The composition comprising the substance tramadol and acetaminophen, and method of treatment using it

 

(57) Abstract:

The invention is intended for use in medicine in the treatment of severe pain. The pharmaceutical composition of analgesic action contains tramadol and acetaminophen at a mass ratio of 1:1 to 1600. A method of treating a mammal provides for the introduction to be effective amount of farbkomposition. The objective of the invention is the reduction of side effects when using drugs with increased efficacy of analgesia. 2 S. and 9 C.p. f-crystals, 1 Il., table 1.

Patent N 3652589 the United States reveals the class of analgesics - ethers of phenol, substituted cycloalkanones having a primary amino group in cycloalkene ring. Specifically, there is disclosed the compound (1RS,2RS)-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol. A series of articles on pharmacology, toxicology and clinical study tramadol, placed in Arzneim. Forsch. (Drug Res.), 28(1), 114 (1978). Driessen et al. , Arch. Pharmacol. 341, R104 20 (1980), discloses that tramadol exerts its analgesic effect via a mechanism that is not fully opioiddependent or non. In Abstracts of the VI th World Congress on Pain, April 1 - 6 (1990) revealed that hydrochl the technical experience, what is in tramadol lack many of the typical side effects of opioid agonists, such as respiratory depression (W. Vogel et al., Arzneim. Forsch. (Drug Res.), 28(1), 183 (1978)), constipation (I. Arend. et al., Arzneim. Forsch. (Drug Res.), 28(1), 199 (1978)), addictive (L. Flohe et. al., Arzneim. Forsch. (Drug Res.), 28(1), 213 (1978)) and the ability to cause addiction (T. Yanagita, Arzneim. Forsch. (Drug Res. ), 28(1), 158 (1978)). At the dose of 50 mg by rapid IV injection tramadol can cause certain side effects that are unique to tramadol, including hot flashes and sweating. Despite these side effects, combination of tramadol and non-opioid activity makes tramadol truly unique. Currently tramadol is marketed Grunenthal GMBH as an analgesic.

Opioids for many years was used as analgesics to treat severe pain. They are, however, cause undesirable side effects, the result can not be applied repeatedly or in high doses. See, for example, J. Jaffe and W. Martin in chapter 15, "The Pharmacological Basis of Therapeutics", editors L. Goodman and A. Gilman, 5th Edition, 245 (1975), where it is shown that morphine and its derivatives, such as codeine, hydrocodone and oxycodone, analgesics are a type of opioid agonists, which are side effects, so native use of opioids used as analgesics, non-drugs, such as acetaminophen (APAP) and aspirin. APAP like aspirin is not subject to habituation, addiction and has no toxicity opioid analgesics. However, APAP and aspirin is able to weaken only moderate pain, while opioid analgesics can reduce more severe pain; see /Woodbury, D. and Fingl, E. in "The Pharmacological Basis of Therapeutics, 5th Ed.; Goodman, L. and Gliman, A., Chapter 15, pages 325 (1975).

To reduce the problems associated with the side effect of opioids, opioids combined with other drugs, including the pain relief funds, which reduces the amount of opioid required to obtain an equivalent degree of analgesia. It was stated that some of these combination products in addition have the advantages of causing a synergistic analgesic effect. For Example, A. Takemori, Annals New York Acad. Sci., 281, 262 (1976) discloses that compositions comprising combinations of opioid analgesics with drugs not related to analgesics, show a number of effects, for example, subadditivity /inhibitory/, additive or superadditive /sverhsummarny/.

R Taber et al., J. Pharm. Expt. Thera., 169(1), 29(1969) reveals that the combination of morphine and methadone, another opioid analgesic, is manifested additivity, and ibuprofen, non-analgesic, is provided superadditivity effect when the components are in a certain ratio.

A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) reported superadditive anesthesia using a mixture of 1 : 125 butorphanol, another opioid analgesic, and acetaminophen (APAP), non-analgesic, while a mixture of 1 : 10 does not show any statistically significant superadditive effect of anesthesia.

To avoid side effects associated with opioids, were also obtained combination of non-analgesics, and these combinations, as shown, have the advantage of requiring less

each ingredient and providing superadditive action. G. Stacher et. al., Int. J. Clin. Pharmacol. Biopharmacy, 17, 250 (1979) reported that the combination of non-analgesics, such as tolmetin and APAP, can significantly reduce the number of tolmetin required to induce anesthesia. In addition, U.S. patent N 4260629 reveals that orally applicable composition of APAP and zomepirac, non-analgesic, in a specific weight ratio causes superadditive the pain in mammals. Furthermore, in U.S. patent N 4132788 revealed that pronom show superadditive antiarthritic activity. However, there are warnings on the daily intake of mixtures of non-analgesics and a single dose non-opioid analgesics in large quantities or over long periods (see D. Woodbury and E. Fingl on page 349).

