in increments of 25% to 50% of the previous dose level. If the dose level must be reduced (if a higher dose produces a good therapeutic effect or in the case of an AE), this should also be done in increments of 25% to 50% of the previous dose.

[0083] These recommendations are then used in a series of subsequent clinical trials (Phase III clinical trials).

[0084] A further clinical trial was conducted in 180 male and female patients aged 18 to 80 years with cancer pain. The patients were divided into two groups:

[0085] - Group 1 patients (n=120) received Taphalgin (solution for subcutaneous administration) in an individually selected dose throughout the study.

[0086] - Group 2 patients (n=59) received oral morphine as a comparator for 28 days from the end of the dose selection phase (Period 1). After this (Period 2), patients in this group were reassigned to subcutaneous Taphalgin solution, which was administered in an individualized dose until the end of clinical trial participation.

[0087] For patients randomized to study drug, the initial dose of Taphalgin solution for subcutaneous injection was 4 mg. The single dose of the drug was increased or decreased in 2 mg increments (if necessary). The maximum single dose of Taphalgin was 7 mg. The maximum daily dose of Taphalgin was 42 mg. The duration of study drug treatment did not exceed 94 ± 2 days.

[0088] The primary efficacy evaluation was performed during the following visits: Visit 1 (Day 1 of tetrapeptide treatment), Visit 2 (Day 28±2 of tetrapeptide treatment), Visit 3 (Day 56±2 of tetrapeptide treatment), and Visit 4 (Day 86±2 of tetrapeptide treatment).

[0089] Efficacy Endpoint:

[0090] The following endpoints were used to evaluate treatment efficacy:

[0091] Primary endpoint:

[0092] Maintenance rate of analgesic response at day 28.

[0093] Treatment response was considered maintained if all of the following conditions were met:

[0094] 1. No more than 2 dose increases of the test / comparator drug are required from the start of treatment to day 28 of treatment at the selected dose.

[0095] 2. The average daily pain intensity at the end of the 28-day treatment period remained <50% of the intensity at the start of titration.

[0096] Secondary endpoints:

[0097] The proportion of patients requiring dose increases at Visits 2, 3, and 4 from the start of treatment at the selected dose.

[0098] The proportion of patients who did not respond to Taphalgin / morphine treatment at visits 2, 3, and 4.

[0099] The proportion of patients who had at least one episode of breakthrough pain at Visits 2, 3, and 4 from the start of treatment at the selected dose.

[0100] Trends in daily mean NRS pain intensity scores from the start of treatment at the selected dose to Visits 2, 3, and 4.

[0101] The proportion of patients requiring concomitant analgesic treatment at visits 2, 3, and 4.

[0102] · Patients' quality of life scores based on the SF-36 questionnaire.

[0103] Treatment efficacy as assessed by the Investigator at the end of the dose selection phase at Visit 1 and at Visit 2.

[0104] Treatment efficacy as assessed by patients at the end of the dose selection phase at Visit 1 and at Visit 2.

[0105] Safety endpoints:

[0106] Total number of adverse events (AEs) stratified by severity and frequency;

[0107] The rate of adverse drug reactions;

[0108] The proportion of serious adverse events (SAEs) associated with Taphalgin / morphine treatment;

[0109] The proportion of patients with at least one reported AE;

[0110] Proportion of patients who discontinued treatment due to AEs.

[0111] The proportion of patients with a preserved analgesic treatment response by day 28 was 98.97% (96 / 97) in group 1 (Taphalgin) and 100% (46 / 46) in group 2 (morphine). The difference in the proportion of patients with a preserved analgesic treatment response by day 28 between group 1 (Taphalgin) and group 2 (morphine) was 0.0103 (1.03%). The lower limit of the 95% CI for the difference in proportions was -0.0862 (8.62%) and the upper limit was 0.0643 (6.43%).

[0112] Comparative analysis of the proportion of patients with a retained analgesic treatment response by Day 28 failed to identify a statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (one-sided Fisher's exact test, p=0.6783).

[0113] The proportion of patients requiring a dose increase by Visit 2 was 4.12% (4 / 97) in Group 1 (Taphalgin) and 6.52% (3 / 46) in Group 2 (morphine). Comparative analysis of the proportion of patients requiring a dose increase by Visit 2 failed to identify a statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (Fisher's exact test, p=0.6809).

[0114] There were no non-responders to Taphalgin or morphine treatment in Group 1 (Taphalgin) or Group 2 (morphine) at Visit 2. Comparative analysis of the proportion of non-responders to Taphalgin / morphine treatment at Visit 2 failed to identify a statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (Pearson chi-square test, p=1.0000).

[0115] No non-responders to Taphalgin treatment were identified by Visit 3.

[0116] No non-responders to Taphalgin treatment were identified by Visit 4.

[0117] The proportion of patients with at least one episode of breakthrough pain at Visit 2 was 0.00% (0 / 97) in Group 1 (Taphalgin) and 2.17% (1 / 46) in Group 2 (morphine). Comparative analysis of the proportion of patients with at least one episode of breakthrough pain at Visit 2 failed to identify a statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (Fisher's exact test, p=0.3217).

[0118] The proportion of patients who had at least one episode of breakthrough pain at visits 3 and 4 despite treatment with Taphalgin was 1.40% (2 / 143).

