Tapentadol for treatment caused by osteoarthrosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of tapentadol for manufacturing medication for treatment of pain caused by osteoarthrosis, in which at the beginning of treatment amount of taken in tapentadol is gradually increased in order to avoid side effects (titration from 25 mg two times per day to 200 mg two times per day).

EFFECT: reduction of prevalence of treatment side effects: day drowsiness, nausea, vomiting, dizziness and dry mouth.

13 cl, 4 dwg, 4 ex

 

The invention relates to the use of tapentadol for the treatment of pain in osteoarthritis.

Osteoarthritis (arthrosis, deforming arthrosis) is the most common disease of the joints of the person. It is dynamic, but slowly progressive, degenerative disease of the cartilage or other tissue complex joints, especially in older people with recurrent inflammatory episodes. It may differ from other rheumatic diseases lack of inflammatory parameters, limited mobility, short-term stiffness and radiological signs.

Osteoarthritis or wear and aging of the joints is damaged joints, which begins with degradation of the cartilage of the joints. In severe cases, it ultimately leads to the transformation process in the adjacent bone and the surface of the joint is destroyed. Therefore, the effects of the disease are pain and stiffness of joints with limited movement. The joints can become deformed and become, eventually, a fully ossified. Osteoarthritis usually progresses slowly. As a result, the shell of cartilage, most importantly, become thinner and the chondrocytes become more metabolically active. Changes in the subchondral trabeculae lead to reduction & other fix spot labeling is key spongy bone.

Recovering the fabric is subjected to a greater load and progress of the disease varies equilibrium towards destruction. Radiograph reveals a narrowing of the surfaces of the joint and the formation of osteophytes at the edges. For further details it is possible, for example, to refer to D Höffler et al., AVP Therapieernpfehlungen der Arzneimittelkommission der Deutschen Ärzteschaft, Arzneiverordnung in der Praxis, "Degenerative Gelenkerkrankungen", 2nd Edition 2001; and Bröll H et al., CliniCum, Special Edition September 2001, Konsensus-Statement, "Arthrose - Diagnostik % Therapie".

In principle, all joints can be affected astrochicken changes. However, the most frequently affected knee (gonarthrosis) and hip joint (coxarthrosis), which must bear a large amount of weight. The disease often occurs in small vertebral joints (spondylarthrosis) and in the joints of the fingers. ICD-10 (international classification of diseases 10th edition) defines osteoarthritis of the hip joints and knee joints as a primary disease of the cartilage associated with painful restriction of movement (pain, following periods of inactivity, pain, weight load or difficulty walking. Inflammation, such as synovitis, maybe, but not necessarily installed.

Basic and early symptoms of osteoarthritis are pain (early triad: pain, following periods of inactivity, pain, you the bathroom fatigue, pain weight load; late triad: constant pain, night pain, muscle pain). The specified restrictions in movement, sensitivity to weather changes and crunch. Cases of pain in osteoarthritis are, firstly, the result of irritation in the periarticular tendons and connective ligaments, secondly, inflammation, stretching of the capsule of the joints, reactive effusion, increased pressure in the subchondral bone and microcracks.

In the early stages, the pain occurs only on weight and will go away if the movement continues, for example when further away, after a few minutes. When accompanied by inflammation, typical symptoms of activated osteoarthritis is the following: the joints are painful, felt the heat, and are swollen. Mobility is restricted. Inflammation often takes place even without treatment. This explains largely episodic for osteoarthritis: phase more severe pain and limited movement alternated with phases less pain and good mobility. As progress of the disease signs of wear and aging increase, one painful phase runs for another more quickly. In the end, the pain becomes constant.

There is a kind suitable drug and non-drug treatment, which can be applied separately or in the combination:

- conventional measures, such as swimming, Biking, targeted exercises, the use of technical AIDS, diets, etc.;

- physiotherapy, for example, heating packs, electrotherapy and kinesiotherapy, etc.;

- pharmacotherapy;

- orthopedic tools, such as bandages, orthoses, etc; and

- surgical treatment such as transplantation of autologous cartilage cells, replacement of artificial joints, etc.

The European League against rheumatism (EULAR) recommends to determine the success of special treatment to apply the index Lekena, i.e. an overall assessment physician assessment of pain by the patient. In addition, to evaluate the swelling, redness and resistance to pressure joints, control food and drugs recommends that pain and function were assessed by the index of osteoarthritis of the universities of Western Ontario and McMaster (WOMAC) index and Lekena. For drugs used for symptomatic treatment of osteoarthritis research Society of osteoarthrosis recommends scales for assessing pain syndrome WOMAC as the primary criterion and scale limitations of mobility WOMAC, or index Lekena as a second criterion, additional General assessment of the patient and the doctor.

