RU2433825C2 - Method of treating neuropathic pain and associated with it syndromes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be applied for treatment of chronic neuropathic pain. For this purpose introduced is therapeutic dose of ibudilast, effective for reaching maximal concentration of it in plasma, at least, nearly 125 ng/ml. It is also possible to introduce ibudilast in combination with additional medication, effective in treatment of chronic neuropathic pain.

EFFECT: introduction makes it possible to relieve chronic neuropathic pain of various genesis.

28 cl, 1 tbl, 5 ex, 6 dwg

Description

FIELD OF THE INVENTION

The present invention relates to methods for treating neuropathic pain. In particular, the present invention relates to methods for treating or preventing neuropathic pain and related symptoms by administering an ibudilast preparation, hereinafter (3-isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine).

BACKGROUND OF THE INVENTION

In recent years, the tactics of dealing with pain has become a focus of attention in occupational medicine, which can partly be explained by an increase in the proportion of older people in the population, lifestyle problems, and an increase in the number of patients reportedly suffering from pain. Pain is both a sensory and emotional experience, which is usually associated with tissue damage or inflammation. Typically, pain is divided into two general categories: acute pain and chronic pain. Both types of pain differ in etiology, pathophysiology, diagnosis, and, most importantly, treatment methods.

Acute pain does not last long and, as a rule, is caused by an easily recognizable cause. Patients with acute pain tend to respond well to drugs. In contrast, in chronic pain, which, according to medical criteria, is defined as pain lasting from 3 to 6 months or longer, it is often not possible to find an obvious pathology in the body, although patients can actually suffer from lingering pain that lasts for months or even years after the initial damage. If acute pain is mainly amenable to medical treatment, then chronic pain is usually much more difficult to treat, and usually such treatment requires the attention of a specialist. According to the American Chronic Pain Association, more than 86 million Americans suffer from chronic pain, and medical strategy and tactics for chronic pain have long been classified as unmet needs. In most cases, chronic pain is inherently neuropathic (also called neuralgia). For example, neuropathic pain can manifest as a burning sensation, puncture, or shock.

Unfortunately, the tactics of managing patients with neuropathic pain are at best contradictory and often ineffective. This is partly due to the subjective nature of pain, but is also associated with poor diagnosis, especially in cases where chronic pain does not have a clear connection with nerve damage or other organic pathology. In addition, when assessing historical perspectives, we must admit that too few drugs have been developed to treat chronic pain, if any. Instead, modern medicines used to treat chronic pain are “borrowed” from the practice of treating other diseases: most often these are antiepileptic drugs and antidepressants.

First-line drugs for treating chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. With prolonged use of opioids, unwanted side effects can be observed, such as drug tolerance, chemical dependence, and even physiological addiction. Of all the chronic pain regimens currently in use, at best, 30% are effective, giving significant pain relief, but over time their effectiveness may be lost. Although there are many pharmacological agents for treating neuropathic pain, a radical therapy has not yet been found.

In cases where treatment with one drug is unsuccessful, they often try to switch to second-line combination therapy. For example, such combination therapy may consist of using an opioid agent together with an auxiliary analgesic, although the relative doses of each drug are often the subject of lengthy clinical trial trial and error. In many cases, triple drug therapy is needed. Such therapy usually involves a combination of a tricyclic antidepressant, an anticonvulsant, and systemic administration of a local anesthetic. However, if for treatment it is necessary to use several pharmacological agents, then the discipline of patients in the performance of medical appointments is significantly reduced. Recently, the results of a randomized scientific study using a combination of morphine and gabapentin to suppress neurogenic pain have been published (Gilron, I., et al., New Eng. J. of Medicine, Vol. 352: 1281-82, No. 13, March 31, 2005).

In addition, it is important to consider not only general pain relief, but also the type of pain relief. For example, chronic pain is typically seen as allodynia or hyperalgesia. Allodynia is a sensation of pain when exposed to a stimulus that is not normally considered painful. Usually, allodynia is caused by a physical stimulus, and therefore it is considered as tactile or mechanical allodynia. Hyperalgesia is an abnormally heightened sensation of pain when exposed to a normal pain stimulus. Hyperalgesia is observed when many stimuli are exposed, but most often it is the patient's response to thermal and cold stimuli. It is important to note the opinion of doctors that modern medicines are more effective in alleviating hyperalgesia, while most patients suffer from allodynia, especially mechanical allodynia.

In addition to poor and / or intermittent effectiveness, these drugs have several other undesirable properties, for example, adverse side effects, insufficient duration of action, and also great difficulties in the selection and titration of doses.

The most common side effect of non-opium drugs is sedation or drowsiness. According to data that can be gleaned from the packaging inserts of such drugs, a sedative effect is manifested in 20-30% of patients. As mentioned above, the very risk group suffering from chronic pain are the elderly. For older people, a pronounced and stable sedative effect is associated with the risk of other complications, mainly with impaired motor function. Such a violation of the motor function can be manifested by frequent falls and inability to perform everyday activities, such as driving a car.

Insufficient duration of action is also considered a limitation for most drugs. This is especially important because pain, and especially night pain, can lead to depression, insomnia and other pathological manifestations that reduce the patient’s overall quality of life. The results of a recent study suggest that patients with chronic pain, as well as concomitant major depression and insomnia, have the highest level of pain-related disorders. In addition, this study found that insomnia in the absence of major depression also shows an association with severe physical pain and malaise (Wilson et al., Clin. J. Pain. 2002 Mar-Apr; 18 (2): 77-83) . Therefore, the ability to relieve pain for a long time, including at night, is an important factor in the effectiveness of drugs for neuropathic pain. Medicines for pain relief, in particular gabapentin, to achieve a therapeutic effect, it is necessary to take one or even several times at night - this disrupts sleep and worsens the overall quality of life of patients.

And finally, the selection of doses of essential drugs, in particular gabapentin, can be quite difficult. For example, the recommended starting dose of gabapentin for adults with postherpetic neuralgia is a single dose of 300 mg on the 1st day, 600 mg on the 2nd day (2 times 300 mg) and 900 mg on the 3rd day (3 times 300 mg ) If these doses do not bring relief, subsequent titration of the daily dose up to 1800 mg (taken in three fractional parts per day) is possible until the therapeutic effect is achieved. In clinical trials to study the effectiveness, a comparable effect of different doses in the range from 1800 to 3600 mg per day was demonstrated (complete information on the prescription of the drug Neurontin ^® in the USA). Approximately equally sophisticated dose selection schemes with similar difficulties are characteristic of other antiepileptic drugs and antidepressants - they make it difficult to clearly follow medical prescriptions, increasing the chances of improper dosage and even overdose of drugs. In addition, the abolition of such drugs is also fraught with a number of problems. For example, the complete information about the prescription of Neurontin ^® in the USA states the following: “... When a dose is reduced, the drug is discontinued or replaced with another drug, gradual changes that take at least 1 week are required."

Neuropathic pain (NB) is usually considered as a chronic condition with a violation of adaptation, in which the pathology of the nerves serves as a source of pain, and often the intensity of the pain far exceeds the scale of this pathology. Pathology of the nerves may be due to physical damage, such as trauma or chemical damage, for example, as a result of chemotherapy (for example, Paclitaxol). Neuropathic pain of this type is an important component of many syndromes of various etiologies, a common sign of which is the development of a long and pronounced pain status. Such conditions include spinal cord injury, postherpetic neuralgia, diabetic neuropathy, phantom pains in the extremities, pain in the stump with neuroma formation, postischemic pain (stroke), fibromyalgia, reflex sympathetic dystrophy (RSD), complex regional pain syndrome (SJS), neuropathic pain induced by chemotherapy for cancer, herniated discs, trigeminal neuralgia and others.

However, it has recently been found that neuropathic pain can also occur in the absence of obvious damage at the level of nerves. These conditions include AIDS and pain like mirror image. The presence of overt chronic pain in the absence of a recognizable neural pathology has generated increased interest in the role of glial cells in the manifestation of neuropathic pain status (Watkins and Maier (2004) Drug Disc. Today: Ther. Strategies 1 (1): 83-88). In a narrower sense, recent studies have shown that glial cells release neurotransmitters that transmit pain information to the spinal cord and, even more impressive, release substances that increase the excitability of pain neurons in the spinal cord. These substances, the so-called pro-inflammatory cytokines, create and support an excessive or pathological pain response. Blocking glia activation reduces the activity of pro-inflammatory cytokines and leads to the reverse development of pathological pain. So far, there are no officially approved drugs for use, the mechanism of the therapeutic effect of which with neuropathic pain is presumably associated with a weakening of the pathological effects of glia. Molecules that play the role of glia attenuators can be of great importance in the treatment of neuropathic pain.

The small molecule, ibudilast, (3-isobutyryl-2-isopropylpyrazolo [l, 5-a] pyridine) is a non-selective inhibitor of the cyclic nucleotide phosphodiesterase (PDE) (Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Ibudilast also acts as an anti-inflammatory LTD4 receptor antagonist, a PAF antagonist (platelet activating factor), and a vasodilator (Thompson Current Drug Reports). It is believed that ibudilast activates a neuroprotective mechanism in the central nervous system of mammals, apparently by suppressing the activation of glial cells (Mizuno et al. (2004) Neuropharmacology 46: 404-411). Ibudilast is widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. Marketing indications for ibudilast in Japan include its use as a vasodilator, a treatment for allergies, regeneration of eye tissue, treatment of eye diseases, including allergies (Thompson Current Drug Reports). Recent clinical studies have examined its use in the treatment of multiple sclerosis, an inflammatory disease of the central nervous system (News.Medical.Net; Pharmaceutical News, 2 Aug 2005). Despite the fact that the available literature describes the use of ibudilast for many indications, as far as the applicant knows, its use for the treatment of neuropathic pain and related conditions, including allodynia, is still practically unexplored.

In light of the above shortcomings in modern approaches to the treatment of chronic pain, there is an urgent need to improve the compositions of drugs and methods of treating pain, in particular neuropathic pain and related symptoms, especially neuropathic pain associated with certain conditions, for example fibromyalgia, among others, approaches should ideally overcome one or more of the problems associated with existing treatments for chronic pain. The present invention meets these needs.

SUMMARY OF THE INVENTION

The presented invention is associated with a new approach to the treatment of neuropathic pain and is based on the unexpected discovery of the fact that neuropathic pain can be successfully treated or prevented using ibudilast. Using standard models of neuropathic pain, the inventors found that the systemic use of ibudilast is effective in preventing and alleviating, if not completely eliminating, chronic neuropathic pain, for example, associated with various syndromes. In some cases, the use of ibudilast can provide effective treatment for conditions associated with neuropathic pain that are not amenable to existing methods of therapy. In addition, it was found that ibudilast is effective for significantly reducing mechanical allodynia, and this effect continues at night - thus ibudilast has a significant advantage over existing medicines for chronic pain, in particular gabapentin. Such a long-term therapeutic effect is uncharacteristic for most drugs used for neuropathic pain.

Thus, in one respect, this invention provides a method of treating mammals that suffer from neuropathic pain by administering to these subjects a therapeutically effective amount of ibudilast.

In one embodiment of the invention, this method includes the step of selecting a mammal suffering from neuropathic pain and then administering to the subject an initial therapeutic dose of ibudilast that is effective enough to achieve a maximum plasma concentration of ibudilast of the order of 100-125 ng / ml or higher, as a result of which the subject will experience relief (i.e., either a weakening, or a decrease, or elimination, or the reverse development of neuropathic pain).

Mammals that can be selected for such treatment include subjects suffering from postherpetic neuralgia, trigeminal neuralgia and neuropathic pain accompanying any pathological condition from the following group of conditions: herpes, HIV infection, traumatic nerve damage, stroke, post-ischemic condition, fibromyalgia , reflex sympathetic dystrophy, complex regional pain syndrome, and neuropathic pain induced by cancer chemotherapy.

In one or more alternative embodiments of the invention, the initial therapeutic dose of ibudilast is that dose which is sufficient to achieve a maximum plasma concentration of ibudilast of 100, 125, 150, 175, 200, 225, 250, 275 or 300 ng / ml.

In another embodiment of this method, ibudilast is used in daily doses ranging from 30 to 200 mg per day or from 30 to 100 mg per day.

The therapeutic dose can be achieved with a single daily dose (i.e., in a single dose), twice daily dose (i.e. in two divided doses), triple daily dose or when using multiple doses over a certain period of time: several days, several weeks or even a few months. Such an introduction is typical for a period of time sufficient to achieve the desired result: reduction, and in the ideal case, elimination or even reverse development of neuropathic pain. Approximate options for the duration of treatment: at least about one week, from 1 week to 1 month, from two weeks to 2 months, up to about 6 months, up to about 12 months, and even longer. In one particular embodiment of the invention, the treatment lasts from about 1 week to about 50 weeks.

