Combination for prevention, correction and therapy of pain related to neurodegeneration or associated with somatoform disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a combination for the prevention, correction and therapy of pain related to neurodegeneration and/or associated with somatoform disorders, characterised by the fact that it consists of buspirone and doxepin taken in therapeutically effective amounts.

EFFECT: invention provides creating the combination providing the prolonged analgesic effect, including in persistent chronic pains.

5 cl, 2 ex, 2 tbl

 

The invention relates to the field of pharmaceutical industry and medicine and relates to a new means against pain associated with neurodegeneration, or associated with somatoform disorders.

Over the last 10-15 years, the results of epidemiological studies of the prevalence of chronic pain is definitely a significant increase in the number of people who have often recurrent and chronic pain in the lumbar and around the pelvic areas, joints, head, and visceral pain, different pain syndromes of the musculoskeletal and neurogenic origin. This situation persists and has a tendency to expand even though there are new drugs analgesic actions.

During a large-scale study Pain in Europe, which was attended by 46,000 people from 16 countries, found that one in five adults Europeans suffers from chronic pain. The average duration of chronic pain is 7 years. While every fifth patient had chronic pain for 20 years or more [Fricher J. Pain in Europe report. Pain in Europe journal//2006]. According to the Russian Association for the study of pain, chronic pain syndromes in Russia varies from 13.8% to 56.7%, averaging 34,3 cases per 100 people. More than 40% of people suffering from the HRO is practical pain indicate that pain very seriously reduces their quality of life [ahno N., Kukushkin M., David M., Danilov A.B., Amelin A.V., Kulikov S.M. Results of epidemiologic studies of the prevalence of neuropathic pain, its causes and characteristics in a population of ambulatory patients seeking physician-neurologist /Pain. 2008. 3 (20).].

One of the major reasons of low efficiency of drug therapy is the lack of doctors ' understanding of the pathogenesis of chronic pain, lack and/or absence of knowledge about the physiological and neurochemical mechanisms of its development.

Chronic pain, as defined by the International Association for the study of pain (IASP), pain is a feeling that lasts beyond the normal healing period. The most appropriate time to assess pain as a chronic, is its duration more than 3 months (NM Merskey, N. Bogduk, 1994).

Chronic pain, regardless of the original cause, is a consequence of the deployment process in the peripheral and Central nervous system as a response to a long painful stimulation of a number of cascading changes over time, acquiring the character of a typical pathological process. One of the major changes of this pathological way (M. Kukushkin, VK Reshetnyak, 1997; GN. Kryzanowski the th, 2002; D.Borsook, 1997) activation of the NMDA receptor neurons in the posterior horns of the spinal cord; high levels released into the synapses of specific neurotransmitters and neuromodulators, such as glutamate, calcium ions, nitric oxide, substance P, neurokinin-1, c-fos oncogenic protein and other; the lower threshold of the Central sensitization with subsequent depletion and death of neurons, probably due to an excessive number of signals in the cell with the further development of zones of secondary hyperalgesia.

Some work was first put forward evidence-based assumption that chronic pain may be related to neurodegenerative processes.

MRI (magnetic resonance tomographic studies) showed that patients with chronic pain, the density of gray matter decreases, especially in the prefrontal cortex and the thalamus [Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, et al. (2004) Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. The Journal of neuroscience: the official journal of the Society for Neuroscience 24: 10410-10415.; Schmidt-Wilcke T, Leinisch E, Straube A, Kampfe N, Draganski B, et al. (2005) Gray matter decrease in patients with chronic tension type headache. Neurology 65: 1483-1486.; Schmidt-Wilcke T, Leinisch E, Ganssbauer S, Draganski B, Bogdahn U, et al. (2006) Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients. Pain 125: 89-97.; Seminowicz DA, Labus JS, Bueller JA, Tillisch K, Naliboff BD, et al. (2010) Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology 139:48-57 e42.]. Apkarian and to the legs said, in patients with chronic pain disrupted the structure of emotional problem solving, and performance of this test (for tasks), is directly related to the functional properties of the frontal lobes. The authors explain their findings from the point of view of loss of gray matter in the frontal lobe of patients with chronic pain [Apkarian AV, Sosa Y, Krauss BR, Thomas PS, Fredrickson BE, et al. (2004) Chronic pain patients are impaired on an emotional decision-making task. Pain 108: 129-136.]. As far as we know, this was the first study directly linking neurodegeneration, chronic pain and specific cognitive deficits.

Thus, influencing chronic pain, in addition to analgesic activity, it is necessary to interrupt the pathological way, almost the main factor which is neurodegeneration.

It is also worth noting that in recent clinical specialists increasingly seen such a complex nosological process, as somatoform disorders. "Somatoform disorder" in international and national classifications reflect the complex transformational processes in clinical psychiatry, entered into "mostosroitely period of its development. This marks a departure from previous ideas about the hard boundaries between mental illness and thus from an exceptional position in the systematics of nosological forms allocated as the only possible taxonomic units. This change create conditions for the construction of theoretical concepts to a greater extent than traditional corresponding to the accumulated empirical data. While scientific research has shifted to one of the main problems of psychopathology - value "symptom - syndrome".

