Pharmaceutical products for use in the treatment, management and / or prevention of pain

Abstract

The proposed group of inventions relates to the medical field, in particular to methods for the treatment, management, and prevention of pain using the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2), and to pharmaceuticals based on this tetrapeptide. These can be used to treat acute or chronic pain, particularly in cancer patients and in the early postoperative period after various surgical procedures. A method for the treatment, management, and prevention of pain is proposed, which involves administering H-Tyr-D-Arg-Phe-Gly-NH2 in a single dose of 2 to 7 mg, not exceeding 42 mg per day, with at least 4 hours between doses, for a maximum pain treatment course of 96 days, with the possibility of repeating the course multiple times.

Description

[Technical Field]

[0001] The proposed group of inventions relates to the field of medicine, in particular to the treatment, management and prevention of pain using the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Specifically, this tetrapeptide-based medicine can be used in acute or chronic pain, especially in cancer patients and in the early postoperative period after various surgical procedures. [Background technology]

[0002] Acute and chronic pain is one of the most unbearable and psychologically burdensome symptoms of diseases, including cancer, and in the early postoperative period after various surgical procedures. The high prevalence of pain necessitates the continuous search and selection of new treatments for its prevention or relief.

[0003] The current spectrum of pharmacological analgesics includes various drug groups, such as opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), combination preparations, corticosteroids, and anticonvulsants. However, the search for new analgesics and their application-based treatments remains a significant challenge. Existing analgesics have many significant drawbacks. Opioid drugs are known to pose a high risk of drug dependence in chronic pain patients and to be associated with a wide range of adverse effects (AEs), including nausea, drowsiness, cognitive impairment, fatigue, balance impairment (increased risk of falls), and immunosuppression. Unlike opioid drugs, other medications, such as NSAIDs, corticosteroids, and anticonvulsants, do not pose a high risk of drug dependence or adverse effects, but their analgesic effects are not always sufficient, especially in cancer patients.

[0004] The development of peptide-based analgesics is a particularly attractive field in the search for new methods for the treatment, prevention, and management of pain. In particular, the high analgesic activity of the tetrapeptides H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-Sar-OH has been reported in many publications (Patent JPS58213743(A), published December 12, 1983, and Patent JPS6054400(A), published March 28, 1985).

[0005] As a prototype of the present invention, a method for the prevention and / or treatment of acute or chronic pain was selected, which comprises administering the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH in a dose of 0.5 to 10 mg / dose (patent RU 2622980).

[0006] The prototype method allows for a broad single-dose range of 0.5 to 10 mg per dose. According to the patent's full description, this range was determined "based on extrapolation to humans" of the results of a study on the effects of the tetrapeptides H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH on the behavioral responses of animals (Example 8 of Patent RU 2622980). However, no large-scale clinical trials have been conducted. Example 9 of Patent RU 2622980 details the administration of these tetrapeptides to only six patients. Furthermore, "The prototype drug was used when the patient was eligible for treatment with a morphine-based analgesic, according to the WHO system, but for some reason, the drug was unavailable. When regular morphine preparations became available, treatment with the experimental prototype drug was discontinued." Of the six patients, five had stage IV cancers at different sites (pancreatic, colon, and breast cancer), and one had a spinal fracture. Preparations 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 at a dose of 0.7-3 mg twice daily (usually for 4-5 days when morphine was unavailable). According to the description in patent RU 2622980, the analgesic effect appeared 10-15 minutes after administration and lasted for 4-10 hours.

[0007] In the prototype method, the therapeutic range of the tetrapeptide was selected based on "human extrapolation" and no large-scale clinical trials have been conducted, leaving doubts about the safety and efficacy of the proposed single-dose range (0.5-10 mg / dose). There is a lack of adequate evidence for the efficacy of the lowest dose (0.5 mg) in the specified range, the safety of the highest dose (10 mg), and the specific doses used clinically in six patients (0.7 mg, 1 mg, 1.5 mg, and 3 mg). The prototype method also lacks information about the maximum daily dose of the tetrapeptide. Furthermore, there is no information about the maximum duration of use of the prototype method for analgesia. (As mentioned above, the clinical trial of the prototype method included only six patients and detailed only a short period of drug use when the prescribed morphine for these patients was unavailable for some reason.) Furthermore, the specific examples of drug use do not 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, so it cannot be said with certainty that clinical efficacy has been confirmed specifically for the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2.

[0008] As a result, there is an increasing need to develop optimal doses, administration regimens and treatment courses of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 based on large-scale clinical trials to improve the efficacy and safety of analgesia using this tetrapeptide.

[0009] Also of importance is the development of pharmaceuticals based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 for use as medicines for the treatment and / or prevention and / or management of pain.

[0010] The prototype patent RU 2622980 describes a means for the treatment and / or prevention of pain based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH, in particular an injectable preparation prepared in the form of a solution. Claims 12 and 15 describe the composition of the solution, which contains certain additives in specific ratios.

[0011] Original claim 12 recites a pharmaceutical composition containing the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or H-Tyr-D-Arg-Phe-Sar-OH and additives such as buffers, fillers, stabilizers, and solvents, specifying possible ranges of content for each component. However, these component content ranges are not fully supported by specific examples in the patent's complete description. Specifically, while the claim specifies a tetrapeptide content range of 0.01-0.5 wt%, the examples only list compositions containing 0.15 wt% tetrapeptide. Furthermore, the patent description lacks information on compositions with tetrapeptide contents (mg) other than 1.5 mg (all liquid injectable compositions listed in the examples contained 1.5 mg tetrapeptide). Therefore, the development of pharmaceutical agents for use in the treatment, management, and / or prevention of pain remains a significant need. Summary of the Invention [Problem to be solved by the invention]

[0012] The aim of the present invention is to improve the efficacy and safety of medicines for the treatment and / or prevention and / or management of pain, particularly in cancer patients and in the early postoperative period after various surgical procedures, by developing optimal doses, administration regimens and treatment courses of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2. [Means for solving the problem]

[0013] This object is solved by a medicinal product for use in the treatment, management and / or prevention of pain according to any one of claims 1, 12 or 20. Advantageous modifications and developments are detailed in the dependent claims. DETAILED DESCRIPTION OF THE INVENTION

[0014] "The administration pattern includes the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide The phrase "includes 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 a dosing pattern.

[0015] In one aspect of the present invention, this object is achieved by a pharmaceutical for use in the treatment of pain, wherein the administration pattern of the pharmaceutical comprises administering the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 to 7 mg, not exceeding a daily dose of 42 mg, with an interval of at least 4 hours between doses. The duration of the pain treatment course is preferably up to 96 days, and the course can be repeated multiple times.

[0016] This medicine has the following individual aspects: Preferably, the medicament is a medical product for use in the treatment, management and / or prevention of pain in humans. In preferred embodiments, administration patterns include administration for the relief of pain in cancer patients and in the early post-operative period following various surgical procedures.

[0017] Preferably, the administration pattern includes administering the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in the form of a subcutaneous injection solution.

[0018] In a preferred embodiment, the administration pattern includes increasing or decreasing the single dose and / or the number of doses per day and / or the interval between doses and / or the duration of the treatment course as needed while monitoring the severity of the pain and / or the patient's response to the tetrapeptide, i.e., the single dose and / or the number of doses per day and / or the interval between doses and / or the duration of the treatment course are increased or decreased as needed depending on the severity of the pain and / or the patient's response to the tetrapeptide.

[0019] Preferably, the administration pattern involves daily injections of the tetrapeptide or injections every one to several days, depending on the severity of the pain.

[0020] In a preferred embodiment, the administration pattern includes determining the total duration of pain treatment based on the patient's condition. In cancer patients, the duration of a single pain treatment course can be up to 96 days or more, and the course can be repeated multiple times. It is recommended that repeated courses be performed with a break of at least 2 to 5 days between courses, and the number of repeated courses is determined by the patient's condition.