[0119] The mean daily NRS pain intensity scores (mean ± SD) for the entire population were 0.38 ± 0.47 at the start of treatment at the selected dose and 0.34 ± 0.40 at Visit 2. The mean daily NRS pain intensity scores (mean ± SD) in Group 1 (Taphalgin) were 0.42 ± 0.48 at the start of treatment at the selected dose and 0.38 ± 0.44 at Visit 2. The mean daily NRS pain intensity scores (mean ± SD) in Group 2 (morphine) were 0.30 ± 0.47 at the start of treatment at the selected dose and 0.28 ± 0.30 at Visit 2.

[0120] The average daily NRS pain intensity scores (mean ± SD) for the entire population were 0.38 ± 0.46 at the start of treatment at the selected dose, 0.35 ± 0.54 at Visit 3, and 0.35 ± 0.65 at Visit 4. The analysis failed to determine significant differences between visits (p = 0.0770), indicating a flattening trend in the average daily NRS pain intensity scores with Taphalgin treatment by Visits 3 and 4.

[0121] The mean SF-36 physical health score in the entire study population was 33.91 ± 11.39 at Visit 0 and 51.18 ± 11.50 at Visit 2. The mean SF-36 physical health score in Group 1 (Taphalgin) was 34.71 ± 11.64 at Visit 0 and 51.96 ± 11.36 at Visit 2. The mean SF-36 physical health score in Group 2 (morphine) was 32.22 ± 10.76 at Visit 0 and 49.52 ± 11.73 at Visit 2.

[0122] The mean SF-36 mental health score in the entire study population was 34.84 ± 13.12 at visit 0 and 48.13 ± 10.22 at visit 2. The mean SF-36 mental health score in group 1 (Taphalgin) was 36.46 ± 13.30 at visit 0 and 49.06 ± 9.71 at visit 2. The mean SF-36 mental health score in group 2 (morphine) was 31.42 ± 12.16 at visit 0 and 31.42 ± 12.16 at visit 2.

[0123] At visit 2 in group 1 (Taphalgin), the proportion of patients with an "excellent response" to treatment was 55.67% (54 / 97), with a "good response" was 41.24% (40 / 97), and with a "satisfactory response" was 3.09% (3 / 97). At visit 2 in group 2 (morphine), the proportion of patients with an "excellent response" to treatment was 32.61% (15 / 46), with a "good response" was 67.39% (31 / 46), and with a "satisfactory response" was 0.00% (0 / 46). Comparative analysis of the proportions of patients with different investigator-assessed treatment efficacy scores at visit 2 showed statistically significant differences between the study groups (Pearson chi-square test, p=0.0103).

[0124] The study included the following safety evaluation phases: dose selection; Phase 1, the comparative phase of the study (28±2 days from the start of treatment at the selected dose); and Phase 2, the non-comparative phase of the study (56±2 days after Phase 1).

[0125] The prevalence of patients reporting AEs in Group 1 (Taphalgin) during Phase 1 was 34.17% (41 / 120): a total of 95 AEs were reported in 41 patients. The prevalence of patients reporting AEs in Group 2 (morphine) during Phase 1 was 71.19% (42 / 59): a total of 119 AEs were reported in 42 patients. Comparative analysis of Group 1 and Group 2 patients for AEs in Phase 1 showed significant differences between the study groups (Pearson chi-square test, p<0.00001).

[0126] AEs reported during Phase 1 in Group 1 patients were mild in 66.32% (63 / 95) of cases and moderate in 33.68% (32 / 95) of cases; in Group 2 patients, they were mild in 65.55% (78 / 119) of cases, moderate in 33.61% (40 / 119) of cases, and severe in 0.84% ​​(1 / 119). Comparative analysis showed no significant difference between Group 1 and Group 2 in terms of AE severity (p=0.6693).

[0127] Based on investigator assessment, a causal relationship between AEs in Phase 1 and treatment in Group 1 was considered certain in 1.05% (1 / 95) of cases, probable in 3.16% (3 / 95) of cases, possible in 44.21% (42 / 95) of cases, unlikely in 13.68% (13 / 95) of cases, conditional in 12.63% (12 / 95) of cases, and unattributable in 1.05% (1 / 95) of cases. In group 2, it was considered definite in 13.44% (16 / 119) of cases, probable in 29.41% (35 / 119), possible in 38.66% (46 / 119), unlikely in 11.76% (14 / 119), conditional in 0.84% ​​(1 / 119), unclassifiable in 0.84% ​​(1 / 119), and unrelated in 5.04% (6 / 119). Comparative analysis of the causal relationship between AEs and treatment in phase 1 in groups 1 and 2 showed significant differences between the study groups (Pearson chi-square test, p<0.00001).

[0128] To further evaluate the differences between Group 1 and Group 2, a comprehensive analysis of AEs within the groups was performed. This evaluation showed that the incidence of patients reporting AEs was lower in Group 1 (Taphalgin), 36.69% (44 / 120), compared to 72.88% (43 / 59) in Group 2 (morphine). In addition, the number of cases in which the investigators reported a causal relationship between the AE and the treatment as "definite", "probable" or "possible" was higher in Group 2 (morphine): 46 AEs in Group 1 (Taphalgin) vs. 97 AEs in Group 2 (morphine); in addition, in Phase 1, no one in Group 1 receiving Taphalgin withdrew from treatment due to AEs.