Analysis of this ratio allows you to open the General methodological perspectives, including in the field of psychopathology study of somatoform disorders. This will be the subject not only this, but all the others below works on various aspects of somatoform disorders.

Based on the fundamental principles of the General doctrine of syndromes (the national mental health these principles more fully formulated AV snezhnevsky, a specific set of symptoms (syndrome) is associated causal relationship with a certain (often hypothetical) neurobiological substrate. The syndrome is considered pathological hierarchical structure that reflects the stereotype of the disease.

For the treatment of pain taking into account the neurochemical mechanisms of its development, developers have proposed various combinations of drugs.

For example, the known patent US 7534806 (B2), publ. 2009-05-19 describing the treatment of neuropathic pain and associated symptoms combination ibudilast (3-isobut the RIL-2-isopropylpyrazole [1,5-a] pyridine) and the second component, such as gabapentin, memantine, morphine, cannabinoid, tramadol DULOXETINE tricyclic antidepressants.

Also known patent US 6251863 (B1), publ. 2001-06-26 describing the treatment of neurodegenerative diseases accompanied by pain, using a combination of relaxing with estrogen or glucosamine.

Known patent US 6245802 (B1), publ. 2001-06-12 describing a method of treating pain, comprising the introduction of mammals analgesic combinations containing DULOXETINE and NSAIDs or paracetamol. The pain may be pain from the group consisting of neuropathic pain, diabetic neuropathy, fibromyalgia, pain associated with somatoform disorders, pain in joints, pain in cancer, pain in neck, shoulder, back pain, headaches, migraine, herpes neuralgia, phantom limb pain, Central pain, dental pain, NSAID-resistant pain, visceral pain, surgical pain, post-operative pain, pain in the bones, injury, pain during labor and delivery, pain resulting sunburn, post partum pain, angina pain, pain associated with the genitourinary system and nociceptive pain.

This source can be specified as the nearest equivalent.

The present invention is to create a combination that provides prolonged pain, including those with persistent chronic pain, due to the impact (or Prieur the cation) in the pathological process of the appearance or functioning of the pain pathway/route.

The authors have developed a new combination of such well-known products, such as Buspirone (INN) and Doxepin (INNS). This composition may interrupt the formation or break already formed a pathological way chronic, persistent pain associated with neurodegeneration, but also prevent the development of pain associated with somatoform disorders. And, thus, to promote the correct pathogenetic effects on painful process.

Thus, the object of the invention is the Combination for the prevention, correction and treatment of pain associated with neurodegeneration, or associated with somatoform disorders, characterized in that it comprises a therapeutically effective amount of Buspirone and Doxepin.

Optimal therapeutically effective amount of components in the compositions depends on the route of administration of the medication, indications for which medicine is injected, the individual characteristics of patienta (e.g., body weight, General health, gender, age etc).

In particular, they may be of 0.03-0.15 mg/kg for buspirone and for the 0.05-0.5 mg/kg of Doxepin.

Preferably, therapeutically effective amount is for buspirone 0.03 mg/kg and for Doxepin 0.05 mg/kg

The combination may further comprise pharmaceutically acceptable prophetic is TBA, which are necessary to form suitable for delivery into the body preparative dosage forms.

The combination can be represented in the form: tablets, including sublingual form, capsules, dosage forms with modified release, injectable form, candles, powder for preparation of a drink, drops, including nose drops, transdermal, transbukkalno, aerosol form.

Doxepin

,

is dibenzoxepin tricyclic compound, which is used as an antidepressant for more than 40 years. Doxepin blocks α2-adrenergichesky-, N-methyl-D-aspartate - and gistaminergicheskie H2-receptor 1A (5-HT1A), inhibits reuptake of 5-HT, serotonin and noradrenaline, and implements its functions, mainly as a depressant in the Central nervous system. Doxepin, as previously established, is a strong blocker of Na+-channels, including, determines its peripheral analgesic activity, which is better in action than bupivacaine in rats [Local Anesthetic Properties of a Novel Derivative, N-Methyl Doxepin, Doxepin Versus and Bupivacaine, Yukari Sudoh, MD*, Elaine Elliott Cahoon, BS*, Umberto De Girolami, MDf, andGing Kuo Wang, PhD*].

Has an analgesic effect, which is believed to be associated with changes in the concentration of monoamines in the Central nervous system, especially serotonin, and impact on e is gogenie opioid system. The mechanism of anxiolytic action is associated with a reduction in the rate of excitation of locus ceruleus by regulating the functions of alpha 2 - and beta-adrenergic receptors and turnover of noradrenaline. Improves mood, eliminates depression, apathy, depression, state of inner tension and fear. Has a therapeutic effect in autonomic disorders neurotic origin.