[0021] Preferably, the administration pattern includes determining the total duration of treatment depending on the patient's condition. In patients with pain in the early postoperative period after various surgical procedures, the duration of pain treatment is preferably 1 to 10 days.

[0022] In a preferred embodiment, the administration pattern involves using a single 4-7 mg dose of the tetrapeptide.

[0023] In a preferred embodiment, the dosing pattern includes a 4 mg recommended starting single dose of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). The inventors have demonstrated that optimal compositions for the manufacture of pharmaceutical products based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 contain the tetrapeptide at levels far exceeding the 0.15 wt% (or 1.5 mg) set forth in RU 2622980. This is because, as shown below, a 4 mg recommended starting dose of the tetrapeptide is advantageous.

[0024] Preferably, the dosing pattern includes increasing or decreasing a single dose by 25-50% relative to the previous value as needed.

[0025] In a preferred embodiment, the dosing pattern involves administering 4 mg of the tetrapeptide two to three times daily. The inventors have demonstrated that optimal compositions for the manufacture of pharmaceuticals based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 contain the tetrapeptide at levels far exceeding the 0.15 wt% (or 1.5 mg) disclosed in RU 2622980. As shown below, an optimal course for the treatment, management, and / or prevention of pain is advantageously achieved by administering 4 mg of the tetrapeptide two to three times daily.

[0026] This object is also achieved by proposing a medicament for use in pain management, wherein the administration pattern comprises administering the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 to 7 mg, not exceeding a daily dose of 42 mg, with an interval of at least 4 hours between doses. Specific aspects of this medicament are as described above or in the dependent claims for the treatment of pain, respectively.

[0027] This object is also achieved by proposing a medicament for use in the prevention of pain attacks, wherein the administration pattern comprises administering the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 to 7 mg, not exceeding a daily dose of 42 mg, with an interval of at least 4 hours between doses. Specific aspects of this medicament are as described above or in the dependent claims for the treatment of pain, respectively.

[0028] In a preferred embodiment, the pharmaceutical product comprises the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) and the additives sodium chloride, mannitol, glycine, sodium acetate trihydrate, acetic acid and water in the following proportions (by weight): Tetrapeptide 0.380~0.420 Sodium chloride 0.475~0.525 Mannitol 0.475~0.525 Glycine 0.475~0.525 Sodium acetate trihydrate 0.0380~0.0420 Acetic acid until pH reaches 4.0-6.0 Water until it reaches 100.

[0029] The proposed medicinal product is characterized by the following preferred embodiments: Preferably, the pharmaceutical product is characterized by the following proportions of ingredients (wt%): Tetrapeptide 0.40 Sodium chloride 0.50 Mannitol 0.50 Glycine 0.50 Sodium acetate trihydrate 0.04 Acetic acid until pH reaches 4.0-6.0 Water until it reaches 100.

[0030] Preferably, the medicament is characterized by the following proportions of ingredients (mg): Tetrapeptide 3.8~4.2 Sodium chloride 4.75~5.25 Mannitol 4.75~5.25 Glycine 4.75~5.25 Sodium acetate trihydrate 0.38~0.42 Acetic acid until pH reaches 4.0-6.0 water until it reaches 1 mL.

[0031] Preferably, the medicament is characterized by the following proportions of ingredients (mg): Tetrapeptide 4.00 Sodium chloride 5.00 Mannitol 5.00 Glycine 5.00 Sodium acetate trihydrate 0.40 Acetic acid until pH reaches 4.0-6.0 water until it reaches 1 mL.

[0032] Preferably, the medicament is prepared or provided in the form of a solution for subcutaneous injection.

[0033] Unless otherwise specified, all technical and scientific terms used herein have meanings generally accepted among experts in the fields relevant to the invention. For terms with multiple definitions, the definitions set forth in this application apply. When a URL or similar address or identifier is cited as a reference, the specific identifier may obviously change, and specific information on the Internet may or may not be displayed, but equivalent information may be found online using a search engine. Reference to specific information is intended to indicate that this information is available and disseminateable. The foregoing brief description and the following detailed description of the invention are provided for reference purposes only and are not intended to limit the claimed subject matter in any way. The use of "comprises," "including," and their equivalents should not be construed as restrictive or limiting in any way. It should be noted that the methods and compositions described in this invention are not limited to the specific methodology, protocols, constructs, and reagents described herein, which may vary. It should also be noted that the terminology used herein is used only to describe specific embodiments of the invention and does not limit the scope of the described methods and compositions, which are limited only by the scope of the appended claims.

[0034] Clinical trials were conducted in which the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) was administered to patients via subcutaneous injection in a finished drug product called Taphalgin.

[0035] The tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) is a highly specific μ1 opioid receptor agonist that exhibits minimal interaction with other opioid receptors (its interaction with the δ receptor is three 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 are recognized: activation of the μ1 receptor causes significant analgesia, while activation of the μ2 receptor causes respiratory depression, cardiovascular disturbances such as bradycardia, and inhibition of intestinal motility. Therefore, the high specificity of this tetrapeptide for the μ1 opioid receptor ensures the absence of side effects typical of most opioid narcotic drugs. This tetrapeptide interacts with both peripheral and central receptors, but acts primarily at the spinal cord level. After the tetrapeptide binds to the μ1 receptor, a G protein complex is released, inhibiting neurotransmitter release by the cell. This reduces the amount of cAMP produced, closes calcium channels, and opens potassium channels, resulting in the inhibition of pain signal transmission in nociceptors. The tetrapeptide activates the antinociceptive system, thereby interfering with the interneuronal transmission of pain signals at different levels of the CNS and acting on higher brain centers to alter the intensity of pain perception.

[0036] Taphalgin is a subcutaneous injection solution containing the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) as the active ingredient and sodium acetate trihydrate, sodium chloride, mannitol, glycine, and water as excipients in the following proportions:

[0037] Tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide: 0.4 wt% Sodium acetate trihydrate: 0.04 wt% Sodium chloride: 0.5 wt% Mannitol: 0.5 wt% Glycine: 0.5 wt% Water: up to 100 wt% The content of each component may vary within a range of 15 to 20% of the above respective values.

[0038] Taphalgin 4 mg / mL was used.

[0039] To prepare Taphalgin, the excipients are dissolved in water, then the peptide is dissolved in the resulting solution, and the solution is sterilized, filtered and filled into ampoules or syringes.

[0040] An initial Phase I clinical trial was conducted in 39 healthy male volunteers to evaluate the safety, tolerability, and pharmacokinetics of Taphalgin. The study was conducted in dose-escalating cohorts (0.05 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg) with subsequent cohorts. Taphalgin was administered by subcutaneous injection only once, starting with the lowest dose cohort. Each participant received only one dose. Dose escalation for subsequent cohorts was performed only after comprehensive evaluation of data regarding AEs / serious AEs (SAEs), vital signs, electrocardiogram results, physical examination results and laboratory data, and the occurrence of dose-limiting toxicities (DLTs). If a DLT was identified in one subject in any cohort, the number of volunteers had to be increased by three. If none of the volunteers receiving Taphalgin in the expansion cohort developed dose-limiting toxicity (i.e., one DLT was observed in one of six), dose escalation in the next cohort could be continued. To assess the pharmacokinetics of Taphalgin, 22 blood samples were collected from each volunteer (pre-dose (0 h), 10, 20, 30, 45 min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 96, 120 h post-dose). The following parameters were calculated: area under the curve (AUC) during the follow-up period; 0-t ), area under the curve from dose to infinity (AUC 0-∞ ), maximum concentration (C max ), time to reach maximum concentration (Tmax ), half-life (T 1 / 2 ), mean residence time in plasma (MRT), elimination rate constant (K el ) and volume of distribution (V d ). Plasma concentrations of Taphalgin were measured by high-performance liquid chromatography / tandem mass spectrometry (HPLC-MS / MS) using a Triple Quad 4500 system (AB Sciex)

[49] . Clinical and biochemical blood tests were also performed, and coagulation parameters were investigated during the final phase of the study. The total study period for each volunteer did not exceed 14 days. This study demonstrated good safety and tolerability of 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) when administered once to healthy volunteers. The highest dose achieved by dose escalation was 7 mg, and no cases of dose-limiting toxicity were recorded (AE severity grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE)). Investigators' assessment described Taphalgin as "good" or "excellent" in all patients. The most frequently reported AEs during the study (>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 most fully recovered.

