() is a complex ethyl ester of trans-2-dimethylamino-1-phenyl-3 - cyclohexen - trans-1-carboxylic acid in the form of primary orthophosphate and solid pharmaceutical composition exhibiting analgetic activity


(57) Abstract:

The object of the invention is (a) an ester of TRANS-2-dimethyl-amino-1-phenyl-3-cyclohexen-TRANS-1-carboxylic acid in the form of primary orthophosphate, which is an active ingredient of the solid pharmaceutical composition. The specified connection is manifested analgetic activity. Containing the composition has a prolonged action. 2 S. p. f-crystals, 1 Il.

The invention relates to derivatives of cyclohexene with valuable biological properties, in particular to the new salts are known derived cyclohexanecarbonyl acid having analgetic activity.

Known derivatives cyclohexanecarbonyl acid of General formula

< / BR>

R1and R2the same or different and denote lower alkyl or together with the nitrogen atom to which they are linked, form a heterocyclic ring,

R3is methyl, ethyl, n-propyl and n-butyl,

as well as their salts with pharmacologically tolerated acids (see patent DE N 1518959, MKI: C 07 C, A 61 K, 1970). Receive and describe only hydrochloride, which according to the said patent may be contained in the pharmaceutical compositions as active is one [()-complex ethyl ester of TRANS-2-dimethylamino-1-phenyl-3-cyclohexen-TRANS-1-carboxylic acid)] (see Rompps Chemie-Lexikon, 8th edition, 1988, volume 6, page 4272). Tilidin used in the form of the hydrochloride hemihydrate in the liquid pharmaceutical composition with analgesic activity, in particular the solutions or suspensions contained in capsules soft gelatin (see the specified source, page 4463; commercial product "Valoron N").

Thanks to the very favorable properties in the fight against pain Valoron he was in Germany one of the major painkillers. Containing tilidin hard drugs are not yet available commercially, since neither the base nor hydrochloride do not have sufficient stability for a long time. But the need for solid galenically the form of Tilidine still exist, in particular considering the fact that only hard drug allows adjustable extended action Tilidine. Because tilidin operates in a relatively short time and therefore even struggle with pain for an extended period of time, for example during the night, only one dose is required for normal release of active substances, as is the case when giving liquid medications is problematic, making preparation of the prolonged action is a greater tsya high level of the active substance over a long period of time, as, for example, if you struggle with chronic or severe pain in cancer or burns.

The objective of the invention is the creation of a salt of Tilidine, stable in hard drugs and drugs extended actions, in particular tablets, coated tablets or suppositories, and also stable during storage of the pharmaceutical composition containing the salt of Tilidine as the active substance.

This problem is solved ()-complex ethyl ester, TRANS-2-dimethylamino-1-phenyl-3-cyclohexen-TRANS-1-carboxylic acid in the form of primary orthophosphate which has excellent stability and is suitable as the only still Sol for solid medications, as it in solid form, i.e. in combination with solid excipients, almost no decomposition. In addition, the new Sol unexpectedly shows pharmaceutically-technological properties, which are better not only properties known hydrochloride and other properties comparable salts Tilidine, as, for example, acid sulfate Tilidine or sour fumarata of Tilidine, so that, for example, without special air-handling requirements of the work places and corrosion protection used equipment and tools is aniah stable to storage for a long time.

Therefore, a further object of the invention is a solid pharmaceutical composition, which in addition to at least one pharmaceutically suitable carrier has primary phosphate Tilidine as an active substance in an effective amount.

The term "solid pharmaceutical composition" you should also understand the composition of the prolonged action.

It turned out that the receipt of the proposed phosphate is critical and it must be done in certain conditions, otherwise it is impossible to obtain a crystalline product of high purity. For salt formation extend from approximately 80 - 90%, preferably about 85 to 88% orthophosphoric acid, which is dissolved in sufficient for complete dissolution of the amount of aqueous isopropanol (water content of 4 to 10 wt.%, preferably 6 weight. %). The resulting solution is mixed with about 0.8 to 12-molar, preferably about 1-molar solution of base Tilidine in isopropanol specified water contents at a temperature of 30 - 50oC, preferably 40 5oC, and the acid and base take approximately stoichiometric quantities. Obtained in this suspense the aqueous water contents get thus more than 90% of primary orthophosphate of Tilidine with a degree of purity of 99.5%. The water content and the temperature of the salt formation are very important parameters, since at temperatures below 35oC and water content than the above range, get contaminated solvent and poorly crystallized products that are no longer amenable to complete drying and to which isopropanol hard Pilipets.

To obtain a solid pharmaceutical compositions of the prolonged action proposed Tilidine using standard methods, including the means for their implementation, which have negatively affected the stability of the active substance. A particularly suitable composition is a tablet extended action produced by the method of fusion described in the European patent N 0043254. As providing prolonged action of suitable means, as a rule, insoluble substances, such as lipids or lipoid substances, such as, for example, stearic acid and, in particular, gidrirovannoe castor oil, or hydrophilic polymers, which results in swelling of the slow return of the active substance (see J. Pharm. Sci. page 974 (1966). For throttling the selection of the active substance can also be used a method according to e is s drug substance of the prolonged action is governed by the viscosity of the added hydrophilic polymer, as, for example, methylcellulose or carboxymethylcellulose, based on the fact that the release rate increases with increasing viscosity.

To prove the unexpected superiority of primary orthophosphate conducted the following experiments.