In a preferred embodiment of the method, the administration of the drug continues for such a time that allows you to achieve the desired result, i.e. elimination of neuropathic pain.

In yet another embodiment of the invention, the administration of ibudilast has the effect of reducing the intensity of neuropathic pain experienced by the subject for at least 16 hours after administration of the drug.

In a further embodiment of the method, the administration of ibudilast is not accompanied by the administration of an antiemetic.

In a further embodiment of the method, ibudilast is used in combination with at least one other agent effective in treating pain. Such medicines include, but are not limited to, gabapentin, memantine, pregabalin, morphine and related opiates, cannabinoids, tramadol, lamotrigine, carbamazepine, duloxetine, milnacipran, and tricyclic antidepressants. In a preferred embodiment, the second drug used to treat neuropathic pain has a different mechanism of action than ibudilast.

In another embodiment, ibudilast, used alone or as part of combination therapy, is introduced into the body either systemically or centrally (for example, intrathecal, i.e. into the cerebrospinal fluid surrounding the spinal cord). Such an introduction of ibudilast creates a new mechanism for weakening pathological disease states, potentially associated with suppression of glial activation.

According to another embodiment of the invention, ibudilast is administered systemically, for example, via intravenous, subcutaneous, oral, intranasal, sublingual or other systemic routes, and is used for mammalian subjects, for example for humans, for the treatment of neuropathic pain, for example a neuropathic pain syndrome.

In another aspect, the invention provides a composition or combination for treating neuropathic pain. The composition includes a combination of the following components: (i) ibudilast and (ii) at least one additional agent effective for treating neuropathic pain, each component either being in a single composition or dosage form (e.g., a mixture), or it is single object (for example, in a set).

The composition in this invention may optionally include one or more pharmaceutically acceptable excipients.

In a further aspect, the invention provides a kit consisting of a combination of drugs for treating neuropathic pain or a syndrome associated with it and comprising (i) ibudilast and (ii) at least one additional agent effective for treating neuropathic pain, these components can be used simultaneously, sequentially or separately.

It is understood that any of the features of the invention described herein is applicable to any and each of the options described herein, unless specifically indicated otherwise.

Additional objectives, advantages and new features of the invention will be presented in the following description and will be partly obvious to people who are knowledgeable in this field when reading, or can be understood as a result of the practical use of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

ХКП 35% ПЭГ400 в солевом растворе

ХКП с 10 мг/кг ибудиласта

ХКП с 7,5 мг/кг ибудиласта

ХКП с 2,5 мг/кг ибудиласта

n=4 на группу при имитации и ≥ 5 на группу при ХКП. *=p < 0,05 по сравнению с векторным контролем по t-критерию Стьюдента.FIGURE 1 represents the period of action of the drug and the dose dependence of the therapeutic response to weaken mechanical allodynia with intraperitoneal (i / p) administration of ibudilast twice a day using a rat model of neuropathic pain in the presence of chronic constrictive damage (CKP) described in Example 1. Pain is indicated at the 50% withdrawal threshold for von Frey fibers. Data points represent averages with standard error (+/-). Simulation with 35% PEG in saline

HKP 35% PEG400 in saline

CKD with 10 mg / kg ibudilast

CKD with 7.5 mg / kg ibudilast

CKP with 2.5 mg / kg ibudilast

n = 4 per group for simulations and ≥ 5 per group for CKD. * = p <0.05 compared with vector control by t-student test.

FIG.2 represents the period of action of the drug and the dose dependence of the therapeutic response to weaken mechanical allodynia with the oral administration of ibudilast twice a day using the rat model of neuropathic pain against chronic constrictive damage (CKP) described in example 1. The pain is indicated by 50% the cancellation threshold for von Frey fibers. Data points represent averages with standard error (+/-). Vector control simulation (10% HCO-60, 10% PEG400, saline) (filled circle); HKP with vector control (open triangle); CKP with 50 mg / kg ibudilast (filled triangle). n ≥ 5 per group. * = p <0.05 compared with vector control by t-student test.

имитация с 10 мг/кг ибудиласта

ХКП с 10 мг/кг ибудиласта

n≥5 на группу.FIG.3 represents the period of action of the drug and the weakening of mechanical allodynia with twice daily intravenous administration of ibudilast on the rat model of Chang's neuropathic pain with a determination of 50% withdrawal threshold when evaluated by von Frey fibers. The details of the experiment are presented in Example 2. Data points include average values with a standard error interval (+/-). Simulation with 35% PEG in saline

imitation with 10 mg / kg ibudilast

CKD with 10 mg / kg ibudilast

n≥5 per group.

таксол + 7,5 мг ибудиласта (закрашенный кружок). n ≥ 5 на группу для животных с аллодинией и ≥2 на группу для животных в контрольной группе без воздействия таксола. Точки данных по средним величинам в группе ибудиласта на 22-й, 24-й и 25-й день статистически значимо отличаются от векторного контроля по t-критерию Стьюдента. ФИГ.4B представляет материалы другого исследования и отображает предупреждение развития аллодинии в той ситуации, когда лечение ибудиластом (как на ФИГ.4A) начиналось в самой ранней стадии развития невропатии, индуцированной химиотерапией рака (на 12-й день после начала лечения таксолом). Точки данных представляют средние величины со стандартной ошибкой (±) при измерении аллодинии на задней конечности. Контрольные животные (крысы), которым не вводили таксол, но вводили вектор таксола, а затем вектор ПЭГ в солевом растворе (треугольник) или ибудиласт (ромб) сравнивались с крысами, получавшими таксол, а затем ПЭГ/вектор (черный квадрат) или ибудиласт два раза в день из расчета 7,5 мг/кг интраперитонеально (кружок). FIGA and 4B represent the period of action of mechanical allodynia on a rat model of neuropathic pain induced by taxol with a determination of 50% withdrawal threshold. See example 3. Ibudilast was administered twice a day, and allodynia was measured before the morning administration of ibudilast. FIG. 4A depicts the attenuation of allodynia after the complete development of taxol-induced neuropathy. Data represent mean allodynia on both hind legs. Data points represent mean values with standard error (±): Taxol + 35% PEG in saline

taxol + 7.5 mg ibudilast (filled circle). n ≥ 5 per group for animals with allodynia and ≥2 per group for animals in the control group without exposure to taxol. The data points for the average values in the ibudilast group on the 22nd, 24th and 25th day are statistically significantly different from the vector control according to the Student t-test. FIG.4B presents materials from another study and displays a warning of the development of allodynia in the situation when treatment with ibudilast (as in FIG.4A) began at the very early stage of development of neuropathy induced by cancer chemotherapy (on the 12th day after the start of treatment with taxol). Data points represent mean values with a standard error of (±) when measuring allodynia on the hind limb. Control animals (rats) that were not injected with taxol but introduced the taxol vector, and then the PEG vector in saline (triangle) or ibudilast (rhombus) were compared with rats treated with taxol, and then PEG / vector (black square) or ibudilast two once a day at the rate of 7.5 mg / kg intraperitoneally (circle).

FIGS. 5A and 5B represent the pharmacokinetics of ibudilast and its tissue distribution in rats after intraperitoneal (5A) or oral (5B) administration of this drug, as described in Example 4. Data points represent the average concentration of ibudilast at each time point and in each representative tissue. Plasma and tissues are indicated on the legend insert to the figure. N = 3 rats per time point. The pharmacokinetic parameters of nonlinear analysis using the WinNonlin program are described.

FIG.6 represents the immunochemistry of glial fibrillar acid protein (GFAP) in the lumbar spinal cord in control rats with CKP (vector) and in animals treated with ibudilast. Starting from the eighth day after surgical CKP, rats received ibudilast (7.5 mg / kg) or vector control (35% PEG in saline) and / n twice a day for 5 days. The slides shown represent the results of an examination of 4 animals in each group of the experiment at a 40-fold increase. Left side = animal from the vector control group; right side = animal receiving ibudilast.

DETAILED DESCRIPTION OF THE INVENTION

The practice of using this invention implies, unless otherwise indicated, traditional methods of chemistry, biochemistry and pharmacology, with sufficient competence in these areas. These methods are fully explained in the literature. See, for example, AL Lehninger, Biochemistry (Worth Publishers, Inc., current supplement); Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc., current supplement); J. March, Advanced Organic Chemistry (McGraw Hill, current supplement); Remington: The Science and Practice of Pharmacy, A. Gennaro, Ed., 20 ^th Ed .; Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, LL Limbird, A. Gilman, 10 ^th Ed.

Thus, all publications, patents, and patent applications cited herein, both above and below, are incorporated herein by reference in their entireties.

Definitions

Before describing the invention in full detail, it is necessary to understand that it is not limited to special methods of administration, special contingents of patients, etc., since both can vary, as will be seen from the accompanying descriptions and illustrations.

It should be noted that the singular forms used in the description of the invention and in the claims include the plural objects of reference, unless the context clearly indicates otherwise. So, for example, a reference to a “drug” includes both one drug and two or more similar or other drugs, a link to an “optional excipient” refers to either one excipient of choice, or two or more similar or other optional fillers, etc.

The following terminology will be used in the descriptions and claims of the present invention in accordance with the following definitions.

A “pharmaceutically acceptable excipient or carrier" is an excipient that may optionally be included in the compositions of this invention without causing significant adverse toxicological effects in the patient.

The term “pharmaceutically acceptable salt” includes, but is not limited to, amino acid salts, salts prepared from inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide and nitrate, or salts prepared from the corresponding inorganic acid in any of the above forms, for example, hydrochloride, etc., or salts prepared on the basis of organic acids, for example, malate, maleate, fumarate, tartrate, succinate, ethyl succinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, paratoluene sulfate, palm t, salicylate and stearate, as well as estolate, gluceptate and lactobionate. Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).

The terms “active molecule” or “active agent” in this text means any agent, drug, compound, composition of a substance or mixture that produces a certain, often useful, pharmacological effect that can be demonstrated in vivo or in vitro. These include food products, food additives, nutrients, food products with the additives included in the composition, drugs, vaccines, antibodies, vitamins and other beneficial agents. In this text, these terms mean any physiologically or pharmacologically active substance that produces a local or systemic effect in the patient's body.

The terms “essentially” or “mainly” mean an almost complete amount, for example 95% or more.

The terms “optional” or “optionally” mean that the fact described after them may or may not occur, so the description includes such cases when the fact occurs, and such cases when the fact does not occur.

The term “pathological pain” means any pain caused by a pathological nature, for example, functional disorders and / or pathological changes, injuries, burns, etc. One form of pathological pain is “neuropathic pain,” which is pain that was originally associated with nerve damage, but that continued or was complicated by other mechanisms, including glial cell activation. Examples of pathological pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain, pain due to irritable bowel or other diseases of internal organs, endometriosis pain, phantom limb pain, complex regional pain syndromes , fibromyalgia, lower back pain, cancer pain, pain as a result of infection, inflammation or trauma to the peripheral nerves or central nervous system, pain with multiple sclerosis, pain at infringement etc.

The term “hyperalgesia” means an excessively heightened sensation of pain, i.e. pain as a result of increased pain sensitivity. Examples of hyperalgesia include, but are not limited to, cold or thermal hyperalgesia.

“Hypalgesia” (or “hypoalgesia”) is a reduced sensation of pain.

“Allodynia” is pain resulting from exposure to a normal (non-harmful) stimulus on the skin or on the surface of the body. Examples of allodynia include, but are not limited to, cold or thermal allodynia, tactile or mechanical allodynia, and the like.

“Nociception” is defined in this text as a feeling of pain. The term “nociceptor” in this text defines the structure mediating nociception. Nociception may be the result of exposure to a physical stimulus, for example, mechanical, electrical, thermal or chemical. Nociceptors are present in almost all body tissues.

“Analgesia” in this text is defined as anesthesia without loss of consciousness. An “analgesic” is an agent or drug that can relieve pain again without loss of consciousness.

The term “central nervous system” or “CNS” means the totality of all cells and tissues of the vertebral brain and spinal cord. Thus, this term includes, but is not limited to, neural cells, glial cells, astrocytes, cerebrospinal fluid (CSF), interstitial spaces, etc.

“Glial cells” are various CNS cells, also known as microglia, astrocytes and oligodendrocytes.

The terms “subject,” “individual,” or “patient” are used interchangeably in this text to refer to vertebrates, primarily mammals. Mammals include, but are not limited to, murine, rodents, monkeys, humans, farm animals, sport animals, and domestic animals.

