DE2327636A1 - PHARMACEUTICAL PREPARATION - Google Patents

Description

30 May 1973

Dr. Ing.A. van der Werft 'Dr. f taui Lederer 2327636

PATENT LAWYERS

RAN 4O81 / 65

F. HoiFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Pharmaceutical preparation

The present invention relates to an anti-depression and insomnia effective preparation, a method of manufacturing of such a preparation and a method for the treatment of depression or sleep disorders.

The pharmaceutical preparation according to the invention is characterized in that it contains L-5-hydroxy-?

tryptophan or a pharmaceutically acceptable salt thereof

1 p

as well as N- (DL-Seryl) -N- (2,3,4-trihydroxybenzyl) -hydrazine or contains a pharmaceutically acceptable salt thereof in amounts having a weight ratio between L-5-Hydroxytryptophan and

1 2

N - (DL-Seryl) -N - (2,3 * ^ - trihydroxybenzyl) -hydrazine of about 1: 5

up to about 2: 1.

The method according to the invention for the treatment of depression or sleep disorders is characterized in that that you can get L-5-Hydroxytryptophan or a pharmaceutical

Hh / 4/27/73 30988 3/1400

1 2

compatible salt thereof and N - (DL-Seryl) -N - (2,3,4-trihydroxybenzyl) hydrazine or a pharmaceutically acceptable salt thereof is used.

If L-5-Hydroxytryptophan is administered alone, very high doses (e.g. up to 3 g per day or more) are necessary to To effectively eliminate symptoms of depressive genesis. L-5-hydroxytryptophan has the disadvantage at these doses various undesirable side effects, including an increase in blood pressure and gastrointestinal complaints, which are serious Can take forms and force the drug to be discontinued. By administering the combination according to the invention can the required amount of the L-5-Hydroxytryprophanomponente be kept low. The unwanted side effects stay away or they become minor

Mass reduced. Due to the potentiating effect of the

1 ?

N - (DL-Seryl) -N- (2,3,4-trihydroxybenzyl) -hydrazine on the low-dose L-5-hydroxytryptophan is a rapidly onset, strong and lasting antidepressant effect achieved.

The preparation according to the invention has the additional advantage that it can remedy severe sleep disorders. This is particularly important in the treatment of depression, because the normalization of the sleep rhythm essentially helps to raise the mood of the patient, so that the antidepressant component of the preparation can be used to its best advantage.

According to the invention, the L-5-hydroxytryptophan can be used as such or can be used in the form of a salt. as Salts include the usual pharmaceutically acceptable salts

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with bases, such as those with strong bases, such as sodium, potassium or ammonium hydroxide, or the usual pharmaceutically acceptable salts with acids, such as Hydrochloric acid, hydrobromic acid. Maleic acid, Oxalic acid, tartaric acid, etc.

1 2

N - (DL-Seryl) -N - (2,2,4-trihydroxybenzyl) hydrazine

used as a free base or in the form of an acid addition salt with organic or inorganic acids. Suitable inorganic salts include: hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. Suitable salts with organic acids are obtained for example _? B. using acetic acid, benzoic acid / lactic acid, malic acid, maleic acid,

Salicylic acid, etc. Preference is given to -N - (DL-Seryl) -N - (2,3,4-trihydroxybenzyl) hydrazine in the form of an acid addition salt, in particular the hydrochloride, for use.

The pharmaceutical preparations of the present ^ER: invention can easily, for example, be prepared by mixing the two active ingredients. The mixture obtained can then be converted into suitable preparation forms. For enteral administration, the mixtures are transferred, for example, into tablets, which can be provided with coatings, into suppositories or into solutions, syrupy liquids / oily suspensions, etc. The resulting mixtures can also be filled into capsules, eg hardened gelatin capsules * If desired, the mixtures can also be converted into preparation forms suitable for parenteral administration * The methods customary for the production of such preparation forms are used.

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In the preparation of the therapeutically active agents of the present invention can be used as auxiliaries or Carriers that are usually used for this purpose in pharmaceutical Substances used in industry are used. For example, the following can be used in the manufacture of tablets Auxiliary materials are used: fillers such as precipitated aluminum hydroxide / calcium carbonate, dicalcium phosphate, mannitol, Lactose * disintegrants such as corn starch, cellulose; lubricant such as talc, calcium or magnesium stearate, acidulants to prevent decomposition of the preparation, such as citric acid, tartaric acid, etc. Also for the production of the liquid Forms of preparation, such as solutions, syrupy liquids, suspensions in oil, are used for the production of the same Usual pharmaceutical auxiliaries and carrier materials used, e.g. water, sugar solutions, vegetable oils such as arachis oil, which can also contain suitable edible suspending agents, additives and preservatives.