[0041] The time to reach maximum drug concentration after subcutaneous injection averaged 30 minutes, indicating rapid absorption from subcutaneous adipose tissue. After a single dose, Taphalgin was actively distributed not only to the bloodstream but also to peripheral tissues, with a distribution volume (average 24-39 L) far exceeding the circulating blood volume. Distribution was followed by a relatively rapid elimination phase: the drug's half-life was 1.3-2.5 hours, and therefore it was completely eliminated from the systemic circulation in approximately 15 hours.

[0042] In general, similar clearance values ​​are typical for therapeutic polypeptides, of which Taphalgin is a representative. The mean residence time of a single drug molecule in the human body was 3.03 ± 0.42 hours.

[0043] A phase II clinical trial evaluated the efficacy and safety of various doses of Taphalgin in cancer patients experiencing pain. Furthermore, the optimal dosing schedule was selected, and pharmacokinetic parameters were evaluated during multiple doses. Pain intensity was assessed using a 0-10 numerical rating scale (NRS). The study included male and female patients aged 18-70 years who had a documented cancer diagnosis, severe cancer pain managed with morphine at enrollment (NRS pain intensity score <3 at screening, maximum daily dose of 60 mg intramuscular morphine, and stable morphine therapy for at least 7 days prior to screening), and a life expectancy of at least 1 month. Patients received no analgesics other than those specified in the protocol. Patients' physical activity scores ranged from 0 to 3 on the Eastern Cooperative Oncology Group (ECOG) performance status scale, meaning they were either active and spent ≥50% of their waking hours awake (ECOG grade 2) or were only able to provide limited self-care and spent ≥50% of their waking hours in bed or a chair (ECOG grade 3). The study was conducted in two phases. The total duration of each patient's study was ≤20 days. In the first phase (duration: 10 days), the dose of Taphalgin was selected: each participant received a randomized single initial dose (2, 3, 4, 5, 6, or 7 mg) of the drug, which was subsequently titrated according to established procedures. The number of doses depended on the individual patient's pain intensity as assessed by the NRS scale. A parallel-group design with different starting doses in each group was selected because a phase I clinical trial demonstrated an acceptable safety profile for various Taphalgin doses. In the second phase, patients received Taphalgin (a subcutaneous solution in a personalized dose selected in the first phase; maximum single dose = 7 mg, maximum daily dose = 42 mg) or the comparator drug morphine (an intramuscular solution in a personalized dose selected before the start of the first phase).

[0044] For breakthrough pain, morphine was to be used in the form of an injectable solution of 10 mg / 1 mL.

[0045] The comparator was selected based on its widespread use in this type of patient and on the results of preclinical studies of Taphalgin, which justified the hypothesis that its analgesic effect is comparable to morphine in strength. The primary efficacy endpoint was the proportion of patients achieving sufficient analgesia throughout the day. This efficacy was understood as the mandatory compliance of the following two criteria: achieving a daily average NRS pain intensity score of <3 and requiring no more than two morphine injections (10 mg intramuscularly) within 10 days to manage breakthrough pain. To confirm the analgesic effect of Taphalgin, the following secondary endpoints were additionally selected: · Trends in average daily NRS pain intensity scores (points); · Time-averaged NRS pain intensity score between the first and second administration at visit 10; · Trends in daily doses (mg) of add-on analgesics for managing breakthrough pain; Nighttime sleep quality on a 3-point Likert scale based on patient diary (duration of nighttime sleep uninterrupted by pain was scored as follows: 1 = good sleep quality (6-8 hours), 2 = moderate quality (4-6 hours), 3 = poor quality (less than 4 hours)); · Frequency of drug dose increases; · Incidence of need for treatment changes.

[0046] Patients were divided into six groups that received different initial doses of Taphalgin: 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 demographic characteristics (p > 0.05).

[0047] Phase 1 revealed statistically significant differences between mean daily NRS pain intensity scores in groups receiving Taphalgin at doses of 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), indicating a favorable trend in pain severity and a reduction in pain intensity associated with the study drug in these groups. Comparative analysis of mean daily NRS pain intensity scores on days 1-10 revealed no significant differences between study groups, and even the lowest single dose investigated of Taphalgin (2 mg) demonstrated sufficient efficacy, even when the mean daily dose on day 10 within the subgroup was 8.33 mg, compared with the mean starting dose of morphine in this subgroup of 18.33 mg.

[0048] In the second phase of the study, no significant differences were observed in NRS pain intensity scores between study days in the morphine group. Thus, the trend in pain sensation within the groups was flat (p = 0.88079). The trend in average daily NRS pain intensity scores in the Taphalgin group also remained flat, meaning that patients' pain sensation remained stable (p = 0.46607). Therefore, between-group comparisons showed that this product managed pain intensity similarly to morphine throughout the second phase (p > 0.05).

[0049] [Table 1]

[0050] Analysis of sleep quality showed improvement in patients treated with Taphalgin: by study days 9-10, sleep quality was fair in 76-79% and good in 20-23%.

[0051] All patients participating in Phase 1 of the study were receiving a personalized dose of morphine that ensured adequate pain relief at the start of the study. At baseline, the mean stable daily dose of this product across all Taphalgin dose subgroups was 20.31 mg; 14 patients (33.33%) were receiving 10 mg of morphine, 18 patients (42.86%) were receiving 20 mg, 6 patients (14.29%) were receiving a daily dose of 30 mg, 3 patients (7.14%) were receiving a daily dose of 40 mg, and 1 patient (2.38%) was receiving a dose of 60 mg. The Taphalgin dose was adjusted until a daily dose that ensured adequate pain relief was achieved during Phase 1. The mean daily dose of medication at Visit 10 was 8.25 mg in the pooled 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. As a result, we were able to compare personalized daily doses of morphine and Taphalgin for each patient evaluated in the study. Patients, on average, were receiving a stable dose of medication by Day 6 or Day 7 of the first phase of the study. The mean daily dose from Days 7 through 10 was included in the analysis and compared with each patient's predetermined morphine dose. In general, the mean daily dose of Taphalgin was one-third of the morphine dose for the same patients.

[0052] The survey results regarding adverse events (AEs) are shown in Table 2 below.

[0053] [Table 2]

[0054] In the second phase of the study, 30 SAEs were reported in 10 of 32 patients (31.25%). An analysis of the incidence of AEs during the second phase of the study in the Taphalgin and morphine groups is shown in Table 2. The safety profile was significantly better 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 in 1 patient. The incidence of AEs in the Taphalgin group was only 12.5%, with 3 AEs reported in 2 patients. Comparative analysis of AEs revealed a significant difference between the groups (p = 0.022). At the same time, no significant differences were observed between the groups regarding the severity of AEs, causal relationship to treatment, or outcome of AEs.

[0055] Furthermore, the trend of opioid-related conditions in patients switched from morphine to Taphalgin was evaluated, showing a decrease in the incidence of opioid-related conditions throughout the 10 days of dose titration: from 59.52% (25 / 42) at baseline to 14.29% (6 / 42) at the end of 10 days of Taphalgin treatment. Thus, Taphalgin, far from causing opioid-related AEs, contributed to reducing these AEs in patients receiving morphine.

[0056] These data demonstrate substantial clinical efficacy of Taphalgin. The use of this product allowed for the maintenance of adequate analgesia achieved with intramuscular morphine throughout the study. Data regarding dosing frequency indicate that the drug can control tumor-related pain for 8–12 hours, even at low doses (2–4 mg) with a favorable safety profile. However, to achieve adequate pain control, the Taphalgin dose must be selected on a case-by-case basis, as pain etiology, pain perception intensity, and pain severity vary among individuals. The clinically effective dose is 2 mg, but other doses up to 7 mg are well tolerated and not associated with dose-limiting toxicities. The maximum daily dose of Taphalgin should not exceed 42 mg. The drug should be administered at dosing intervals of at least 4 hours.