Pharmacotherapeutic range of g is UPP active substances, suitable for the treatment of osteoarthritis includes

- non-opioids, such as paracetamol;

- nonsteroidal anti-inflammatory drugs (NSAIDs), such as acemetacin, acetylsalicylic acid, aceclofenac, diclofenac, ibuprofen, Ketoprofen, mefenamovaya acid; tiaprofenic acid, indomethacin, lonazolac, naproxen, proglumetacin, meloxicam, piroxicam, rofecoksib, celecoxib;

- opioid analgesics, such as Dihydrocodeine, tramadol, Tilidine-naloxone, morphine, buprenorphine, oxycodone, fentanyl and hydromorphone;

subcutaneously injected anti-inflammatory and hyperemic substances;

- glucocorticosteroid crystalline suspension for intra-articular injection; and

- other active ingredients for oral administration or intra-articular injection, such as glucosamine, ademethionine, oxaceprol, hyaluronic acid, etc.

Opioid analgesics do not belong to the normal range of medicines for the treatment of osteoarthritis, but may be unavoidable in certain situations. However, traditional opioid analgesics sometimes have significant side effects, particularly constipation, nausea, vomiting, headache, sedation, fatigue, respiratory depression, and sometimes a fall in blood pressure. These side effects complicate long-term treatment b is whether in connection with osteoarthritis. Therefore, the traditional treatment of opioid analgesics mainly indicated when all other treatment options have been exhausted, such as in the case of patients who cannot be affected by the operation, but suffer from extreme pain at rest, which does not react to other substances with analgesic effect.

Condition exists for alternative pharmacotherapeutic methods of osteoarthritis, which is characterized by the effective control of pain and reduced side effect profile.

Therefore, the aim of the invention was to find songs that are effective in controlling pain in osteoarthritis and have advantages over traditional analgesics.

This goal is achieved by using the subject of the claims.

The invention relates to the use of tapentadol for the manufacture of a medicine for treatment of pain in osteoarthritis.

Unexpectedly it was found that tapentadol, preferably as a composition of extended release (PV) (synonym composition of extended release (PV)), i.e. compositions with extended-release in the value of the European Pharmacopoeia, combining excellent efficacy in the treatment of pain in osteoarthritis, reduced range of side effects. Extended release about what the rule refers to the value of the modified release which differs from the traditional release dosage forms that are entered in the same way. Modification of release is usually achieved by the special design of the dosage form or a special method of manufacture.

Figure 1 shows a schematic representation of the titration scheme applied during the research on the effectiveness of tapentadol for the treatment of pain in osteoarthritis.

Figure 2 shows a schematic representation of the effectiveness of tapentadol (100 mg and 200 mg) compared with placebo and oxycodone.

Figure 3 shows the mathematical analysis of the distribution of serum concentrations within groups of patients, following receiving different doses of tapentadol.

Figure 4 shows the mathematical analysis of the relationship between serum concentrations of tapentadol and its effect on pain relief in patients on the basis of data from various clinical studies.

Tapentadol, i.e. the (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is a synthetic, centrally acting analgesic that is effective in the treatment of moderate to severe acute or chronic pain.

Tapentadol shows a dual mechanism of action, on the one hand, as an agonist at µ-opioid receptor, and on the other hand, as the inhibitor vector of norepinephrine. L. the dei affinity tapentadol to recombinante obtained µ-opioid receptor is 18 times less than morphine. However, clinical studies have shown to relieve pain action tapentadol, which is only two or three times less than that of morphine. Only slightly reduced analgesic efficacy with both 18-fold lower affinity for recombinantly µ-opioid receptor indicates that the property tapentadol to inhibit carrier norepinephrine also contributes to its analgesic efficacy. Consequently, it is possible to conclude that tapentadol has analgesic efficacy similar to pure agonist at µ-opioid receptor, but has far fewer side effects associated with the µ-opioid receptor. The composition may be applied in the form of its free base or as a salt, or MES. Making free base is known, for example, from EP-A 693475.

For descriptive purposes, "tapentadol" means (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and the corresponding pharmaceutically acceptable salt and solvate.

Suitable pharmaceutically acceptable salts include salts of inorganic acids, such as, for example, hydrochloric acid, Pomodoro and sulfuric acid, and salts of organic acids such as methane sulfonic acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic acid, malic is islote, tartaric acid, almond acid, lactic acid, citric acid, glutamic acid, acetylsalicylic acid, nicotinic acid, aminobenzoic acid, alpha-acid, hippuric acid and aspartic acid. The preferred salt is hydrochloric.