Preferred dosage units for enteral administration contain approximately 25-250 mg per dosage unit L-5-hydroxytryptophan or an equivalent amount of one Salt of this compound and about 25r-250 mg of N - (DL-Seryl) -N - (2,3 * 4-trihydroxybenzyl) hydrazine or an equivalent Amount of an acid addition salt of these compounds with the proviso that the above weight ratios between the Active ingredients are to be observed.

When producing the dosage units, it is advisable to add the active ingredients in an excess of approximately 2-3% . Preferred dosage forms are those made for enteral administration,

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for example tablets, capsules and suppositories.

The frequency with which the active ingredients are administered appropriately depends on the needs of the patient to be treated and is advantageously carried out by the treating patient Doctor set. Under normal circumstances it is advisable to use a daily dose corresponding to about 25-1000 mg, preferably about 50-750 mg of L-5-hydroxytryptophan and about

1 2

100-500 mg, preferably about 200-400 mg of N - (DL-Seryl) -N (2,3,4-trihydroxybenzyl) hydrazine to administer. The daily dose is expediently divided into three individual doses (morning, noon and in the evening).

The combination of L-5-hydroxy-tryptophan and N - (DL-SeryI) ^ N ² - (2,3,4-trihydroxybenzyl) hydrazine is preferably administered together in a single dosage form because it is an effective control the medication facilitated. However, it is also possible to administer the two active ingredients separately. This achieves the same benefits as when a single dosage form is administered.

The antidepressant effect of the combination according to the invention can be demonstrated on the basis of the increased serotonin content in the brain of appropriately treated rats. The animals received ip 225 mg DL-5-hydroxytryphophan per kg alone or 30 minutes after ip 50 mg N ¹ - (DL-seryl) -N ² - (2,3,4-trihydroxybenzyl) hydrazine per kg. Decapitation was carried out 2 hours after injection of the amino acid. The serotinine content of the brain in μg / g tissue was measured spectrofluorimetrically. While the brains of the control animals had a serotonin content of 0.36-0.03 μβ / g, the brains of rats pretreated with DL-5-hydroxytryptophan contained 0.89-0.04 μg serotonin per g tissue, i.e. the serotonin

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salary is increased by a factor of 3. Brains from animals that had received DL-5-hydroxytryptophan + N - (DL-Seryl) -N - (2,3,4-trihydroxybenzyl) -hydrazine showed a serotonin content of 1.11-0.06 ig / g tissue, ie the effect is increased.

1 2

As mentioned above, the IT - (DL-Seryl) -N -

(2,3,4-trihydroxybenzyl) hydrazine undesirable increase in blood pressure, which can be produced by administration of L-5-hydroxytryptophan alone. This effect can be detected on anesthetized dog (chloralosis):

Were measured

- Pressure in the pulmonary artery

- Pressure in the great circuit

- heart rate

The procedure and individual data are given below Table shown:

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Sequential
Procedure Pressure in the pulmonary artery
nalis, mm Hg Dog no. 2 Pressure in a big circle
lye, mm Hg Dog no. 2 • heart rate
per min. Dog no. 2 Before starting the infusion Dog no. 1 25/5 Dog no. 1 , 140/100 Dog no. 1 120 Infusion of L-
5-hydroxytrypto ~
phan (4 mg / min
for 15 minutes) 23/5 32/5 140/90 160/110 120 130 c *> 45 minutes after
End of the infusion 30/8 27/5 170/110 160/110 140 120 09883 / UOO Infusion of "N -
(DL-Seryl) -N -
(2,3,4-trihydroxy-
benzyl) hydrazine
(100 mg / kg in
15 minutes) 20/5 40/5 145/90 210/135 120 120 15 minutes after En
de the infusion 25/5 30/5 160/110 180/120 ■. 110 115 Infusion of L-5-
Hydroxy tryptophan
(4 mg / min during
22 minutes) 25/5 26/5 / 160/100 , 170/120 110 115 24/4 140/100 110

Dog no. II 11 kg
Dog no. 2: 7 kg

The infusion of L-5-Hydroxytryptophan leads to an increase in blood pressure, especially in the pulmonary artery. On the other hand, L-5-Hydroxytryptophan becomes more prevalent Infusion of N - (DL-Seryl) -N - (2,3,4-trihydroxybenzyl) hydrazine infused, the blood pressure does not rise.

The heart rate remains practically, unaffected during the entire experiment.

The experiment thus shows that N - (DL-Seryl) -Sr- (2,3,4-trihydroxybenzyl) hydrazine is able to control a serious side effect of L-5-Hydroxytryptophane, namely the increase in blood pressure, especially in A, pulmonalis (in the "small circulation") to prevent.

