RU2723952C1 - Suppositories for treatment of moderate and high-intensity pain syndrome - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, namely to suppositories for treating moderate and high-intensity pain syndrome. Rectal suppository pharmaceutical composition contains 0.1–10 g/100 g of nefopam or its pharmaceutically acceptable salt, from 10 % to 100 % of particles of which have size from 90 mcm to 1000 mcm, and up to 100 g/100 g of a lipophilic base with pharmaceutically acceptable additives selected from a preserving agent, an emulsifying agent and a stabilizer or mixtures thereof.EFFECT: invention provides prolongation of analgesic effect and shelf life of composition more than 2 years.7 cl, 5 tbl, 5 ex

Description

The invention relates to the field of medicine and the pharmaceutical industry, specifically to the creation, production and use of a rectal drug for the treatment (relief) of moderate and high intensity pain in various fields of medicine, in particular in oncology.

Pain is an integrative function of many body systems to protect against a harmful factor. These include consciousness, sensation, memory, motivation, autonomic mechanisms, behavioral reactions and emotions. In cancer patients, this phenomenon usually manifests itself in the form of a chronic pain syndrome. The pain aggravating the life of a cancer patient is a serious medical and social problem. The quality of life and the results of any treatment in oncology cannot be evaluated without taking into account the dynamics of chronic pain. According to the WHO, in the world annually 7 million cancer patients are identified, 5 million die from tumor progression. In Russia, more than 450 thousand patients with malignant neoplasms are registered annually. In large cities, about 14% die within 1 month, and 40% within 1 year after confirming the diagnosis due to neglect of the disease. More than 70% of patients in the terminal period consider pain the main symptom of a tumor.

Known systemic drugs containing opioid analgesics (buprenorphine, tramadol, nalbuphine) for the treatment (relief) of pain of medium and high intensity. Buprenorphine is produced and used in the form of injectable solutions and transdermal therapeutic systems, tramadol in the form of injectable solutions, oral drops, capsules, tablets and suppositories. Nalbuphine is produced and used in the form of solutions for injection, as well as in the form of oral forms. It should be clarified that the use of opioid analgesics can be associated with a certain risk for patients, since with prolonged use or at high dosages, pronounced sedative effect, respiratory depression, nausea, vomiting, gastrointestinal paresis, bile and urinary tract dysfunction can be observed.

A sufficiently effective non-opioid analgesic of central action is Nefopam, which is a benzoxazosine derivative, namely 5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazosine. The pharmacological effect of the drug is realized at the spinal and supraspinal levels of the central nervous system by influencing the downward monoaminergic ways of controlling the pain impulse, namely, by inhibiting the reverse synaptic uptake of serotonin, norepinephrine and dopamine.

It should be clarified that such dosage forms of nefopam as injection and coated tablets are known in the world, in Russia only solutions for injection are registered. Injection solutions have a number of disadvantages: trauma to the patient with the introduction of the drug, the need for a sterile syringe and medical personnel, the possibility of infection of the patient with infections associated with the provision of medical care, especially in case of skin disorders, etc.

An alternative to injectable treatment and oral administration can be the use of nefopam in a new dosage form of rectal suppositories.

Rectal suppositories, as a dosage form, have certain advantages: high relative bioavailability of the drug substance, which determines the effectiveness of the pharmacotherapeutic action, comparable with its effectiveness when injected; simplicity and the possibility of use on an outpatient basis, the absence of an effect on the active substance of intestinal juice, the possibility of use in patients with a vomiting reflex, and the absence of trauma during administration.

Known patent RU 2661617 - 07.17.2018, revealing nefopam in the form of rectal suppositories, including polyethylene oxide 400 and a hydrophilic emulsion base, where up to 90% of suspended particles of nefopam hydrochloride have a size of from 0.5 to 90 microns with an average median particle size of not more than 30 microns . This source may be indicated as the closest analogue.

It should be noted that the proposed technological solution has a shelf life of about 2 years, which is due to the largely used base and distribution of nefopam hydrochloride particles.

Thus, there is a need for a systemic painkiller with strong analgesic activity, the use of which would not be complicated on an outpatient basis and would not be limited in patients with vomiting reflex and muscle dystrophy, and a shelf life of more than 2 years. For this, pharmaceutical compositions in the form of rectal suppositories can be proposed as technical solutions.