Buspirone has the following structure:

Buspirone, the chemical name is 8-[4-[4-(2-pyrimidinyl)-1-piperazinil]-butyl]-8-azaspiro(4,5)-decane-7,9-dione is

pharmaceutically active compound that has been found effective in the treatment of anxiety (fear) and depression.

However, Buspirone has a high degree of primary metabolism and, in General, only about 4% of a therapeutic dose of Buspirone gets into the bloodstream nematerializiranih form after oral administration (Mayol et al., Clin. Pharmacol. Ther.. 37, p.210, 1985). Also observed large differences in the absorption of Buspirone in different people. This was demonstrated by measuring the maximum concentration of drug substance in plasma of patients up to 10-fold differences (Gammans et al., American J. Med., 80, Suppl. 3B, pp.41-51, 1986).

Possesses high affinity to pre-(agonist) and postsynaptic (partial agonist) of serotonin is scored receptor subtype 5-HTlA. Decreases the synthesis and release of serotonin, the activity of serotonergic neurons, including in the dorsal nucleus. Selectively blocking (antagonist) pre - and postsynaptic B2-dopamine receptors (has moderate affinity) and increases the rate of excitation of dopamine neurons in the midbrain. There is some evidence that an impact on other neurotransmitter systems. It has an affinity to benzodiazepine receptors, does not affect the binding of GABA. However Buspirone produces its therapeutic activity gradually, unlike Doxepin.

Therapeutic result:

The possibility of application in somatoform disorders,

Ensuring rapid onset of therapeutic effect,

Enhancement of therapeutic effect with extension, without any additional and/or excessive side effects,

The possibility of using the recommended low therapeutic doses, with a pronounced therapeutic effect, as if, were used high therapeutic doses

Convenience destination for clinicians,

Ease of use for patients

The possibility of carrying out the invention can be demonstrated by the following experiments:

The experiments were conducted in may 2012 in accordance with the Manual is on experimental (preclinical) study of new pharmacological substances (edited by R.N. Khabriev, Moscow, 2005). Animals (a total of 60 mice) were divided into groups of 7 animals each. The experiments were conducted so-called blind. Groups of animals were desirability after receiving all data.

1 group 7 mice. Animals of this group received firstvar.

2 group 7 mice. Animals of this group received Doxepin 25 mg (breeding for animal model).

3 group 7 mice. Animals of this group received Buspirone 10 mg (in breeding for animal model).

4 group 7 mice. Animals of this group received Doxepin 10 mg + Buspirone 5 mg

5 group 7 mice. Animals of this group received Doxepin 25 mg + Buspirone 10 mg

All substances were injected into mice inside of the stomach using a metal probe for mice (e.g FTSS-20S-38) firm Salomon Scientific (USA) in a volume of 1 ml Control group was injected 1: saline in the same volume. After the 1st hour after administration of the substances under study, mice were injected intraperitoneally with 0.75% solution of acetic acid at a rate of 0.1 ml per 10 g of body weight of the animal and within 15 minutes were counting the number of writhing for each animal.

RESEARCH AND RESULTS

The influence of the studied substances on the number of writhing induced in a/b introduction to 0.75% acetic acid in mice. Shows the average value±the standard error of the mean of (M±m) into groups of 10 animals.

Table 1
N g.The investigated substances and dosageThe average number of "cramps" for 15 min and standard error to it, M±mNo significant difference with the control
1Control: acetic acid33.07±1.221
2Buspirone 10 mg21.70±0.12p<0,002
3Doxepin 25 mg23.80±0.91P>0.04 (nd)
5Buspirone 5 mg + Doxepin 10 mg14.15±0.68p<0,001
6Buspirone 10 mg + Doxepin 25 mg11.90±1.85P<0,001

Statistical analysis of the results shows that the combination of substances Buspirone + Doxepin causes a statistically significant decrease in the number of writhing in mice. Indicators a one-way ANOVA were: F2,29=103,7 (p<0.0001), further analysis is Astia individual groups using the test Bonferroni revealed a highly reliable effect of combination doses of Buspirone 5 mg + Doxepin 10 mg (p< 0.001) and Buspirone 10 mg + Doxepin 25 mg (p<0,001).

Analysis of the effect of a separate input Buspirone also revealed a statistically significant inhibitory effect dose of Buspirone 10 mg

Doxepin dose of 25 mg also had a dampening effect (p<0,001, t-test t-test) at the agony caused by acetic acid in mice.

A further result of the analysis was to compare the effectiveness of the combination of Buspirone + Doxepin with action separately entered Buspirone and Doxepin. This applies to dvukhmotorny analysis of variance with one factor was "substance" and another factor - "dose".

A table to compare the actions of the combination of Buspirone and Doxepina at the agony caused by acetic acid in mice. The table shows the average number of writhing in 15 minutes observations ± standard error of the average for a group of 7 animals.