In a preferred embodiment, the drug is a solid dosage form. Preferably, the drug is formulated for oral administration. However, other dosage forms are also possible, for example transbukkalno, sublingual, transmucosal, rectal, vnutriyazychno, intraperitoneal, transdermal, intravenous, intramuscular, vnutrigodovye, intradermal and subcutaneous.

Depending on the dosage form, the drug preferably contains suitable additives and/or excipients. Suitable additives and/or auxiliary substances, for the purposes of the invention are all substances to achieve galenical compositions known to the expert from the prior art. The choice of these auxiliary substances and their number is dependent on how the drug is taken, i.e. orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, transbukkalno or locally.

p> Suitable for oral administration are medicines in the form of tablets, chewable tablets, pills, capsules, granules, drops, extracts or syrups; suitable for parenteral, external and inhalation intake are solutions, suspensions, readily soluble dry medicines and sprays. Additional opportunity suppositories are for rectal use. Application in deporations the form of a foil carrier or a plaster, optionally with the addition of substances that activate skin penetration, are examples of suitable applications for subcutaneous injection.

Examples of auxiliary substances and additives for oral forms of acceptance are leavening agents, lubricants, binders, fillers, form release agents, optionally solvents, fragrances, sugar, particularly carriers, diluents, colorants, antioxidants, etc.

For the suppository may use, among others, waxes and esters fatty acids for parenteral methods of reception, carriers, preservatives, retardants, etc.

Excipients can be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropyleneglycol, glucose, fructose, lactose, sugars is, dextrose, molasses, starch, modified starch, gelatin, sorbitol, Inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, acetylcellulose, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic resins, gum acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, literallayout, sodium lauryl sulphate, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polypropylene esters of fatty acids, esters and fatty Corbetta acid, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crosspovidone, agar and bentonite.

The manufacturer of the drug and pharmaceutical compositions is performed using means, devices, methods and processes that are well known in the prior art technology of preparation of medicines, such as described, for example, in"Remington''s Pharmaceutical Sciences", ed. AR Gennaro, 17th edition, Mack Publishing Company, Easton, pa. (1985), in particular in part 8, sections 76-93.

For example, solid compositions such as tablets, the active substance of the medicinal product may be granulated with the use of a pharmaceutical carrier, e.g. conventional components of the tablet, such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums and pharmaceutical diluents, such as water, for example, in order to form a solid composition comprising the active substance in a homogeneous distribution. Homogeneity is understood here in the sense that the active ingredient is homogeneously distributed throughout the composition so that it can easily be divided into equally effective separate dosage forms such as tablets, capsules, pills. The solid composition is then split into separate dosage forms. Tablets or pills can be coated with, or made in a slightly different way, with the aim of providing dosage forms with delayed release. Suitable covering compositions, among others, are polymeric acids and mixtures of polymeric acids with such materials as shellac, for example cetyl alcohol and/or acetylcellulose.

Quantities is tapentadol, proper for the reception of patients, differs depending on the weight of the patient, route of administration and the severity of the disease. In a preferred embodiment, the drug contains tapentadol in the amount of 10-300 mg, more preferably 20-290 mg, even more preferably 30-280 mg, most preferably 40-260 mg, as an equivalent dose based on the free base.

Delayed release of tapentadol possibly compositions for oral, rectal or subcutaneous administration. Preferably, the drug is prepared to accept once a day, twice a day (bid) or three times a day, with a particularly preferred technique twice a day (bid).

Delayed release of tapentadol may, for example, be achieved by retardation using matrix, coatings or systems release from osmotic effect (see, for example, US-A-2005-58706).

In a preferred embodiment, the mean serum concentrations of tapentadol, following the admission medication twice a day for a period of at least three days, more preferably at least four days and in particular at least five days is the average of at least 5.0 ng/ml, at least to 10.0 ng/ml, at least to 15.0 ng/ml, or, at m is re, to 20.0 ng/ml, more preferably at least 25,0 ng/ml, or at least about 30.0 ng/ml, even more preferably at least 35,0 ng/ml, or at least to 40.0 ng/ml, most preferably at least 45,0 ng/ml, or at least to 50.0 ng/ml and in particular at least 55,0 ng/ml, or at least by 60.0 ng/ml, This means that tapentadol is made within a period of at least three days twice a day and then, preferably after 2 h after administration, serum concentrations are measured. Reliable numerical value is then achieved as the average for all study patients.