The prior art does not, however, reveals that tramadol "atypical" opioid analgesic, can or should be combined with another analgesic, to reduce the side effects of each, or what you want to create a composition comprising the drug tramadol and a different analgesic, which are superadditive anesthesia.

Summary of the invention

It was found that the drug tramadol, which includes different forms of tramadol, as explained hereafter, may be combined with APAP to get pain relief. In combination are used in smaller amounts as drug tramadol and APAP, what would be necessary to obtain the same level of pain, if each of them were used separately. By using smaller quantities of both drugs side effects associated with each, reduced the number and level. It has been unexpectedly found that a composition comprising the substance tramadol and APAP, testuya to this invention, can also be used in the treatment of conditions involving cough.

A brief description of the drawing

The drawing is isobologram showing the analgesic effect of the composition of tramadol hydrochloride and acetaminophen on abdomipolyp spasms in mice induced by acetylcholine.

A detailed description of the invention

The present invention relates to compositions comprising a preparation of tramadol and acetaminophen. Tramadol is one of the (1R,2R or 1S,2S) (dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol, its N-oxide derivative ("tramadol N-oxide"), and its O-desethylene derivative ("O-desmethyl-tramadol"), or a mixture thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of amines, such as hydrochloride, solvate and polymorph modification of the drug tramadol. Tramadol commercially available from Grunenthal or can be obtained using the method described in U.S. patent N 3652589, which is included here by reference.

N-oxide tramadol is obtained by treatment of tramadol in the form of a free base, oxidizing agent, such as hydrogen peroxide (30%), in an organic solvent, for example methanol I), B. Kelentey et al., Arzneim. Forsch., 7, 594 (1957).

When heated, the reaction takes about 1 hour, whereas without heating the reaction requires about 3 days. After oxidation, the mixture is treated with an agent such as PtO2or preferably Pt/C, for about days, in order to destroy excess hydrogen peroxide. After filtration of the mixture, the filtrate is evaporated and then the residue is recrystallized from a mixture of organic solvents, for example methylene chloride /ethyl acetate.

O-desmethyltramadol obtained by treatment of tramadol in the form of free base in the reaction conditions, O-demethylation, for example by reaction with a strong base, such as NaH go KH, thiophenols and diethylene glycol (DEG) at reflux. See Wildes et.al., J. Org. Chem., 36, 721 (1971). The reaction takes about an hour, followed by cooling and quenching the reaction mixture with water. The quenched mixture is acidified, extracted with an organic solvent such as ethyl ether, alkalinized and then extracted with a halogenated organic solvent such as methylene chloride. The extract is then dried in the solvent evaporated, leaving O-dezetilirovanny product which can be subjected to rapid PE telesouth of a mixture of organic solvents, for example, ethanol/ethyl ether.

Pharmacology of acetaminophen summarizes B. Ameer et al., Ann. Int. Med., 87, 202 (1977), and receiving acetaminophen disclosed in U.S. patent N 2998450, which is included here by reference.

APAP and drug tramadol is usually present in a weight ratio of the drug tramadol to APAP from 1 : 1 to 1 : 1600. Certain ratios result in a composition which exhibits a synergistic analgesic effect. For example, in the composition comprising the drug tramadol and APAP in the ratio of the drug tramadol: APAP, preferably ranges from 1:5 to 1:1600 and, more preferably, from about 1:19 to 1:800.

The most preferred ratios are from about 1:19 to 1:50. The composition of the drug tramadol and APAP in these weights have been shown to exhibit synergistic analgesic effect. In addition, the composition that deserves special attention, in which the ratio of the components is about 1:1 and about 1:5, included in the present invention.

Pharmaceutical compositions comprising the drug tramadol and acetaminophen as the active ingredients, in direct mixture with the pharmaceutical basis can be obtained generally of the drug to the desired introduction, for example, intravenous, oral or parenteral. The composition can also be entered and applied in aerosol form. When preparing the compositions for oral dosage forms may be used any conventional pharmaceutical environment. For example, in the case of oral liquid medicines /such as suspensions, elixirs and solutions/ may be used water, glycols, oils, alcohols, flavoring agents, preservatives, tinted substance, etc. In the case of solid oral medicines /such as, for example, powders, capsules and tablets/ can be used in devices such as starches, sugars, diluents, granulating agents, sliding agents, binding, dezintegriruetsja agents, etc. because of the ease of use of tablets and capsules are oral dosage forms, with the greatest benefits, in the case of which usually are dense pharmaceutical carriers. If desired, tablets may be coated with sugar or coating soluble in the intestine, using standard methods. Carriers for parenteral dosage forms will typically include sterile water, as well as other ingredients, for example, to increase the solubility or DL the th media suspendresume agents, etc.