The objective of the invention is the creation of new pharmaceutical compositions in the form of rectal suppositories containing nefopam or its pharmaceutically acceptable salt on lipophilic bases with additives intended for the treatment (relief) of moderate to high intensity pain attacks with an effective and prolonged analgesic effect in the absence of a laxative effect , as well as in the development of methods for producing these compositions.

The problem is solved in that the pharmaceutical composition for the treatment of acute and chronic pain in the form of rectal suppositories contains nefopam or its pharmaceutically acceptable salt as an active component, from 10% to 100% of particles of which have a size of from 90 microns to 1000 microns and a lipophilic base with pharmaceutically acceptable additives selected from a preservative, emulsifier and stabilizer or mixtures thereof, in the following ratio of components, g / 100 g of the composition:

nefopam or a pharmaceutically acceptable salt thereof 0.10-10.00

lipophilic base with additives up to 100

Preferably, the pharmaceutically acceptable salt of nefopam are its pharmaceutically acceptable acid salts, in particular nefopam hydrochloride.

Derivatives of solid fat consisting of fractions of mono-, di-, and triglycerides C ₁₀ -C ₁₈ (for example, capric and / or stearic acids), such as trademarks of vitepsols, can be used as base substances for suppositories. Vitepsol H-15, Supposire Base NAIS 10, NA are preferred.

Preferably, PEG 1500 and PEG 400 may be included as stabilizers, for example, in a volume ratio of 8: 2, respectively.

As preservatives, for example, sodium benzoate, nipagin, nipazole or mixtures thereof can be used.

In one embodiment, a preservative mixture is used as an additive to the base, which is paraben (s) and sodium benzoate, an emulsifier and stabilizer in a weight ratio of 1: 1: 4: 7, respectively.

The emulsifier can be selected from the group comprising mono- and diglycerides of fatty acids, esters of glycerol, fatty and organic acids, lecithins, polysorbates and their derivatives, sorbitan esters, SPENs, polyglycerol esters. In particular, tween-80, lanitol, monoglycerodistillate (MHD), emulsifier No. 1, T-2 emulsifier can be used as emulsifiers.

It should be noted that from 10% to 100% of suspended Nefopam particles have a size of 90 to 1000 microns (determination is carried out according to OFS.1.2.1.0008.15 “Determination of particle size distribution by laser light diffraction" State Pharmacopoeia of the Russian Federation XIII, Volume 1) .

The claimed ratio of nefopam and lipophilic base with additives is optimal.

We give specific examples of the invention.

Example 1

Per 100 suppositories: The crushed particles of nefopam or its pharmaceutically acceptable salt are introduced into the melt of the hydrophobic base with additives and mixed until homogeneous (30 minutes). The resulting suspension is poured into pre-cooled suppository forms and placed in a refrigerator at -4 ° C. The drug is used as rectal suppositories.

Examples of formulations are shown in Table 1 (g / 100 g weight).

Example 2

Studies were conducted on the analgesic activity of nefopam with rectal administration of suppositories on a model of inflammatory hyperalgesia (carrageenan edema) in male rats. Previously, in all rats, baseline pain sensitivity threshold (PBC) was determined using a Ugo Basile 37215 analgesimeter, stimulating a pain response on the right hind paw.

After that, no less than 30 minutes later, in all rats, aseptic exudative inflammation was reproduced on the right hind paw by subplant implantation of 0.1 ml of 1% carrageenin solution. 1 hour after the reproduction of the pathology in 3 groups of rats, the nephopam was once administered rectally with a probe in appropriate doses in the form of lipophilic suppository masses containing 0.10 mg / g of active ingredient. In the 4th group of rats, nefopam in the form of a solution for injection was injected intramuscularly into the femoral muscle of the hind left paw.

0.5, 1, 2, 3, and 4 hours after the administration of nefopam in all rats, determine the threshold of pain sensitivity (PBC) and calculated analgesic activity (AA) by the level of decrease in the degree of hyperalgesia compared with control animals, expressing AA in percent:

где

Where

ΔPBCho - the percentage of change in the level of pain sensitivity in the experimental group before and after the reproduction of inflammatory hyperalgesia and the introduction of the test drug;

ΔPBChk - the percentage change in the level of pain sensitivity in the group of control animals before and after the reproduction of inflammatory hyperalgesia.