The terms “pharmacologically effective amount” or “therapeutically effective amount” of a composition or agent in this text mean a non-toxic, but sufficient to achieve the desired therapeutic response, in particular to reduce or reverse the development of neuropathic pain, the amount of the drug composition or agent. The exact amount needed to achieve this goal is subject to individual variability from subject to subject, depending on the species, age and general health of the subject, on the severity of the condition being treated, on the particular drug or drugs used with this purpose, from the method of introduction into the body, etc. The corresponding “effective” amount in each case can be determined on the basis of ordinary competence in the field using the standard experimental approach and the information set forth in this text.

The term “about” (approximately), especially with respect to a given amount, means a five percent tolerance in the direction of increase or decrease.

A “treatment” or “therapy” of neuropathic pain includes (1) prevention of pain, i.e. preventing the development of pain or its development with less intensity in a subject predisposed to pain, but not yet experiencing pain, (2) suppression of pain, i.e. pause or reverse development of pain; or (3) pain relief, i.e. reduction in pain experienced by the subject in quantitative terms.

By “treating existing pain” is meant the mitigation, weakening or reverse development of neuropathic pain in a subject who has been experiencing pain for at least 24 hours, 24-96 hours or more, for example, 25 ... 30 ... 35 ... 40 ... 45 ... 48 ... 50 ... 55 ... 65 ... 72 ... 80 ... 90 ... 96 ... 100, etc. hours.

Treatment Methods for Neuropathic Pain

As described above, the applicants discovered that ibudilast is surprisingly effective in treating neuropathic pain, for example, neuropathic pain associated with certain syndromes, in particular with viral neuralgia (herpes, AIDS), with diabetic neuropathy, with phantom pains in the extremities, with pain in stump / neuromas, with postischemic pain (stroke), with fibromyalgia, with reflex sympathetic dystrophy (RSD), with complex regional pain syndrome (SJS), with cancer pain, with herniated discs, with trigeminal neuralgia neuralgia, neuropathic pain induced by cancer chemotherapy, etc. Based on the results of studies using standard pain models, as described in this text, the applicants found that the administration of ibudilast in different quantities and not too often, for example once a day, gives an amazing effect, providing a measurable decrease in the severity of neuropathic pain and, especially, a measurable decrease in severity, if not the reverse development of certain types of neuropathic pain, such as mechanical allodynia. Additional features of the invention are described in this document.

Ibudilast

The methods for treating neuropathic pain proposed by this invention are based on the administration of an ibudilast molecule. Ibudilast is a compound molecule with a small molecular weight (230.3), having the structure shown below.

Links to ibudilast are also found in the ChemBank ID 3227, CAS # 50847-11-5 and in the Beilstein directory under the reference number 5-24-03-00396. The molecular formula of ibudilast is: C ₁₄ H ₁₈ N ₂ O. Ibudilast is also known by various chemical names, including 2-methyl-1- (2- (1-methylethyl) pyrazolo (1,5-a) pyridin-3-yl) - 1-propanone; 3-isobutyryl-2-isopropylpyrazolo (1,5-a) pyridine and 1- (2-isopropyl-pyrazolo [1,5-a] pyridin-3-yl) -2-methylpropan-1-one. Other synonyms of ibudilast include Ibudilastum (Ibudilastum - Latin name), BRN 0656579, KC-404, MN-166. The synonymous trade name for ibudilast is Ketas ^® . It is understood that the ibudilast referred to in this text includes any pharmaceutically acceptable salt prodrug (e.g., the corresponding ketal), solvates, and the like. in accordance with the instructions for administration in the intended form.

Ibudilast is a non-selective nucleotide phosphate esterase inhibitor (PDE) with the highest activity against PDE-3 and PDE-4, in addition, according to reports, it has antagonistic activity against LTD4 and platelet activating factor. Its profile looks effective anti-inflammatory and unique in comparison with other PDE inhibitors and anti-inflammatory drugs. PDE catalyzes the hydrolysis of the phosphodiester bond of 3'-carbon to form the corresponding 5'-nucleotide monophosphate. Thus, the cellular concentration of cyclic nucleotides is regulated. Since the extracellular receptors of many hormones and neurotransmitters use cyclic nucleotides as secondary messengers (intermediaries), PDE also regulates the response of cells to these extracellular signals. There are at least eight classes of PDE: Ca ²⁺ / calmodulin-dependent PDE (PDE1); cGMP-stimulated PDE (PDE2); cGMP-inhibited PDE (PDE3); cAMP-specific PDE (PDE4); cGMP-binding PDE (PDE5); photoreceptor PDE (PDE6); cAMP-specific PDEs with high affinity (PDE7) and cGMP-specific PDEs with high affinity (PDE9). Ibudilast inhibits inflammation by acting on inflammatory cells (for example, glial cells) and leading to suppression of the release of both pro-inflammatory and neuroactive mediators. The following references are referred to above: Obernolte, R., et al. (1993) "The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family" Gene 129: 239-247; Rile, G., et al. (2001) "Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells" Thromb. Res. 102: 239-246; Souness, JE, et al. (1994) “Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone” Br. J. Pharmacol. Ill: 1081-1088; Suzumura, A., et al. (1999) "Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in CNS" Brain Res. 837: 203-212; Takuma, K., et al. (2001) "Ibudilast attenuates astrocyte apoptosis via cyclic GMP signaling pathway in an in vitro reperfusion model" Br. J. Pharmacol. 133: 841-848.

As indicated above, references to any of the drugs described here (one or more), in particular ibudilast, include, where applicable, any enantiomers and mixtures of enantiomers, including racemic mixtures, prodrugs, pharmaceutically acceptable salt forms, hydrates (e.g. monohydrates, dihydrates, etc.), solvates, various physical forms (for example, crystalline solids, amorphous solids), metabolites, etc.

Route of administration

As indicated above, the present invention is directed to a method for treating mammals suffering from neuropathic pain by administering a therapeutically effective dose of ibudilast. Such an administration is effective in reducing the severity of pain experienced by a subject, i.e. to reduce or even reverse the development of neuropathic pain, as demonstrated by the accompanying examples. Ibudilast is preferably administered in an initial dose effective to achieve its maximum plasma concentration (C _max ) of at least 100 ng / ml, 125 ng / ml, 150 ng / ml, 175 ng / ml, 200 ng / ml, 225 ng / ml, 250 ng / ml, 300 ng / ml and above. In a preferred embodiment, ibudilast is administered in a dose effective to achieve a C _{max of} at least 125 ng / ml. It is even more preferable to administer ibudilast at an initial therapeutic dose that correlates with detectable efficacy and is associated with a C _max of at least about 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700 or 1800 ng / ml and higher.

The method associated with this invention, in some cases, includes the stage of selection of a subject suffering from neuropathic pain, and this stage precedes treatment of the subject with ibudilast. Such subjects are typically selected from among subjects suffering from postherpetic neuralgia, trigeminal neuralgia and neuropathic pain associated with a condition that belongs to the group of conditions including herpes, HIV, traumatic nerve damage, stroke, postischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord damage, phantom pains in the extremities, multiple sclerosis, sciatica and neuropathic pain of cancer origin, or induction bathroom anticancer chemotherapy. In some cases, a subject selected for treatment that suffers from neuropathic pain is one of the subjects with normal natural insulin production (i.e., not suffering from diabetes).

As can be seen from the accompanying examples, the method proposed by this invention is effective not only for significantly reducing neuropathic pain, such as mechanical allodynia, but even for its reverse development. Shortly after the start of treatment with ibudilast, its administration in a therapeutically effective dose demonstrates a stable therapeutic effect: pain relief is persistent and long-lasting. Thus, unlike many other drugs against neuropathic pain, presented on the modern pharmaceutical market, ibudilast gives a persistent therapeutic effect to alleviate neuropathic pain, which lasts all night. For example, a therapeutically effective dose of ibudilast gives a therapeutic effect in relation to neuropathic pain, which lasts at least 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours and even 20 hours or more. Such efficacy of ibudilast when administered orally once a day, which was observed in animal studies and which is expected to be applied to humans, based on the pharmacokinetic projections of the ibudilast form with prolonged release, is highly unlikely when using the usual form of ibudilast with the recommended frequency (two or three times per day) according to existing clinical indications.

Ibudilast can also be used in combination with any additional agent effective in the treatment of neuropathic pain. In a preferred embodiment, the mechanism of action of such an additional agent is fundamentally different from the mechanism of action of ibudilast. Examples of such drugs are gabapentin, memantine, pregabalin, morphine and related opiates, cannabinoids, tramadol, lamotrigine, lidocaine, carbamazepine, duloxetine, milnacipran and tricyclic antidepressants. As noted in Example 1, the administration of ibudilast in combination with a typical pain medication, morphine, is not accompanied by a decrease in the therapeutic efficacy of each drug: ibudilast does not reduce the opiate analgesic effect of morphine, and morphine does not reduce the therapeutic effect of ibudilast. Combination therapy has such therapeutic efficacy that is superior to the known effects of each of the drugs used alone.

As shown in example 3, the effectiveness of ibudilast is not only to reduce neuropathy induced by anticancer chemotherapy, but also that it prevents the development of such neuropathy. Taxol, vinblastine and vincristine are examples of chemotherapeutic agents that can cause neuropathy in cancer patients. The administration of ibudilast is effective in alleviating or reversing the development of neuropathic pain associated with cancer chemotherapy with such drugs.

Another advantage of the present invention is that the administration of ibudilast in a therapeutically effective dosage for treating neuropathic pain surprisingly avoids the vomiting associated with such a therapy in patients that would be expected with the recommended therapeutic doses. In accordance with this, in one embodiment of the invention, the use of ibudilast is not accompanied by the use of an antiemetic. Those. based on the results obtained in animal models, it is expected that in certain cases the therapeutic effect in humans will be observed with ibudilast dosing regimens that do not induce vomiting at all or can cause it at the beginning of treatment (for example, after several initial doses of ibudilast are administered), but at the end of this initial period (lasting 1, 2, 3, 4 or 5 days), vomiting ceases to be a problem.

The treatment method based on this invention has an additional advantage over existing methods of treatment of neuropathic pain, since other modern drugs for the treatment of neuropathic pain have a pronounced sedative side effect, while ibudilast does not have such an effect.

Preferred methods for delivering ibudilast to the body for treating neuropathic pain include systemic or localized delivery, i.e. direct delivery to the central nervous system. Such methods include, but are not limited to, the oral, intraarterial, intrathecal (intrathecal), intraspinal (intracranial), intramuscular, intraperitoneal (intraperitoneal), intravenous, intranasal, and inhalation routes.

In particular, the ibudilast-based dosage form recommended in this invention can be administered for therapeutic purposes by any suitable method without limitation, including oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous intramuscular, intravenous and intradermal), intrathecal and pulmonary. Of course, the preferred route of administration varies depending on the condition and age of the recipient, on the particular neuralgia syndrome, and on the specific combination of drugs used.

The preferred method of administering ibudilast is its direct delivery to the nervous tissue, in particular to the peripheral nerves, retina, ganglion of the back root, neuromuscular junction, as well as to the central nervous system, in particular to the target glial cells of the spinal cord by injection, for example, into the ventricular region, as well as into the striatum (in particular, into the caudate nucleus or putamen of the striatum), into the spinal cord and neuromuscular junction using a needle, catheter, or similar device using conventional neurosurgical techniques, in particular stereotactic injection (see, for example, Stein et al., J. Virol. 73: 3424-3429, 1999; Davidson et al., PNAS 97: 3428-3432, 2000; Davidson et al., Nat. Genet. 3: 219-223, 1993; and Alisky and Davidson, Hum. Gene Ther. 11: 2315-2329, 2000).

The most preferred way to deliver the drug to the target cells of the cerebrospinal glia is, rather, its intrathecal administration than direct injection into the tissue of the spinal cord.

Another preferred method of administering the ibudilast-based drug composition of the invention is to deliver it to the neurons of the ganglia of the posterior roots (GZK), in particular by injection into the epidural space followed by diffusion into the GZK. For example, an ibudilast-based drug composition can be introduced into the body via intrathecal cannulation provided that ibudilast is diffused into the GZK. See, for example, Chiang et al., Acta Anaesthesiol Sin. (2000) 38: 31-36; Jain, K.K., Expert Opin. Investig. Drugs (2000) 9: 2403-2410.

Another way of administering a drug to the central nervous system is based on a convection enhancement delivery system (CED). With this method of administration, ibudilast can enter numerous cells in the most extensive areas of the central nervous system. For the introduction of ibudilast, you can use any device that enhances convection. In a preferred embodiment, such a device is an osmotic pump or an infusion pump. Both osmotic and infusion pumps are commercially available from various suppliers, such as Alzet Corporation, Hamilton Corporation, Alza, Inc., Palo Alto, California. In a typical embodiment, the ibudilast-based drug composition of the invention is administered using a CED device as follows. A catheter, cannula or other injection device is inserted into the central nervous system tissue of the subject selected for treatment. Stereotactic cards and positioning devices are available, for example, from ASI Instruments, Warren, MI. Positioning can also be carried out using anatomical maps obtained on the basis of CT and / or MRI, which helps to more accurately enter the injection device at the selected target point. A detailed description of drug delivery using CED technology is given in US patent No. 6309634, fully incorporated into this document by reference.

