NL7906215A - GLAUCINE SALTS. - Google Patents

Description

f * i THE DOW CHEMICAL COMPANY, Midland, Michigan, Ver. St. v. America Glaucine Salts.

This invention relates to salts of 1- and φΐ-glaucine and mixtures thereof, pharmaceutical preparations containing them, and their use against coughing and pain.

Glaucine, the structure of which is indicated on the formula sheet, has a center of asymmetry indicated by an asterisk in the formula. Thus, two optical isomers are possible. One of these, the right-turning form (d-glaucine), occurs in nature and can be isolated from the yellow poppy. The measure, d, l-glaucine, can be prepared from papaverine by the method of Frank and Tietze (Angewandte Chemie (1967) 10 815-6), and it can also be synthesized in various ways, for example as described by Chan and Maitland in J. Chem. Soc. (C) 1966, 753 and by Cava et al. In J. Org.

Chem. 35 (1970) 175. Separation of the two enantiomers can be effected in the usual manner by means of an optically active acid, for example d- or 1-tartaric acid, after which the diastereoisomeric salts are separated by fractional crystallization.

D-glaucine hydrobromide and d-glaucine hydrochloride are known to work against coughing, see Donev in Farmatsia (Sofia) 12, No. 4 (1962) 17 and Aleshinskaya in Chim. Farm. Zh. [0 (1976) 144-147 (Chemical Abstracts 84: 159 725 w). In addition, mentions

Aleshinskaya that glaucine from the yellow horn poppy (the d-form) in doses of 50-100 mg / kg prolongs the duration of the sleep induced by hexenal and chloral hydrate in mice and also has analgesic, as well as adrenolytic activity.

Recent research has shown that the counterclockwise and racemic forms of glaucine hydrobromide are more effective against coughing than the previously suggested counterclockwise form, see Belgian Patent 866,079.

As can be seen from the formula, glaucine in its structure is 7906215 JK ^

V

2 related to other alkaloids such as codeine. Codeine and related compounds, such as the hydrocodone, are known to work against coughing and also narcotically (see tderklndex). Although these compounds also give rise to habituation and even addiction, they still remain the strongest and most widely used cough suppressants.

Anti-cough medicines are usually given orally, usually as liquids (elixirs or syrups) or as lozenges to keep in the mouth until dissolved. In both cases, the bitter taste of the alkaloid is a known drawback of these preparations. Various formulations have been developed to mask the unpleasant taste and aftertaste of codeine, with varying degrees of success. However, none of these techniques have been entirely successful. Like codeine, glaucine has an unpleasant, bitter taste.

Surprisingly, it has been found that the phosphoric acid salts of l-1 and d, l-glaucine are better at coughing than d-glaucine, if pain killers are surprisingly superior to d-glaucine and have little incitement to addiction; in addition, their solubility and stability are particularly favorable and their taste makes them particularly suitable for oral administration. These new salts consist of phosphoric acid and 1-glau-20 cine in combination with an equimolecular amount or less of d-glaucine; one may also say from phosphoric acid and d, 1-glaucine or a mixture of 1 and d, 1-glaucine.

The new salts according to the invention are crystalline substances which are prepared by reacting the free base glaucine with phosphoric acid.

These crystalline salts contain 0.3 or 0.4 to 0.6 or 0.7 mole excess of phosphoric acid, i.e. generally 1.4 to 1.6 mole H 2 PO 4 per mole glaucine. The predominant crystalline phosphate, easily obtained with an excess of phosphoric acid, contains 1.4 to 1.6 and usually 1.5 moles of H 2 PO 3 per mole of 1 or d, 1-glaucine. This salt can be referred to as glaucine. 1 Η Ρ Ρ Ρ met gla als als als (gla gla gla gla gla gla gla gla gla gla gla gla gla De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De De DeDe.

The 1 and d, 1-glaucine phosphates melt in the range of 7906215 3 3 from about 240 ° to about 254 ° C, and have useful water solubility but are less soluble in organic liquids such as methylene chloride, acetone and diethyl ether . Their. solutions are acidic, and a solution has a pH between 2.4 and 2.6. The precise melting point of some formulation may vary depending on the method of preparation and purification, indicating that factors such as hydrate water and co-crystallized solvent may play a role.