According to the first experience and the hydrochloride hemihydrate Tilidine, b) acid fumarate Tilidine, in) acid sulfate Tilidine and g) the first phosphate Tilidine rubbed together with dihydrate hydrochloride naloxone and standard pharmaceutical excipients. Hemihydrate of naloxone hydrochloride is an active antagonist of morphine, which is contained in commercially available preparations of Tilidine. After storage for 28 days at a temperature of 60oC significant differences were found between these four salts. While containing salt a) - C) of the mixture showed significant staining containing salt g) the mixture changed color, indicating the absence of decomposition.

According to the second experience three different salts Tilidine together with dihydrate hydrochloride naloxone, gidrirovanny castor oil, lactose, hydroxyethyl cellulose, stearic acid, tabletti and stearate Magnolia shows a strong green color. Tablets hydrochloride hemihydrate Tilidine painted in orange-grey color after two days of storage at a temperature of 22oC in containers made of brown glass. Tablets with primary phosphate Tilidine did not change color even after six months storage in the same conditions.

Primary phosphate Tilidine exhibits good technological properties. For example, he in no case is not gigroskopicheskimi, does not react with the metal materials and is inert relative to the electrostatic charge. At a relative humidity of 63% hydrochloride hemihydrate already absorbs significant amounts of water and cause corrosion on unprotected instruments. Salt of sulfuric acid already at a relative humidity of 58% absorbs water and is more aggressive than the hydrochloride hemihydrate. Acid fumarate displays a pronounced tendency to electrostatic charge. This can lead to inaccuracies in the weighing of the components of the medicinal product and to the partial destruction of homogeneity of the mixture of excipients and active substances.

The following examples illustrate the invention.

Example 1. The floor is 94% isopropanol (6% water) by heating to a temperature of about 40oC (5oC). With stirring the solution 11,54 kg 85 - 88% orthophosphoric acid (respectively 9,844 kg = 100,46 mol of 100% acid) in 99 l 94% isopropanol at a temperature of 40oC for 3 hours. For better crystallization constantly add seed crystals. The suspension is slowly cooled with stirring to room temperature. The crystals are removed by centrifugation and washed twice 94% isopropanol, taken in an amount of 10 liters of the Obtained white salt is dried at a temperature of 50 - 60oC. the Output is 33,89 kg (92,09% of theory). According to high performance liquid chromatography salt has a purity of 99.5%. The melting point is 137,0oC and molar mass - 371,37. The IR spectrum shown in the drawing.

Example 2. Tablet extended to the containing 120 mg primary orthophosphate of Tilidine.

960 g primary orthophosphate of Tilidine in example 1 is mixed with 70,4 g dihydrate hydrochloride naloxone, 740 g of lactose and 700 g of hydrogenated castor oil and the resulting mixture is slowly heated with stirring to a temperature of 83oC. the resulting molten mass is passed through a sieve hole size 2.5 mm After cooling to communticate, methyl methacrylate and chloride complex trimethylammoniumchloride of methacrylic acid, 32 g of magnesium stearate and 24 g of silicon dioxide, and then evenly vmeshivat in pellets. Then by means of an eccentric press the mixture was transferred into a round, slightly convex tablets with a diameter of 10 mm and the radius of convexity of 11 mm, having a given weight of 350 mg of the Obtained tablets have the following composition, mg:

Primary phosphate Tilidine - 120,0

The dihydrate hydrochloride naloxone - 8,8

Lactose - 92,5

Gidrirovannoe castor oil to 87.5

The specified copolymer - 34,2

Magnesium stearate - 4,0

Silicon dioxide - 3,0

Tablets have the following properties:

weight: the average of 351 mg, at least 340 mg, maximum 362 mg, the relative standard deviation of 1.8 %;

tensile strength: the average value of 82 H, a minimum of 64 H, 90 H, the relative standard deviation of 8.4%;

fragility: 0,23;

disintegration: at 3 o'clock

Example 3. Suppositories containing 59,93 mg primary orthophosphate of Tilidine.

9700 g hardened fat with a hydroxyl number of 40 - 50 (trade product of Witepsol 35), or 9700 g hardened fat with a hydroxyl number of up to 2 (trade product Weight Astrium P 299) floor is ri, transparent melt to a temperature of 36 - 38oC it is dispersed 300 g primary orthophosphate of Tilidine using a stirrer-type Ultra-Turra. If necessary, the temperature of the mass is maintained at 36 - 38oC by cooling the boiler shell. Then dosing-sealing machine melt served in depressions made in the three-layer film. The temperature in the metering site is kept at 37oC. During the pouring temperature of the boiler is 37oC. the Number of dosing of the melt is 2.0 g of 5%. Suppositories are cooled by solidification during transport through the cooling channel, which has a temperature of 20 - 22oC. Then carried out of hot sealing, and then separate suppositories Vistanova. Thus every hour can produce up to 9000 suppositories. From this initial mixture get 4850 suppositories containing 59,93 mg primary orthophosphate of Tilidine (respectively 50 mg hydrochloride Tilidine).

1. ()-Complex ethyl ester of TRANS-2-dimethylamino-1-phenyl-3-cyclohexen-TRANS-1-carboxylic acid in the form of primary orthophosphate.

2. Solid pharmaceutical composition exhibiting analgetic activity containing the active substance on the basis of the tives such as those she as salts derived cyclohexanecarbonyl acid contains ()-complex ethyl ester of TRANS-2-dimethylamino-1-phenyl-3-cyclohexen-TRANS-1-carboxylic acid in the form of primary orthophosphate in an effective amount.


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