[0057] None of the patients receiving Taphalgin experienced sedation, which is associated with decreased alertness and concentration. Drowsiness, impaired memory and concentration are classic AEs associated with opioid use and have a significant impact on patients' quality of life and ability to work.

[0058] Another important factor is that Taphalgin, unlike opioid drugs, does not depress the respiratory center: none of the patients receiving this product showed shortness of breath, whereas shortness of breath was observed in the morphine group.

[0059] Therefore, these studies indicated that the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) should be administered for pain in a single dose of 2–7 mg, with a daily dose of no more than 42 mg, and with an interval of at least 4 hours between doses.

[0060] The recommended starting dose is 4 mg. The dose and frequency of administration are then individualized taking into account the severity of the pain and response to treatment. If the single dose needs to be increased, this should be done in steps of 25-50% of the previous dose level. If the dose level needs to be decreased (if a higher dose produces a better therapeutic effect or an AE occurs), this should also be done in steps of 25-50% of the previous dose.

[0061] These recommendations were then used in the next series of clinical trials (Phase III clinical trials).

[0062] Furthermore, a clinical trial was conducted on 180 men and women aged 18 to 80 years with cancer pain. The patients were divided into two groups: Patients in Group 1 (n = 120) received Taphalgin, a solution for subcutaneous administration, at individually selected doses throughout the study. Patients in Group 2 (n = 59) received an oral morphine formulation as a comparator for 28 days after the end of the dose selection period (Period 1). After that (Period 2), patients in this group were reassigned to Taphalgin subcutaneous solution, which they received at an individualized dose until the end of study participation.

[0063] For patients randomized to receive the study drug, the initial dose of Taphalgin subcutaneous injection solution was 4 mg. The single dose of the drug was increased or decreased in 2 mg increments as needed. The maximum single dose of Taphalgin was 7 mg. The maximum daily dose of Taphalgin was 42 mg. The duration of treatment with the study drug did not exceed 94 ± 2 days.

[0064] Primary efficacy assessments were performed at 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).

[0065] Efficacy endpoints: The following endpoints were used to evaluate treatment efficacy:

[0066] Primary endpoint: Maintenance rate of analgesic response up to 28 days. A treatment response was considered sustained if all of the following conditions were met: No more than two dose escalations of test / comparator drugs were required from the start of treatment through day 28 at the selected doses. Average daily pain intensity at the end of the 28-day treatment period remained less than 50% of the intensity at the start of titration.

[0067] Secondary endpoints: Proportion of patients requiring dose escalation from treatment initiation to Visits 2, 3, and 4 at the selected dose. Proportion of patients who did not respond to Taphalgin / morphine treatment by Visits 2, 3, and 4. Proportion of patients experiencing at least one breakthrough pain episode from the start of treatment through Visits 2, 3, and 4 at the selected dose. Trends in mean daily NRS pain intensity scores from treatment initiation to Visits 2, 3, and 4 at selected doses. Percentage of patients requiring concomitant analgesic therapy by visits 2, 3, and 4. Patient quality of life scores based on the SF-36 questionnaire. Investigator assessment of treatment effect through Visit 1 and Visit 2 at the end of the dose selection period. Patient evaluation of treatment effect through Visit 1 and Visit 2 at the end of the dose selection period. total number of adverse events (AEs) stratified by severity and frequency; rate of adverse drug reactions; Rate of serious adverse events (SAEs) associated with Taphalgin / morphine treatment; the proportion of patients who reported at least one AE; Proportion of patients who discontinued treatment due to AEs.

[0068] The retention rate of analgesic response through 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 analgesic response through 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 proportion was -0.0862 (8.62%), and the upper limit was 0.0643 (6.43%). Comparative analysis of the proportion of analgesic treatment response retention up to day 28 revealed no statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (one-sided Fisher's exact test, p =0.6783).

[0069] 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). A comparative analysis of the proportion of patients requiring a dose increase by visit 2 revealed no statistically significant difference between group 1 (Taphalgin) and group 2 (morphine) (Fisher's exact test, p =0.6809).

[0070] No patients in either Group 1 (Taphalgin) or Group 2 (morphine) had failed to respond to Taphalgin or morphine treatment by Visit 2. A comparative analysis of the proportion of patients who had failed to respond to Taphalgin / morphine treatment by Visit 2 revealed no statistically significant difference between Group 1 (Taphalgin) and Group 2 (morphine) (Pearson's chi-square test, p =1.0000).

[0071] No patients had failed to respond to Taphalgin treatment by Visit 3.

[0072] No patients had failed to respond to Taphalgin treatment by Visit 4.

[0073] The proportion of patients who experienced at least one breakthrough pain episode by visit 2 was 0.00% (0 / 97) in group 1 (Taphalgin) and 2.17% (1 / 46) in group 2 (morphine). A comparative analysis of the proportion of patients who experienced at least one breakthrough pain episode by visit 2 revealed no statistically significant difference between group 1 (Taphalgin) and group 2 (morphine) (Fisher's exact test, p =0.3217).

[0074] The proportion of patients who experienced at least one breakthrough pain episode by visits 3 and 4 despite treatment with Taphalgin was 1.40% (2 / 143).

[0075] The mean daily NRS pain intensity score (mean ± standard deviation) for the entire population was 0.38 ± 0.47 at the selected dose at baseline and 0.34 ± 0.40 at Visit 2. The mean daily NRS pain intensity score (mean ± standard deviation) for Group 1 (Taphalgin) was 0.42 ± 0.48 at the selected dose at baseline and 0.38 ± 0.44 at Visit 2. The mean daily NRS pain intensity score (mean ± standard deviation) for Group 2 (morphine) was 0.30 ± 0.47 at the selected dose at baseline and 0.28 ± 0.30 at Visit 2.

[0076] The mean daily NRS pain intensity score (mean ± standard deviation) for the entire subject population was 0.38 ± 0.46 at the start of treatment, 0.35 ± 0.54 at Visit 3, and 0.35 ± 0.65 at Visit 4 at the selected dose. Analysis showed no significant differences between visits (p = 0.0770) and a flat trend in mean daily NRS pain intensity scores with Taphalgin treatment up to Visits 3 and 4.

[0077] The mean SF-36 physical health score for the entire study population was 33.91 ± 11.39 at Visit 0 and 51.18 ± 11.50 at Visit 2. In Group 1 (Taphalgin), the mean SF-36 physical health score was 34.71 ± 11.64 at Visit 0 and 51.96 ± 11.36 at Visit 2. In Group 2 (morphine), the mean SF-36 physical health score was 32.22 ± 10.76 at Visit 0 and 49.52 ± 11.73 at Visit 2.

[0078] The mean SF-36 mental health score for the entire study population was 34.84 ± 13.12 at Visit 0 and 48.13 ± 10.22 at Visit 2. In Group 1 (Taphalgin), the mean SF-36 mental health score was 36.46 ± 13.30 at Visit 0 and 49.06 ± 9.71 at Visit 2. In Group 2 (morphine), the mean SF-36 mental health score was 31.42 ± 12.16 at Visit 0 and 31.42 ± 12.16 at Visit 2.

[0079] At Visit 2 in Group 1 (Taphalgin), the percentage of patients with an "excellent response" to treatment was 55.67% (54 / 97), a "good response" was 41.24% (40 / 97), and a "satisfactory response" was 3.09% (3 / 97). At Visit 2 in Group 2 (morphine), the percentage of patients with an "excellent response" to treatment was 32.61% (15 / 46), a "good response" was 67.39% (31 / 46), and a "satisfactory response" was 0.00% (0 / 46). Comparative analysis of the proportion of patients with investigator-assessed treatment effect scores at Visit 2 revealed a statistically significant difference between the study groups (Pearson's chi-square test, p = 0.0103).