Even if the elemental analysis confirms the 2: 3 structure, this glaucine phosphate may still contain a minor amount of another glaucine-phosphoric acid combination, which is believed to be diglaucin phosphate and can be recognized by differential calorimetry: there is then a peak at about 219-221 ° C. This peak can be removed by treating this product with a little extra phosphoric acid to obtain a glaucine phosphate without lower melting contamination.

These salts can also be prepared in combination with unused phosphoric acid if a large excess is used. Excess and accompanying phosphoric acid can be removed by conventional techniques such as filtration or partial neutralization. If an excess of 1 or d, 1-glaucine is used, these salts can also be obtained in combination with unreacted glaucine, depending on the reaction conditions and the solvent used. Unconverted glaucine can be removed by conventional purification methods such as recrystallization and washing, but can also be converted to phosphate with additional phosphoric acid.

The compounds are easily prepared by reacting the free base glaucine with phosphoric acid. The reaction proceeds easily in the presence of an inert organic solvent such as acetone, ethanol, chloroform, methylene chloride, methanol, diethyl ether and ethyl acetate. The phosphate generally precipitates and can be separated in a conventional manner, such as filtration or decanting, and purified in a conventional manner, such as by recrystallization and washing.

The reaction is generally carried out by dissolving the free 7906215 4 base glaucine in an inert organic liquid at a temperature between room temperature and the boiling point of the mixture, and mixing this solution with excess phosphoric acid. A 0.5 to 3-fold excess of phosphoric acid is used. Use of equimole-5 amounts or excess of glaucin can result in a mixture of glaucine phosphate with unreacted or partially converted glaucin.

In such products, the impurities can still be converted into the desired 2: 3 glaucine phosphate with additional phosphoric acid.

When using excess phosphoric acid to obtain relatively pure 2: 3 glaucine phosphate, the excess phosphoric acid can be greatly reduced by partial neutralization and then recrystallization. In such a manner, a determination is first made on the obtained salt to find the excess phosphoric acid, and then the solid salt can be mixed with alcoholic lye (NaOH 15 or KOH in methanol or ethanol), with enough lye to neutralize the excess phosphoric acid. The 2: 3 salt can then be purified by ordinary recrystallization, for example from ethanol. Partial neutralization is generally not necessary to obtain a crystalline and useful salt. Preferably, the product is digested by holding it in boiling ethanol for 4-8 hours before recrystallizing and drying.

When the salts are in solution, the ratio of glaucine to phosphoric acid can be increased by known techniques, for example, by titration, so that the phosphoric acid content is reduced. Such a method can lead to mixtures of glaucine with glaucine phosphate, and can also cause the free base to precipitate. The addition of excess phosphoric acid above the amount required to form the 2: 3 salt generally causes the glaucine phosphate to precipitate.

Mixtures of d, 1 and 1 glaucine phosphates and the salts, whether or not associated with supplemental phosphoric acid or with minor amounts of unreacted or partially converted glaucine, are all useful for coughing and as analgesics. For the sake of convenience, they are further referred to as being single phosphates of 1 or d, 1-glaucine 35. The preferred salt is the salt with 1.5 moles of H 2 PO 4 per mole of 7906215 * 5 d, 1-glaucine.

The glaucine phosphates are highly effective, orally effective anti-cough agents and are therefore analgesic, in combination with a surprisingly good taste and a desirable stability and solubility, and are also largely free of undesirable side effects such as addiction thereto. For anti-coughing, they can be administered in doses of 0.1 to 40 mg / kg or more, and as analgesics in doses of 0.1 to 60 mg / kg, preferably orally. They are also parenterally effective against coughing and pain.

When using these salts, they are administered internally to an animal, generally to a mammal in need of it.

The administration can be both parenteral (intravenous, intramuscular or intraperitoneal) and via the gastrointestinal tract by oral or rectal administration (for example, as a throat spray preparation).

How much of these salts are needed to suppress or at least relieve coughing depends on various factors such as the size, type and age of the animal to be treated, which salt or salt mixture is used exactly, the method of administration and how often that does, the severity of the cough and its cause, as well as the time it takes to administer. The same considerations also apply to the amounts used to treat pain.

When administered orally these phosphates are low compared to those for parenteral administration. While in cough control with codeine phosphate in intraperitoneal administration, an ED ^ q of 10.9 mg / kg and in oral administration an ED, q of 86.6 mg / kg are found, these two values lie at “(d, 1 -glaucine) ^ · 3H ^ P0 ^ very close together, namely 17.8 and 17.3 mg / kg. In any case per se, the dose to be administered can be found with the usual scaling techniques, for example by checking the action with different dosages.