If the ibudilast drug composition of the invention contains more than one active agent, it can be administered as a single mixture containing a combination of ibudilast and at least one other active agent effective in treating neuropathic pain. From the point of view of patient discipline and ease of use, this approach is preferable, as patients are often negatively inclined towards taking many different tablets or dosage forms, which sometimes have to be done several times a day throughout the course of treatment. An alternative, although less preferred, method of administering the drugs in this invention is to take different dosage forms in parallel. In those cases where the drugs included in the therapeutic composition of this invention are administered in different dosage forms and their concomitant use is required, ibudilast and each of the additional drugs can be administered either simultaneously or sequentially (in any order) , or separately.

Dosage

Therapeutic doses that can be determined empirically can vary depending on the particular condition to be treated, on the individual characteristics of the subject, as well as on the effectiveness and toxicity of each of the active agents included in the composition. The actual dose administered will vary depending on the age, weight and general condition of the subject, as well as the severity of the condition being treated, the expert judgment of the attending physician, and the specific combination of drugs prescribed to the patient.

Therapeutically effective doses of drugs are determined by specialists competent in this field, and are selected according to individual need in each case. In general, a therapeutically effective amount of ibudilast, taking into account the total daily dose for daily use, can vary from the following: from about 0.1 to 200 mg per day, more preferably 1-200 mg per day, 30-200 mg per day , 1-100 mg per day, 30-100 mg per day, 30-300 mg per day, 1-60 mg per day, 1-40 mg per day or 1-10 mg per day, and it is possible to administer ibudilast as a single daily dose, and in the form of several fractional doses throughout the day. Preferred doses exceed 10 mg x 2 or 3 times daily. In other words, the preferred total daily dose of ibudilast exceeds 20 mg or 30 mg with daily use. The daily dose of ibudilast can be selected from the following options: 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day and higher . Depending on the selected daily dose and the specific condition for which treatment is being carried out, the drug can be administered once, twice or three times a day for several days, weeks, months and even years, and sometimes throughout the patient’s life. Typical treatment regimens have a duration of at least about a week, from about 1 to 4 weeks, from 1 to 3 months, from 1 to 6 months, from 1 to 50 weeks, from 1 to 12 months or more.

More specifically, a single dose of any composition proposed in this invention or an active agent can be used in different schemes and schedules depending on the expert evaluation of the attending physician, the needs of the patient, etc. A specific dosing schedule will be well known to those of ordinary skill in the art, or may be determined experimentally using conventional standard methods. Typical dose schedules of therapy include the following options: without limitation, administration five times a day, four times a day, three times a day, twice a day, once a day (with daily use), and also every other day, three times a day weekly, twice a week, once a week, twice a month, once a month, etc.

Neuropathic Pain Management Approaches

Modern methods of analgesic therapy are aimed primarily at neurons that play the role of a relay in the transmission of pain signals. These neurons are part of a long-described and evolutionarily conservative pathway in vertebrates that transmits signals from the periphery to the somatosensory cortex. The scientific literature has accumulated hypothesized evidence that neurons are not the only link in the development of persistent pain states (Watkins and Maier (2003) Nat. Rev. Drug Discov. 2: 973-85). In well-developed animal models, it was found that glial cells (microglia and astrocytes) are key links in the development of neuropathic pain (Wieseler-Frank et al. (2004) Neurochem. Int. 45: 389-95), and their participation is also implied in the pathogenesis of neuropathic pain in humans (Watkins and Maier (2002) Physiol. Rev. 82: 981-1011).

Glia activation occurs under the influence of various stimuli, such as immune provocations, infection and / or peripheral inflammation and substances released during prolonged interneuronal transmission (in particular, neurotransmitters, substance P, fractalkin, etc.). As a result of activation, the function of glia changes significantly, which is accompanied by an increased release of neuroactive substances. These substances also increase the growth of nerve transmission, enhancing afferent signals and, thus, exacerbating pain.

Experimental data have shown that glia activation and subsequent events play a key role in trying to relieve pain in experimental animals. For example: (i) administration of pro-inflammatory cytokines (glia activators), in particular interleukin-1β (IL-1β) or tissue necrosis factor α (TNFα), exacerbate existing neuropathies; (ii) the pharmacological blockade of glial activation blocks and / or reverses pain relief in each studied animal model; (iii) pain relief can be blocked and / or reversed by antagonism of neuroactive substances released by activated glia; (iv) pain responses in healthy animals do not change either during glial activation blockade or as a result of antagonism of pro-inflammatory products; (v) glial cells also release other neuroactive substances, including pro-inflammatory cytokines, excitatory amino acids and prostaglandins, which can increase neuropathic pain.

Ibudilast is a powerful suppressor of glial activation (Mizuno et al. (2004) Neuropharmacology 46: 404-411). It has been established that ibudilast with a dose-dependent effect inhibits the production of nitric oxide (NO), reactive oxygen species, interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) and, at the same time, enhances the production of inhibitory cytokine in activated microglia, IL-10 and additional neurotrophic factors, including nerve growth factor (NGF), glial neurotrophic factor (GDNF) and neurotrophin (HT) -4. Thus, it was found that the neuroprotection mediated by ibudilast is mainly associated with the inhibition of inflammatory mediators and the upregulation of neurotrophic factors.

When administered systemically, ibudilast crosses the blood-brain barrier (Sugiyama et al. (1993) No To Shinkei 45 (2): 139-42; FIG. 5), thereby eliminating the need for more invasive routes of administration to provide access to central areas of inflammation involved in the pathogenesis of neuropathic pain. Other known compounds capable of attenuating glial activation include fluorocytrate and minocycline, which have been shown to be effective in experimental models of neuropathic pain in rodents. However, both drugs are unacceptable for treating people. Fluorocytrate cannot be used in humans since it can block the glial uptake of excitatory amino acids (Berg-Johnsen et al. (1993) Exp. Brain Res. 96 (2): 241-6), an important function of glia in maintaining normal CNS homeostasis. Minocycline, although potentially useful in preventing glial activation, does not appear to reverse the existing relief of glial pain (Raghavendra et al. (2003) J. Pharmacol. And Exp. Therapeutics 306: 624-630). Therefore, the discovery of the effectiveness of ibudilast for neuropathic pain presented here, with systemic administration at a well-tolerated dose level, is the basis of a unique therapy.

Taken together, glia and its pro-inflammatory products may provide an opportunity to develop new strategies to combat pain. Of all the substances released by activated glia, pro-inflammatory cytokines (especially IL-10 and TNFα) are critical for this type of pain relief. Thus, according to another embodiment of the invention, the administration of ibudilast is effective for blocking the release of pro-inflammatory cytokines.

Pain models

The ability of ibudilast to treat neuropathic pain can be assessed using any standard pain model known in the art. Examples of such models are given below.

Carrageenan-induced paw hyperalgesia model in animals : The paw hyperalgesia carrageenan test is a model of inflammatory pain. A subcutaneous injection of carrageenan is carried out in the left hind paw of rats. The drug selected for testing is administered to rats either prior to the injection of carrageenan, for example 30 minutes, or after the injection of carrageenan, for example after two hours. Then, three hours after the injection of carrageenan, the sensitivity of the paws to pressure is examined using an analgesimeter in each animal. See Randall et al., Arch. Int. Pharmacodyn (1957) 111: 409-419.

Using this test, the effects of selected drug agents on paw edema induced by carrageenan can be studied. This test (see Vinegar et al., J. Phamacol. Exp. Ther. (1969) 166 : 96-103) allows us to evaluate the ability of the test compound to reverse or prevent the formation of edema caused by injection of carrageenan into the paw. A paw swelling test is performed using a plethysmometer to measure paws. After administration of the selected agent, the carrageenan solution is injected subcutaneously into the lateral foot pad on the plantar surface of the left hind paw. Three hours after the injection of carrageenan, the volume of the treated paw (left) and the volume of the unprocessed paw (right) are measured using a plethysmometer.

Von Frey filament test : The effect of compounds on mechanical allodynia can be determined using the von Frey filament test in rats with tight ligation of the spinal nerve L-5: on a model of peripheral pain neuropathy. A surgical procedure is performed as described by Kim et al., Pain (1992) 50: 355-363. To evaluate mechanical allodynia, a calibrated series of von Frey fibers is used (Chaplan et al., J. Neurosci. Methods (1994) 53: 55-63). Fibers of increased stiffness are applied perpendicularly to the midsolear surface in the area of distribution of the branches of the sciatic nerve on the left hind paw. The fibers are slowly pressed until they bend, and then hold for 4-6 seconds. The fiber stacking procedure and the number of attempts are determined by the Dickson method up and down (Chaplan et al., Supra). Shaking, licking and pulling paws from the side of applying the ligature are considered a positive response.

Chronic constrictive damage : In rats with chronic constrictive damage (CKP), as described below, reactions can be assessed by the type of thermal and cold allodynia, as well as the sensation of mechanical allodynia. Unilateral mononeuropathy in rats can be induced using the chronic constrictive lesion model described in Bennett et al., Pain (1988) 33: 87-107. CKP in rats undergoing anesthesia is caused as follows. The lateral surface of each hind paw of rats is shaved and peeled with nolvasan. Using an aseptic technique, an incision is made on the lateral surface of the hind paw in the middle of the thigh. The biceps femoris is stupidly stratified, exposing the sciatic nerve. Four tight ligatures are placed on the right hind paw of each rat (for example, 4.0 chrome catgut; Ethicon, Johnson & Johnson, Somerville, NJ), located around the sciatic nerve at a distance of about 1-2 mm from each other. An identical incision is made on the left side of each rat, with the exception that ligatures are not applied to the sciatic nerve (control imitation). The stratified muscle is closed with a continuous suture, for example 4-0 Vikril (Johnson & Johnson, Somerville, NJ), and the skin incision is closed with wound braces. In order to identify the rats, they are labeled with ear tags, after which they are returned to the animal enclosure.

Chang rat neuropathic pain model : In rats with spinal nerve damage (e.g., ligation, cross-section), as described below, reactions can be assessed by the type of thermal and cold allodynia, as well as the sensation of mechanical allodynia. The details of this technique were originally described in SH Kim and JM Chung, Pain (1992) 50: 355-363.

Hargreaves Test : The Hargreaves Test (Hargreaves et al., Pain (1998) 32: 77-88) is also a model of pain caused by radiant heat. CKD rats are tested for thermal hyperalgesia at least 10 days after surgery. The testing apparatus is a design with a raised glass platform, heating to 80-82 ° F. At one time, eight rats representing all test groups are placed under individual inverted plastic caps on the glass floor of the platform at least 15 minutes before the test. A radiant heat source, placed under the glass, directs radiation to the plantar surface of the hind legs of each rat. The supply of thermal radiation continues until the rat begins to withdraw its paws (the waiting time for the pain reaction), or until 20 seconds pass. The same test is carried out on the control simulation of the operated limb. From two to four test attempts are alternately carried out on each foot with an interval between them of at least 5 minutes. The average value for all attempts and represents the waiting time for a pain reaction (pulling legs).

Cold model of allodynia : The design of the apparatus and behavioral testing techniques are described in detail in Gogas et al., Analgesia (1997) 3: 111-118. The apparatus for testing cold allodynia in rats with neuropathy (CKP) consists of a Plexiglass chamber with a metal plate located at a distance of 6 cm from the bottom of the chamber. The chamber is filled with ice and water 2.5 cm above the metal plate, maintaining the bath temperature at 0-4 ° C during the entire experiment. Each rat is placed in a chamber separately, the timer is turned on, and the waiting time for the pain reaction is measured, to the nearest tenth of a second. The “answer” is defined as the quick and complete pulling of the right hind paw with the ligature on top of the water when the animal is in a stationary state (does not rotate). Excessive lameness is not considered a painful response when an animal runs around the camera and spins. Basic indicators of the waiting time before pulling a limb with a ligature out of water for experimental animals are typically 7-13 seconds. The maximum dive time is 20 seconds with a 20-minute interval between attempts.