Nefopam has an analgesic effect upon rectal administration to rats in the form of suppositories on all types of bases (Table 1).

In this method of application, nefopam showed not only the highest level of activity, but also exceeded the level of activity of the injectable form by the totality of observations. At the same time, 1 hour after administration, the level of activity of nefopam in the form of a rectal suppository in Example 1 approached the indicator with intramuscular administration and then after 2, 3 and 4 hours it exceeded this indicator by approximately 2 times. It should also be noted the long duration of analgesic activity, a statistically significant level, which was observed for 4 hours (table 2).

Thus, rectal suppositories containing nefopam have an analgesic effect in the test of carrageenin edema.

Example 3

A formalin pain test to detect analgesic activity.

Male outbred rats were placed in individual plastic boxes. An acute inflammatory reaction (edema) was caused by subplanar (under the plantar aponeurosis) injection of 50 μl of 5% formalin. The number of pain reactions (tapping the paw on the floor, biting paws, etc.) was recorded in the first 5-10 minutes - phase I (effect on the primary afferents of pain) and from 30-50 minutes - phase II (pain resulting from inflammatory reactions) (Bannonetal., 1998). The criterion of the analgesic effect was considered a significant decrease in the number of pain reactions in the experimental group relative to the control group.

The test sample 1 — the suppository of Example C, was once administered rectally with a probe in the form of suppository masses simultaneously with formalin to male non-linear white rats weighing 200-300 g. Suppository masses without an active substance were introduced into the control animals using a probe. The results are shown in Table 3.

Table 3 shows that rectal suppositories containing nefopam reduce pain sensitivity in phase I of formalin pain, which characterizes the effect on primary afferents, and do not have an anti-inflammatory effect in phase II caused by the development of inflammation.

Thus, rectal suppositories containing nefopam have an analgesic effect in the formalin pain test.

Example 4

The study of rectal suppositories with nefopam in a test of neurogenic pain syndrome caused by transection of the sciatic nerve, as a model of neuropathic pain to detect analgesic activity.

The experiments were performed on male nonlinear white rats weighing 200-250 g. Neurogenic pain syndrome in male outbred rats was created by transection of the sciatic nerve at the level of the popliteal fossa above the place of its trifurcation by n. tibialis, n. peroneus and n. suralis and its subsequent ligation to prevent regeneration. The development of pain was determined by the appearance of signs of autotomy on the operated leg. The intensity of autotomies was evaluated on a 11-point scale: 1 point — damage to the 1st claw; 2, 3, 4 and 5 points - damage to 2, 3, 4 and 5 claws; 6 points - damage to the phalanx of one finger; 7, 8, 9 and 10 points - damage to the phalanges on the 2nd, 3rd, 4th and 5th fingers, respectively; 11 points damage to the metatarsal bones. The dynamics of the development of pain in rats of the experimental and control groups was observed for 25 days (Kryzhanovsky G.N. et al. 1991).

In the control group animals, on the day of sciatic nerve transection and the next 10 days after surgery, suppository masses without an active substance were introduced using a probe, and suppository masses with nephopam in Example 1 at a dose of 10 mg / kg were administered using the probe in the same time period using a probe.

In the control group of rats, the development of autotomy after transection of the sciatic nerve appeared in 50% of animals on day 6 after surgery. The intensity of pain reactions was 2.8 ± 0.7 points. On the 9th day of administration, a pain reaction was observed in 60% of the animals, corresponding to an intensity of 3.5 ± 2.4 points. On day 18, pain reactions developed in 70% and amounted to 6.0 ± 2.5 points.

The introduction of suppository masses without an active substance did not prevent the development of autotomies after transection of the sciatic nerve (40% of animals on day 6 after surgery). The intensity of pain reactions was 2.0 ± 1.0 points. On the 9th day of administration, a pain reaction was observed in 50% of the animals, corresponding to an intensity of 3.9 ± 2.4 points. On day 18, pain reactions developed in 60% and amounted to 4.7 ± 2.7 points.

The introduction of suppository masses with nefopam prevented the development of pain. On days 6 and 9, pain reactions were not observed. On the 13th day of the experiment, on the 5th day after the administration of the compound was canceled, a pain reaction appeared in 10% of the animals with an average intensity of 1.0 ± 1.0 points, and on the 18th day - in 10% of the animals, the average reaction intensity was 1.8 ± 1.0 points.