Good anti-coughing effects can be obtained if one of these salts per kg body weight is 0.1 to about 0.2 to about 0.5 to about 1 to about 10 to about 20 to 25 to 30 to 40 to about 80 mg orally or 0.1 to 40 mg / kg intraperitoneally. In general, it is desirable to administer the smallest amounts of these salts that suppress coughing in the desired amount in the 7906215 V-f 6, as far as in harmony with a manageable administration schedule. Oral administration is generally preferred. Thus, the glaucine phosphates of this invention combine high cough activity with good taste.

Unit dosages suitable for oral administration such as tablets, capsules, lozenges, elixirs, syrups and the like are preferred and the active substance therein may also have a prolonged action in a conventional manner.

The glauine phosphate preparations preferably contain 0.001 to 95% by weight of active substance, in addition pharmaceutically acceptable carriers and / or other auxiliary substances. The latter are non-toxic and non-sensitizing under the conditions of use. They are prepared using known techniques. Thus, tablets, capsules, cough drops, lozenges, dragees, suppositories, solutions, syrups, emulsions, dispersions, wettable and effervescent powders and, if necessary, sterile injection preparations are prepared. As with phosphates in general, the liquid preparations must be substantially free of cations that give soluble phosphates.

The glaucine phosphates can be administered together with other substances against coughing and / or pain and also in combination with other active substances. The latter may be anti-histamines, throat softeners, mucus agents, bronchodilators, anti-constipation agents and antibacterial agents or topical anesthetics. Combinations of that type are generally useful to combat combinations of coughing and pain with other symptoms.

Particularly desirable formulations are those in unit dose form (tablets, capsules, lozenges, etc.) or in metered amounts of liquid formulation containing from 0.1 to 20 to 30 to 40 mg of anti-coughing glaucine phosphate or 0.1 to 30 to 30 about 60 mg for relieving pain.

Example I Preparation of d, 1-glaucine phosphate A. 200 ml of deionized water and 43.5 g (0.1 gmol) of glaucine.HBr were introduced into a separatory funnel. To this was added 50 ml of 10% aqueous NaOH, and this mixture was extracted with 2 x 100 ml of chloroform. The combined chloroform extracts were 7906215? 7 dried on Na 2 SO 4, filtered and evaporated under reduced pressure.

The residual white matter was free d, 1-glaucine with m.p. 139 ° C (yield 96%). If desired, such a preparation can be further purified by recrystallization from ethyl acetate.

B. In 150 ml 95% ethanol was heated to 60 ° C

3.6 g (0.01 µmol) of d, 1-glaucine dissolved. To this was slowly added a solution of 2.0 g of 85% (0.022 gmol) phosphoric acid in 100 ml of 95% ethanol with stirring over about 20 minutes. The d, 1-glaucine phosphate started to precipitate during the addition of the phosphoric acid.

The product was filtered off and found to have a melting point of 240 ° C (with decomposition).

The white crystalline product was recrystallized by mixing it with 80:20 ethanol / water, heating to reflux, then cooling to room temperature. The recrystallized product was then stirred with a mixture of 3 parts diethyl ether and 1 part ethanol, filtered again, and dried. It now had a melting point of 247 ° G (with decomposition). Yield 94.3%.

Elemental analysis: C 50.29%, H 6.03%, N 2.93%; Calculated for C 1 H N NO 1 H 3 PO 4: G 50.2%, H 5.91%, N 2.79%.

Differential calorimetry showed the product to be at least 95% pure, with a single major peak at 247 ° C and up to 5% in a minor peak at 221 ° C attempting to obtain di (d, 1-glaucine) phosphate to be. The crystals of the (d, 1-glaucine) ^ ^ H ^ PO ^ are well-formed, colorless rods and needles.

C. In another preparation, 2 grams of 1-glaucine hydrobromide was suspended in water, 5 ml of 10% NaOH was added thereto, and the whole was extracted with 2 x 50 ml of chloroform. The extracts were dried, filtered and evaporated to dryness. The free base thus obtained was reacted in accordance with 1B with 0.25 mol of phosphoric acid. The crystalline product was separated, taken up in 5 ml of 95% ethanol and reprecipitated by adding diethyl ether, and then crystallized again from ethanol. The white crystalline (1-glaucine) 2 * SH2 PO2 was found to have a melting point of 242.9 ° C (under decomposition).