Table 2
1st Factor: substance2nd Factor: dose mg/kg
210
Buspirone + Doxepin14.15±0.6811.90±1.85
Buspirone vs. Doxepin 21.70±0.1223.80±0.91

The analysis showed a highly reliable impact factor of a substance is a strong influence of dose, and the lack of interaction between "substance" x "dose". Thus, the combination of Buspirone + Doxepin statistically, the phrase" inhibits cramps caused by acetic acid than separately administered Buspirone and Doxepin. Statistical analysis showed a statistically significant effect of the combination. However, the analysis of Bonferroni revealed a statistically stronger effect of the combination of Buspirone 5 mg + Doxepin 10 mg Buspirone 10 mg + Doxepin 25 mg compared with doses of Buspirone 10 mg Doxepin 25 mg (p<0,001). The combination of Buspirone 5 mg + Doxepin 10 mg were not statistically different from the separately administered Buspirone 10 mg + Doxepin 25 mg

Conclusion

The results of the study demonstrate that the combination of substances Buspirone + Doxepin clearly and effectively reduce the number of writhing induced in a/b introduction to 0.75% acetic acid in mice. This dampening effect was realized after the introduction of combination Buspirone 5 mg + Doxepin 10 mg Buspirone 10 mg + Doxepin 25 mg strength of inhibitory action combination was statistically significantly superior effect of separately administered Buspirone and Doxepin in maximum doses. This marked statistical differences between doses combined the Nations Buspirone 5 mg + Doxepin 10 mg Buspirone 10 mg + Doxepin 25 mg, it is not revealed. Thus, the strength of inhibitory action on cramps caused in b/W the introduction of acetic acid, the most effective was the combination of Buspirone 5 mg + Doxepin 10 mg

EXAMPLE 1

The influence of the studied composition at the mechanical allodynia in animal models of neuropathic pain with neurodegeneration caused by chronic constrictive injury (HKP).

METHODS

Doxepin in the form of a substance is a white crystalline powder. This powder daily prepared solution for oral administration. The appropriate number of doxepin was dissolved in sterile saline solution (0.9% for injection).

Buspirone hydrochloride is a white crystalline powder. Also it is soluble in water. According to a similar pattern was prepared solution oral administration.

Doxepin in an amount of 10 mg Buspirone 5 mg, was dissolved in saline in a volume of 2 ml. Next to bring therapeutic concentrations to dose animals, bred by the formula: "(10 mlastname/70(srmas person))×7". Was 1 ml solution, which was administered to animals with the help of a gastric probe. The same dilution was applied separately to Doxepine in the dosage of 25 mg and separately for Buspirone in dosage 10 mg

Animals. In experiments were used are free from pathogenic agents adult saltycrax Wistar rats weighing 220-260 g Rats were kept in rooms with constant temperature (21-23°C) and lighting with a sufficient number of standard feed for rodents and water that the animals could consume without restrictions. Behavioral testing was performed during the light cycle.

Chronic constrictive injury (HKP): HKP created at the level of the mid thigh of the right hind limb. Four sterile absorbable ligatures of the surgical catgut (company Ethicon) was badly delayed around the surgically selected sciatic nerve under anesthesia. Sciatic nerves from control group with simulation of surgical exposure, exposed but not ligated. The location of the ligatures was established after attanasio animals, through inspection. Randomization into groups, alternative therapies and the treatment was carried out after 7-8 days after the operation.

Behavioral assessment using yarns von Frey.

Used strands/strips von Frey (von Frey), the so-called test von Frey in the area of innervation of the saphenous vein in the rear paws branches of the sciatic nerve. "A series of 10 calibrated monofilaments von Frey was randomly applied to the right hind paws of the animals to determine the threshold rigidity of the intensity of the stimulus needed to call the response of otdergivanija feet. Were ten Kali the training stimulus.

The definition of assessments conducted before, the so-called zero level after administration of the tested combinations after a certain period of time. The response of animals were used to calculate the 50% threshold otdergivanija legs, the so-called absolute threshold.

Research of efficiency

Learning

Were selected for the study a small sample of animals 4 animals per group; group - simulation control, chronic constrictive injury (HKP) with the introduction of fishriver, HKP with the introduction of the composition Doxepin-Buspirone, HKP with the introduction of Buspirone, HKP with the introduction of Doxepin.

Long-term study of the efficacy in neuropathic pain

The study was conducted over 7 days in groups of animals. Simulation control, chronic constrictive injury (HKP) with the introduction of fishriver, HKP with the introduction of the composition Doxepin-Buspirone, HKP with the introduction of Buspirone, HKP with the introduction of Doxepin oral introduced appropriate therapeutic agents.

The treatment combination Doxepin-Buspirone significantly weakened the value of allodynia in rats with HKP. It was also noted within 5 days from the start of treatment effect was manifested in a more stable form by using a combination Doxepin-Buspirone and also after the introduction. Short-term effectiveness does not always have to be, to value the positive quantity of drugs, used for pain of neuropathic origin.