Thus, rectal suppositories with nefopam according to example 1 exhibit analgesic effect in the test of neurogenic pain syndrome caused by transection of the sciatic nerve.

Example 5

Based on the obtained results, suppositories according to Example A were used to determine the analgesic activity of nefopam for rectal administration in different doses. The obtained research results are presented in Table 4.

Nefopam has an analgesic effect when rectally administered to rats in the form of suppositories according to Example 1 in doses of 0.125 mg / kg and above (Table 4). The highest level of analgesic activity was recorded 1-2 hours after rectal administration of a suppository mass containing nefopam. Further, the activity of the drug either disappeared (doses of 0.125-0.25 mg / kg) or gradually decreased (doses of 0.50-1.50 mg / kg) (Table 4). At doses of 1.00-1.50 mg / kg, analgesic activity persists for 4 hours, while intramuscular injection of an injection solution of AA persists for only 3 hours with a maximum of AA per 1 hour. In the period from 2 to 4 hours after rectal administration of nefopam in doses of 1.00-1.50 mg / kg, the analgesic activity significantly exceeds AA with intramuscular injection of a solution for injection at a dose of 1.00 mg / kg.

The developed composition during rectal administration allowed maintaining a high level of analgesic activity in rats for a rather long time (longer than with intramuscular injection of a solution for injection), which, when used in humans, will achieve a longer interval between doses of the drug and a higher analgesic effect.

Thus, studies have confirmed that the drugs in accordance with the invention have an effective analgesic effect in rectal administration, have a prolonged analgesic activity. The effectiveness and duration of the analgesic effect makes it possible to choose the optimal dose and suppository basis of the drug for use in various clinical situations. Rectal administration of drugs is atraumatic, not complicated on an outpatient basis, and is not limited in patients with vomiting reflex and muscle dystrophy.

The resulting composition contains nephopam on a lipophilic basis with additives, meets the regulatory requirements for pharmacotechnological tests of suppositories and uniformity of the content of the active substance and have a shelf life of up to 3 years (Table 5). Substantiated methods for producing these compositions.

All of the above confirms the fulfillment of the objective of the invention - the creation of new pharmaceutical compositions in the form of rectal suppositories containing nefopam or its pharmaceutically acceptable salt on lipophilic bases with additives intended for the treatment (relief) of moderate to high intensity pain episodes with effective and prolonged analgesic action, as well as in the development of methods for producing these compositions.

Claims (8)

1. A pharmaceutical composition for treating acute and chronic pain in the form of rectal suppositories, characterized in that it contains nephopam or a pharmaceutically acceptable salt thereof as an active component, from 10% to 100% of the particles of which have a size of from 90 μm to 1000 μm, and lipophilic base with pharmaceutically acceptable additives selected from a preservative, emulsifier and stabilizer or mixtures thereof in the following ratio of components, g / 100 g of the composition: nefopam or a pharmaceutically acceptable salt thereof 0.10-10.00 lipophilic base with additives up to 100 2. The pharmaceutical composition according to claim 1, characterized in that the lipophilic base is a solid fat consisting of fractions of mono-, di- and triglycerides of C ₁₀ -C ₁₈ carboxylic acids. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that the lipophilic base contains, as an additive, a mixture of preservatives, which is paraben (s) and sodium benzoate, an emulsifier and stabilizer in a weight ratio of 1: 1: 4: 7, respectively. 4. The pharmaceutical composition according to claim 2, characterized in that said carboxylic acids are selected from capric and / or stearic acids. 5. The pharmaceutical composition according to claim 1 or 2, characterized in that the emulsifier is selected from the group: mono- and diglycerides of fatty acids, esters of glycerol, fatty and organic acids, lecithins, polysorbates and their derivatives, sorbitan esters, SPENs, polyglycerol esters. 6. The pharmaceutical composition according to claim 3, characterized in that it contains nipagin and nipazole as parabens. 7. The pharmaceutical composition according to claim 1 or 3, characterized in that the stabilizer is selected from a mixture of polyethylene glycol 1500 and polyethylene glycol 400, taken in a volume ratio of 8: 2, respectively.