7906215 * - - 8

In the same preparation, but with one more recrystallization from ethanol, the melting point was found to be 253 ° C.

D. In another preparation, a solution of 56.8 grams of d, 1-glaucine in 250 ml of ethanol was poured into a solution of 32 grams of 85% phosphoric acid in 500 ml of ethanol. The product obtained showed differential peaks at differential calorimetry, one at 245 ° C and a smaller peak at about 219 ° C (for the di (d, 1-glaucine) phosphate. The main product was dried at 120 ° C for eight hours. Elemental Analysis: G 50.66%, H 6.06%, N 3.23%, 0 30.09%, and P 10.07%, calculated for C 21 H 25 NO 4, 1 PO 2, C 50.20%, H 5.91%, N 2.79%, \ 31.85% and P 9.25%.

E. In yet another preparation, a product of slightly different composition was obtained:

Elemental analysis: C 50.80%, Η 6.00%, N 2.95% and P 8.22%; Calculated for C21 H25 N (V 1.4 H3 PO4: C 51.15%, H 5.97%, N 2.84% and P 8.8%.

(The N analysis was the average of four determinations).

F. A sample of the d, 1-glaucine phosphate obtained at 1. D, m.p. 245.2 ° C, washed thoroughly with diethyl ether / ethanol 3: 1 and dried; the melting point was then 250.7 ° C. A mixture of washed and unwashed crystals was found to melt at 242.2 ° C, indicating the presence of two different crystalline solvates.

G. 1 gram (2.8 mg mol) of d, 1-glaucine was dissolved in 30 ml of freshly distilled acetone and 0.3 gram (3.0 mg mol) of 85% H 3 PO 4 was added to this. The resulting white precipitate was filtered off, washed with 20 ml of dry acetone, air dried and then overnight at 50-55 ° C under vacuum. Yield 1.0 gram; m.p. 240 ° -243 ° C.

Elemental analysis: C 51.2%, H 6.07%, N 2.96%;

Calcd for C 1 H N NO 1.5 H 3 PO 4: C 50.2%, H 5.91%, N 2.79%.

In another preparation, 0.6 g of d, l-glaucine in 20 ml of acetone and 0.4 g of phosphoric acid were obtained after about 2 | drying under vacuum at 60 ° C for a day. 240-242 ° C.

Elemental analysis: C 49.3%, H 5.91%, N 2.76%;

Calculated for C 3 H NO NO 1.6 H 3 PO 4: C 49.24%, H 5.86%, N 2.73%.

35 7906215 9% H. To a mixture of 2.5971 kg (5.95 gmole) d, 1-glaucine.

HBr 10.0 L deionized water and 3.5 L methylene chloride were slowly added 500 ml 50% NaOH with rapid stirring. The addition vessel was then rinsed with 100 ml deionized water. After everything was added, stirring was continued for another 15 minutes. The stirrer was then stopped and the mixture was allowed to stand for 10 minutes so that it could separate.

The methylene chloride layer was drained and stored. The water layer was mixed with 3.5 L of methylene chloride and stirred quickly for 15 minutes. This mixture was left to stand for 10 minutes to allow it to mix. here too the methylene chloride layer was tapped. Another 200 ml of methylene chloride was added to the water layer, and after stirring and demixing it was also drained.

The combined methylene chloride layers were mixed with 3 L of deposited water and stirred vigorously for 15 minutes, after which 15 minutes were allowed to mix. The methylene chloride layer was drained and added with stirring to a solution of 1.4235 kg of 85% (12.35 gmol) phosphoric acid in 9.8 L of toluene denatured absolute ethanol.

A heavy white suspension formed. It was stirred for 15 minutes and then it was left under nitrogen for 14-16 hours. The stirrer was then turned on again and the slurry was slowly poured into 3 L sintered glass filters. The solid thus obtained was placed in large flat trays and first dried in air and then under vacuum at 50-65 ° C. This gave 2.902 kg (97.1%) of d, 1-glaucine phosphate.

Of this, 1,500 kg was slurried in 15 L of ethanol / water 80:20, and this mixture was heated to boiling under stirring, under nitrogen and under reflux. After boiling for 5-6 hours, it was allowed to cool to 22.25 ° C, after which the mixture was slowly filtered over sintered glass funnels. After washing thoroughly with toluene denatured absolute ethanol, it was again air dried and then vacuum at 50-65 ° C. This gave 1.375 kg of d, l-glaucine phosphate (91.7% yield).