Further information on neuropathic pain patterns is provided in the following publications. Bennett GJ, Xie YK (1988) "A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man" Pain 33: 87-107; Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) "Quantitative assessment of tactile allodynia in the rat paw" J. Neurosci. Meth. 53: 55-63; Fox A., Gentry C., Patel S., Kesingland A., Bevan S. (2003) "Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigin and gabapentin in a model of neuropathic pain in the rat and guinea-pig "Pain 105: 355-362; Milligan ED, Mehmert KK, Hinde JL, Harvey LOJ, Martin D., Tracey KJ, Maier SF, Watkins LR (2000) "Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein, gpl20 "Brain Res. 861: 105-116; De Vry J., Kuhl E., Franken-Kunkel P., Eckel G. (2004) "Tharmacological characterization of the chronic constriction injury model of neuropathic pain" Eur. J. Pharmacol. 491: 137-148. Polomano RC, Mannes AJ, Clark US, Bennett GJ (2001) "A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel" Pain 94: 293-304.

SUMMARY OF THE INVENTION

In addition to including ibudilast, the therapeutic formulation of the invention may optionally contain one or more of the components described below.

Fillers / carriers

In addition to ibudilast, the neuropathic pain medicament compositions of the invention may also contain one or more pharmaceutically acceptable excipients or carriers. Typical fillers include (without limitation) polyethylene glycol (PEG), hydrogenated castor oil (HCM), cremophores, hydrocarbons, starches (e.g. corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants, e.g., talc, disintegrants, diluents, buffers, acids, bases, film coatings, combinations of the above, and the like.

The drug composition of the present invention may include one or more hydrocarbons, such as sugar, a sugar derivative, such as aldite, aldonic acid, esterified sugar and / or sugar polymer. Specific hydrocarbon fillers include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like, disaccharides such as lactose, sucrose, trehalose, cellobiose and the like, polysaccharides such such as raffinose, melesitosis, maltodextrins, dextrans, starches, etc., as well as aldites, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucite), pyranosyl sorbitol, myoinositis, etc.

Potato starch and corn-based starches such as sodium starch glycolate and directly compressible modified starch are also suitable for use in the pharmaceutical compositions of this invention.

Other representative excipients include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, monobasic sodium phosphate, monobasic sodium phosphate, and combinations thereof.

The drug composition of the present invention containing ibudilast may also include an antimicrobial agent, for example, to prevent or inhibit the growth of microbes. Examples of antimicrobial agents suitable for the present invention (but not limited to) are benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyrimidine chloride, chlorobutanol, phenol, phenylethyl alcohol, phenyl ruton nitrate, thimersol, and combinations thereof.

The composition of the present invention may also contain one or more antioxidants. Antioxidants are used to prevent oxidation, i.e. deterioration in the quality of the drug (s) or other components of the drug. Suitable antioxidants for use in the present invention include, but are not limited to, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium sulfoxylate formaldehyde sodium, sodium metabisulfite, and combinations thereof.

Additional excipients include surfactants such as polysorbates, in particular “Tween 20” and “Tween 80”, and pluronics (surfactants) such as F68 and F88 (both supplied by BASF, Mount Olive, NJ), sorbitan esters, lipids (in particular phospholipids such as lecithin and other phosphatidylcholines and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc and other suitable cations.

In addition, the composition of the present invention may optionally include one or more acids or one or more bases. Examples of acids that can be used in the pharmaceutical composition of the present invention, but are not limited to, are those selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acids, perchloric acid, sulfuric acid, fumaric acid, as well as combinations thereof. Examples of suitable bases include, but are not limited to, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate potassium sulfate, potassium fumarate, as well as combinations thereof.

The amount of any individual excipient in the drug composition will vary depending on the role of the excipient, the dose requirement for the components of the active agent, and the particular properties of the particular drug composition. In a typical case, the optimal amount of any individual filler is determined by standard experiments, i.e. preparation of compositions containing a different amount of filler (from small to large) with the subsequent study of their stability and other parameters, as well as determining the range in which the optimal therapeutic effect can be achieved in the absence of significant side effects.

However, in general, the excipient will be present in the drug composition in an amount of from about 1% to about 99% by weight, more preferably from about 5% to about 98% by weight, and even more preferably from about 15% to about 95% by weight mass. In general, the amount of excipient in the ibudilast drug composition of the invention is selected from the following options: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40 %, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% by weight.

These aforementioned pharmaceutical excipients, along with other excipients, are described in the following publications: "Remington: The Science & Practice of Pharmacy", 19 ^th ed., Williams & Williams (1995); Physician's Desk Reference, 52 ^nd ed., Medical Economics, Montvale, NJ (1998); Kibbe, AH, Handbook of Pharmaceutical Excipients, 3 ^rd Edition, American Pharmaceutical Association, Washington, DC, 2000.

Other active substances

The drug composition (or kit) in accordance with this invention may include, in addition to ibudilast, one or more additional active agents capable of giving a therapeutic effect in neuropathic pain. In a preferred embodiment, such an active agent has a different mechanism of action than ibudilast. Such active agents include gabapentin, memantine, pregabalin, morphine and related opiates, cannabinoids, tramadol, lamotrigine, carbamazepine, duloxetine, milnacipran and tricyclic antidepressants.

Gabapentin, also known as Neurontin ^® , is structurally associated with the neurotransmitter GABA. Despite its structural association with GABA, gabapentin does not interact with GABA receptors, does not metabolize to GABA or a GABA agonist, and is not an inhibitor of GABA absorption or degradation. Gabapentin is not active at the level of GABAA or GABAA receptors for GABA absorption vehicles in the brain, but instead interacts with a high-affinity binding site in the brain membranes (an additional subunit of the potential-sensitive Ca ²⁺ channels). The exact mechanism of action is not known, it is only known that the physiological site of action is the brain. The structure of gabapentin allows it to easily pass through the blood-brain barrier. In in vitro experiments, gabapentin has many pharmacological effects, including modulation of the action of the GABA-synthetic enzyme, an increase in non-synaptic responses to GABA in the nervous tissue, and a decrease in the release of some monoamine neurotransmitters. The daily dose of gabapentin typically varies from about 600 to 2400 mg per day, more preferably from about 900 to 1800 mg per day, and this dose is taken in fractional parts, for example, three times a day. Common dosage forms of gabapentin are 300 or 400 mg capsules or 600 or 800 mg tablets.

The active agent memantine is a receptor antagonist. Memantine is believed to act as a low- or mid-affinity, non-competitive (open-channel) N-methyl-D-aspartate receptor antagonist (NMDA) that binds cation channels driven by NMDA receptors. The recommended daily dose typically ranges from about 5 to 20 mg.

Opiate, morphine, exerts its effects through the activation of opiate receptors, which are widespread in the brain and other somatic tissues. After the opiate enters the brain, it quickly activates the opiate receptors located in many parts of the brain, producing an effect that is associated with the involved part of the brain. There are several types of opiate receptors, in particular delta, mu and kappa receptors. Opiates and endorphins act by blocking pain signals by binding to the mu receptor site.

Cannabinoids, in particular tetrahydrocannabinol, bind to the cannabinoid receptors referred to as CB ₁ . CB ₁ receptors are located in the brain and peripheral tissues. In large numbers, CB ₁ receptors are present in the central nervous system, exceeding the level of almost all neurotransmitter receptors. An additional subtype of cannabinoid receptors, also known as “CB _2, " was also identified. See, e.g., Martin, BR, et al., The Journal of Supportive Oncology, Vol. 2, Number 4, July / August 2004.

Although the mechanism of action of the tramadol opioid has not yet been fully elucidated, it is believed that it exerts its effects through modulation of GABAergic, noradrenergic and serotonergic systems. It was found that tramadol and its metabolite, known as M1, bind mu-opioid receptors, i.e. extend their effect to GABAergic transmission, suppressing the reverse absorption of 5-HT and norepinephrine. It is believed that there is a second mechanism of action, since the analgesic effects of tramadol are not completely blocked by the mu-opioid receptor antagonist naloxone. Typical daily doses vary from about 50 to 100 mg every 4-6 hours, with a total daily dose not exceeding 400 mg.

Lamotrigine is a phenyltriazine that stabilizes neural membranes by blocking the voltage-sensitive sodium channels that inhibit the release of glutamate and aspartate (excitatory amino acid neurotransmitters). A typical daily dose of lamotrigine varies from 25 mg per day to 500 mg per day. Typical daily doses include 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 300 mg per day and 500 mg per day, not exceeding 700 mg per day.

Carbamazepine acts by blocking the voltage-sensitive sodium channels. A typical adult dose varies from 100 to 200 mg once or twice daily with daily intake to an increased daily dose of 800-1200 mg, usually taken in fractions 2-3 times a day.

Duloxetine is a potent inhibitor of serotonin and norepinephrine uptake by neurons, as well as a weak inhibitor of dopamine reuptake. A typical daily dose varies from about 40 to 60 mg with a single dose during the day or 20-30 mg 2 times a day.

Milnacipran acts as an inhibitor of the reverse absorption of serotonin and norepinephrine. A typical daily dose varies from about 500 to 100 mg once or twice a day.

The doses described here should be taken only as a general guide, and the exact amount of the secondary active agent used in combination therapy in combination with ibudilast, of course, should be determined individually depending on factors such as the target group of patients, a specific symptom or neuropathic pain syndrome subject to treatment, potential synergies between active agents in combination therapy, etc., and this amount is determined by a specialist competent in this field and, based on the directions given in the description.

Long-Delivery Drug Formulations

In a preferred embodiment of the invention, the pharmaceutical compositions are selected so as to improve the stability of ibudilast and to extend its half-life. For example, ibudilast can be delivered to the body in a sustained release formulation. Medicinal composition with a controlled or sustained release formulations are made by combining ibudilast with a carrier or diluent, such as liposomes, with nonabsorbable leakproof polymers such as copolymers of ethylene and copolymers Hytrel ^®, with swellable polymers such as hydrogels, or resorbable polymers such as collagen , as well as with some polyacids or polyesters, such as those used to make absorbable suture materials. In addition, ibudilast can be encapsulated, adsorbed and / or adhered to carriers in particulate form. Examples of carriers include substances recovered from polymethyl methacrylate polymers, as well as microparticles recovered from poly (lactides) and poly (lactide-soglycosides), known as PLG. See, for example, Jeffery et al., Pharm. Res. (1993) 10: 362-368; and McGee et al., J. Microencap. (1996).

Delivery Forms

The ibudilast compositions described herein cover all types of formulations and especially those suitable for systemic or intratracheal administration. Dosage forms for oral administration include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules and beads. Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilisates to be reconstituted, as well as liquids. Examples of suitable diluents for reconstituting solid compositions, for example, before injection include bacteriostatic water for injection, 5% aqueous dextrose solution, buffered phosphate saline, Ringer's solution, physiological saline, sterile water, deionized water, and combinations thereof. As for liquid pharmaceutical compositions, this refers to solutions and suspensions. In a preferred embodiment, the ibudilast composition of the invention is an oral composition.

Turning to oral delivery forms, it should be noted that tablets can be made by pressure or compression, including optionally one or more additional ingredients or additives. Compression tablets are made, for example, in a suitable tablet machine, and the active ingredients in granular form, such as powder or granules, are optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), a glidant, an inert diluent, a preservative, a disintegrating agent (e.g. sodium starch glycolate crosslinked by povidone crosslinked by carboxymethyl cellulose) and / or with a surface active or dispersing agent.

Compressed tablets are made, for example, by compression in a suitable tablet machine by mixing powder components moistened with an inert liquid diluent. The tablets may optionally be coated or corrugated, and also formulated in such a way as to provide a slow or controlled release of the active ingredients, for example, using hydroxypropyl methylcellulose, which in different proportions creates the desired release profile. The tablets may optionally be coated, such as a thin film, a sugar layer or an enteric coating (soluble in the intestine), providing release not in the stomach, but in other parts of the digestive tract. The processes, equipment and manufacturers of intermediates for tablets and capsules are well known to those skilled in the art.

Compositions for topical administration in the oral cavity include lozenges containing the active ingredients, typically a flavoring base such as sucrose and gum arabic or tragacanth gum, as well as lozenges containing the active ingredients in an inert base, in particular gelatin and glycerol, or in sucrose and gum arabic.

A topical pharmaceutical composition may also be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.

Alternatively, the drug formulation may be in the form of a patch (eg, a transdermal patch) or a dressing, in particular a bandage or adhesive patch, impregnated with the active ingredients and, optionally, one or more fillers or diluents. Topical formulations may include a compound that enhances the absorption or penetration of ingredients through the skin or other affected tissues, such as, in particular, dimethyl sulfoxide, bisabolol, oleic acid, isopropyl myristate and D-limolene among the few substances of this kind.