[0129] The incidence of patients reporting AEs and / or SAEs during Phase 2 was 12.74% (20 / 157). During Phase 2, a total of 35 AEs and / or SAEs were reported in 20 patients. During Phase 2, the incidence of patients reporting AEs was 7.64% (12 / 157). During Phase 2, a total of 24 AEs were reported in 12 patients. AEs reported during Phase 2 were mild in 54.17% (13 / 24) of cases and moderate in 45.83% (11 / 24) of cases. Based on the investigator assessment, the causal relationship between the AEs reported in phase 2 and treatment with the study drug Taphalgin was considered to be definite in 16.67% (4 / 24) of cases, possible in 33.33% (8 / 24), unlikely in 12.50% (3 / 24), conditional in 4.17% (1 / 24), and unrelated in 33.33% (8 / 244). The analysis of the frequency of AE outcomes showed that by the end of phase 2, recovery without sequelae was observed in 83.33% (20 / 24) of cases, and improvement was observed in 16.67% (4 / 24).

[0130] In general, the safety evaluation showed that the incidence of patients reporting adverse events was lower in the Taphalgin group (36.69% (44 / 120) compared to 72.88% (43 / 59) in the morphine group. In addition, the number of cases in which the investigators reported a causal relationship between the adverse event and treatment as "definite," "probable," or "possible" was higher in the morphine group: 46 adverse events in the Taphalgin group vs. 97 adverse events in the morphine group.

[0131] Another clinical trial focused on the treatment of pain in the early postoperative period following a variety of surgical interventions, including urological, gynecological, and other surgeries. The study was conducted in 100 patients, with the patients divided into five groups of 20 each; three groups received different doses of Taphalgin (2 mg twice daily, 4 mg twice daily, and 4 mg three times daily), and two groups received the comparator drug Promedol (20 mg three times daily).

[0132] If the NRS pain intensity score is ≥4, treatment with Taphalgin (or the comparative drug Promidol) is started on the first day after surgery. If the NRS pain intensity score is ≥4 on the second day, Taphalgin is administered at the same dose and the same dosing interval, but if necessary, the dosing regimen can be adjusted within the same day (the number of doses is usually reduced due to the establishment of pain control). If the NRS pain intensity score is ≤4 on the second day, only paracetamol is administered by IV injection as needed, and the maximum daily dose is 4 mg. The total duration of treatment does not exceed 8 days. Pain is usually under control within 1 to 2 days in the early postoperative period.

[0133] The proportion of patients who achieved greater than 50% pain relief 1 hour after receiving the initial dose was 65.0% in the group treated with Taphalgin 4 mg twice daily, 55.0% in the group receiving Taphalgin 2 mg three times daily, 80.0% in the group receiving Taphalgin 4 mg three times daily, and 50% in the group receiving Promidol 20 mg three times daily.

[0134] The daily mean NRS pain intensity score was 2.35 ± 0.70 points in the group receiving treatment with Taphalgin 2 mg three times a day, 2.51 ± 0.84 in the group receiving Taphalgin 4 mg twice a day, 2.14 ± 0.94 in the group receiving Taphalgin 4 mg three times a day, and 2.16 ± 0.66 in the group receiving promidol 20 mg three times a day. On the second day, the score was 1.45 ± 2.06 in the group receiving Taphalgin 2 mg three times a day, 1.48 ± 1.83 in the group receiving Taphalgin 4 mg twice a day, 0.92 ± 1.77 in the group receiving Taphalgin 4 mg three times a day, and 1.41 ± 1.92 in the group receiving promidol 20 mg three times a day. The mean changes in pain intensity were 60.0 ± 25.45% in the group receiving Taphalgin 2 mg three times daily, 57.56 ± 21.12% in the group receiving Taphalgin 4 mg twice daily, 67.21 ± 20.11% in the group receiving Taphalgin 4 mg three times daily, and 55.44 ± 33.17% in the group receiving Promidol 20 mg three times daily.

[0135] Of the patients in the group receiving Taphalgin 2 mg 3 times daily on day 1 who required repeated dosing on day 2, 16.67% were dosed 3 times, 66.67% were dosed 1 time, and 16.67% were dosed 2 times.

[0136] Of the patients in the group receiving Taphalgin 4 mg twice daily on day 1 who required repeated dosing on day 2, 50.00% were dosed 2 times, and 50.00% were dosed once.

[0137] Of the patients in the group receiving Taphalgin 4 mg three times daily on day 1 who required repeated dosing on day 2, 11.11% were dosed three times, and 89.89% were dosed twice.

[0138] Of the patients in the group receiving Promidol 20 mg three times daily on day 1 who required repeat dosing on day 2, 16.67% did so three times, and 83.33% did so twice.

[0139] AEs were observed in 23 of 100 patients. AEs were mild in 76.74% of patients and moderate in 23.53%. AEs were observed in 35% of patients in the group treated with Promidor, in 15% of patients treated with Taphalgin 2 mg three times a day, in 10% of patients treated with Taphalgin 4 mg twice a day, and in 20% of patients treated with Taphalgin 4 mg three times a day. Based on the investigator's assessment, the causal relationship between the AE and treatment with the study drug or the comparator drug was considered to be certain in 73.53% of cases, very likely in 5.88% of cases, possible in 11.76% of cases, unlikely in 5.88% of cases, and no relationship was established in 2.94% of cases.