Pharmaceutical compositions typically presents dosage forms such as tablets, capsules, powders, injections, teaspoons, etc., containing from 0.1 to about 800 mg/kg and preferably from about 0.3 to 200 mg/kg of active ingredients.

The following experimental examples in more detail describe the invention and are intended to illustrate but not to limit the invention.

Example 1: Receiving the combined doses of tramadol and APAP

Cooking combinations with different ratio of tramadol /APAP is carried out by first preparing an initial solution tramadol with concentration, expressed in mg of drug in 10 ml of distilled water. For example, 8 mg of the free base of tramadol dissolved in 10 ml of water to obtain the original solution tramadol highest dose. The original solution tramadol then diluted with sufficient quantity of distilled water to obtain a lower dose of tramadol in 10 ml of distilled water. The combination is then obtained by adding 10 ml of each dilution to the appropriate amount of mg APAP order to obtain the desired ratio of tramadol to Ara with 2 drops of TWEEN 80, pharmacological dispersant manufactured by Fisher Scientific Company, to receive a combination with a ratio of 1:50, i.e., /8 mg:400 mg/ 10 ml of water. Each ratio was prepared separately in a similar manner and were injected with the volume of 10 ml/kg for the mouse.

Example 2: Receiving the combined doses tramadol N-oxide and APAP

Preferably, tramadol N-oxide was obtained as set forth below. Hydrochloride tramadol (0.5 mol) was converted to the free base in podelochnojj water (pH > 9) and then was extracted with ether. The ether evaporated to obtain crystalline hydrate tramadol. The solid residue is then heated steam under high vacuum to remove as much water to get 131, 5mm g of substance. The substance was dissolved in methanol (500 ml) and was added 65 g 30% H2O2. The solution which was for 3 hours and then added additional 65 g 30% H2O2. The reaction mixture was which for 2.5 days at room temperature. About 10 mg PtO2coal (using Pt/C available due to the ease of its removal) was added to the reaction mixture, and was observed very low foaming. Additionally added 10 mg PtO2and the reaction mixture was which during the night and then filter 40oC. the Residue was extracted with methylene chloride. As methylenechloride solution contained a colloidal platinum solution was diluted with ethyl acetate to 1 l and filtered through a nylon filter membrane (pore size 0.45), getting clear, colourless filtrate. The filtrate was concentrated to 600 ml and then by heating the solution as long as the temperature of the vapors reached 74oC, was continuously added ethyl acetate, keeping the volume of 800 ml and Then the solution was cooled to room temperature. The solid residue was collected by filtration, washed with ethyl acetate and dried under vacuum, obtaining 126,6 g N-Okada tramadol (so pl. 159,5-160oC).

C16H25NO3Theory.: C, 68.78; H, 9.27; N, 5.01

The detection.: C, 68.65; H, 9.22; N, 4.99

Obtaining combinations with different ratios tramadol N-oxide/APAP were performed, starting with the preparation of the starting solution tramadol N-oxide, having a concentration, expressed in mg of drug in 10 ml of distilled water. For example, 8 mg tramadol N-Okada in the form of the free base was dissolved in 10 ml of days of water to obtain the initial solution tramadol highest dose. The original solution tramadol N-oxide is then diluted with sufficient quantity of distilled in the and by adding 10 ml of each dilution to the appropriate amount of mg APAP, in order to achieve the desired ratio of tramadol N-oxide to APAP. For example, for a ratio of 1:50:400 mg APAP in the form of a free base suspended in 10 ml 8 mg tramadol N-oxide and 2 drops of TWEEN 80, pharmacological dispersant manufactured by Fisher Scientific Company, to receive a combination with a ratio of 1:50, i.e., (8 ml:400 mg) and 10 ml of water. Each ratio were separately prepared similarly and were injected with the volume of 10 ml/kg for the mouse.