[0080] The study included the following safety evaluation phases: dose selection; Period 1, the comparative phase of the study (28 ± 2 days from the start of treatment at the selected dose); and Period 2, the non-comparative phase of the study (56 ± 2 days after Period 1).

[0081] The incidence of patients with AEs reported during Period 1 in Group 1 (Taphalgin) was 34.17% (41 / 120): a total of 95 AEs were reported in 41 patients. The incidence of patients with AEs reported during Period 1 in Group 2 (morphine) was 71.19% (42 / 59): a total of 119 AEs were reported in 42 patients. A comparative analysis of AEs in patients in Groups 1 and 2 during Period 1 revealed a significant difference between the study groups (Pearson's chi-square test, p <0.00001).

[0082] During period 1, AEs reported in patients in group 1 were mild in 66.32% (63 / 95) of cases and moderate in 33.68% (32 / 95) of cases; in patients in group 2, AEs were mild in 65.55% (78 / 119) of cases, moderate in 33.61% (40 / 119) of cases, and severe in 0.84% ​​(1 / 119) of cases. Comparative analysis revealed no significant difference in AE severity between groups 1 and 2 (p = 0.6693).

[0083] Based on investigator assessment, the causal relationship between AEs and treatment in period 1 was determined in group 1 as definite in 1.05% (1 / 95) of cases, probably related in 3.16% (3 / 95), possibly related in 44.21% (42 / 95), unlikely related in 13.68% (13 / 95), conditional in 12.63% (12 / 95), unclassifiable in 1.05% (1 / 95), and unclassifiable in 24.21% (23 / 95). in group 2, 13.44% (16 / 119) of cases were assessed as definite, 29.41% (35 / 119) as probably related, 38.66% (46 / 119) as possibly related, 11.76% (14 / 119) as unlikely related, 0.84% ​​(1 / 119) as conditional, 0.84% ​​(1 / 119) as unclassifiable, and 5.04% (6 / 119) as unrelated. Comparative analysis of the causal relationship between AEs and treatment in groups 1 and 2 in period 1 revealed significant differences between the study groups (Pearson's chi-square test, p < 0.00001).

[0084] To further evaluate the differences between Groups 1 and 2, AEs were analyzed comprehensively within the groups. This evaluation showed that the incidence of patients with reported AEs was lower in Group 1 receiving Taphalgin (36.69% (44 / 120)) than in Group 2 receiving morphine (72.88% (43 / 59)). Furthermore, the number of cases in which investigators reported a causal relationship between the AE and treatment as "definitely," "probably related," or "possibly" was higher in the morphine group: 46 AEs in the Taphalgin group vs. 97 AEs in the morphine group; furthermore, there were no treatment discontinuations due to AEs in Group 1 receiving Taphalgin during Period 1.

[0085] The incidence of patients with AEs and / or SAEs reported during Period 2 was 12.74% (20 / 157). A total of 35 AEs and / or SAEs were reported in 20 patients during Period 2. The incidence of patients with AEs reported during Period 2 was 7.64% (12 / 157). A total of 24 AEs were reported in 12 patients during Period 2. AEs reported during Period 2 were mild in 54.17% (13 / 24) of cases and moderate in 45.83% (11 / 24) of cases. Based on investigator assessment, the causal relationship between AEs reported during Period 2 and the study drug Taphalgin was assessed as 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 / 24). Analysis of AE outcome frequency showed that by the end of Period 2, recovery without sequelae was observed in 83.33% (20 / 24) of cases, and improvement was observed in 16.67% (4 / 24) of cases.

[0086] Overall, the safety assessment showed that the incidence of patients with reported adverse events was lower in the Taphalgin group (36.69% (44 / 120)) than in the morphine group (72.88% (43 / 59)). Furthermore, the number of cases in which investigators reported a causal relationship between the adverse event and treatment as "definitely," "probably related," or "possibly" was higher in the morphine group: 46 adverse events in the Taphalgin group and 97 adverse events in the morphine group.

[0087] Furthermore, additional clinical trials were conducted focusing on the treatment of pain in the early postoperative period after various surgical procedures (including urological, gynecological, and other surgeries). These studies included 100 patients divided into five groups (20 patients each); three groups received Taphalgin at various doses (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).

[0088] Treatment with Taphalgin (or comparator Promedol) was initiated if the NRS pain intensity score was ≥4 on postoperative day 1. If the NRS pain intensity score was ≥4 on postoperative day 2, Taphalgin was administered at the same dose and at the same dosing interval, but the daily dosing schedule could be adjusted as needed (usually reducing the number of doses once pain control was established). If the NRS pain intensity score was ≤4 on postoperative day 2, paracetamol alone was administered intravenously as needed, with a maximum daily dose of 4 mg. The total duration of treatment did not exceed 8 days. Pain in the early postoperative period was usually controlled within 1–2 days.

[0089] The percentage of patients achieving greater than 50% pain relief 1 hour after the initial dose was 65.0% in the group treated with Taphalgin 4 mg twice daily, 55.0% with Taphalgin 2 mg three times daily, 80.0% with Taphalgin 4 mg three times daily, and 50% with Promedol 20 mg three times daily.

[0090] The mean daily NRS pain intensity scores were 2.35 ± 0.70 points in the group treated with Taphalgin 2 mg tid, 2.51 ± 0.84 in the group treated with Taphalgin 4 mg bid, 2.14 ± 0.94 in the group treated with Taphalgin 4 mg tid, and 2.16 ± 0.66 in the group treated with Promedol 20 mg tid. On day 2, the scores were 1.45 ± 2.06 in the group treated with Taphalgin 2 mg tid, 1.48 ± 1.83 in the group treated with Taphalgin 4 mg bid, 0.92 ± 1.77 in the group treated with Taphalgin 4 mg tid, and 1.41 ± 1.92 in the group treated with Promedol 20 mg tid. The mean change in pain intensity was 60.0 ± 25.45% with Taphalgin 2 mg three times a day, 57.56 ± 21.12% with Taphalgin 4 mg twice a day, 67.21 ± 20.11% with Taphalgin 4 mg three times a day, and 55.44 ± 33.17% with Promedol 20 mg three times a day.

[0091] Of patients receiving Taphalgin 2 mg three times daily on day 1 who required repeat dosing on day 2, 16.67% received three doses, 66.67% received one dose, and 16.67% received two doses.

[0092] Of patients receiving Taphalgin 4 mg twice daily on day 1 who required repeat dosing on day 2, 50.00% received two doses and 50.00% received one dose.

[0093] Of patients receiving Taphalgin 4 mg three times daily on day 1 who required repeat dosing on day 2, 11.11% received three doses and 89.89% received two doses.

[0094] Of patients in the group receiving Promedol 20 mg three times daily on day 1 who required repeat dosing on day 2, 16.67% received three doses and 83.33% received two doses.

[0095] 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 Promedol-treated group, 15% of patients treated with Taphalgin 2 mg three times daily, 10% of patients treated with Taphalgin 4 mg twice daily, and 20% of patients treated with Taphalgin 4 mg three times daily. Based on investigator assessment, the causal relationship between the AEs and the study drug or comparator was assessed as definite in 73.53%, probably related in 5.88%, possibly related in 11.76%, unlikely related in 5.88%, and not established related in 2.94%.

[0096] The proposed pharmaceutical product for use in human administration is embodied as follows: Pain management and / or treatment and / or prevention is achieved using a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). In a particular embodiment, it is Taphalgin, which is a subcutaneous injection solution containing the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) (4 mg / mL) as the active ingredient and sodium acetate trihydrate, sodium chloride, mannitol, glycine, and water as excipients in the following proportions: Tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide: 0.4 wt% Sodium acetate trihydrate: 0.04 wt% Sodium chloride: 0.04 wt% Mannitol: 0.04 wt% Glycine: 0.04 wt% Water: up to 100 wt% The content of the components can vary within the range of 15-20% of the respective values ​​mentioned above.

