DE2059747B2 - ORAL OR RECTAL ADMINISTRATIVE PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF MIGRAENE - Google Patents

Description

can be alleviated or eliminated by antihistamines 65 The effect softened by the administration of the

can, but the effect is based on the fact that the preparation according to the invention is achieved, is so far

the antihistamines down the action of the histamine - the details have not yet been elucidated, it has

weaken or abolish. The pain or, however, is fundamentally different from the effect that

³ 4

it is then observed if the incidence of l-p-chlorobenzhydryl cannot be brought under control, if

4-p- (tert, buty) -benzylpiperaz, administered in all. in the preparations according to the invention in combination

It is believed that the Analget.cum used nation active ingredients used separately to different W gain of the LP-chlorobenzhydryl-4-p- (tert-times which are administered and even butvO-benzylpiperazins is used. However, since the period 5 then not if the piperazm mentioned between the separate administrations of the analgesic is shorter than that of the individual active ingredients, it can be less than a certain range of, for example, 30 minutes then achieved when the alleviation achieved subsides and the symptoms of the active ingredients break through again in the specified proportions - migraines and even administered at the same time except for consonants, even then, trolle advised Individual preparations are available.Therefore, it may be necessary to occur m intervals after which, within the scope of the invention, also prepa rate to administer further component a) in the form of a unit dose and analgesic aHeine from the first administration of the preparation according to the invention in order to maintain the level of component b) in a unit dose of the analgesic. The amount of 4-p- (tert-butyl) -benzylpiperazine between 2.5 and the analgesic to be administered in such subsequent doses as the unit dose of 1-p-chlorobenzhydryl can be the same as that which conveys 24 mg and which ' Unit dose of the analgesic was included in the starting dose. For example, the total amount of 1p-chlorobenzhydrylazine fluctuates between 20 and 200 times the dose of the pipework.

4-p- (tert.-butyl> benzylpiperazine and analgesic, the so The lp-chlorobenzhydryl ^ p-itert.-butylVbenzylin the initial dose of the preparation according to the invention piperazine and the analgesic can be administered, for example, 12.5 or 1000 mg, then packaged in the form of tablets or capsules as a suitable dose of the analgesic subsequently administered and given in pairs in a pack, for example 1000 mg. be packaged, the tablets or capsules also intervals of 3 to 4 hours after the first session, so that the patient did not have any difficulties with the preparation according to the invention in selecting the respective active ingredients,
but only if this is necessary to maintain freedom from pain in the preparations according to the invention. of course the two active ingredients also in a single one

Investigations using the administration form according to the invention should be included, with each of the preparations having shown almost 90% successes with such two active ingredients in a separate piece of patients who contain the preparation in tablet form of this administration form. For example, when a migraine attack is developing, the form of administration is a gelatin capsule or it has already occurred. Practice has shown, in question, which is divided by a central wall into two different capsule parts in cases where the migraine is predictable, one part with attack, the preparations according to the invention prophylactically, one active ingredient and the other part with table should be taken. A preparation containing the other active ingredient can thereby take advantage of the preparations according to the invention. When ingested, the median wall is made up of its prophylactic destruction either mechanically or by the gastric effect being dissolved over a considerable period of time, so that the two active ingredients are stretched, this period of time in some cases up to are released at the same time.
can be up to 3 days. Normally, the inventive pre-

The preferred dose of this analgesic depends on the parate packaged in a single dosage form.

the selected connection. In the case of ionized, for example as tablets, capsules, suspen-

N-acetyl-p-aminophenol, salicylamide and acetylsions, syrups or suppositories. This appointment

salicylic acid, the preferred doses are around 300, and forms can be prepared as follows:
1000 mg, while in the case of p-ethoxyacetanilide

the preferred dose between 300 and 600 mg 1. tablets

fluctuates. l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiper-

Preferably pre- according to the invention 50 can azine dihydrochloride is with the powdered binder Parate codeine in an amount from 7.5 to 22.5 ° / _00, or medium fine triturated. It is then mixed with N-acetyl-dextropropoxyphene in an amount of 12.5 to p-aminophenol and passed through a sieve with a 37.5 / ₀₀ , based on 1 part by weight of effective mesh size of about 0.21 mm . With substance b) included. this powder becomes any required color