Example 3: (-) and (+) enantiomer O-desmethyltramadol: their synthesis and preparation of doses O-desmethyltramadol with APAP

First received O-desmethyltramadol, as set forth below. When cooled to potassium hydride (9.5 g) was added diethylene glycol (125 ml) at a temperature that is supported on the damage < 50oC. To the solution was added thiophenol /10 ml, dissolved in diethylene glycol (25 ml) and then (-)-tramadol in the form of the free base (9.3 g) in diethylene glycol. The final reaction mixture was slowly heated under reflux for 45 minutes. The mixture was cooled and then extinguished with water. Brought the pH to about 3, and the mixture was extracted with ethyl ether. Brought the pH to about 8, and the resulting mixture is still 5 times were extracted with methylene chloride.

Extract wasusually (Kugelrohr), was dissolved in tetrahydrofuran, treated with a solution of ethanol /HCl, to obtain 2.3 g of salt. The salt was recrystallized from a mixture of ethanol/ ethyl ether, and dried to obtain 1.80 g of salt (-)-enantiomer O-desmethyl tramadol (so pl. 242-3oC) [] 2D5=-32.9 (C=1, EtOH). C15H23NO2HCl Theory: C, at 63.04; H, 8.46; N, 4.90

The detection.: C, 63.00; H, 8.51; N, 4.94

To obtain (+)-enantiomer of the compound named in the title, the reaction was carried out under the same conditions, except to use the (+)-tramadol, in the form of free base instead of (-)-tramadol to obtain 2.8 g of (+)-enantiomer of O-desmethyltramadol (so pl. 242-3oC) [] 2D5=+32.2 (C=1, EtOH).

C15H23NO2HCl Theory: C, 63,04; H, 8,46; N, 4.90

The detection.: C, 63.14; H, 8,49; N, 4.86

Cooking combinations with different ratios of O-desmethyl/-APAP is done by first cooking the original solution of O-desmethyltramadol having a concentration, expressed in mg of drug in 10 ml of distilled water. For example, 8 mg O-desmethyltramadol in the form of the free base was dissolved in 10 ml of water to obtain the original solution of O-desmethyltramadol with the highest dose. The original solution of O-desmethyltramadol then again in the 10 ml of distilled water. Then prepare a combination by adding 10 ml of each dilution to the appropriate amount of mg APAP order to achieve the desired ratio of O-desmethyltramadol to APAP. For example, for a ratio of 1:50:400 mg APAP in the form of a free base suspended in 10 ml 8 mg O-desmethyltramadol and 2 drops of TWEEN 80, pharmacological dispersant manufactured by Fisher Scientific Company, to receive a combination with under 1:50, i.e. (38 mg:400 mg) in 100 ml of water. Each ratio were separately prepared similarly and were injected with the volume of 10 ml/kg for the mouse.

Example 4: Analgesic activity

Male CD1 mice weighing from 18 to 24 g were used to determine the analgesic effects associated with the compositions of this invention. All mice orally injected dose tramadol hydrochloride (calculated as base), which were completely dissolved in distilled water, and acetaminophen (calculated as base), which is completely dissolved in distilled water or in distilled water with 2% by volume of tween 80 containing 100% Polysorbate 80. The amount of dose was 10 ml/kg

When determining and comparing the analgesic activity of different classes of anesthetics likely spasm, caused by acetylcholine in mice. (H. Collier et al., Br. J. Pharmacol., 32, 295 (1968)).

Mice, which by intubation has introduced various doses of one tramadol hydrochloride, one acetaminophen, combined doses of tramadol hydrochloride and acetaminophen or media, such as distilled water or distilled water containing 2% by volume of tween 80, was intraperitoneally injected with provocative dose of acetylcholine bromide.

Acetylcholine is completely dissolved in the distilled water at a concentration of 5.5 mg/kg and were injected with the dose of 0.20 ml/20, For evaluation purposes "abdominal spasm was defined as a reduction of abdominal muscles, accompanied by bending of the back and stretching of the limbs. Mice were observed for 10 minutes in the presence or absence of response, abdominal spasm, starting immediately after injection of the dose of acetylcholine, which was made 30 minutes after oral administration of tramadol hydrochloride, acetaminophen, combined doses of tramadol hydrochloride and acetaminophen or media. Each mouse was used once.