[0097] This product is administered to patients as a single dose of 2-7 mg 1-6 times daily, with a maximum daily dose of 42 mg, at least 4 hours between doses. The recommended starting dose is 4 mg. The specific dose is selected on a case-by-case basis depending on the severity of pain, the achievement of an analgesic effect after administration, and the presence or absence of post-administration adverse events (AEs). Dose selection is typically performed during the first few days of treatment, and pain severity is then monitored during treatment, with the dose and number of daily doses adjusted as needed. As previously mentioned, the recommended starting dose of this product is 4 mg. The recommended optimal dosing regimen is 4 mg 2-3 times daily. If a single dose needs to be increased, this should be done in steps of 25-50% of the previous dose. If a dose needs to be decreased, this should also be done in steps of 25-50% of the previous dose.

[0098] Taphalgin can be used for long-term therapy; the duration of treatment is usually decided by your doctor.

[0099] Treatment courses in cancer patients in Phase III clinical trials lasted up to 96 days. In Phase III clinical trials in patients with early postoperative pain after various surgical procedures, treatment typically lasted 1 to 10 days.

[0100] When the product is used to treat chronic pain, it is preferably administered at regular intervals according to a fixed schedule.

[0101] In the case of long-term use, the need to extend drug therapy should be periodically assessed (e.g., by briefly interrupting treatment) and the dosage reviewed. Thus, multiple courses of up to 96 days of treatment can be repeated, with at least 2-5 days between courses.

[0102] The tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2) can be used to prevent pain attacks in the setting of chronic pain. This is especially important for cancer patients. In such cases, the product is administered according to a fixed schedule, not only during severe pain episodes, but also to prevent pain attacks.

[0103] Proposed pharmaceutical agents and their administration patterns for use in the treatment, management and / or prevention of pain are illustrated by the following examples.

[0104] Example 1 Patient N, 65 years old, male.

[0105] Diagnosis: Left retroperitoneal sarcoma, T2N1M1 Stage IV; metastases to peritoneum and bone. Chronic severe pain.

[0106] The patient is receiving outpatient treatment, is able to self-care but is unable to work, and spends more than 50% of his waking hours awake (Karnofsky scale score of 50-60).

[0107] Prior to the proposed course of treatment, pain was managed with 20 mg of morphine daily, which was associated with opioid-related AEs, including dizziness, sleep disturbances, sedation, weakness, and constipation.

[0108] According to the proposed administration pattern, pain was treated with Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 3 mg twice daily, 12 hours apart (9:00 AM and 9:00 PM) for 14 days. Pain intensity was assessed 0.5-1.5 hours before treatment, immediately after treatment, 1 hour after treatment, and daily at 1:00 PM. NRS pain scores were usually estimated at 1-2 (rarely 3 or 0) before treatment and always decreased to 0 after treatment (pain intensity scores 1 hour after administration were usually 0; assessments at 1:00 PM were usually 0-1). Patients noted improvements in their physical and mental state and improved sleep.

[0109] Reported AEs were limited to two episodes of transient mild dizziness and two episodes of constipation. However, the relationship of the AEs to Taphalgin treatment was not assessed as clear. The AEs resolved spontaneously.

[0110] Example 2. Patient N, 64 years old, male.

[0111] Diagnosis: Middle third esophageal cancer, T4N0M1 Stage IV. Chronic severe pain.

[0112] The patient is receiving outpatient treatment, is able to self-care but is unable to work, and spends more than 50% of his waking hours awake (Karnofsky scale score of 50-60).

[0113] Prior to the proposed course of treatment, pain was managed with 20 mg of morphine daily, which was associated with opioid-related AEs, including sedation and constipation.

[0114] A proposed pain management administration pattern was employed using Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 4-6 mg twice daily at 12-hour intervals (9:00 AM and 9:00 PM) for 14 days. Pain intensity was assessed 0.5-1.5 hours before treatment, immediately after treatment, 1 hour after treatment, and daily at 1:00 PM. For the first 1.5 days, the drug was administered as a single 6 mg dose, followed by 4 mg. NRS pain intensity scores were estimated at 3 before treatment on day 1, 3 at 9:00 AM on day 2, and 2 at 9:00 PM on day 3. Pain intensity scores decreased to 0-1 after administration. For days 3-14, the product was administered at 4 mg twice daily. Pain intensity scores were usually 1 (rarely 2) before administration and decreased to 0 after administration. At the 1:00 pm assessment, pain intensity was also reported as 0 (rarely 1). Patients noted improvement in their physical and mental state and improved sleep.

[0115] AEs included isolated episodes of mild insomnia and dry mouth. However, the relationship between the AEs and Taphalgin treatment was not assessed as clear. The AEs resolved spontaneously.

[0116] Example 3. Patient N, 68 years old, male.

[0117] Diagnosis: Left retromolar malignant tumor, T3N1M1 stage 3. Keratinizing squamous cell carcinoma. Chronic pain (pain intensity score 2-3). Patients are unable to perform heavy physical work but are able to perform light or sedentary tasks (such as housework or office work) (Karnofsky scale score of 70-80).

[0118] Prior to the proposed course, morphine 30 mg daily was used for pain management, which was associated with opioid-related AEs, including sedation.

[0119] A proposed pain management dosing pattern was employed using Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 2–4 mg twice or three times daily at 6- or 12-hour intervals for 14 days. Pain intensity was assessed 0.5–1.5 hours before treatment, immediately after treatment, 1 hour after treatment, and daily at 1:00 PM. For the first 4 days, the product was administered at 4 mg twice daily. Before drug treatment, NRS pain intensity scores were typically 2–4 (rarely 5 or 1) and always decreased to 0–1 after administration. On days 5–6, the product was administered at 2 mg twice daily. Pain intensity was typically estimated at 1 before administration and 0 after administration. On day 7, the product was administered at 2 mg twice and 4 mg once; the dose was increased because the pain intensity score was 5. The pain intensity score after administration was 2. On days 8-14, the product was administered at 4 mg three times daily, 6-8 hours apart. The pain intensity score decreased from 2-4 to 0-2. The patient noted improved physical and mental state and improved sleep.

[0120] AEs observed included mild drowsiness, loss of appetite, and mild fever, but their relationship to Taphalgin treatment was assessed as unlikely.

[0121] Example 4. Patient N, 64 years old, male.

[0122] Diagnosis: Cancer of unknown primary site, metastases to subclavian, liver, retroperitoneal, inguinal, and bone lymph nodes. Chronic pain. Patient is on outpatient care and is able to care for himself but is unable to work. He spends more than 50% of his waking hours awake (Karnofsky scale score 50-60).

[0123] Prior to the course with the proposed dosing pattern, morphine 30 mg per day was being used for pain management.

[0124] According to the proposed administration pattern, pain was treated with Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 4–5 mg three times daily at 6- or 8-hour intervals for 14 days. Pain intensity was assessed 0.5–1.5 hours before treatment, immediately after treatment, 1 hour after treatment, and daily at 1:00 PM. For the first 2 days, the drug was administered as a single 4 mg dose, followed by 5 mg. NRS pain intensity scores were estimated at 2–4 before treatment on Day 1 and 3–4 on Day 2. The pain intensity score decreased to 2 after administration. For Days 3–14, the product was administered at 5 mg three times daily. Pain intensity scores were typically 1 before administration and decreased to 0 after administration. Patients noted improved physical and mental status and improved sleep.

[0125] AEs observed included isolated episodes of mild somnolence, mild dizziness, and mild fever. However, the relationship between the AEs and Taphalgin treatment was assessed as unlikely. The AEs resolved spontaneously.

[0126] Example 5. Patient N, 57 years old, female.

[0127] Diagnosis: Cervical cancer, pT2abNxM0, stage IIab. Chronic pain.

[0128] Patients are unable to perform heavy physical work but are able to perform light or sedentary tasks (such as housework or office work) (Karnofsky scale score of 70-80).