The efficiency of the combination is also confirmed by the fact weakening hyperactively glial cells (astrocytes) in rats with HKP in the treatment combination Doxepin-Buspirone. After a 7-day monitoring of the groups of animals from each group research, 1, animals were taken animals (4 animals per group) from the control group with HKP, received only the carrier, and from HKP receiving ibudilast, from each group, then painlessly were euthanized to highlight tissues of the spinal cord in the lumbar spine and its coloration, to assess the activation of astrocytes. Increased, as a sign of increased activation of astrocytes, was observed in animals of group a model of neuropathic pain, in this case the animal with HKP. The animal taken from the group, which used a combination Doxepin-Buspirone showed marked reduction in the activation of glia, as measured by staining. Clinically it has been observed in the pronounced weakening of allodynia. Animals treated only Doxepin or only Buspirone was observed staining of glial cells, as a characteristic activity, similar to the picture of the animal from the control group.

Summary

In animal models of neuropathic pain, namely, HKP in rats, where the main parameter to evaluate is effektivnosti - this mechanical allodynia, regular daily administration of a combination Doxepin-Buspirone oral, led to a pronounced decrease in allodynia. therapeutic effect of such combination exceeds the effects of each of the active substances in monoprinting.

Comparative studies of combination Doxepin-Buspirone in animal models of persistent pain induced by Paclitaxel (INNS).

therapeutic effect of the combination Doxepin-Buspirone on mechanical allodynia was studied on animal models in rats, persistent pain induced by Paclitaxel, as described below.

METHODS

In substances, including the combination Doxepin-Buspirone were prepared as in the previous experiment. Substance gave every morning about 9 o'clock in the morning or in the afternoon (usually 3 hours a day).

Animals: experiments were used are free from pathogenic agents of adult male Wistar rats weighing 220-260 g Rats were kept in rooms with constant temperature (21-23°C) and lighting with a sufficient number of standard feed for rodents and water that the animals could consume without restrictions. Behavioral testing was performed during the light of day.

The Model Of Paclitaxel.

Neuropathic pain was induced by the introduction of intraperitoneal injection of 1 mg/kg Paclical is eaten in different days (0, 2nd, 4th and 6th). Attack pain was most pronounced about the 19th day after the administration of Paclitaxel. Introduction the control group, this group was 2, four animals in each group. And started in 19-th day, as a model of treatment (group 1)or day 12 (group 2), as a model preventive effect. The effect of therapy in relation to allodynia was determined, usually in the morning before the introduction of therapeutic substances to animals.

Behavioral assessment in the test von Frey

Test von Frey conducted in the area of innervation of the saphenous vein in the rear paws branches of the sciatic nerve as described in Example 1 for research on models HKP.

RESEARCH AND RESULTS

Study the effectiveness of combination for neuropathic pain in a multi-day model on animals.

Docupen in the amount of 10 mg Buspirone 5 mg, was dissolved in saline in a volume of 2 ml. Next to bring therapeutic concentrations to dose animals, bred by the formula: "(10 mlastname/70(srmas person))×7". Was 1 ml solution, which was administered to animals with the help of a gastric probe. The same dilution was applied separately to Doxepine in the dosage of 25 mg and separately for Buspirone dosage 10 mg

Mechanical allodynia measured every day before the first dose of a therapeutic in the substances.

The introduction of an investigational combination reduced the size of allodynia in rats treated with Paclitaxel.

The scheme is the introduction of the investigational combination with daily introduction, especially in the model of preventive treatment, showed a significant weakening of allodynia throughout the period of therapy, the results of elongation threshold reactions otdergivanija legs, which were determined each day before taking the drug. The cessation of the composition (therapy) returned rats in the initial state allodynia within 3 to 5 days.

Prevention of persistent pain induced by Paclitaxel.

Study of prophylactic introduction conducted by the same model with a multi-day study described above, however, the introduction of an investigational combination or introduction fishriver in the control group, was launched on the 12th day, which had the appearance of the first symptoms of allodynia. Treatment studied composition prevented the further development of persistent pain. Which was sold through the allodynia and reduced the initial manifestations of allodynia to such a level that was in a small deviation from the control group of animals which did not undergo toxic chemotherapy, while monoprinting included active substances such result was not called.

Summary

Inresult of the received data using a model of persistent pain may be argued, system introduction the study of the composition of the rats treated with Paclitaxel, weakens the intensity of the mechanical allodynia. The reduced severity of allodynia daily introduction the study of the composition is of long standing. It was established as a result of subsequent observations and measurements of the mechanical allodynia on the following day. However, it was noted that withdrawal of treatment led to the return of the original condition of allodynia rats on the 3rd day. It must be emphasized that the introduction of the study of the composition can prevent the development of neuropathy, as shown in the model allodynia caused by anti-cancer substance Paclitaxel.

Based on these data it is possible to make the following assumption.