At differential calorimetry, this product showed a single peak with a melting point of 253 ° C.

Elemental Analysis: C 50.2%, H5.97%, N 2.67%; 7906215

-V

10

Calculated for C 5 H 5®). 1.5H3PO4: C 50.2%, H 5.91%, N 2.79%.

I. The 1-glaucine phosphate obtained as described above was recrystallized three times from ethanol to give a fine powder with particularly good analysis.

Elemental analysis: C 50.20%, H 5.91%, N 2.73%;

Calculated for: C01H .NO, .I, 5H "P0. : C 50.2%, H 5.9l%, N 2.79%.

21 25 4 i 4 J. The crystal density of the d, 1-glaucine phosphate was measured by suspending at least four crystals thereof in a mixture of benzene and carbon tetrachloride, and adjusting the ratio of those two liquids so that their specific gravity was exactly the same as that of the crystals suspended therein. Their specific gravity was then measured with a pycnometer. A crystal density of 1,460 kg / dm was thus found.

The dimensions of the unit cell of the 15 d, 1-glaucine-1.5 H 2 PO 2 were determined by a single crystal X-ray image.

These were: a = 89.854 A, b = 8.565 A and c = 23.830 A; the crystals are monoclinic with a β-angle of 93.7 °. The theoretical density was calculated with the smallest apparent cell volume V = 1/8 abc sin β = 2.286 A ^ (2.286 x 10 ^ cnf *) and Z = 4 molecules per small cell volume. For a 1: 1 glaucine phosphate, a theoretical density _ Molecular weight_ Z_ is calculated

number of Avogadro V.

3 of 1,319 g / cm. For a l: 2 salt, the density should be theoretically 1.602 g / cm, for a 2: l salt more than 2.3 g / cm, and for the d, l glaucine. 1.5Η ^ Ρ0 ^ a theoretical density of 1.460 g / cm which corresponds well with the observed value.

Example II

Individual groups of guinea pigs received different doses of the test substances orally, and a blank group received distilled water only. One hour after this oral administration, the guinea pig was exposed to an aerosol containing 5% citric acid for 10 minutes.

The number of coughs in the last 5 minutes that the animals had to sniff citric acid was noted, and from the results, the dose needed to • reduce the number of coughs by 50% was calculated. A 7906215 11, anti-cough effect was only recognized if the number of coughs during the last 5 minutes of the experiment was at least 2 times the standard deviation less than the blank group average.

In these experiments, codeine phosphate was found to have an oral ED of 86.6, d-glaucine.HBr, an ED of 89.0, d-glaucine phosphate and an ED of 170.1, d-1-glaucine phosphate ( 2.: 3 salt) an ED, q of 17.8 and the 1-glaucine phosphate (the 2: 3 salt) one of 10.9 mg / kg.

The 95% confidence limits for these ED values were for codeine phosphate, d, 1 glaucine phosphate and L glaucine phosphate 52.3-232.6, 6.0-53.1 and 0.4-33, respectively. 8. This shows that the glaucine phosphates in this test work 4-8 times stronger than the codeine phosphate.

Example III

The test of Example II with the citric acid aerosol was repeated, except that the test substances were now administered intraperitoneally; the blank group received only distilled water. The ED values were calculated from the measurement results. This was 10.9 mg / kg for codeine phosphate, d-glaucine.HBr 10.0 mg / kg, and d-glaucine phosphate (the 2: 3 salt) 17.3 mg / kg.

Example IV

The basis for a cough syrup was made from 1600 g of cane sugar, 600 g of sorbitol and 21 g of ethanol with water to a total of 4 l.

The solubility of d, 1-glaucine.HBr in this base was found to be 0.3% (15 mg in 5 ml), but that of d, 1-glaucine phosphate was 1% (50 mg in 5 ml).

Example V

The stability of d, 1-glaucine phosphate in the syrup of Example IV was determined. After 1 month at room temperature, 40 ° C and 55 ° C, the syrup with original 0.6% d, 1-glaucine phosphate 30 was found to retain 101.3%, 100.0% and 98.4% of its original concentration, respectively. to have.