[0129] Before treatment with the proposed administration pattern was administered, pain was uncontrolled despite weak opioid analgesics ± NSAIDs ± adjunctive treatment (excluding pain due to other causes not related to breakthrough pain or persistent pain).

[0130] According to the proposed administration pattern, pain was treated with Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 4-6 mg, one to three times daily for 84 days. Pain intensity was assessed 1-1.5 hours before treatment and 1-1.5 hours, 4 hours, and 12 hours after treatment.

[0131] For the first 5 days, the product was administered at 4 mg three times daily, 7-8 hours apart. Pain intensity was typically estimated as an NRS score of 3-4 before administration and 1-3 after administration (1 and 4 hours). On days 3-5 of treatment, the pain intensity score was 1-2 before administration and 0 after administration (1 and 4 hours). From days 6-42, the product was administered at 4 mg once daily. The pain intensity score was typically 1-2 before administration and 0 after administration (1 and 12 hours), continuing through day 37 of treatment. From days 37-42, the pain intensity score was 2 before administration, 1 after administration, and 1-2 after administration (4 hours). From days 43-84, the product was administered at 6 mg once daily. Pain intensity was typically estimated as 1 before administration and 0 after administration (1 and 12 hours).

[0132] No AEs related to the analgesic Taphalgin were reported.

[0133] Example 6 Patient N, 49 years old, male.

[0134] Diagnosis: Right renal cell carcinoma, T4N0M1, stage IV. Moderate chronic pain.

[0135] The patient is receiving outpatient treatment, is able to self-care but is unable to work, and spends more than 50% of his waking hours awake (Karnofsky scale score of 50-60).

[0136] Before treatment with the proposed administration pattern was administered, pain was uncontrolled despite weak opioid analgesics ± NSAIDs ± adjunctive treatment (excluding pain due to other causes not related to breakthrough pain or persistent pain).

[0137] A proposed pain management administration pattern was employed using Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in a single individualized dose of 4 mg once daily for 83 days. Pain intensity was assessed 1-1.5 hours before treatment and 1-1.5 and 12 hours after treatment.

[0138] During the first 2 days of treatment with Taphalgin, pain intensity was usually estimated as an NRS score of 3-4 before administration and 0-2 after administration (1 hour and 12 hours). From the third day onwards, pain intensity was usually estimated as 1 before administration, 0 at 1 hour and 12 hours after administration.

[0139] The patient's overall physical and mental state and sleep improved.

[0140] No Taphalgin-related AEs were reported.

[0141] Example 7 Patient N, 43 years old, female.

[0142] Diagnosis: Right breast cancer, T3N1M0, stage IIB. Moderate chronic pain.

[0143] Patients are unable to perform heavy physical work but are able to perform light or sedentary tasks (such as housework or office work) (Karnofsky scale score of 70-80).

[0144] Before treatment with the proposed administration pattern was administered, pain was uncontrolled despite weak opioid analgesics ± NSAIDs ± adjunctive treatment (excluding pain due to other causes not related to breakthrough pain or persistent pain).

[0145] According to the proposed administration pattern, pain was treated with Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 4 mg, 1 to 3 times daily for 83 days. Pain intensity was assessed 1-1.5 hours before treatment and 1-1.5 hours, 4 hours, and 12 hours after treatment.

[0146] For the first 3 days, NRS pain intensity was estimated as 1 before administration and 1-4 hours after administration as 2. The product was administered twice daily for these 3 days.

[0147] Thereafter, the product was administered at 4 mg once daily. Pain intensity scores were typically 1 pre-dose and 0 post-dose (1 hour and 12 hours). On isolated days, the pain intensity score remained 0 throughout the day.

[0148] Reported AEs included mild numbness in the lower extremities, which was well tolerated by the patient, did not interfere with daily activities, and caused minimal discomfort. A causal relationship to Taphalgin was assessed as possible. The AE resolved spontaneously and did not require treatment or Taphalgin dose adjustment.

[0149] Example 8 Patient N, 67 years old, female.

[0150] Diagnosis: Left breast cancer, T1N0M0, stage I. Moderate chronic pain.

[0151] The patient is receiving outpatient treatment, is able to self-care but is unable to work, and spends more than 50% of his waking hours awake (Karnofsky scale score of 50-60).

[0152] Before treatment with the proposed administration pattern was administered, pain was uncontrolled despite weak opioid analgesics ± NSAIDs ± adjunctive treatment (excluding pain due to other causes not related to breakthrough pain or persistent pain).

[0153] According to the proposed administration pattern, pain was treated with Taphalgin subcutaneous injection solution, a product based on the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH2). Taphalgin was administered subcutaneously in individualized single doses of 4 mg, 1 to 3 times daily for 85 days. Pain intensity was assessed 1-1.5 hours before treatment and 1-1.5 hours, 4 hours, and 12 hours after treatment.

[0154] For the first 5 days, the product was administered at 4 mg three times daily, 6-8 hours apart. For the first 3 days, NRS pain intensity was estimated at 3-4 pre-dose and 0-1 at 1 and 4 hours post-dose. On days 4 and 5, pain intensity scores were typically 2-3 pre-dose and 0-1 at 1 and 4 hours post-dose.

[0155] The product was then administered at 4 mg once daily. Pain intensity scores typically decreased to 1 before administration and 0 after administration, remaining at this level throughout the day.

[0156] The patient noted improvement in his physical and mental state.

[0157] No Taphalgin-related AEs were reported.

[0158] Example 9. Patient N, 43 years old, female.

[0159] Diagnosis: uterine fibroids.

[0160] Surgical procedures: hysteroscopy, mini-laparotomy, myomectomy, pelvic lavage, active drainage of the peritoneal cavity.

[0161] Taphalgin was administered at 2 mg three times daily to control early postoperative pain.

[0162] On day 1, the NRS pain intensity score was initially 6 before treatment, 6 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. Because the pain intensity score was 8, the patient received an additional 500 mg of paracetamol. Thereafter, on days 1, 2, and 3, Taphalgin was used as the only product for pain relief; the NRS pain intensity score was 4-5 before administration, 3-2 at 0.5-1 hours after administration, and 0-2 at 4-6 hours after administration.

[0163] No AEs were observed.

[0164] Example 10. Patient N, 30 years old, female.

[0165] Diagnosis: Infertility; bilateral hydrosalpinx.

[0166] Surgical procedures: laparoscopy, bilateral salpingectomy, hysteroscopy, separate diagnostic curettage of the uterine cavity and cervix.

[0167] Taphalgin was administered at 4 mg twice daily to control early postoperative pain.

[0168] On Day 1, the NRS pain intensity score was initially 4 before product treatment, 4 30 minutes after administration, 3 1 hour after administration, 3 2 hours after administration, 6 4 hours after administration, and 3 6 hours after administration. Because the pain intensity score was 6 (4 hours after the first Taphalgin dose), the patient received an additional 500 mg of paracetamol. Subsequently, on Days 1 and 2, Taphalgin was used as the sole product for pain relief; the NRS pain intensity score was 4-3 before administration and 3-2 1 hour after administration, remaining at this level for 4-6 hours. On Day 2, the pain intensity score decreased to 2 before administration and 0 after administration, remaining at this level for 4-6 hours. No AEs were observed.

[0169] Example 11 Patient N, 36 years old, female.

[0170] Diagnosis: uterine fibroids.

[0171] Surgical procedures: Minilaparoscopy, hysteroscopy. Myomectomy without uterine cavity damage. Pelvic lavage.

[0172] Taphalgin was administered at 4 mg three times daily to control early postoperative pain.

[0173] On day 1, the NRS pain intensity scores were initially 4 before product treatment, 4 30 minutes after administration, 4 1 hour after administration, 5 2 hours after administration, 3 4 hours after administration, and 2 6 hours after administration. Because the pain intensity score was 5 (2 hours after the first Taphalgin dose), the patient received an additional 500 mg of paracetamol. Thereafter, on days 1, 2, and 3, Taphalgin was used as the only product for pain relief; the NRS pain intensity scores were 2-1 before administration and 1 6 hours after administration.