As tests on the rat have shown, the combination is non-toxic: a group of 8 males and 8 female animals were treated with 200 mg L-5-hydroxy-

1 2

tryptophan per kg and day and with 100 mg N - (DL-Seryl) -N (2,3,4-trihydroxybenzyl) hydrazine treated per kg and day for 13 weeks (once a day, 5 times a week). It could neither changes in general condition, nor in weight development, nor in hematological and histological ones Examination in comparison to untreated control animals.

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example 1

125 parts of N ¹ - (DL-Seryl) -N ² - (2,3 * ^ - trihydroxybenzyl) hydrazine hydrochloride, 50 parts of L-5-hydroxytryptophan, 5 parts of citric acid, 255 parts of microcrystalline cellulose and parts of corn starch are used in the usual way granulated and dried. The mixture is mechanically comminuted, homogenized after adding 5 mg of magnesium stearate and pressed into tablets with a weight of 500 mg. Each tablet has the following composition:

N ¹ - (DL-Seryl) -N ² - (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride L-5-hydroxy-tryptophan citric acid

Microcrystalline cellulose corn starch

Magnesium stearate

500 mg

Example 2

In the same way as indicated in Example 1, tablets of the following composition are obtained:

125 mg 50 mg 5 mg 255 mg 60 mg 5 mp;

- (DL-Seryl) -N ² - (2,3,4-trihydroxy-

benzyl) hydrazine hydrochloride 100 mg

L-5-hydroxy-tryptophan 100 mg

Citric acid 5 mg

Microcrystalline cellulose 230 mg

Corn starch 60 mg

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Magnesium stearate 5 g _m

500 mg

Example 3

142.5 parts of N ¹ - (DL-Seryl) -N ² - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride, 50 parts of L-5-hydroxy-tryptophan and 102.5 parts of mannitol are mixed together homogeneously and sifted. The resulting powder mixture is well moistened with 250 parts of a 2 ^ solution of polyvinylpyrrolidone in methylene chloride and then granulated, dried and sieved again. 1.5 parts of magnesium stearate and 18.5 parts of talc are added to the granules thus obtained, after which the mixture is filled into No. 0 capsules. Each capsule has the following composition;

N ¹ - (DL-Seryl) -N ² - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride

L-5-hydroxy tryptophan Mannitol

Polyvinylpyrrolidone magnesium stearate

Talk

142.5 mg 50 mg 107.5 mg 5 mg 1.5 mg 18.5 mff 325.0 mg

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Claims (4)

Claims η \ Pharmaceutical preparation with effectiveness against depression and sleep disorders, characterized in that it contains L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof and N - (DL-Seryl) -N - (2,3,4-trihydroxy-benzyl) - hydrazine or a pharmaceutically acceptable salt thereof in amounts which are in a weight ratio 1 2 between L-5-hydroxytryptophan and N - (DL-Seryl) .- N - (2,3,4-trihydroxybenzyl) hydrazine from about 1: 5 to about 2: 1. 2. Preparation according to claim 1, characterized in that it consists of a suitable for enteral administration Formulation consists of about 25 mg per dosage unit up to about 250 mg of L-5-hydroxytryptophan or an equivalent amount of a pharmaceutically acceptable salt of this 1 2 binding and about 25 mg to about 250 mg. N - (DL-Seryl) -N - (2,3, 4-trihydroxybenzyl) hydrazine or an equivalent amount of a pharmaceutically acceptable salt of this compound. 3. Process for the manufacture of pharmaceutical Preparations effective against depression and sleep disorders, characterized in that L-5-hydroxytryptophan or a pharmaceutically acceptable salt thereof with N- (DL-Seryl) -N - (2,3 »4-trihydroxybenzyl) hydrazine or a pharmaceutically acceptable salt thereof mixed in amounts corresponding to a weight ratio between L-5-Hydroxytrypto, phari and N - (DL-Seryl) -N - (2,3 * 4-trihydroxybenzyl) -hydrazine of about 1: 5 to about 2: 1. 4. The method according to claim 3 »characterized * that preparation forms suitable for enteral administration are produced which contain about 25 to about 250 mg of L-5-hydroxytryptophan or an equivalent amount of a pharmaceutically acceptable salt of this compound and about 25 to about 250 mg per dosage unit mg N ¹ - (DL-Seryl) -N ² - (2,3 ^ -trihydroxy- 309883 / UGO 2327S36 benzyl) hydrazine or an equivalent amount of a pharmaceutically acceptable salt of this compound. 309883 / UOO