[0140] The proposed pharmaceutical product for administration to humans is as follows:

[0141] Products based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) are used for the control and / or treatment and / or prevention of pain. In a particular embodiment, it can be Taphalgin (solution for subcutaneous injection), containing as active ingredient the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) (4 mg / mL) and excipients including sodium acetate trihydrate, sodium chloride, mannitol, glycine, and water in the following component ratios:

[0142] Tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide: 0.4wt%,

[0143]

[0144]

[0145] The content of the ingredients may vary within the range of 15% to 20% of their respective values ​​specified above.

[0146] The product is applied to patients with a maximum daily dose of 42 mg and a dosing interval of 4 hours or longer with a single dose of 2 to 7 mg 1 to 6 times a day. The initial dose of the suggestion is 4 mg. A specific dose is selected based on the specific situation, depending on the severity of pain, the analgesic effect achieved after administration, and the presence or absence of AEs (adverse events) after administration. Dose selection is usually carried out on the first day of treatment, followed by monitoring the severity of pain during treatment, and if necessary, adjusting the dose and the number of daily doses. As mentioned above, the recommended initial dose of the product is 4 mg. The best dosage regimen suggested is 4 mg 2 to 3 times a day. If a single dose must be increased, this should be done at a range of 25% to 50% of the previous dose. If the dose must be reduced, this should also be done at a range of 25% to 50% of the previous dose.

[0147] Taphalgin can be used for long-term treatment; the duration of treatment is usually determined by the attending physician.

[0148] In Phase III clinical trials in cancer patients, treatment courses lasted up to 96 days. In Phase III clinical trials in patients with early postoperative pain following multiple surgical interventions, treatment typically lasted 1 to 10 days.

[0149] If the product is used to treat chronic pain, it should preferably be administered at regular intervals according to a fixed regimen.

[0150] In the case of long-term use, the need for extended treatment with the drug should be verified at regular intervals (e.g. by taking short breaks in treatment) and the dosage should be reviewed. For this reason, a course of treatment of up to 96 days can be repeated multiple times, but a break of at least 2 to 5 days should be taken between courses.

[0151] The tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) can be used to prevent pain attacks against a chronic pain background. This is particularly important for cancer patients. In such cases, the product is administered on a regular basis according to a fixed regimen, but the dosage administered is for preventing pain attacks, rather than only during episodes of severe pain.

[0152] The proposed pharmaceutical products for administration in the treatment, control and / or prevention of pain and their modes of administration are illustrated by the following examples.

[0153] Example 1.

[0154] Patient N, aged 65 years, male.

[0155] Diagnosis: Left retroperitoneal sarcoma, T2NIMI St.IV, metastasis to peritoneum and bones, chronic severe pain.

[0156] The patient is being treated on an outpatient basis, he is able to take care of himself but cannot work.He spends more than 50% of his waking time ambulatory (50 to 60 points on the Karnofsky scale).

[0157] Prior to the course of treatment according to the proposed mode of administration, pain was managed with morphine at a dose of 20 mg per day. This was accompanied by opioid-related adverse events (AEs) such as dizziness, sleep disturbance, sedation, asthenia and constipation.

[0158] Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)) is used to treat pain according to the proposed mode of administration. Taphalgin is administered by subcutaneous injection twice daily at 12-hour intervals (at 9am and 9pm) in an individualized single dose of 3mg for 14 days. Pain intensity is evaluated 0.5 to 1.5 hours before treatment, immediately before treatment, 1 hour after treatment, and at 1pm daily. NRS pain score is usually evaluated as 1 to 2 (in individual cases, 3 or 0) before treatment, and always drops to 0 after treatment (pain intensity score is usually 0 1 hour after administration; it is usually 0 to 1 when evaluated at 1pm). Patients indicate that physical and mental state is improved, and sleep is improved.

[0159] The reported AEs were limited to two transient episodes of mild dizziness and two episodes of constipation. However, the relevance of the AEs to treatment with Taphalgin was not assessed as definitive. The AEs were self-limited.

[0160] Example 2.

[0161] Patient N, aged 64 years, male.

[0162] Diagnosis: Cancer in the middle third of the esophagus, T4NOMI St IV. Chronic severe pain.

[0163] The patient is being treated on an outpatient basis, he is able to take care of himself but cannot work.He spends more than 50% of his waking time ambulatory (50 to 60 points on the Karnofsky scale).

[0164] Prior to the course of treatment according to the proposed mode of administration, pain was managed with morphine at a dose of 20 mg per day. This was accompanied by opioid-related adverse events (AEs), such as sedation and constipation.

[0165] The proposed mode of administration of pain control is adopted using Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)). Taphalgin is administered by subcutaneous injection twice daily at 12-hour intervals (at 9am and 9pm) in an individualized single dose of 4 to 6mg for 14 days. Pain intensity is evaluated 0.5 to 1.5 hours before treatment, immediately before treatment, 1 hour after treatment and at 1pm daily. During the first 1.5 days, the drug is administered with a single dose of 6mg and then with 4mg. The NRS pain intensity score is evaluated as 3 on the first day before treatment, 3 at 9am on the second day and 2 at 9pm. The pain intensity score drops to 0 to 1 after administration. From the 3rd to the 14th day, the product is administered twice daily at a dose of 4mg. Pain intensity scores were usually 1 (rarely 2) before dosing and decreased to 0 after dosing. Pain intensity was also reported as 0 (rarely 1) at 1 pm assessment. Patients reported improved physical and mental state and improved sleep.