Mechanical allodynia is a frequent and severe complication of chronic and/or persistent pain, observed in animal models and in humans suffering from chronic neuropathic pain. Thus, described herein are the first known discovery of possibilities for therapeutic combination for the treatment of various syndromes and types of chronic and/or persistent pain in mammals, particularly such syndromes characteristic symptom of which is mechanical allodynia.

EXAMPLE 2

Dosage forms

The dosage form can be recip is by using a known pharmaceutically acceptable substances. "Pharmaceutically acceptable" when used in connection with the invention compositions refers to molecular entities and other ingredients of such compositions that are physiologically tolerated and typically do not cause adverse reactions when administered to a mammal (e.g. human). As auxiliary substances can be used in liquid media such as water, saline solutions, aqueous dextrose solutions of glycerol and/or oils, including oils, petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and other oils. Suitable pharmaceutical carriers are described in the reference "Remington''s Pharmaceutical Sciences" by A.R. Gennaro, 20th Edition.

For oral administration in the form of tablets or capsules are used binding agents (for example, corn starch, polyvinylpyrrolidone or hypromellose, gum Arabic, tragakant or alginates), fillers (e.g. lactose, sucrose, glucose, mannitol, sorbitol and other sugars or sugar alcohols, microcrystalline cellulose, calcium sulfate or secondary acid phosphate of calcium), sliding substances (for example, magnesium stearate, talc or silica, stearic acid, sodium fumarate, glycerinated, calcium stearate and p), dezintegriruetsja agents (e.g., potato starch or sodium starch glycolate), wetting agents (e.g. sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, carboxymethylcellulose, polyethylene glycols, waxes, etc.

Tablets may be coated with sugar or polymeric membranes.

To prepare formulation in the form of soft gelatin capsules the active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substances using the above-mentioned excipients for tablets, for example lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules can be filled with liquid or semi-solid forms of medication.

Preparations for oral administration can be conveniently arranged to provide a modified release of the active compounds.

To stabilize the dosage forms can also add stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid).

For introducing the composition through inhalation convenient delivery method can be aerosol is prey, that is packing under pressure, or a nebulizer with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of the use of an aerosol under pressure, a single dose can be determined using the valve, allowing to deliver a measured amount of the drug. For use in inhaler or insufflator can be made capsules and cartridges of, for example, from gelatin, which contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

Can be custom made solutions for parenteral injection by injection in the form of aqueous solutions. These solutions may also contain stabilizing agents and/or buffering agents and conveniently be supplied in vials with different doses of drugs.

Standard dosage forms for rectal injection can be made in the form of suppositories containing the active components in a mixture with a neutral fat base, as well as in the form of a gelatine rectal capsules containing the active substance in a mixture with vegetable oil or paraffin oil.

Example tablets (but not exclusive)

buspirone 5 mg

doxein 10 mg

lactose monohydrate 200 mg

corn starch 50 mg

<> calcium hydrogen phosphate dihydrate, 10 mg

Aerosil 2 mg

sodium starch glycolate (type a) 8 mg

microcrystalline cellulose 110 mg

magnesium stearate 5 mg

1. The combination for the prevention, correction and treatment of pain associated with neurodegeneration and/or associated with somatoform disorders, characterized in that it consists of taken in therapeutically effective quantities of Buspirone and Doxepin.

2. The combination according to claim 1, characterized in that the pain is a persistent pain.

3. The combination according to claim 1, characterized in that therapeutically effective amount is for Buspirone 0.03 mg/kg and for Doxepin 0.05 mg/kg

4. The combination according to claim 1, characterized in that it includes the additional pharmaceutically acceptable substances.

5. The combination according to claim 4, characterized in that it is presented in the form of tablets, including the sublingual form, capsules, dosage forms with modified release, injectable forms, suppositories, powder for preparation of a drink, drops, including nose drops, transdermal, transbukkalno, aerosol form.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular, to surgery and can be applied for prolonged anesthetisation in early post operational period of patients with haemorrhoids of III-IV stage. For this purpose 1% solution of morphine in dose 0.1 ml per 10 kg of weight is introduced one time per day in peridural space between vertebras L2-L3 , or L3-L4 through catheter. Said quantity is diluted with 6 ml of physiological solution. Such volume of narcotic medicine ensures effective anesthetisation within 18-20 hours. After that, after said time expiry, 6.0 ml of 2% solution of lidocaine are additionally introduced, which ensures anesthetisation effect within 4 hours. Claimed procedure is repeated on 2 and 3 day in the same succession.

EFFECT: invention ensures prolonged anesthetisation in early post operational period within 3 days, due to reduction of introduced narcotic analgesic (morphine) dose, which makes it possible to reduce probability of development of addiction and development of side effects in patients.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (hetero)arylcyclohexane derivatives of formula , where values of Y1, Y1', Y2, Y2', Y3, Y3', Y4, Y4', R1-R3 are given in the first claim, having affinity for the µ- opioid receptor and ORL 1-receptor.