Syrups with 0.2% codeine phosphate after 1 month at room temperature, 40 ° G or 55 ° C contain 97.5%, 104.5% and 100% of their initial content, respectively. With 0.2% d, 1-glaucine.HBr, this was 99%, 96% and 89.5%, respectively. After 3 months, the results were 7906215

V »-V

s 12 shelf life test as follows:% of initial content after 3 months at

Substance 40 ° C 55 ° C

5 d, 1-glaucine phosphate (2: 3) 101.6 101.1 98.7

Codeine phosphate 101.3 101.1 88.4 d, l-glaucine.HBr 100.8 93.3 91.4

After 12 months at 55 ° C, the glaucine phosphate syrup was still at 101.8% and the hydrobromide syrup at 87.3%.

Example VI

In a test similar to that of Example V, test syrups were placed in brown stained glass vials and in colorless glass vials and stored at room temperature under continuous illumination (24 hours a day with a combination of incandescent bulbs 15 and fluorescent tubes, approximately 2,000 feet in total). candela. :).

After a month, the content of d, l-glaucine.HBr in the brown bottles was 84% and that in the colorless bottles was 74.5%. But the d, l-glaucine phosphate in the brown bottles came to 97.7% and in the colorless bottles to 90%. Codeine phosphate was completely stable and reached 100% in both types of vials.

In the same experiment, the crystalline glaucine phosphate (the 2: 3 salt) was found to have retained more than 98% of its original content after 2 months at 40 ° C.

Example VII

The probability of abuse with d, 1-glaucine phosphate was investigated in two monkeys in an experiment as described by Deneau et al. In Psychopharmacologia 16-16 (1969) 30-48.

In this experiment, the monkeys, which have limited movement, receive a catheter in the jugular vein, so that they inject the substance to be tested when they press down a switch. First, the test monkeys are accustomed to self-administer codeine at doses of 100 µg / kg per injection. The two monkeys thus conditioned administered 100-150 shots of 100 µg of codeine in a 2-hour experiment. When d, 1-glaucine phosphate (the 2: 3 salt) was substituted for codeine 35, the response of the monkeys dropped from 100-150 bumps to t 7906215 13 10-20 bumps per 2 hours, after the 100 µg / kg of codeine was replaced with 50,100,200 and 400 µg / kg d, 1-glaucine phosphate.

Example VIII

Susceptibility to habituation to this alkaloid was determined using the method of Saelens et al. (Arch. Int. Pharmacodyn. 190 (1971) 213-8). Mice are given increasing doses of the test substance at certain intervals for two consecutive days. last dose on the second day, the mice are given intraperitoneally 100 mg / kg of the morphine antagonist naloxone, and then the mice are observed to display the curious jumping typical of opiate abstinence after being used to it, typically for a morphine antagonism.

In these experiments, morphine sulfate in mice caused stimulation and the so-called Straub tail, and after treatment with naloxone 15 jumped in 5 of the 9 mice (96 jumps in total). Codeine phosphate caused the Straub tail and stimulation, and after treatment with naloxone, 2 out of 6 mice jumped (23 jumps in total). In contrast, d-1-glaucine phosphate (2: 3 salt) did not give any Straub tail and no jump even at the highest dose (100 mg / kg) in the 8 test mice.

Example IX

0.2% solutions in distilled water were made from various d, 1-glaucine salts. These were tested for taste by applying a few drops to the tongue. In these tests, in which also a seasoned formulation expert, familiar with formulating codeine and dextromethorphan, was given samples without prior knowledge, the taste of the hydrobromide was found to be objectionable, namely bitter, pungent and increasingly metallic.

The sulfate, maleate, citrate, acetate, and p-toluenesulfate were rated just as the hydrobromide and therefore objectionable as well.

The salicylate and succinate were found to be even worse than the hydrobromide. However, d-glaucine phosphate (2: 3 salt) was found to lack the sharp metal taste and was without objection.

Example X.

A. A tasty cough syrup with the following composition 35 was prepared: 7906215 V "· • v 14

Sucrose 26.4 grams

Sorbitol syrup 10 ml

Glycerol 5 ml

Alcohol 5.4 ml 5 Piperonal 10.0 mg

Vanillin 7.5 mg

Ethylvanillin 10.0 mg

Ethylmaltol 7.5 mg

Menthol 7.5 mg 10 d, 1-Glaucine phosphate (2: 3 salt) 600 mg

Water up to 100 ml

This syrup contained 0.6% d, 1-glaucine phosphate and 5 ml of this (1 teaspoon) contains 30 mg of active substance. This syrup can be packed in 5 ml portions in plastic-coated pouches or else in ordinary glass bottles. It is also possible to prepare syrups containing 15 mg or 20 mg of active substance per teaspoon, namely by taking not 600 mg but 300 or 400 mg d, 1-glaucine phosphate in the above recipe.