In emulsions, the oily phase consists of known ingredients mixed in a known manner. Along with the fact that this phase can only be an emulsifier (emulsifier), it preferably contains a mixture of at least one emulsifier with fat and / or oil. In a preferred embodiment, a hydrophilic emulsifier is introduced into the composition together with a lipophilic emulsifier, which acts as a stabilizer. Taken together, the emulsifier (s) with stabilizer (s) or without create a so-called emulsifying wax, and this wax, together with oil and / or fat, creates a so-called emulsifying ointment base, which forms a dispersed oily phase of pharmaceutical formulations in the form of creams. Typical emulsifiers and emulsion stabilizers include Tween-60, Span-80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

Formulations for rectal administration are typically in the form of suppositories with a suitable base, which consists, for example, of cocoa butter or salicylate.

Vaginal formulations are usually available in the form of suppositories, tampons, creams, gels, pastes, foams or sprays.

Formulations for nasal use, in which the carrier is a solid, include coarse powder, for example, with a particle size of about 20-500 microns. Such compositions are usually administered by rapid inhalation through the nasal passage, for example, from a powder container held close to the nose. Alternatively, the composition for nasal use may be in the form of a liquid, for example, a nasal spray or nasal drops.

Aerosol formulations for inhalation may be produced in the form of a dry powder (for example, suitable for administration by means of a dry powder inhaler) or, alternatively, in the form of a liquid form, for example, for a nebulizer. Aerosol nebulizers are presented in AERx ™ (Aradigm), Ultravent ^® (Mallinkrodt) and Acorn II ^® (Marquest Medical Products) models. The composition according to the invention can also be administered using an internal pressure metered dose inhaler (MDI), for example, Ventolin ^® brand, containing a solution or suspension of a combination of the drugs described herein in a pharmaceutically inert liquid propellant, for example chlorofluorocarbon or fluorocarbon.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions, as well as aqueous and non-aqueous sterile suspensions.

The parenteral formulations of this invention may optionally contain single-dose or multi-dose hermetically sealed containers, such as ampoules and vials, and can be stored in a lyophilized state when a sterile liquid carrier, e.g., water for injection, is required to be added to them immediately before use. Improvised solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the above types.

The composition of the present invention may also be a sustained release form, allowing each component of the drug to be released or absorbed more slowly compared to conventional formulations. Sustained release formulations may use prodrug forms of the active agent, sustained release drug delivery systems, such as liposomes or polymer matrices, hydrogels or covalent additives to polymers with an active agent, for example polyethylene glycol.

In addition to the ingredients detailed above, the formulations of the present invention may optionally include other agents conventionally used in the pharmaceutical field, as special formulations, for example, forms for oral administration. In addition, compositions for oral administration may include additional agents such as sweeteners, thickeners, or flavoring agents.

The compositions of this invention can also be prepared in a form suitable for use in veterinary medicine.

Sets

This document also provides a kit containing at least one combined composition of the present invention with its instructions for use.

For example, in cases where the medicines included in the formulation are administered in individual or mixed dosage forms, the kit necessarily contains ibudilast in addition to each of the medicines in the kit that is proposed by this invention, as well as instructions for using this kit . The components of the drug can be packaged in any suitable way, provided that the packaging along with the instructions for use will clearly indicate how each of the components of the kit must be administered.

For example, for an illustrative kit containing ibudilast and gabapentin, it can be provided for use over any suitable period of time, for example, one day. In particular, a representative kit for the first day may include appropriate single doses of ibudilast and gabapentin. If each drug must be taken twice a day, the kit may include, in accordance with the first day, two rows of single doses of ibudilast and gabapentin along with instructions on the time of administration. An alternative is that if the different drugs included in the kit differ from each other in time of administration or in the number of single doses, then all these differences should be clearly reflected on the packaging and in the instructions for use. Various options related to the above can be easily imagined, which, of course, depends on the particular combination of drugs used for treatment with ibudilast, their respective single doses, recommended doses, the target group of patients, etc. The form of packaging can correspond to any traditional pharmaceutical packaging and use such characteristic features as various colors, wrapping paper, protection against unauthorized access, blister packaging, liners with desiccant, etc.

It should be understood that since the invention has been described together with its preferred specific uses, the above description, as well as the following examples, intended to illustrate, do not limit the scope of this invention. Other aspects, advantages, and modifications within the scope of the invention will be apparent to those skilled in the art to which this invention pertains.

EXAMPLES

EXAMPLE 1

INFLUENCE OF IBUDILAST ON MECHANICAL ALLODINIA IN EXPERIMENTS ON A RAT MODEL OF NEUROPATHIC PAIN TYPE CKP

The effect of ibudilast on mechanical allodynia was evaluated in a rat model of neuropathic pain due to chronic constrictive damage (CKP).

METHODS

Test Agents: Ibudilast as a pure powder was obtained from Sigma (St. Louis, MO) or Haorui Pharma (Edison, New Jersey). A solution for intraperitoneal (ip) administration was prepared daily from this powder. An appropriate amount of ibudilast was dissolved in 100% polyethylene glycol (PEG) 400 (Sigma), and then diluted with sterile saline (0.9% for injection) to a final concentration of PEG400 of 35%.

Administration of the test substance : Ibudilast was administered at doses of 2.5 mg / kg (0.9 ml / kg from 2.8 mg / ml in 35% PEG / saline), 7.5 mg / kg (2.7 ml / kg from 2.8 mg / ml in 35% PEG / physiological saline) or 10 mg / kg twice daily (3.7 ml / kg of 2.7 mg / ml in 35% PEG / physiological saline) every morning (usually 8 hours) and in the afternoon (usually 3 pm). In the study of oral efficacy, ibudilast was administered at a dose of 50 mg / kg in 10% HCO-60 solution, 10% PEG 400, saline or could be administered at a dose of 21-25.5 mg / kg (7-8 ml / kg of 3 mg / ml in 35% PEG / saline), which also led to a weakening of mechanical allodynia in rats with CKP. The stability and concentration of the drug was evaluated using GHUR / MS / MS.

Animals : In all experiments, pathogen-free adult male Sprague-Dawley rats weighing 280-350 g (Harlan Labs) were used. Rats were kept in rooms with controlled temperature (23 ± 3 ° C) and lighting (light to dark time ratio 12:12 for 0700 hours) with a sufficient amount of standard food for rodents and water, which animals could consume without restrictions. Behavioral testing was performed during the light cycle.

Chronic Constrictive Damage (CKP) : CKP was created at the mid-thigh level of the right hind limb. Four sterile absorbable surgical chromium catgut ligatures (cuticular 4-0 chromium catgut 27 "cutting FS-2, Ethicon, Somerville, NJ) tightly tightened around a carefully selected sciatic nerve under isoflurane anesthesia (manufactured by Phoenix Pharm., St. Joseph , MO). The sciatic nerves in control rats with simulated surgery were exposed but not bandaged. The position of the ligatures was typically verified after sacrifice of the animals by visual inspection. Randomization to alternative groups therapy and treatment initiation was carried out 7-8 days after surgery.

Behavioral assessment in the von Frey test: The von Frey test was performed in the innervation zone of the saphenous saphenous vein by the branches of the sciatic nerve. A logarithmic series of 10 calibrated Semmes-Weinstein monofilaments (von Frey hairs; Stoelting, Wood Dale, Illinois) was randomly applied to the animals' right hind legs to determine the threshold stiffness of the stimulus intensity needed to trigger the paw withdrawal response. The logarithmic stiffness of the hairs was determined as the value of the decimal logarithm (milligrams × 10). Ten stimuli demonstrated the following logarithmic stiffness values (values in milligrams are enclosed in brackets): 3.61 (407 mg), 3.84 (692 mg), 4.08 (1202 mg), 4.17 (1479 mg), 4, 31 (2041 mg), 4.56 (3630 mg), 4.74 (5495 mg), 4.93 (8511 mg), 5.07 (11749 mg) and 5.18 (15136 mg). The range of monofilaments used in these experiments (0.407-15.136 g) produces a logarithmic graded slope. The interpolated data for the 50% response threshold was expressed as the intensity of the stimulus in decimal logarithms (milligrams × 10) or as the gram force of the fiber. Assessment was carried out before (baseline) and after intraperitoneal administration of the drug at certain intervals. Persons who conducted behavioral testing were not aware of the animals belonging to alternative treatment groups (blind testing method). The animal responses were used to calculate the 50% paw withdrawal threshold (absolute threshold) by fitting the Gaussian integral psychometric function using the maximum likelihood approximation method, since this fitting method allows for parametric statistical analysis.

RESEARCH AND RESULTS

Dose selection study: Preliminary studies aimed at assessing rat tolerance to single and multiple intraperitoneal doses of ibudilast. Ibudilast in intravenous doses> 20 mg / kg in 35% PEG / saline solution, administered in a volume of ≤ 5 ml / kg, caused adverse behavioral effects in rats lasting up to 1 hour. These included head stretching, an increase in respiratory rate, occasional rotational behavior, vocalization, and lethargy. Rats treated with vehicle only in the same dose volumes showed no adverse effects. In contrast, animals generally tolerated ip doses of ≤ 15 mg / kg.

Acute efficacy study : At the initial stage of the study, a small sample of animals (3-4 animals per group; imitation control groups, CKP with vehicle administration, CKP with ibudilast administration) was tested for an acute decrease in the severity of allodynia after a single intravenous injection of the test agent into dose of 10-15 mg / kg. Mechanical allodynia was quantified at baseline (immediately before the dose of the drug), as well as 1, 2, 4, and 16 hours after drug administration. CKD rats treated with ibudilast showed a reduction in allodynia compared to control animals receiving only vehicle. Allodynia is defined as a painful withdrawal reaction in response to a normal harmless stimulus. This result was obvious after 1 hour, reached a maximum after 2 hours with the subsequent return of the animals to their original state after 16 hours (actual data are not presented, but see also FIG. 1). It is important to note that there were no changes in the threshold for paw withdrawal in control animals (with CKP imitation) after the administration of ibudilast, and this indicated that the effectiveness of reducing neuropathic pain in rats with CKP was not associated with obvious anesthesia.

A multi-day study of the effectiveness of neuropathic pain : Based on the results of a preliminary study of acute efficacy, indicating a transient effect, the applicants conducted a 1-week study in which the animals (4 individuals in the group with simulated damage and 5-8 individuals in the groups with CKD) twice a day was administered intraperitoneally or ibudilast in doses of 2.5; 7.5 or 10 mg / kg, or a carrier (35% PEG / saline), followed by monitoring of mechanical allodynia at regular intervals after administration of the test drug. After the morning dose was administered, the time points +1 hour and +2 hours were checked. Testing before the introduction of the next dose was carried out daily approximately 16 hours after the previous evening dose in order to assess the duration of the therapeutic effect.

As shown in FIG. 1, treatment with ibudilast weakened the magnitude of allodynia in rats with CKD. It is noteworthy that the reverse development of pain was significant both biologically and statistically, stably manifesting +2 hours after the dose of the drug was administered. In addition, during the two days of treatment according to this scheme with a two-time administration of the drug, the effect manifested itself in a more stable form when using doses above 2.5 mg / kg, so that the reverse development of neuropathic pain was evident within 16 hours after the administration of ibudilast. Such long-term efficacy is uncharacteristic for most drugs against neuropathic pain and may not necessarily be predicted based on the pharmacokinetic profile.

Study of the weakening of the activation of glial cells in rats with CKP during treatment with ibudilast : At the end of the five-day study, animals (4 individuals per group) from the control group with CKP receiving only the carrier, and from the group with CKP receiving ibudilast were euthanized, followed by isolation of the spinal tissue brain in the lumbar region and its staining with antibodies reactive against glial fibrillar acid protein (HFCP) to evaluate astrocyte activation by the method described in BA Winkelstein and JA DeLeo, Brain Research (2002) 956: 294-301. 6 depicts a typical staining profile in animals with CKP treated with a carrier. Enlarged (activated) astrocytes, typically observed in individuals with neuropathic pain (in this case, rats with CKP), were indeed found in the CKP group. In contrast, the representative image presented here from rats treated with ibudilast demonstrates good attenuation of allodynia. In animals treated with ibudilast, reduced activation of glial cells, as measured by GFPC staining, was observed.

Oral efficacy study : A five-day study was undertaken in which the animals (8 animals per group) were administered ibudilast at a dose of 21 mg / kg or vehicle (35% PEG in saline) twice daily, for two days and then a dose ibudilast was increased to 25.5 mg / kg for the remaining three days. Testing for mechanical allodynia before and after drug administration was carried out at different time intervals on the 1st, 3rd and 5th day of the experiment. After the morning dose was administered, observations were recorded at +1 hour and +2 hours. On the same days, testing was carried out before the introduction of the next dose to assess the duration of the therapeutic effect. In animals treated with ibudilast, weakening of allodynia was observed, which manifested itself already 4 hours after the first dose and was of a long nature (lasted from the evening dose until testing before the morning dose the next day) after two days of treatment (data not shown).