EFFECT: enabling use of the derivatives in drugs for treating pain.

10 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 4-aminocyclohexane derivatives of general formula I: where: R1 and R2 independently denote C1-3-alkyl, H or R1 and R2 together with an N tom form a (CH2)3, (CH2)4 ring; R3 optionally denotes a phenyl or thienyl linked through a C1-3-alkyl chain, each unsubstituted; or an unsubstituted C1-6-alkyl; R4 denotes indole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, optionally mono- or multi-substituted with a substitute selected from a group comprising F, CI, Br, CN, CH3, C2H5,' NH2, tert-butyl, Si(ethyl)3, Si(methyl)2(tert-butyl), SO2CH3, SO2-phenyl, C(O)CH3, NO2, SH, CF3, OCF3, OH, OCH3, OC2H5, N(CH3)2; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers or separately an enantiomer or diastereomers; bases and/or salts of physiologically compatible acids or cations; as well as a drug based on compounds I for treating neuropathic pain.

EFFECT: improved properties.

14 cl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to therapy and neurology, and concerns using fatty acid/fatty acids Omega-3 as a part of an analgesic drug. That is ensured by administering an analgesic and/or preventative drug that contains the above acid/acids in the free or bound agent in the amount of more than 2 g. The administration is single oral or intravenous.

EFFECT: administering Omega-3 fatty acid/fatty acids in the above doses provides the analgesic effect regardless of causes of the pain.

10 cl, 3 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to synthetic peptide amides of formula I

, which are agonists of a kappa-opiate receptor and show a low inhibition degree P450 CYP and lower brain penetration degree. Besides, the invention refers to pharmaceutical compositions containing the above compounds.

EFFECT: possibility of using compounds for prophylaxis and curing of pain and inflammation, which are related to different diseases and states.

17 cl, 9 tbl, 8 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted quinoxaline-type bridge piperidine compounds of formula

,

or pharmaceutically acceptable derivatives thereof, where: a equals 0; b is an integer selected from 0 or 1; each R5 is independently selected from -H; R1 is -(C9-C14)bicycloalkyl, each substituted with 1 or 2 independently selected R3 groups; each R3 independently selected from -(C1-C4)alkyl. The invention also relates to a pharmaceutical composition, capable of modulating ORL-1 receptor function, based on said compound.

EFFECT: obtaining novel compounds which can be used in medicine to treat pain, memory disorder, obesity, constipation, depression, dementia, Parkinsonism, anxiety, cough, diarrhoea, high blood pressure, epilepsy, anorexia, urinary incontinence or drug dependence.

27 cl, 2 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted indole derivatives of formula , where A and B are independently CH2 or C=O, X is indolyl, unsubstituted or mono- or polysubstituted; T is (CR5a-cR6a-c)n, n=1 or 2. Q is (CR7a-cR8a-c)m, m=0, 1 or 2, the values of the rest of the radicals are given in claim 1, which act on the ORL1 receptor.

EFFECT: improved method.

13 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of general formula , with values of radicals, presented in description, as well as in form of separate stereoisomer or their mixture, free compounds and/or their physiologically compatible salts, which have affinity to ORL 1 - receptor and µ-opioid receptor. Invention also relates to medical preparation, which contains said compounds, and application of said compounds for obtaining medical preparation for treatment of pain, panic attack, stress and syndromes, associated with stress, depressive diseases, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, malfunctions of education and memory (as nootropic agent), abstinent syndromes, abuse and/or addiction to alcohol and/or drugs and/or medications, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, itch, migraine, hearing impairment, disturbance of gastrointestinal tract motility, nutrition irritability, anorexia, bulimia, locomotive malfunctions, diarrhea, cachexia, enuresis, or as muscle-relaxant, anticonvulsive preparation or analgesic medication, or for combined introduction in treatment with opioid analgesic, or anesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulation of motion activity, for modulation of neuromediator release and treatment of associated with it neurodegenerative diseases, for treatment of abstinence syndromes and/or for reduction of possibility of becoming addicted to opioids.

EFFECT: obtaining novel compounds.

10 cl, 36 ex

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

EFFECT: drug form by invention is stable to rupture and stable against abuse.

16 cl, 21 dwg, 6 ex

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to a storage-stable composition containing PTHrP (Parathyriod Hormone-Related Protein), and to a method for using a PTHrP analogue and PTHrP compositions declared in accordance with the present invention for bone mass gain and bone tissue improvement.

EFFECT: composition is storage-stable, and can be generally stored at room temperature for at least several weeks that facilitates the easy parenteral infusion into the patients.

28 cl, 2 dwg, 7 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: what is presented is using 1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide as an active drug base for the purpose of correcting the nitroxydergic malfunctions.