B. Tablets were prepared as follows: A mixture of 40 g of 1-glaucine phosphate and 150 g of modified starch (Sta-Rex 1500) was wetted with ethanol / water 3: 1 and granulated. After drying, the granulate was mixed to 300 g with 15 g of plain starch, 1.5 g of stearic acid, 0.5 g of hydrogenated vegetable oil, 3 g of colloidal silica and with microcrystalline cellulose. Tablets ad 300 mg, each containing 40 mg of 1-glaucine phosphate, were punched with a stamp of 8.7 mm diameter.

C. Capsules were filled with 300 mg of a mixture of 5 g d, 1 glaucine phosphate, 5 g 1 glaucine phosphate, 3 g colloidal silica, 2 g stearic acid and 285 g lactose. This gave IQ mg 30 mg of glaucine phosphate per capsule. Larger unit doses of 15.20 or 25 mg can be prepared by taking 15.20 or 25 g of glaucine phosphate in this recipe and reducing the amount of lactose accordingly. Of course one can also make unit doses with smaller amounts of active substance.

35 D. Troches (a type of suction ball) were prepared by mixing 30 g of 7906215 Η 15 »d, 1-glaucine phosphate (2: 3 salt), 435 g of powdered sugar and 35 g of powdered gum arabic, adding enough water to obtain a kneadable mass, and roll this mass into a cylinder, which is then divided into segments of 0.5 g each.

5 Example XI

The acute toxicity of the d, 1-glaucine phosphate (2: 3 salt) was determined in mice. On intraperitoneal administration, the LD, (after 72 hours) was 178 mg / kg; the oral LD ^ q was at least 681 mg / kg.

When comparing these LD values with the ED values of Examples II and III, the therapeutic index (LD / ED) of 50 turns out to be this cough salt 38 for oral administration and 10 for intraperitoneal administration.

Also, 1 and d-glaucine phosphate (2: 3 salts) were orally administered to individual guinea pigs and were injected at certain intervals. .

determined the 1 or d-glaucine in the blood plasma. It was found that the 1-glaucine phosphate gave high plasma levels within 15 minutes after administration, which remained high, generally 3 to 6 times higher than the plasma levels when administered with d-glaucine, at least during the 2 hour trial .

Example XII

Some substances were tested for analgesic effect with the mouse wringing test of Hendershot & Forsaith (J. Pharmacol.

Exptl. Therap. 125 (1959) 237). The test substances were administered orally 30 minutes prior to loading with phenyl p-25 quinone. In these experiments, the ED values for d-glaucoma HBr, codeine phosphate and d, 1-glaucine phosphate (2: 3 salt) were found to be 34.0, 21.1 and 23.0 mg / kg, respectively.

30 7906215

Claims (12)

1. The phosphoric acid salts of 1-glaucine, d, 1-glaucine and mixtures thereof. 2. Salt according to claim 1, characterized in that it is 1 - 5 glaucine phosphate. Salt according to claim 2, characterized in that it contains 1-2 moles of phosphoric acid per mole of 1-glaucine. Salt according to claim 2, characterized in that it contains 15 moles of phosphoric acid per mole of 1-glaucine. Salt according to claim 1, characterized in that it is d, 1-glaucine phosphate. Salt according to claim 5, characterized in that it contains an excess of phosphoric acid (from 0.3-0.7 moles of phosphoric acid per mole of glaucine). Salt according to claim 5, characterized in that it contains 1, 1-glaucine 1 | mole of phosphoric acid. Salt according to claim 6, characterized in that it has a melting point between 240 ° and 254 ° C, and a solution thereof in water has a pH between 2.2 and 2.6. 9. A composition containing 0.01-95% by weight of salt according to any one of the preceding claims. The preparation according to claim 9 which is divided into unit doses, characterized in that it contains 0.1 to 60 mg of glaucine phosphate per dose. Preparation according to claim 9 or 10, characterized in that the active substance contained therein has a gross formula of 1.4-1.6 Η3ΪΌ4. 12. Preparation mainly according to description and / or examples. 7906215 OCH3 CHY ^ CHj 7906215