In a preferred embodiment, the mean serum concentrations of tapentadol most 50% of the patients group, which preferably contains at least 100 patients, more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, particularly at most 10% of patients, following the reception twice a day, for a period of at least three days, more preferably at least four days and in particular at least five days, is on average less than 5.0 ng/ml, preferably less than 7.5 ng/ml, even more preferably less than 10.0 ng/ml, most preferably less than 1.0 ng/ml and in particular, less than 20.0 ng/ml

In a preferred embodiment, the mean serum concentrations of tapentadol most 50% of patients groups containing preferably at least 100 patients, more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, particularly at most 10% of patients, following the reception twice a day, for a period of at least three days, more preferably at least four days and in particular at least five days, is in average more than 300,0 ng/ml, more preferably more than 275,0 ng/ml, even more preferably more than 250,0 ng/ml, most preferably more than 225,0 ng/ml and, in particular, more than 200,0 ng/ml.

Preferably, the average serum concentrations of tapentadol in at least 50% or 55% of the patients group, which preferably contains at least 100 patients, more preferably at least 60%, or 65%, even more preferably at least 70% or 75%, most preferably at least 80% or 85%, in particular at least 90% or 95% of patients following admission twice a day, over a period of at least three days, more preferably at least four bottom and, in particular, at least five days is the average period of 1.0 ng/ml to 500,0 ng/ml, more preferably in the interval from 2.0 ng/ml to 450,0 ng/ml, even more preferably in the range from 3.0 ng/ml to 400.0Hz in units of ng/ml, most preferably in the range from 4.0 ng/ml to 350,0 ng/ml and, in particular, in the range from 5.0 ng/ml to 300,0 ng/ml.

In a preferred embodiment, the percent standard deviation (coefficient of variation) average serum concentrations of tapentadol, preferably in the group of patients out of 100 patients following the administration of the medicine twice a day, for a period of at least three days, more preferably at least four days and in particular at least five days, is the biggest ±90%, most preferably ±70%, even more preferably biggest ±50%, maximum ±45%, maximum ±40%, most preferably most of ±35%, maximum ±30%, maximum ±25% and, in particular, the maximum of ±20%, maximum ±15%, maximum ±10%.

Preferably, the serum concentrations are average values derived from measurements in the group of patients of preferably at least 10, more preferably at least 25, even more preferably at least 50, even more preferably, at the very the least, 75, most preferably at least 100, and in particular at least 250 patients. The skilled person knows how to determine serum concentrations of tapentadol. In this context, refers, for example, TM Tschentke et al., Drugs of the Future, 2006, 31(12), 1053.

In a preferred embodiment,

- the drug is formulated for oral administration;

- the drug is solid and/or pressed and/or film-coated dosage form; and/or

- drug tapentadol has delayed the release of the matrix; and/or

- contains drug tapentadol in an amount of from 0.001 to 99,999 wt.%, more preferably of 0.1 to 99.9 wt.%, even more preferably 1.0 to a 99.0 wt.%, even more preferably 2,5-80,0 wt.%, most preferably of 5.0 to 50.0 wt.% and, in particular, a 7.5-40.0 wt.% from the total mass of the medication; and/or

- the drug contains a pharmaceutically acceptable carrier and/or pharmaceutically acceptable excipients; and/or

- the drug has a total weight in the range from 25 to 2000 mg, more preferably 50-1800 mg, even more preferably 60-1600 mg, even more preferably 70-1400 mg, most preferably 80-1200 mg and, in particular, 100-1000 mg; and/or

- the drug is selected from the group, with the standing of pills capsules, pellets and granules.

The drug can be provided as a simple tablet or coated tablet (for example, as film-coated tablets or pills). Tablets are usually round and biconvex, but the elongated shape are also possible. Granules, spheroids, pellets or microcapsules, which are used for filling sachets or capsules, or compressed into a disintegrating tablets are also possible.

Drugs, containing at least 0.001 to 99,999% tapentadol, in particular low, the active doses are preferred for the purposes of avoiding side effects. The drug contains preferably from 0.01% by weight to 99.99% by weight of tapentadol, more preferably of 0.1 to 90.0% by weight, more preferably 0.5 to 80,0% by weight, most preferably from 1.0 to 50.0% by weight and, in particular, of 5.0 to 20.0% by weight. To avoid side effects may be useful in the beginning of the treatment to increase the quantity of tapentadol gradually (titration), to give the man slowly get used to the current matter. Preferably, tapentadol taken first dose, which is below analgesic active dose.