EFFECT: higher activity of endothelial NO-synthase and high NO production under the action of the declared agent that has higher efficacy as compared to the known analogues, and has no side effects.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: what is used is an oral composition containing a polyguanidine compound expressed by formula (I) and orally acceptable carrier. There are also presented: a method for the target delivery of the composition into the oral cavity, a method for inhibition of the development and prevention of dental caries, a method for the treatment of caries lesions.

EFFECT: group of invention provides the antimicrobial, anti-caries action.

19 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is injected formed in situ depot-composition, which includes absorbable polymer, polyethyleneglycol with molecular weight 450<MW<650 Da and with end groups, selected from methoxy and ethoxy, characterised by temperature of consolidation between 8° and 20°C, pharmaceutically active substance and, optionally, auxiliary substance. Pharmaceutically active substance is selected from small organic molecules, peptides, polypeptides, proteins, carbohydrates, oligonucleotides, DNA and RNA. Preferably, active substance is somatostatin analogue. Preferably polyethyleneglycol dimethyl ether with molecular weight 500 Da is applied.

EFFECT: compositions by invention are stable in storing, are injected without difficulties, are characterised by low haemolytic and toxic potential.

19 cl, 8 dwg, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, pharmaceutics and nanotechnology, more specifically to a pharmaceutical composition of fluconazole that is an antifungal agent from the group of triazole prepared by chemical synthesis, and a method for preparing it. The presented pharmaceutical composition possessing antifungal activity containing fluconazole coating nanotubes of the various external tube diameter - 60-160 nm, the internal diameter - 10-60 nm and the length - 100-5000 nm in the following relations, wt %: fluconazole - 50-60; alumosilicate nanotubes - 40-50. The method for preparing the pharmaceutical composion consists in the fact that fluconazole is mixed with the alumosilicate nanotubes with the aqueous ethanol environment, and mixing the prepared suspension and evaporating ethanol.

EFFECT: using fluconazole applied on the nanotubes enables developing new ointments and gels for treating fungal diseases with the reduced amount of fluconazole.

2 cl, 2 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to pharmaceutical compositions and pharmaceutical kits for treating bacterial infections, and a new method for treating the diseases associated with bacterial infections, including tuberculosis. A pharmaceutical composition containing Rifalazil as rifamycin and Cycloferon as an interferon inducer in pharmacologically effective doses. The invention also concerns a pharmaceutical kit for treating the diseases caused by bacterial infections. The kit comprises rifamycin in pharmaceutically effective doses in the form of tablets, capsules or injections. Cycloferon is presented in the form of tablets, capsules or injections; instructions for administering the ingredients of the same pharmaceutical kit are also provided.

EFFECT: preparing the pharmaceutical compositions and pharmaceutical kits for treating bacterial infections, and presenting the new method of treating the diseases associated with bacterial infections, including tuberculosis.

4 cl, 2 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a combination for treating and/or preventing manifestations of mental, cognitive, behavioural and neurological disorders accompanying organic CNS diseases of various genesis, characterised by the fact that it contains melatonin in the amount of 0.01 mg to 50 mg and memantine in the amount of 0.01 to 100 mg.

EFFECT: invention provides creating the effective combined agent relieving the manifestations of the mental, behavioural, cognitive disorders accompanying the organic CNS diseases of various genesis.

3 cl, 2 ex, 7 tbl

Esmolol concentrate // 2493824

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is composition of esmolol in form of concentrated solution, which includes: a) from 40 to 60 mg/ml of esmolol hydrochloride; b) from 0.01 to 2 m of buffer agent; where value of solutions pH is in the interval from 4.0 to 6.0. Solution is free from agent, which regulates osmotic pressure. Solution is sterile, ready for application and packed into container. Claimed composition of esmolol is safer in comparison with the ones used at present time, which makes it possible for attending doctor to select volume of shock dose for direct injection to patient in more flexible way. Claimed is medical product, which includes concentrated esmolol solution, placed into container, and package, which contains container and application instruction.

EFFECT: application of esmolol composition by invention ensures reduction of possible negative for health consequences resulting from wrong dosage of esmolol concentrate compositions of previous level.

9 cl, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to ophthalmology, and can be applied for treatment of different diseases of eyes. Eye drops contain methylene blue, diphenhydramine hydrochloride, naphazoline hydrochloride, hydroxypropylmethylcellulose, boric acid, polyvinylpyrrolidone and distilled water in defined ratio of components.

EFFECT: invention ensures non-toxic and non-irritating anti-inflammatory, anti-infectious, anti-allergic action.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a method of preventing and treating oral inflammation following a dental surgery, comprising in applying a drug preparation on an incisional wound daily in a patient underwent the implantation procedure and characterised by the fact that the drug preparation used represents a preparation of the strain lactobacillus plantarum 8P-AZ and/or B.bifidum in a dose of at least 10 million live lactic acid bacilli and/or bifidus bacteria.

EFFECT: invention provides simplifying the method of preventing and treating the oral inflammation by making it unnecessary to prepare the drug used if antibiotics are avoided.

2 cl, 9 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

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