[0166] AEs observed were isolated episodes of mild insomnia and dry mouth. However, the relevance of the AE to treatment with Taphalgin was not assessed as definitive. The AE was self-limited.

[0167] Example 3.

[0168] Patient N, aged 68 years, male.

[0169] Diagnosis: Malignant tumor of the left retromolar space, T3NIMI 3st. Keratinizing squamous cell carcinoma. Chronic pain (pain intensity score 2 to 3).

[0170] Patients are unable to perform heavy work but can perform light or sedentary work (eg, housework or office work) (70 to 80 on the Karnofsky scale).

[0171] Prior to the course of treatment according to the proposed mode of administration, morphine was used for pain control at a dose of 30 mg per day. This was accompanied by opioid-related adverse events (AEs), such as sedation.

[0172] The proposed mode of administration for pain control is adopted using Taphalgin solution for subcutaneous injection (a product based on tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)). Taphalgin is administered by subcutaneous injection two or three times a day at intervals of 6 or 12 hours with an individualized single dose of 2 to 4 mg for 14 days. Pain intensity is evaluated 0.5 to 1.5 hours before treatment, immediately before treatment, 1 hour after treatment, and at 1 pm daily. During the first 4 days, the product is administered twice a day at a dosage of 4 mg. Before treatment with the drug, the NRS pain intensity score is usually 2 to 4 (in individual cases, 5 or 1), and always drops to 0 to 1 after administration. On the 5th to 6th day, the product is administered twice a day at a dosage of 2 mg. Pain intensity is usually determined as a score of 1 before administration, and is determined as a score of 0 after administration. On day 7, the product was administered at two doses of 2 mg each and a third dose of 4 mg; the dose was increased because the pain intensity score was 5. The pain intensity score after administration was 2. On days 8 to 14, the product was administered at a dose of 4 mg three times daily at intervals of 6 to 8 hours. The pain intensity score dropped from 2 to 4 to 0 to 2.

[0173] Patients reported improved physical and mental status and better sleep.

[0174] AEs observed were several mild episodes of somnolence, loss of appetite and mild fever. However, the relevance of the AEs to treatment with Taphalgin was assessed as unlikely.

[0175] Example 4.

[0176] Patient N, aged 64 years, male.

[0177] Diagnosis: Cancer of unknown primary site with metastases in subclavian lymph nodes, liver, retroperitoneal lymph nodes, inguinal lymph nodes and bones. Chronic pain. The patient is being treated on an outpatient basis, he is able to take care of himself but cannot work. He spends more than 50% of his waking time ambulatory (50 to 60 points on the Karnofsky scale).

[0178] Before the course of treatment according to the proposed mode of administration, morphine was used for pain control at a dose of 30 mg per day.

[0179] Taphalgin solution for subcutaneous injection (a product based on tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)) is used to treat pain according to the proposed mode of administration. Taphalgin is administered by subcutaneous injection three times a day at intervals of 6 or 8 hours with an individualized single dose of 4 to 5 mg for 14 days. Pain intensity is evaluated 0.5 to 1.5 hours before treatment, immediately before treatment, 1 hour after treatment, and at 1 pm daily. During the first 2 days, the drug is administered with a single dose of 4 mg, and then with 5 mg. The NRS pain intensity score is evaluated as 2 to 4 on the first day before treatment and 3 to 4 on the second day. After administration, the pain intensity score drops to 2. On the 3rd to 14th day, the product is administered three times a day with a dosage of 5 mg. The pain intensity score is usually equal to 1 before administration, and drops to 0 after administration. The patient indicates that physical and mental state is improved, and sleep improves.

[0180] The observed AEs were isolated episodes of mild somnolence, mild dizziness and mild fever. However, the association of the AE with treatment with Taphalgin was assessed as unlikely. The AE was self-limited.

[0181] Example 5.

[0182] Patient N, 57 years old, female.

[0183] Diagnosis: Cervical cancer, pT2abNxMO, st.IIab. Chronic pain.

[0184] The patient cannot perform heavy work but can perform light or sedentary work (such as housework or office work) (70 to 80 on the Karnofsky scale).

[0185] Prior to initiation of treatment according to the proposed mode of administration, the patient had uncontrolled pain (excluding breakthrough pain or pain from other causes not associated with persistent pain) despite treatment with weak opioid analgesics ± NSAIDs ± adjunctive therapy.

[0186] The pain was treated with Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)) according to the proposed mode of administration. Taphalgin was administered by subcutaneous injection one to three times a day in an individualized single dose of 4 to 6 mg for 84 days. The pain intensity was evaluated 1 to 1.5 hours before treatment, 1 to 1.5 hours after treatment, 4 hours and 12 hours.