Particularly preferably, the drug is an oral dosage form, which is prepared for the reception of the active ingredient is GDI a day, and contains tapentadol in the amount of from 20 to 260 mg as an equivalent dose based on the free base.

In a preferred embodiment, the drug has the dosage form with immediate release tapentadol.

In accordance with the invention, tapentadol is used to treat pain due to osteoarthritis. Preferably, osteoarthritis is selected from the group consisting of gonarthrosis, coxarthrosis and spondylarthrosis.

Preferably, pain osteoarthritis is osteoarthritis, as determined in accordance with ICD-10 (international statistical classification of diseases and problems related to health, the publication of the who, preferably text 2007). Preferably, osteoarthritis is selected from polyarthrosis [M15], coxarthrosis [M16], gonarthrosis [M17], osteoarthritis of the first metacarpal-carpal joint [M18], another type of osteoarthritis [M19] and spondylosis [m]. References in square brackets refer to the item ICD-10.

If osteoarthritis is polyarthrosis [M15], preferably selected from the group consisting of primary generalized (osteo)arthrosis [M], nodes Gerbera (with arthropathy) [M], nodes Bouchard (with arthropathy) [M], multiple secondary osteoarthritis (post-traumatic polyarthra) [M], erosive (osteo)arthrosis [M], etc is different polyarthrosis [M] and polyarthrosis unspecified (generalized (osteo)arthrosis not otherwise specified) [M].

If osteoarthritis is coxarthrosis [M16], preferably selected from the group consisting of primary coxarthrosis, bilateral [M], other primary coxarthrosis (unilateral or not otherwise specified) [M], coxarthrosis resulting from the bilateral dysplasia [M], other dysplastic coxarthrosis (unilateral or not otherwise specified) [M], post-traumatic coxarthrosis, bilateral [M], other post-traumatic coxarthrosis (unilateral or not otherwise specified) [M], other secondary coxarthrosis bilateral [M], other secondary coxarthrosis (unilateral or not specified otherwise) [M] and coxarthrosis unspecified [M].

If osteoarthritis is gonarthrosis [M17], preferably selected from the group consisting of primary gonarthrosis, bilateral [M], other primary gonarthrosis (unilateral or not otherwise specified) [M], post-traumatic gonarthrosis, bilateral [M], other post-traumatic gonarthrosis (unilateral or not otherwise specified) [M], other secondary gonarthrosis bilateral [M], other secondary gonarthrosis (unilateral or not otherwise specified) [M] and gonarthrosis unspecified [M].

If osteoarthritis is osteoarthritis of the first carpometacarpal joint

[M18]preferably selects the C group, consisting of primary osteoarthritis of the first carpometacarpal joint bilateral [M], other primary arthrosis of first carpometacarpal joint (unilateral or not otherwise specified) [M], post-traumatic osteoarthritis of first carpometacarpal joints, bilateral [M], other post-traumatic arthrosis of first carpometacarpal joint (unilateral or not otherwise specified) [M], other secondary arthrosis of carpometacarpal joint bilateral [M], other secondary arthrosis of first carpometacarpal joint (unilateral or not otherwise specified) [M] and osteoarthritis of the first carpometacarpal joint, unspecified [M].

If osteoarthritis is another form of osteoarthritis [M19], preferably selected from the group consisting of primary osteoarthritis of other joints (primary osteoarthrosis not specified otherwise) [M], post-traumatic osteoarthritis of other joints (post-traumatic osteoarthrosis not specified otherwise) [M], secondary osteoarthritis of other joints (secondary osteoarthrosis not specified otherwise) [M], other specified osteoarthritis [M] and osteoarthrosis unspecified [M].

Preferably, the pain is moderate to strong. In a preferred embodiment, the pain is selected from the group consisting of the Oli, following periods of inactivity, pain, weight bearing, pain caused by fatigue, periarticular pain under load, radiating pain (such as pain in the knee joint in coxarthrosis), pain at rest after a long time in the same position, constant pain, spontaneous pain, pain with motion, night pain, muscle pain, pain at the end range of motion, bone pain as spontaneous pain and pain at rest.

Even if the medicinal product in accordance with the invention show only a few side effects, in order to avoid certain kinds of dependencies can be useful, for example, in addition to tapentadol to apply the morphine antagonists, in particular naloxone, naltrexone and/or levallorphan.

The invention also relates to a method of treatment of pain in osteoarthritis, in which tapentadol is administered to the patient in a pharmaceutically acceptable amount.