Analysis of possible superadditive activity for compositions for each xed ratio was performed as described the PoE is necessary to obtain a particular level of exposure, such as 50% (ED50mixmixture), and the corresponding total number that would be expected under the simple additivity of the total effect (ED50add). Where it is established that

ED50mix< ED50addfor specific fixed ratio, it was believed that composition with this ratio has superadditive action. Both the number as ED50mixand ED50addhad random values; ED50mixfor each specific fixed ratio established by the response curve of the effect of dose; ED50addwas obtained by combining the ED50 values obtained for the two drugs are assuming additivity. ED50mixthen compare with ED50addusing t-analyzing Student. The ED50 value for hydrochloride tramadol separately it was 5.5(4,8-6,4) mg/kg ED50 Value for one acetaminophen was 164,3 (the 122.7-219,9) mg/kg

Interaction between tramadol and acetaminophen was detected exact ratios of doses of tramadol hydrochloride and acetaminophen. Many (usually 4-6) encoded doses of each selected combination was studied on analgesic efficacy after 30 minutes, using an experiment, which allows us to provide a fully blind assessment of the individual tested is pasma, caused by acetylcholine in mice demonstrated by the data in table 1 and shown on isobologram Loewe drawing (see S. Loewe, Pharm. Rev. , 9; 237 (1957) regarding receipt and the basics of isobologram). In the drawing a diagonal line connecting the ED50 values of the two drugs taken separately, represents a simple additivity of interactions at different ratios of components. The dotted line adjacent to the diagonal line, determine a 95% confidence interval. ED50 values that fall under the curve (between the line and the origin), indicate superadditivity, i.e. unexpected strengthening effect. Diagonal dashed lines diverging radially from the origin, represent relationships doses of APAP doses of tramadol hydrochloride, used in mice receiving doses of combination products. Limited lines passing through the point representing ED50 for compositions tramadol and APAP, represent 95% confidence intervals of ED50 values. Experimental data, as shown in the drawing, confirm that the composition pertaining tramadol to APAP from 1:1 to 1:600 (represented by curved line), provide unexpectedly enhanced activity, as ED50mixless than the ED50add.

2. The pharmaceutical composition under item 1, characterized in that it contains tramadol the hydrochloride.

3. The pharmaceutical composition according to p. 2, wherein hydrochloride tramadol is a racemate.

4. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 1 to 600.

5. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 1.

6. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 5 - 1600.

7. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 5.

8. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 19 - 800.

9. The pharmaceutical composition under item 1, characterized in that the mass ratio of tramadol : acetaminophen is 1 : 19 - 50.

10. The pharmaceutical composition under item 1, characterized in that it contains pharmaceutically acceptable carrier.

11. The method of treatment of a mammal, providing an objective amount of the pharmaceutical composition, described in paragraph 1.

 

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< / BR>
in which R1and R2each independently represents CNS group containing 1 to 4 carbon atoms, R3- H or acylcarnitine group containing 2 to 5 carbon atoms, R4- CNS group containing 1 to 4 carbon atoms, in free form and also, if such exist, in the form of salt

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5 cl, 4 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a method of wood processing, in particular to a method of secoisolariciresinol and dihydroquerticin allocation from wood of screen zone of larch or fir. The method of secoisolariciresinol and dihydroquerticin allocation from wood in which the crushed wood from the screen zone of larch (Larix) or fir (Abies) is extracted using an antifloating admixture of an organic dissolvent with water, at the certain content of dissolvent, with reception of the extract containing secoisolariciresinol and dihydroquerticin, an extract is processed for removal of the dissolvent with reception of the final admixture containing secoisolariciresinol and dihydroquerticin. Method of secoisolariciresinol and dihydroquerticin allocation from wood, as it is described above, thus an admixture containing secoisolariciresinol and dihydroquerticin subject to a selective extraction and crystallisation with allocation of secoisolariciresinol and dihydroquerticin. The method of allocation of secoisolariciresinol and dihydroquerticin from wood as it is described above, thus an extract containing secoisolariciresinol and dihydroquerticin, is processed for excision of non-polar components, a supernatant liquid is removed, and the obtained remainder is chromatographed on a silica gel layer with the subsequent excision of column effluent, receiving a dry admixture of secoisolariciresinol and dihydroquerticin.

EFFECT: possibility reception to obtain secoisolariciresinol and dihydroquerticin simultaneously from larch or fir wood in the form of their admixture or separately.

18 cl, 8 dwg, 17 ex

Vitamin d analogues // 2364584

FIELD: chemistry.

SUBSTANCE: described are biaromatic analogues of vitamin D of general formula (I) , in which- A-Q is -CH2-O; - B-T is -CH2-CH2-; R1 and R2, which are identical or different, are hydrogen atom, linear or branched alkyl radical with 1-5 carbon atoms; R3 is linear or branched alkyl radical with 1-5 carbon atoms; groups R4 are identical and are hydrogen atom. Compounds of formula (I) demonstrate noticeable biological activity.

EFFECT: application for obtaining pharmacological compositions; pharmacological composition; cosmetic composition for body or hair hygiene, as well as application of pharmacological composition for prevention of age-related skin aging or skin aging induced by sun irradiation.

14 cl, 3 tbl, 8 ex

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