In addition, the efficacy of ibudilast was assessed in a 1-week study, in which the rats (n ≥ 6 per group) were dosed orally only once a day (around 9 a.m.). The carrier composition was selected as follows: 10% HCO-60, 10% PEG400 in physiological saline. As shown in FIG. 2, oral administration of ibudilast significantly reduced the allodynia value in rats with CKP after 2 days of treatment (shortly after receiving the morning dose), and the therapeutic effect persisted over the next night, which was observed for 7 days of the study.

Pharmacokinetics Study of the correlation of plasma concentrations of ibudilast with the therapeutic effect : A pharmacokinetic study was conducted on healthy rats with intraperitoneal and oral administration of ibudilast, aimed at assessing the correlation between the level of the drug in plasma and changes in mechanical allodynia (i.e., effectiveness in neuropathic pain). After drug administration (time zero point), serial rats were taken from 3 rats for each time point at six time points distributed from 5 minutes to 6 hours after the dose was administered, plasma was isolated in which the content of ibudilast was determined by high-performance liquid chromatography resolution and two-dimensional mass spectrometry (LC / MS / MS) described in example 4 with a sensitivity threshold of ≤1 ng / ml The maximum concentration of ibudilast in the plasma (C _max ) showed a correlation with the first indications of the weakening of allodynia after the intravenous administration of the drug at a dose of 2.5 mg / kg, and the maximum plasma concentration reached 125 ng / ml. Significant efficacy was observed with neuropathic pain when given intravenously at a dose of 7.5 mg / kg, which showed a correlation with the maximum average plasma concentration reaching 1714 ng / ml. When administered orally at a dose of 21 mg / kg with PEG400 carrier in physiological saline or 50 mg / kg with 10% HCO-60/10% PEG / saline, clearly defined and statistically significant efficacy was observed at an average maximum plasma concentration of 325 ng / ml (Fig. 5B) or 387 g / ml, respectively. In addition, pharmacokinetic-pharmacodynamic analysis by parameters such as C _max , the area under the curve (PPC) and half-life (t _1/2 ) showed that the value of C _max is of key importance in evaluating the effectiveness.

Benefits of combination therapy in combination with morphine : Ibudilast efficacy was studied in rats with CKD, during which the animals were given ipudilast at a dose of 7.5 mg / kg twice daily with 35% PEG in physiological saline, alone or in combination with subcutaneous administration of morphine at a dose of 1 mg / kg (combined treatment was carried out for several days). The reverse development of allodynia with combined treatment was more pronounced compared with the control (morphine and empty carrier), and the combination of morphine + ibudilast was more effective than each of the drugs individually (data not shown). Therefore, with the combined treatment, ibudilast does not have a negative effect on the mechanism of action of opiates and, conversely, i.e. combination therapy enhances the isolated effect of each of the two drugs. Similar results are expected with the combined use of ibudilast with other drugs against neuropathic pain, including gabapentin, symbalta, and others.

FINDINGS

In the classical tested model of neuropathic pain (CKP in rats), where mechanical allodynia is the main indicator for evaluating the effectiveness, systemic daily administration of ibudilast (intraperitoneally or orally) with a frequency of once or twice a day led to a noticeable weakening of allodynia. In addition to this, it was found that ibudilast can be combined with other drugs against neuropathic pain, in particular with morphine, and the therapeutic effect of such a combination is superior to the effects of each drug individually.

The plasma concentration of ibudilast during its systemic administration, which correlates with the effectiveness of treating neuropathic pain, also shows a correlation with the maximum plasma concentration (C _max ) ≥125 ng / ml, which exceeds the plasma concentrations typically observed in patients with asthma or after a stroke, who receive ibudilast treatment. Recommended and most often used in medical practice, treatment regimens with ibudilast include its administration at a dose of 10 mg two or three times a day, leading to a C _{max of} 25 ng / ml (Ketas ^® packaging insert) or a C _{max of} 45 ng / ml in a stable phase with multi-dose administration (Z Cai-Li et al., 2003. Acta Pharmacol. Sin. 4: 342-343). Based on the data presented here, it can be expected that real doses of ibudilast for the optimal treatment of neuropathic pain in adults (when using Ketas ^® and other generic drugs of this type) will exceed 10 mg two or three times a day.

When immunoreactive staining on GFPC of spinal cord tissue from rats experiencing neuropathic pain (CKP procedure), it was shown that platelet activation, typically observed after nerve damage, decreased with systemic (iv) use of ibudilast. In addition, a decrease in GFPC immunoreactivity showed a correlation with the effectiveness of ibudilast in reducing the severity of mechanical allodynia.

EXAMPLE 2

INFLUENCE OF IBUDILAST ON MECHANICAL ALLODINIA IN EXPERIMENTS ON A RAT MODEL OF CHURG NEUROPATHIC PAIN

The effect of ibudilast on mechanical allodynia was evaluated in a rat model of Chang's neuropathic pain.

METHODS

Test Agents : Haorui and Sigma ibudilast formulations were prepared as described above. Ibudilast was administered twice daily at a dose of 10 mg / kg (3.7 ml / kg of 2.7 mg / ml 35% PEG in saline) intraperitoneally, every morning (usually at 8 hours) and in the afternoon (usually at 3 hours of the day).

Animals : In all experiments, adult male Wistar rats weighing 150-200 g (Elevage Janvier) were used free of pathogenic pathogens. Rats were kept in rooms with controlled temperature (23 ± 3 ° C) and lighting (light to dark time ratio 12:12 for <0700 hours) with a sufficient amount of standard food for rodents and water, which animals could use without restrictions. Behavioral testing was performed during the light cycle.

Chang's Model : Rats were anesthetized with isoflurane (administering 4-5% and maintaining 2-3% in 100% oxygen), after which they made an incision at the L4-S2 level to expose the spinal nerves L5 and L6 on the left. Around each nerve the ligature was tightly tightened. After that, the wounds were sutured. Rats received an injection of clamoxyl, after which they were given sufficient time to recover. Animals in the control group underwent the same surgical procedure, with the exception that the nerves were not ligated.

Behavioral assessments in the von Frey test: The von Frey test was performed as described above for the HKP model.

RESEARCH AND RESULTS

A multi-day study of the effectiveness of neuropathic pain : A 3-day study was undertaken during which animals (3-4 individuals in the group with simulated damage and 5 individuals in the group with Chang's anomaly) were given ibudilast at a dose of 10 mg / kg twice a day, or an empty carrier (35% PEG in physiological saline), followed by monitoring of mechanical allodynia at regular intervals after administration of the test drug. After the morning dose was administered, the time points +1 hour, +2 hours and +4 hours were checked. In addition, testing was carried out every day before the introduction of the next dose of the drug in order to assess the duration of the therapeutic effect.

As shown in FIG. 3, treatment with ibudilast weakened the magnitude of allodynia in rats with Chang anomaly. It is noteworthy that prolonged pain relief manifested itself at a point in time +2 hours after the next dose, starting from the 2nd day of treatment according to the two-time regimen of drug administration. In addition, it is obvious that within two days of therapy according to this two-time regimen, the therapeutic effect became longer and the reverse development of neuropathic pain was determined 16 hours after taking the previous dose of ibudilast (testing before the next dose).

FINDINGS

The results of the studies described here using another classic model of neuropathic pain suggest that systemic administration of ibudilast to rats with Chang's anomaly weakens mechanical allodynia. It is important to note that, to some extent, the short-term weakening of allodynia observed after its first administration becomes long on the second day of the treatment regimen with twice daily administration of the drug.

EXAMPLE 3

INFLUENCE OF IBUDILAST ON MECHANICAL ALLODINIA IN EXPERIMENTS ON A RAT MODEL OF NEUROPATHIC PAIN INDUCED BY TAXOL

The effect of ibudilast on mechanical allodynia was evaluated in a rat model of taxol-induced neuropathic pain, as described below.

METHODS

Test Agents : Ibudilast formulations were prepared as described above. Ibudilast was administered at a dose of 7.5 mg / kg (2.7 ml / kg of 2.8 mg / ml 35% PEG in saline) intraperitoneally, every morning (usually at 8 o’clock) and in the afternoon (usually at 3 o’clock in the afternoon )

Animals : In all experiments, pathogen-free adult male Sprague-Dawley rats weighing 280-350 g (Harlan Labs) were used. Rats were kept in rooms with controlled temperature (23 ± 3 ° C) and lighting (light to dark time ratio 12:12 for 0700 hours) with a sufficient amount of standard food for rodents and water, which animals could eat without restrictions. Behavioral testing was performed during the light cycle.

Taxol Model : Neuropathic pain was induced by the administration of 4 ip injections of 1 mg / kg taxol (Paclitaxel ^® , cumulative dose of 4 mg / kg) on different days (0th, 2nd, 4th and 6th). The attack of neuropathic pain was most pronounced approximately on the 19th day after the administration of taxol (day 0). Control administration of an empty ibudilast carrier was started either on the 19th day (treatment paradigm) or on the 12th day (prevention paradigm). The treatment outcomes for allodynia were determined before the morning administration of the vehicle or ibudilast.

Behavioral assessments in the von Frey test: The von Frey test was performed in the innervation zone of the saphenous saphenous vein by the branches of the sciatic nerve, as described above for studies on the CKP model. Evaluation testing was always carried out in the morning before the introduction of the next morning dose of ibudilast.

RESEARCH AND RESULTS

A multi-day study of the effectiveness of neuropathic pain : Ibudilast at a dose of 7.5 mg / kg was administered twice a day for 7 days, starting from the 20th day after the first dose of taxol (day 0). Mechanical allodynia was evaluated every day before the first dose of ibudilast.

As shown in FIG. 4, treatment with ibudilast weakened the magnitude of allodynia in rats treated with taxol. The treatment regimen with twice daily administration of ibudilast supported the weakening of allodynia throughout the entire period of therapy, as evidenced by the increase in the threshold for the withdrawal of the paw, determined every day before taking the next dose of the drug. Discontinuation of ibudilast treatment resulted in the rats returning to the initial state of allodynia within one day.

Prevention of Taxol-Induced Neuropathy : The second study was conducted in almost identical fashion with the multi-day study described above, except that the administration of ibudilast or empty vehicle in the control group began on day 12, i.e. immediately after a clear manifestation of the first ghosts of allodynia. Treatment with ibudilast prevented the further development of neuropathy and weakened the initial manifestations of allodynia to a level that was not significantly different from the control group of animals not exposed to toxic chemotherapy.

FINDINGS

The results of studies described here using a neuropathic pain model suggest that systemic administration of ibudilast to rats treated with taxol weakens mechanical allodynia. The weakening of allodynia with twice daily administration of ibudilast is long-lasting (i.e., lasts all night until the control test the next morning), and after the treatment is canceled, the rats return to the initial state of allodynia. It is important to note, as shown in FIG. 4B, that treatment with ibudilast can prevent the development of neuropathy (in this case, allodynia) induced by anticancer chemotherapy (taxol). It can be expected that such observations obtained on the model of neuropathic pain induced by anticancer chemotherapy will also extend to other cancer chemotherapy options that can lead to the development of neuropathy in patients.

Mechanical allodynia is a frequent and severe complication of neuropathic pain, observed in animal models and in people suffering from chronic neuropathic pain. Thus, the results described here represent the first known discovery of the potential therapeutic use of ibudilast for the treatment of various syndromes and types of chronic neuropathic pain in mammals, especially those syndromes whose characteristic symptom is mechanical allodynia.

EXAMPLE 4

FC IBUDILASTA IN PLASMA AND ITS DISTRIBUTION IN RAT TISSUES

The pharmacokinetics of ibudilast and its distribution in rat plasma, muscle, brain and spinal cord were studied as follows.

METHODS

Test Agents : Ibudilast was prepared in 15% ethanol in physiological saline. The stability and concentration of the drug was evaluated using HPLC / MS / MS (high performance liquid chromatography and two-dimensional mass spectrometry).

Animals : In all experiments, pathogen-free adult male Sprague-Dawley rats weighing 280-350 g (Harlan Labs) were used. Rats were kept in rooms with controlled temperature (23 ± 3 ° C) and lighting (light to dark time ratio 12:12 for 0700 hours) with a sufficient amount of standard food for rodents and water, which animals could eat without restrictions. Behavioral testing was performed during the light cycle.

FC analysis : Ibudilast was administered intraperitoneally at a dose of 5 mg / kg to rats (3 animals per group), and plasma, muscle, brain, and spinal cord samples were collected from animals 5, 15, 60, 180, and 420 minutes after drug administration.