[0187] During the first 5 days, the product was applied three times a day at an interval of 7 to 8 hours with a dosage of 4 mg. Pain intensity was generally determined as an NRS score of 3 to 4 before administration, and was determined as an NRS score of 1 to 3 after administration (at 1 hour and 4 hours). On the 3rd to 5th day of treatment, the pain intensity score was 1 to 2 before treatment, and was 0 after treatment (at 1 hour and 4 hours). On the 6th to 42nd day, the product was applied once a day with 4 mg. The pain intensity score was equal to 1 to 2 before administration, and dropped to 0 after administration (at 1 hour and 12 hours) until the 37th day of treatment. On the 37th to 42nd day, the pain intensity score was 2 before administration, 1 hour after administration, and 1 to 2 4 hours after administration. On the 43rd to 84th day, the product was applied once a day with a dosage of 6 mg. Pain intensity was generally determined as a score of 1 before dosing and as a score of 0 after dosing (at 1 hour and 12 hours after dosing).

[0188] No AEs related to the analgesic Taphalgin were reported.

[0189] Example 6.

[0190] Patient N, aged 49 years, male.

[0191] Diagnosis: Cancer of right kidney, T4NOMI, St.IV. Moderate chronic pain.

[0192] The patient is being treated on an outpatient basis, he is able to take care of himself but cannot work.He spends more than 50% of his waking time ambulatory (50 to 60 points on the Karnofsky scale).

[0193] Prior to treatment according to the proposed mode of administration, the patient had uncontrolled pain (excluding breakthrough pain or pain from other causes not associated with persistent pain) despite treatment with weak opioid analgesics ± NSAIDs ± adjunctive therapy.

[0194] The proposed mode of administration for pain control was adopted using Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered once daily by subcutaneous injection in an individualized single dose of 4 mg for 83 days. Pain intensity was evaluated 1 to 1.5 hours before treatment, 1 to 1.5 hours after treatment, and 12 hours later.

[0195] During the first two days of treatment with Taphalgin, pain intensity was generally determined as an NRS score of 3 to 4 before dosing and as an NRS score of 0 to 2 after dosing (at 1 hour and 12 hours). From the third day onwards, pain intensity was generally determined as a score of 1 before dosing and as a score of 0 at 1 hour and 12 hours after dosing.

[0196] The patient's overall physical and mental state and his or her sleep improved.

[0197] No AEs related to Taphalgin were reported.

[0198] Example 7.

[0199] Patient N, aged 43 years, female.

[0200] Diagnosis: right breast cancer, T3NIMO, St.II B. Moderate chronic pain.

[0201] Patients are unable to perform heavy work but can perform light or sedentary work (eg, housework or office work) (70 to 80 on the Karnofsky scale).

[0202] Prior to treatment according to the proposed mode of administration, the patient had uncontrolled pain (excluding breakthrough pain or pain from other causes not associated with persistent pain) despite treatment with weak opioid analgesics ± NSAIDs ± adjunctive therapy.

[0203] The pain was treated with Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) according to the proposed mode of administration. Taphalgin was administered by subcutaneous injection one to three times a day in an individualized single dose of 4 mg for 83 days. The pain intensity was evaluated 1 to 1.5 hours before treatment, 1 to 1.5 hours after treatment, 4 hours and 12 hours.

[0204] During the first 3 days, NRS pain intensity was determined as a score of 1 before dosing and a score of 2 at 1 to 4 hours after dosing. During these three days, the product was administered twice daily.

[0205] On subsequent days, the product was administered once daily at 4 mg. The pain intensity score was generally 1 before dosing and 0 after dosing (at 1 hour and 12 hours after dosing). On individual days, the pain intensity score remained 0 throughout the day.

[0206] Reported AEs included mild numbness of the lower extremities, which was well tolerated by patients, did not interfere with daily activities and caused minimal discomfort. The causal relationship with Taphalgin was assessed as possible. This AE was self-limited and did not require treatment or Taphalgin dose adjustment.

[0207] Example 8.

[0208] Patient N, aged 67 years, female.

[0209] Diagnosis: left breast cancer урT1NΟMO, St.I. Moderate chronic pain.

[0210] The patient is being treated on an outpatient basis and is able to take care of herself but is unable to work. She spends more than 50% of her waking time ambulatory (50 to 60 points on the Karnofsky scale).

[0211] Prior to initiation of treatment according to the proposed mode of administration, the patient had uncontrolled pain (excluding breakthrough pain or pain from other causes not associated with persistent pain) despite treatment with weak opioid analgesics ± NSAIDs ± adjunctive therapy.

[0212] The pain was treated with Taphalgin solution for subcutaneous injection (a product based on the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2)) according to the proposed mode of administration. Taphalgin was administered by subcutaneous injection one to three times a day in an individualized single dose of 4 mg for 85 days. The pain intensity was evaluated 1 to 1.5 hours before treatment, 1 to 1.5 hours after treatment, 4 hours and 12 hours.

[0213] During the first 5 days, the product was administered at a dose of 4 mg three times daily at intervals of 6 to 8 hours. During the first 3 days, NRS pain intensity was determined as a score of 3 to 4 before dosing and a score of 0 to 1 at 1 hour and 4 hours after dosing. On days 4 and 5, pain intensity scores were generally 2 to 3 before dosing and 0 to 1 at 1 hour and 4 hours after dosing.

[0214] On subsequent days, the product was administered once daily at a dose of 4 mg. Pain intensity scores were generally equal to 1 before dosing, dropped to 0 after dosing, and remained at that level throughout the day.