[0174] An AE in the form of an elevated ESR was observed. The AE was mild, did not require specialized treatment or drug dose adjustment, and resolved without sequelae. A causal relationship to Taphalgin was assessed as possible.

[0175] Example 12 Patient N, 31 years old, male.

[0176] Diagnosis: Right inguinal hernia.

[0177] Surgical procedure: Laparoscopic right inguinal hernia repair (with implant).

[0178] Taphalgin was administered at 4 mg three times daily to treat early postoperative pain.

[0179] On Day 1, the NRS pain intensity score was initially 6 before treatment, 4 30 minutes after administration, 2 at 1 hour after administration, 1 at 2 hours after administration, 0 at 4 hours after administration, and 1 at 6 hours after administration. Then, on Days 1 and 2, the NRS pain intensity score was 2-1 before administration and 1-0 at 6 hours after administration. On Day 3, the pain intensity score decreased to 1 before administration and 0 after administration and remained at this level for 6 hours.

[0180] No AEs were observed.

[0181] Example 13 Patient N, 51 years old, female.

[0182] Diagnosis: Urinary incontinence.

[0183] Surgical procedure: Cystoscopy. Mid-urethral sling urethropexy using a synthetic sling (Urosling).

[0184] Taphalgin was administered at 2 mg three times daily to treat early postoperative pain.

[0185] On Day 1, the NRS pain intensity scores were initially 3 before treatment, 2 30 minutes after administration, 2 1 hour after administration, 2 2 hours after administration, 2 4 hours after administration, and 3 6 hours after administration. Then, on Days 1, 2, and 3, the NRS pain intensity scores were 2-1 before administration and 1-0 6 hours after administration.

[0186] No AEs were observed.

[0187] Example 14. Patient N, 37 years old, female.

[0188] Diagnosis: Asymptomatic right ovarian cyst (dermoid cyst). Malignancy was ruled out by laboratory tests and magnetic resonance imaging.

[0189] Surgical procedure: laparoscopy, adhesiolysis, right oophorectomy.

[0190] Taphalgin was administered at 2 mg three times daily to control early postoperative pain.

[0191] On Day 1, the NRS pain intensity scores were initially 4 before treatment, 3 at 30 minutes after administration, 1 at 1 hour after administration, 1 at 2 hours after administration, 0 at 4 hours after administration, and 0 at 6 hours after administration. Then, on Days 1 and 2, the NRS pain intensity scores were 1 before administration and 0 at 6 hours after administration.

[0192] No AEs were observed.

[0193] In overall conclusion, these studies demonstrate the efficacy and safety of the claimed drug for use in the treatment of pain and its great potential for application in the early postoperative period after various surgical procedures and in long-term pain treatment in cancer patients.

[0194] 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 on it include the absence of serious side effects, such as CNS disorders (e.g., impaired consciousness and euphoria) and effects on the respiratory center. Another positive feature is its wide therapeutic range without significant side effects. These characteristics justify the potential use of the claimed method for pain management, treatment, and prevention in a much broader range of therapeutic areas, including outside of hospital settings. For example, it is crucial that it be used by moderately qualified medical professionals or by the patient themselves, in field or home conditions. This is particularly important for the treatment of cancer pain and early postoperative pain after various surgical procedures.

Claims

1. 1. A medicament for use in the treatment, management and / or prevention of pain, the administration pattern of which comprises administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH 2 ) administered at a single dose of 2 to 7 mg, not to exceed a daily dose of 42 mg, and at intervals of at least 4 hours.

2. 2. The pharmaceutical product for use according to claim 1, wherein the administration pattern comprises administering the tetrapeptide for pain relief in cancer patients or in the early post-operative period following various surgical procedures.

3. The administration pattern includes administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH 2 3. The pharmaceutical composition for use according to claim 1, comprising administering the compound of formula (I) in the form of a solution for subcutaneous injection.

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

5. 5. The pharmaceutical for use according to claims 1 to 4, wherein when the pharmaceutical is used for administration in the treatment of pain, the administration pattern comprises injections of the tetrapeptide every day or every one to several days, depending on the severity of the pain.

6. 6. A pharmaceutical for use according to claims 1 to 5, wherein when said pharmaceutical is used for administration in the treatment of pain, said administration pattern includes the possibility of repeating a course of pain treatment for a maximum duration of 96 days and of repeating said course multiple times.

7. 7. The pharmaceutical for use according to claims 1 to 6, wherein when the pharmaceutical is used for administration in the treatment of pain, the administration pattern includes determining the total duration of pain treatment depending on the patient's condition; the duration of a single pain treatment course in a cancer patient is preferably up to 96 days or more, including the possibility of repeating the course multiple times; the repeated courses are recommended with a break of at least 2 to 5 days between them, and the number of times the course is repeated is determined by the patient's condition.

8. The pharmaceutical for use according to claims 1 to 7, wherein when the pharmaceutical is used for administration in the treatment of pain, the administration pattern comprises determining the total duration of treatment depending on the condition of the patient; and the duration of pain treatment in patients with pain in the early postoperative period after various surgical procedures is 1 to 10 days.

9. The pharmaceutical product for use according to claims 1 to 8, wherein said administration pattern comprises using a single dose of 4 to 7 mg of said tetrapeptide.

10. The administration pattern includes administering the tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH 2 10. The pharmaceutical product for use according to claims 1 to 9, comprising a recommended starting single dose of 4 mg.

11. A pharmaceutical product for use according to claims 1 to 10, wherein the administration pattern comprises increasing or decreasing a single dose as needed, depending on a 25 to 50% increase or decrease relative to the previous value.

12. A pharmaceutical product for use according to claims 1 to 11, wherein the administration pattern comprises administering 4 mg of the tetrapeptide two to three times daily.

13. 13. The pharmaceutical for use according to claims 1 to 4 and 9 to 12, wherein when the pharmaceutical is used for administration in the prevention of pain to humans, the administration pattern comprises administering the tetrapeptide to cancer patients or to patients at risk of pain attacks in the early postoperative period after various surgical procedures.

14. The tetrapeptide tyrosyl-D-arginyl-phenylalanyl-glycinamide (H-Tyr-D-Arg-Phe-Gly-NH 2 ) and additives: sodium chloride, mannitol, glycine, sodium acetate trihydrate, acetic acid and water in the following component ratios (wt%): Tetrapeptide 0.380-0.420 Sodium chloride 0.475 to 0.525 Mannitol 0.475-0.525 Glycine 0.475-0.525 Sodium acetate trihydrate 0.0380-0.0420 Acetic acid until pH reaches 4.0-6.0 Water until it reaches 100 14. A pharmaceutical for use according to any one of claims 1 to 13, comprising:

15. The following component ratios (wt%): Tetrapeptide 0.40 Sodium chloride 0.50 Mannitol 0.50 Glycine 0.50 Sodium acetate trihydrate 0.04 Acetic acid until pH reaches 4.0-6.0 Water until it reaches 100 15. The pharmaceutical for use according to claim 14, characterized by:

16. The following ingredient ratios (mg): Tetrapeptide 3.8-4.2 Sodium chloride 4.75 to 5.25 Mannitol 4.75-5.25 Glycine 4.75-5.25 Sodium acetate trihydrate 0.38-0.42 Acetic acid until pH reaches 4.0-6.0 Water until 1 mL 15. The pharmaceutical for use according to claim 14, characterized by:

17. The following ingredient ratios (mg): Tetrapeptide 4.00 Sodium chloride 5.00 Mannitol 5.00 Glycine 5.00 Sodium acetate trihydrate 0.40 Acetic acid until pH reaches 4.0-6.0 Water until 1 mL 17. The pharmaceutical for use according to claim 16, characterized by:

18. A pharmaceutical product for use according to claims 14 to 17, which is in the form of a solution for subcutaneous injection or is prepared in such a form.

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