The following Examples serve to further explain the invention, but should not be construed as limiting.

Example 1:

Object:

The efficacy and tolerability of tapentadol slow release (PV) and oxycodone HCl with controlled release (KB) was compared with placebo in patients with moderate to severe pain due to osteoarthritis of the knee is on the joint.

Methods randomized, double-blind, placebo-controlled study):

Patients (N=670) were randomly selected and subjected to treatment for 28 days twice a day tapentadol PV 100 mg, tapentadol PV 200 mg, oxycodone HCl KB 20 mg or placebo. The dose was titrated at the beginning of treatment. The main efficacy criterion was the average perception of pain during the preceding 24 hours during the last medical examination (last visit), based on the visual analog 100-mm scale (VAS, 0 mm = no pain, 100 mm = unbearable pain).

The study consisted of a 14-day, double-blind phase titration (3 days → 11 days), followed by a 14-day double-blind maintenance phase (at the highest dose titration scheme in each case; see Figure 1):

- tapentadol PV 100 mg: 25 mg (bid) → 50 mg (bid) → 100 mg (bid);

- tapentadol PV 200 mg: 100 mg (bid) → 150 mg (bid) → 200 mg (bid);

is oxycodone HCl KB 20 mg: 10 mg (bid) → 10 mg (bid) → 20 mg (bid).

The results:

The difference from the calculated standard error (± standard error) in average pain intensity compared with placebo was significant for tapentadol PV 200 mg (- 8.4 mm [±3,30]; P=0,021). Differences from the calculated standard errors (± standard error) in average pain intensity compared with placebo were following what: for tapentadol PV 100 mg 5,9 mm (±3,34; P=0,142) and oxycodone HCl KB 20 mg of 5.4 mm (±3,22; P=0,091), i.e. tapentadol RO 100 and oxycodone HCl KB 20 mg show similar behavior (see Figure 2).

In all groups, gastrointestinal disturbances (including nausea, constipation and vomiting) and disorders of the nervous system (including fatigue and dizziness were the most common side effects:

Side effectsPlaceboTapentadol PV 100 mgTapentadol PV 200 mgOxycodone HCl KB 20 mg
Gastrointestinal23%30%49%56%
Constipation5%7%10%20%
Nervous system15%24%34%43%

Mathematical analysis of the distribution of serum concentrations within groups of patients, following receiving different doses of tapentadol shown in Figure 3.

Clinical data confirm that tapentadol PV 200 mg Ki is effective for 4 weeks in the treatment of moderate to severe chronic pain due to osteoarthritis. In relation to gastro-intestinal side effects and side effects associated with the Central nervous system, clinical data show that tapentadol is better tolerated than oxycodone HCl.

Mathematical analysis of the relationship between serum concentrations of tapentadol and efficacy in pain relief in the group of patients based on data from various clinical trials, are shown in Figure 4.

Examples 2-4:

Object:

The efficacy and tolerability of tapentadol immediate-release (HB) and oxycodone HCl immediate-release (HB) were compared with placebo in patients with moderate to severe pain due to osteoarthritis of the knee or hip.

Example 2:

Methods (90-day phase III, randomized, double-blind, active control of flexible-dose study)

Patients (N=878) randomly been assigned in the ratio of 4:1 to obtain tapentadol HB (50 or 100 mg every 4 to 6 hours, depending on needs; up to 600 mg/day), or oxycodone HCl HB (10 or 15 mg every 4-6 hours, depending on needs; up to 90 mg/day).

The intensity of pain during the 24 hours before each visit was recorded from the date of first dose of study until the last visit, inclusive, using a numeric scale with 11 divisions (0 = UTS is OUTSTA pain, 10 = unbearable pain). Portability was the first day of treatment until the second day after the last day of study treatment.

The results:

All of 679 patients in group tapentadol HB and 170 patients in the group of oxycodone HCl HB were included in the analysis of efficacy and safety. Indications pain intensity were similar between the two groups over time. The average readings of the intensity of the source of the pain level was 7.0 for group tapentadol HB and 7.2 for a group of oxycodone HCl HB. These values decreased to the end of double-blind period to 4.9 and 5.2 for group tapentadol NV and the group of oxycodone HCl HB, respectively. The most common side effects were nausea, vomiting, dizziness, constipation, headache and drowsiness. Patients in group tapentadol HB was significantly (P<0.001 for all measurements) below nausea (18%), vomiting (17%) and constipation (13%) in comparison with a group of oxycodone HCl HB (nausea 29%; vomiting 30%; constipation 27%), while cases of drowsiness, dizziness and headache, were similar in both groups. Serious side effects have been reported for 0.7% of patients in group tapentadol HB and 1.8% of patients in the group of oxycodone HCl HB. However, this did not pertain to your current substance.