[0215] Patients reported improvements in their physical and mental state.

[0216] No AEs related to Taphalgin were reported.

[0217] Example 9.

[0218] Patient N, aged 43 years, female.

[0219] Diagnosis: Uterine fibroids

[0220] Surgical interventions: hysteroscopy, mini-laparotomy, myomectomy, pelvic sanitation, active abdominal drainage.

[0221] Taphalgin was administered at 2 mg three times daily to control early postoperative pain.

[0222] During the first day, the NRS pain intensity score was initially equal to 6 before treatment, 6 at 30 minutes after administration, 5 at 1 hour after administration, 8 at 2 hours after administration, 5 at 4 hours after administration, and 3 at 6 hours after administration. Due to the pain intensity score of 8, the patient was additionally given 500 mg of acetaminophen. Subsequently, on days 1, 2, and 3, Taphalgin was the only product used for pain relief; the NRS pain intensity score was 4 to 5 before administration, decreased to 3 to 2 at 0.5 to 1 hour after administration, and decreased to 0 to 2 at 4 to 6 hours after administration.

[0223] No AEs were observed.

[0224] Example 10.

[0225] Patient N, 30 years old, female.

[0226] Diagnosis: Infertility; bilateral hydrosalpinx.

[0227] Surgical interventions: laparoscopy, bilateral salpingectomy, hysteroscopy, separate diagnostic curettage of the uterine cavity and endocervical canal.

[0228] Taphalgin was administered at 4 mg twice daily to control early postoperative pain.

[0229] During the first day, the NRS pain intensity score was initially equal to 4 before treatment with the product, 4 at 30 minutes after dosing, 3 at 1 hour after dosing, 3 at 2 hours after dosing, 6 at 4 hours after dosing, and 3 at 6 hours after dosing. Since the pain intensity score was 6 (at 4 hours after the first dose of Taphalgin), the patient was given 500 mg of acetaminophen in addition. Subsequently, on days 1 and 2, Taphalgin was the only product used for pain relief; the NRS pain intensity score was 4 to 3 before dosing, dropped to 3 to 2 at 1 hour after dosing, and remained at this level for 4 to 6 hours. On day 2, the pain intensity score was 2 before dosing, dropped to 0 after dosing, and remained at this level for 4 to 6 hours. No AEs were observed.

[0230] Example 11.

[0231] Patient N, 36 years old, female.

[0232] Diagnosis: Uterine fibroids

[0233] Surgical interventions: Microlaparoscopy, hysteroscopy. Myomectomy without uterine rupture. Pelvic cleansing.

[0234] Taphalgin was administered at 4 mg three times daily to control early postoperative pain.

[0235] During the first day, the NRS pain intensity score was initially equal to 4 before treatment with the product, 4 at 30 minutes after administration, 4 at 1 hour after administration, 5 at 2 hours after administration, 3 at 4 hours after administration, and 2 at 6 hours after administration. Due to the pain intensity score of 5 (at 2 hours after the first dose of Taphalgin), the patient was additionally given 500 mg of acetaminophen. Subsequently, on days 1, 2 and 3, Taphalgin was the only product used for pain relief; the pain intensity score was 2 to 1 before administration and was 1 for 6 hours after administration.

[0236] An AE in the form of an increased ESR was observed. This AE was mild, did not require specific treatment or adjustment of the dose of the drug, and resolved without sequelae during recovery. The causal relationship with Taphalgin was assessed as possible.

[0237] Example 12.

[0238] Patient N, 31 years old, male.

[0239] Diagnosis: right inguinal hernia.

[0240] Surgical intervention: Laparoscopic inguinal hernia repair with implant on the right side.

[0241] Taphalgin is administered at a dose of 4 mg three times daily for the treatment of early postoperative pain.

[0242] During the first day, the NRS pain intensity score was initially equal to 6 before treatment, 4 at 30 minutes after dosing, 2 at 1 hour after dosing, 1 at 2 hours after dosing, 0 at 4 hours after dosing, and 1 at 6 hours after dosing. Subsequently, on days 1 and 2, the NRS pain intensity score was 2 to 1 before dosing and 1 to 0 for 6 hours after dosing. On day 3, the pain intensity score was 1 before dosing, dropped to 0 after dosing, and remained at that level for 6 hours.

[0243] No AEs were observed.

[0244] Example 13.

[0245] Patient N, 51 years old, female.

[0246] Diagnosis: Urinary incontinence.

[0247] Surgical intervention: Cystoscopy. Mid-urethral sling urethropexy with Urosling synthetic sling.

[0248] Taphalgin is administered at 2 mg three times daily for the treatment of early postoperative pain.

[0249] During the first day, the NRS pain intensity score was initially equal to 3 before treatment, 2 at 30 minutes after dosing, 2 at 1 hour after dosing, 2 at 2 hours after dosing, 2 at 4 hours after dosing, and 3 at 6 hours after dosing. Subsequently on days 1, 2, and 3, the NRS pain intensity score was 2 to 1 before dosing and 1 to 0 for 6 hours after dosing.

[0250] No AEs were observed.

[0251] Example 14.

[0252] Patient N, aged 37 years, female.