Analysis of tissue concentration : A solution of ibudilast (Haorui) with a concentration of 0.5 mg / ml in dimethyl sulfoxide was used as a working material. This solution was prepared from ibudilast powder provided with test samples and was used as a working material. Plasma standards were calibrated by diluting each preform with 0.5 mg / ml 1: 100 in rat plasma to a concentration of 5000 ng / ml (5 μl + 495 μl), followed by dilution to 2.29 ng / ml by three-fold serial plasma dilution. Standards 3, 5, and 7 were used as variants of low, medium, and high quality control samples, respectively.

Calibration standards, quality control samples, and test plasma samples were prepared for injection by HPLC by precipitating 25 μl of plasma in triplicate (75 μl) of ice-cold acetonitrile containing 50 ng / ml diphenhydramine and 100 ng / ml dextromethorphan as internal standards. Tissue samples were prepared for injection by HPLC by adding 1 μl of water per 1 mg of tissue in a three-fold volume (relative to water) of ice-cold acetonitrile containing 50 ng / ml diphenhydramine and 100 ng / ml dextromethorphan as internal standards, and then the material was homogenized in an electric homogenizer. After centrifugation for 30 minutes with an acceleration of 6100 g, 40 μl of each supernatant was diluted in 200 μl of a 0.2% aqueous solution of formic acid and the analysis was performed under the following LC / MS / MS conditions:

GHUR: Shimadzu VP System Mobile phase: 0.2% solution of formic acid in water (A) and in methanol (B) Speaker: Peeke Scientific DuraGel GC ₁₈ 2 × 10 mm Security Cartridge Injection Volume: 100 μl Gradient: 5-95% B for 2 minutes after 0.75 minute washing Flow rate: 400 μl / min Mass spectrometer: Applied Biosystems / MDS SCIEX API 3000 Interface: Turboionic atomization (ESI) at 400 ° C Ionization Method: Positive ion Ions Q1 / Q3: 231.2 / 161.2 for ibudilast

RESEARCH AND RESULTS

The intraperitoneal administration of ibudilast gives its good plasma concentration, which decreases from the peak value (C _max ) in a two-phase manner. Ibudilast is well distributed in the peripheral (eg, muscles) and central (eg, brain and spinal cord) tissues (FIG. 5A). The maximum concentration (C _max ) in plasma and central nervous system tissues was approximately 1 μg / ml after iv administration of ibudilast at a dose of approximately 5 mg / kg in the above form. The elimination half-life of ibudilast ranged from 100 to 139 minutes in all tissue compartments.

FINDINGS

Based on the above data, it can be seen that ibudilast is well distributed in peripheral and central tissues, and its tissue kinetics after a single injection corresponds to that in the plasma compartment. A pharmacokinetic study of ibudilast prepared in 35% PEG 400 in physiological saline and administered orally to rats at a dose of 21 mg / kg is shown in FIG. 5B. The formulation, dose and route of administration were selected based on previous results obtained by the applicants demonstrating the weakening of allodynia in rats with CKP under similar conditions. The pharmacokinetic parameters obtained in the analysis of plasma concentration depending on the time profile are presented in the table below the graph. Therefore, such parameters reflect the correlation of pharmacokinetic parameters with the effectiveness of easing neuropathic pain.

EXAMPLE 5

A PERSPECTIVE, DOUBLE-BLIND STUDY ON PEOPLE WITH A LOCAL CONTROL FOR THE STUDY OF THE HEALING EFFECTS OF IBUDILAST IN NEUROPATHIC PAIN

The purpose of this study was to compare scores on the visual analogue scale pain index (VASPI) before treatment and at the end of treatment, and to identify differences in these scores between alternative treatment groups. In addition, the study evaluated the safety, tolerability, and pharmacokinetics of ibudilast.

METHOD

It was a double blind study. At the beginning of the study (the first 7 days), an introductory single-blind placebo treatment period was conducted. On the 2nd day of the study, its participants were sequentially divided into subgroups that received a single dose of 10 mg, 20 mg, 30 mg or 40 mg ibudilast. Samples of material for pharmacokinetic analysis were obtained on the 2nd day of the study. VASPI scores were recorded daily. On the 8th day of the study, those subjects who showed a positive response to treatment in the introductory period, determined by a 30% change in initial VASPI scores, were assigned to the placebo group for the next 14 days. Subjects who did not respond to placebo treatment during the introductory period were randomized for subsequent treatment with ibudilast according to different schemes: twice a day or three times a day. In addition, three dose cohorts (20 mg, 30 mg and 40 mg) were envisaged, with 20 subjects included in each cohort. The cohorts were filled in sequential order: the first cohort was composed of subjects receiving 20 mg of ibudilast 2 or 3 times a day, the second cohort was composed of subjects receiving 30 mg of ibudilast 2 or 3 times a day, and the third cohort was from subjects receiving 40 mg ibudilast 2 or 3 times a day. The dose increase with transfer to higher cohorts was carried out in proportion to satisfactory safety indicators and treatment tolerance in lower cohorts. Data are reported on adverse events, clinical and laboratory examinations, and NIH toxicity grading scores (or its equivalent for EU). To maintain the blind nature of the therapy, all patients received the drug three times a day, starting from the 8th day of the study until the 21st day, inclusive.

On the days of sampling for pharmacokinetic analysis, the subjects were in the research center (1st, 2nd, 8th, 9th, 21st and 22nd days).

Surveyed sample: Male and female subjects with diabetic neuropathy or with complex regional pain syndrome. Inclusion criteria: informed patients who signed a voluntary consent, males and females aged 18 to 70 years old, patients diagnosed with diabetic neuropathy or complex regional pain syndrome, established at least 6 months before the start of the study, VASPI score 4 or higher 2 weeks before the study. Women with childbearing potential should either be surgically sterilized or use an effective method of contraception to be included in the study. For female subjects with child-bearing potential, a negative pregnancy test result was needed on the 1st day of the study. Exclusion criteria: subjects with a known hypersensitivity to ibudilast or its components, subjects with a history of any condition that can interfere with the absorption, metabolism or excretion of a drug, subjects with a history of mental illness, drug addiction, drug or alcohol abuse, subjects who have passed donated blood within 90 days before the start of the study or having problems related to donation, subjects with signs of hepatitis B, HIV or nym result of screening for drugs, pregnant women or nursing mothers, as well as those already receiving the drug to be tested is not more than 90 days before the start of the study.

Assessments during the course of the study included safety, in particular adverse events, clinical and laboratory examination results, vital signs, 12-lead ECG, and pharmacokinetics.

Blood samples (1.5 ml) for analysis on ibudilast were collected from subjects in order to determine the level of drug in plasma. Before analysis, the samples were frozen at a temperature of -20 or -70 ° C.

Table
Drug Dosage Schedule for Subjects
and assessment surveys Screening
(day 0) Single dose Multiple doses Day 22 day 1 day 2 days 3-7 day 8 day 9 day 21 Informed consent × Medical history × Vaspi × × × × × × Neuropathic pain scale × × × × × × Medical examination × × Clinical laboratory (clinical and biochemical analysis of blood, urinalysis) × × Test
for pregnancy × × Hepatitis B, HIV screening
on drugs × Functional liver tests only × ECG × × × Vital functions (blood pressure and heart rate) × × × × × × Receiving doses of the drug * × × × × × × FC sampling time Before the dose of the drug - time 0 (for example, 8:00) × × × × × 30 minutes (e.g. 8:30) × × 1 hour (e.g. 9:00) × × × × 2 hours (e.g. 10:00) × × × × 4 hours (e.g. 12:00) × × × × 6 hours (e.g. 2 p.m.) × × 8 hours (e.g. 16:00) × × × × 12 hours (e.g. 20:00) × × 16 hours (e.g. 24:00) 24 hours (e.g. 8:00 on the 7th day) × 28 hours (e.g. 12:00 on the 7th day) × 32 hours (e.g. 16:00 on the 7th day) × Adverse events × × × × × × Concomitant Medicines × × × × × × * On days 1–7, one-time doses at 8:00, on days 8–20 doses at two doses per day: at 8:00 and 20:00, at three doses per day, the time for receiving doses is 8:00, 14:00 and 20:00.

Blood sampling for analysis is carried out before receiving a dose of the drug. Meal time is 9:00, 13:00 and 18:00.

Claims (28)

1. A method of treating a mammalian subject suffering from chronic neuropathic pain, comprising selecting a mammalian subject experiencing chronic neuropathic pain and administering to said subject an initial therapeutic dose of ibudilast effective to achieve a maximum plasma concentration of ibudilast of at least about 125 ng / ml, as a result of which the subject experiences relief of said neuropathic pain. 2. The method according to claim 1, in which the specified stage of administration is effective to achieve a maximum concentration of ibudilast in plasma of at least 200 ng / ml 3. The method of claim 1, wherein said screening step involves selecting a mammalian subject suffering from postherpetic neuralgia, trigeminal neuralgia and neuropathic pain associated with a condition selected from the group consisting of herpes, HIV, traumatic nerve damage, stroke , post-ischemic condition, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom pain in the limbs, multiple sclerosis and neuropathic pain, induction bath chemotherapy for cancer treatment. 4. The method according to claim 1, in which the specified stage of administration includes systemic administration of ibudilast. 5. The method according to claim 4, wherein said ibudilast is administered by a method selected from oral, intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal and sublingual. 6. The method according to claim 1, wherein said step of administration is the central administration of ibudilast by a method selected from intrathecal, intraspinal and intranasal administration. 7. The method according to claim 1, wherein said step of administration comprises administering a daily dose of ibudilast selected from the group consisting of about 30-300 mg, 30-200 mg, and about 30-100 mg ibudilast per day. 8. The method according to claim 7, in which the specified stage of administration includes the introduction of ibudilast from about 30 mg to about 100 mg per day. 9. The method according to claim 7, in which the specified stage of the introduction is the introduction of ibudilast once a day. 10. The method according to claim 7, in which the specified stage of the introduction is the introduction of ibudilast two or three times a day. 11. The method according to claim 1, in which the specified introduction of ibudilast is carried out for a period of time of at least about a week. 12. The method according to claim 7, in which the specified introduction of ibudilast is carried out for a period of time ranging from approximately one week to 50 weeks. 13. The method according to claim 1, in which the specified stage of the introduction of ibudilast is not accompanied by the introduction of an antiemetic. 14. The method according to claim 1, wherein said subject experiences allodynia, and said administration is effective to alleviate allodynia in said subject. 15. The method according to claim 1, wherein said administration is effective for alleviating the neuropathic pain experienced by said subject for at least 16 hours after the administration of ibudilast. 16. The method according to claim 1, wherein said step of administration comprises administering ibudilast in combination with an additional drug effective in the treatment of neuropathic pain. 17. The method according to clause 16, in which the specified additional tool has a mechanism of action different from that of ibudilast. 18. The method of claim 17, wherein said additional agent is selected from the group consisting of gabapentin, memantine, pregabalin, morphine and related opiates, cannabinoids, tramadol, lamotrigine, lidocaine, carbamazepine, duloxetine, milnacipran and tricyclic antidepressants. 19. A method of treating a mammalian subject that suffers from chronic neuropathic pain, comprising administering to said subject a combination of a therapeutically effective dose of ibudilast and an additional agent effective in treating chronic neuropathic pain. 20. The use of ibudilast for the manufacture of a medicament against neuropathic pain, wherein said medicament is administered to a mammal in an initial dose effective to achieve a maximum plasma concentration of ibudilast of at least 125 ng / ml. 21. The use according to claim 20, in which the introduction stage is the introduction of the specified medicinal product to a mammal subject suffering from postherpetic neuralgia, trigeminal neuralgia and neuropathic pain associated with a condition selected from the group consisting of herpes, HIV, traumatic nerve damage , stroke, postischemic condition, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, phantom pain in the limbs, multiple sclerosis Rose, sciatica, as well as neuropathic pain induced by chemotherapy in cancer treatment. 22. The use according to claim 20, in which the stage of drug administration includes systemic administration. 23. The method according to item 21, in which the stage of drug administration is carried out by the oral, intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal or sublingual method. 24. The use according to claim 20, in which the stage of drug administration includes the stage of central administration. 25. The application of claim 20, in which the stage of administration of the drug is not accompanied by the introduction of an antiemetic. 26. The use according to claim 20 for the preparation of a medicine against allodynia, where the stage of drug administration is effective for weakening allodynia experienced by the specified subject. 27. The application of claim 20, in which the stage of administration of the drug is effective to reduce chronic neuropathic pain experienced by the specified subject for at least 16 hours after administration of the specified drug with ibudilast. 28. The application of claim 20, in which the stage of administration of the drug is the introduction of ibudilast in combination with an additional drug effective in the treatment of neuropathic pain.

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