Example 3:

Methods (a phase III, randomized test, double-blind study)

88 patients randomly were assigned to take tapentadol HB (50 or 100 mg; a maximum of 600 mg/day), or oxycodone HCl HB (active control; 10 or 15 mg; maximum 90 mg/day) every 4-6 hours for 90 days. Group treatment were compared using the criteria of the Cochrane-Mantel-Hensel.

The results:

The analysis consisted of 679 patients in group tapentadol HB and 170 patients in the group of oxycodone HCl HB. Patients who have experienced the effects of opioids (i.e. patients who have been taking opioids for at least 5 days a week for 30 days before screening), consisted 49,0% of patients in group tapentadol HB and 48.2% of patients in the group of oxycodone HCl HB. The average values of the readings of pain decreased from baseline to end of study from 7.0 to 4.9 for tapentadol HB and from 7.2 to 5.2 for oxycodone HCl HB. The most common side effects were nausea, vomiting, dizziness, constipation, headache and drowsiness. Significantly less (P<0,001) gastrointestinal side effects have appeared in the group tapentadol HB (nausea 18%; vomiting 17%; constipation 13%)than in the group of oxycodone HCl HB (nausea 29%; vomiting 30%; constipation 27%), while cases of headache, dizziness and drowsiness were similar in both groups. In General, patients who did not use opioids, had more side effects, although this trend was less pronounced for tapentadol HB than for oxycodone HCl HB.

In patients who have experienced dei is a journey of opioids, vomiting appeared in 18% of the group tapentadol NV and in 39% of the group of oxycodone HCl HB, while nausea was reported in 22% of the group tapentadol HB and 35% of the group of oxycodone HCl HB. Patients with experience of using opioids vomiting was recorded in 16% of the group tapentadol HB and 21% of the group of oxycodone HCl HB, while, on the other hand, nausea appeared in 14% of the group tapentadol HB and 23% of the group of oxycodone Hcl HB. Experience in the use of opioids has not led to a decrease in the incidence of constipation in any of the two groups (tapentadol HB: experience with opioid use, 12%; lack of experience with the use of opioid, 14%) (oxycodone HCl HB: experience with opioid use, 27%; lack of experience with the use of opioid, 27%).

Example 4:

Methods (a phase III, randomized, double-blind, placebocontrolled research)

674 patients randomly were assigned to receive placebo, tapentadol HB 50 or 75 mg or oxycodone HCl HB 10 mg every 4-6 hours during waking hours. The results of the study included the total value of pain intensity (SPID) for 5 days (primary endpoint), assessment of the tolerability and analysis of the age and the way to study potential differences between subgroups of a group of people.

The results:

666 randomly selected patients were included in the analysis of security; 659 patients were included in the review of the licensing efficiency. Compared with placebo, tapentadol HB 50 and 75 mg demonstrated significant improvement in pain reduction-based evaluation metric 5-day SPID (P<0,001). The group of oxycodone HCl HB 10 mg also demonstrated significant improvements in the evaluation of indicator 5-day SPID (P<0.001) in the placebo group, thus confirming the accuracy of the test. Based on pre-established criteria 5-day SPID, tapentadol HB 50 and 75 mg were at least as effective as oxycodone HCl HB 10 mg. In all groups active treatment indicators 5-day SPID were similar between patients < 65 and ≥65 years, and between subgroups of men and women. Common side effects include gastro-intestinal side effects and side effects associated with the Central nervous system. In General, the number of cases of gastrointestinal side effects have demonstrated the dose to tapentadol HB 50 and 75 mg (29% and 40%, respectively), which was lower than for oxycodone Hcl HB 10 mg (69%). This trend was also observed within subgroups. Patients < 65 and ≥65 years was noted fewer gastrointestinal side effects with tapentadol HB 50 mg (25% and 36%, respectively)than with 75 mg (42% and 38%, respectively) and in both cases they were lower than with oxycodone HCl HB 10 mg (66% and 74%, respectively). In the subgroups of men and women Gelu the part-intestinal side effects were reported in 21% and 39% of cases, respectively, with tapentadol HB 50 mg and 28% and 54% of cases, respectively, with tapentadol HB 75 mg, in comparison with 58% and 81% respectively for oxycodone HCl HB 10 mg

Conclusions

Clinical data are proof of the effectiveness of tapentadol HB for the treatment of moderate to severe pain due to osteoarthritis. In regard to gastrointestinal side effects, clinical data show better tolerability tapentadol compared to oxycodone HCl.