[0253] Diagnosis: Asymptomatic cyst (dermoid) of the right ovary. Laboratory tests and magnetic resonance imaging ruled out malignancy.

[0254] Surgical intervention: laparoscopy, lysis of adhesions, right oophorectomy.

[0255] Taphalgin was administered at 2 mg three times daily to control early postoperative pain.

[0256] During the first day, the NRS pain intensity score was initially equal to 4 before treatment, 3 at 30 minutes after dosing, 1 at 1 hour after dosing, 1 at 2 hours after dosing, 0 at 4 hours after dosing, and 0 at 6 hours after dosing. Subsequently, on Days 1 and 2, the NRS pain intensity score was 1 before dosing and 0 for 6 hours after dosing.

[0257] No AEs were observed.

[0258] To draw an overall conclusion, we note that these studies provide evidence of the efficacy and safety of the claimed medicinal product for administration in pain treatment and its great potential for application in the early postoperative period after various surgical interventions and in long-term pain treatment in cancer patients.

[0259] Some of the most important features of the biological activity of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 and the drug Taphalgin based thereon include the absence of serious side effects, such as CNS disturbances, manifested as impaired consciousness and euphoria or effects on the respiratory center. Another positive feature is the wide therapeutic range without significant side effects. These features demonstrate the possible use of the claimed method for the control, treatment and prevention of pain in a wider range of therapeutic areas, including use outside the hospital (e.g. in the field or in home conditions) by appropriately qualified health practitioners or by the patients themselves, which is extremely important for the treatment of cancer pain and for the treatment of early postoperative pain after a variety of surgical interventions.

Claims

1. A pharmaceutical product for the treatment, control and / or prevention of pain, wherein the mode of administration of the pharmaceutical product comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 mg to 7 mg at a dosing interval of 4 hours or longer, with the daily dose not exceeding 42 mg.

2. The pharmaceutical product for use according to claim 1, wherein the mode of administration comprises administration of the tetrapeptide for pain relief in cancer patients or in the early postoperative period after various surgical interventions.

3. A pharmaceutical product for use according to claims 1 to 2, wherein the mode of administration comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in the form of a solution for subcutaneous injection.

4. A pharmaceutical product for use according to claims 1 to 3, wherein the mode of administration comprises administering the tetrapeptide while monitoring the severity of pain and / or the patient's response to the tetrapeptide, and increasing or decreasing the single dose and / or the number of daily doses and / or the dosing interval and / or the duration of the treatment course as required.

5. The pharmaceutical product for use according to claims 1 to 4, provided that the pharmaceutical product is for administration in the treatment of pain, wherein the mode of administration comprises injection of the tetrapeptide daily or at intervals of one to several days depending on the severity of the pain.

6. The medicinal product for use according to claims 1 to 5, provided that the medicinal product is intended for administration in the treatment of pain, wherein the mode of administration comprises a duration of a pain treatment course of up to 96 days, which can be repeated several times.

7. A pharmaceutical product for use according to claims 1 to 6, provided that the pharmaceutical product is for administration in the treatment of pain, wherein the mode of administration includes determining the total duration of pain treatment by the patient's condition; wherein in cancer patients, the duration of a single course of pain treatment is preferably up to 96 days or longer, and the course can be repeated multiple times; wherein repetition of the course is recommended after a pause of at least 2 to 5 days between courses, wherein the number of repeated courses is determined by the patient's condition.

8. The pharmaceutical product for use according to claims 1 to 7, provided that the pharmaceutical product is intended for administration in the treatment of pain, wherein the mode of administration includes determining the total duration of treatment by the patient's condition; wherein in patients with pain in the early postoperative period after various surgical interventions, the duration of pain treatment is 1 to 10 days.

9. Pharmaceutical product for use according to claims 1 to 8, wherein the mode of administration comprises the use of a single dose of 4 to 7 mg of the tetrapeptide.

10. A pharmaceutical product for use according to claims 1 to 9, wherein the mode of administration comprises a suggested starting single dose of the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) of 4 mg.

11. Pharmaceutical product for use according to claims 1 to 10, wherein the administration mode comprises increasing or decreasing the dose as required by increasing or decreasing the single dose by 25% to 50% relative to the previous value.

12. Pharmaceutical product for use according to claims 1 to 11, wherein the mode of administration comprises administering the tetrapeptide 2 to 3 times daily at a dose of 4 mg.

13. The pharmaceutical product for use according to claims 1 to 4 and 9 to 12, provided that the pharmaceutical product is intended for administration to humans for the prevention of pain, wherein the mode of administration comprises the administration of the tetrapeptide when there is a risk of pain onset in cancer patients or in the early postoperative period after various surgical interventions.

14. A pharmaceutical product for use according to any one of claims 1 to 13, comprising the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) and excipients: sodium chloride, mannitol, glycine, sodium acetate trihydrate, acetic acid, and water in the following component ratios, in wt %:

15. The pharmaceutical product for use according to claim 14, characterized in that The following component ratios are in wt%:

16. The pharmaceutical product for use according to claim 14, characterized in that The following component ratios, in mg:

17. The pharmaceutical product for use according to claim 16, characterized in that The following component ratios, in mg:

18. The pharmaceutical product for use according to claims 14 to 17, which is a solution dosage form for subcutaneous injection or is prepared as a solution dosage form for subcutaneous injection.

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