1. The use of tapentadol for the manufacture of a medicine for treatment of pain in osteoarthritis, in which at the beginning of treatment the quantity of tapentadol rises gradually to avoid side effects (titration).

2. The use according to claim 1, characterized in that the average serum concentration of tapentadol, following the reception twice a day, for a period of at least three days, is the average of at least 5.0 ng/ml.

3. The use according to claim 1 or 2, characterized in that the average serum concentration of tapentadol most 50% of a group of patients following admission twice a day, for a period of at least three days, is on average less than 5.0 ng/ml

4. The use according to claim 1, characterized in that the average serum concentration of tapentadol most 50% of a group of patients following admission twice a day, for a period of at least three days, is in rednam more than 300,0 ng/ml.

5. The use according to claim 1, characterized in that the average serum concentration of tapentadol in at least 50% of a group of patients following admission twice a day, for a period of at least three days, is on average in the range of 1.0 ng/ml to 500,0 ng/ml.

6. The use according to claim 1, wherein the drug is a solid dosage form.

7. The use according to claim 1, characterized in that the drug is formulated for oral administration.

8. The use according to claim 1, characterized in that the drug is intended for the reception twice a day (bid).

9. The use according to claim 1, characterized in that the medicinal product contains tapentadol in the range from 10 to 300 mg.

10. The use according to claim 1, characterized in that the medicinal product contains a pharmaceutically acceptable carrier; and/or consists of the total mass in the range from 25 to 2000 mg; and/or is selected from the group consisting of tablets, capsules, pellets and granules.

11. The use according to claim 1, wherein the osteoarthritis is selected from the group consisting of gonarthrosis, coxarthrosis and spondylarthrosis.

12. The use according to claim 1, characterized in that the pain is moderate to strong.

13. The use according to claim 1, wherein the pain is selected from the group consisting of pain, following periods Passy is ness, pain weight bearing, pain caused by fatigue, periarticular pain under load, radiating pain, pain at rest after a long time in the same position, constant pain, spontaneous pain, pain with motion, night pain, muscle pain, pain at the end range of motion and bone pain as spontaneous pain and pain at rest.



 

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FIELD: medicine, pharmaceutics.

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30 cl, 255 ex, 40 tbl

FIELD: medicine.

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17 cl, 6 dwg, 17 tbl, 4 ex

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5 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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26 cl, 12 dwg, 1 tbl, 49 ex

FIELD: medicine.

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1 ex, 2 tbl

FIELD: medicine.

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12 tbl, 3 ex

FIELD: medicine.

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4 cl, 8 ex, 6 tbl

S1p application // 2362565

FIELD: medicine.

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17 cl, 24 dwg, 1 tbl

FIELD: chemistry.

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17 cl, 5 tbl, 2 dwg, 8 ex

FIELD: chemistry.

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36 cl, 303 ex

FIELD: medicine.

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FIELD: medicine.

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11 cl, 2 dwg, 3 ex

FIELD: medicine, pharmaceutics.

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10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

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25 cl, 115 ex, 2 tbl

FIELD: medicine.

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3 ex

FIELD: medicine.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is application of IL-1β binding antigen for producing a drug preparation for treating juvenile rheumatoid arthritis in a patient, containing at least one antigen-binding centre which involves a first domain having an amino acid sequence specified in SEQ ID NO:1, and a second domain having an amino acid sequence specified in SEQ ID NO:2. What is presented is a pharmaceutical composition containing said antibody in a combination with pharmaceutically acceptable excipients, solvents or carriers introduced parenterally.

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10 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to pharmaceutical industry, in particular to composition for prevention or therapeutic treatment of inflammatory and/or degenerative condition. Composition for local application for prevention or therapeutic treatment of inflammatory and/or degenerative condition, including (i) woundwort or obtained from woundwort compound or its analogue or derivative, and (ii) tannic acid or its analogue or derivative. Method of prevention or therapeutic treatment of inflammatory and/or degenerative condition (versions). Application of composition for local application for production of medication for prevention or therapeutic treatment of inflammatory and/or degenerative condition. Set, including in two or more containers (i) tannic acid or its analogue or derivative and (ii) woundwort or obtained from woundwort compound or its analogue or derivative or any their combination. Set, including container, which includes composition for local application.

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41 cl, 17 ex

FIELD: medicine.

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12 cl, 21 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

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37 cl, 10 dwg

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