Surprisingly, water containing dissolved water mixed up. In addition, it is stated that by increasing the amount of gelatinized starch paste added that lp-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine the powder is bound. The resulting mixture beyond the required specified amount is achieved through a perforated sieve with a clear mesh increased pain relief. Rather, a width of about 1.3 mm granulated. The resulting was found that when the 1-p-chloro ^c ° granules are ^{dried at 50 '1} C in an oven benzhydryl-4-p- {tert-butyl) -ben7ylpipcrazine in the er and then passed through a perforated sieve with a clear preparation according to the invention in 25 mg considerably over- mesh meanwhile of about 0.8 mm.
Increasing amounts set in, the migraine symptoms Codeinphn-tiha: may become more noticeable with the common equilibrium. mitidn. Lubricants and loosening agents, whereby the migraines can even have their full effect 65 and possibly any pigments can be fine-tuned so that they can no longer be milled by the administration, and this whole mass can then be controlled with the help of further analgesics. Mixed granules. Then these granules are

It has also been found that a migraine latex compresses on a conventional tablet machine.

2. suspension

Codeine phosphate and 1-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperaiine dihydrochloride turn yellow in distilled water. In finely powdered Zuitand present N-acetyl-p-aminophenol is with a further proportion of water,> n which one sufficient amount of a suitable suspending agent is dissolved. mixed. To a different proportion Any colorants, protective substances, buffering agents and flavorings can be added to the water. All Portions of water are then mixed together and produce the desired amount of liquid.

3. Syrup ^1S

p-Acetamol is dissolved in the required amount of propylene glycol and glycerin. Codeine phosphate and 1 -p-chlorobenzhydryM-p-Ctert-butyO -benzylpiperazine dihydrochloride are dissolved in the required amount of water. These two amounts of liquid are mixed with one another, the proportions being selected so that the solids remain dissolved in the solvents available for this purpose. Protective substances, flavorings, buffering as Agents and dyes are then added in aqueous solution, and this mixture as a whole represents the the desired amount of liquid.

example 1

There are tablets, the l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine (as dichlorohydride) and N-acetyl-p-aminophenol in the in the following Table contains the quantities given, prepared.

preparation No.

1-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine per tablet

(mg)

N-Acetyi- ρ-aminophenol per tablet

(mg)

1 6.25 500 2 5 500 3 3.75 500 4th 10 500

4. Hard capsules

l-p-Chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine dihydrochloride and codeine phosphate are finely ground together with N-acetyl-p-aminophenol. A suitable lubricant such as magnesium stearate is added and mixed therewith. The entire amount is then passed through a sieve with fine mesh openings and mixed again. The resulting powder is then put into hard gelatin capsules on a conventional encapsulation machine filled.

5. Soft gelatin capsules

The active ingredients are needed in powder form along with protective substances, buffering agents Amount of oil binding agent added, which is a mixture of a hydrogenated oil and beeswax contains that the powder is suspended. The entire amount is then passed through an appropriate one Given to the mill and mixed again. Then the mixture is vented and finally on one conventional encapsulation machine.

6. Suppositories

The active ingredients in finely powdered form be added to the appropriate amount of suppository base that was previously added to a just above Its melting point lying temperature has been heated, added. The powder is using well distributed in the molten base mass using a suitable stirrer. It may be required then pass the melted mass through a mill. This depends on the particle size. the Suppository mass is then poured into suitably shaped suppository molds.

The invention is illustrated in more detail in the following examples.

^30th

35 The

Grind lp-chlorobenzhydryl ^ p-itert.-butyO-benzylpiperazine dihydrochloride with powdered starch to a free-flowing powder. The resulting powder is mixed in the appropriate proportionate amounts with the N-acetyl-p-aminophenol, and the mixture is passed through a sieve with a mesh size of 0.21 mm. Water is mixed in and then enough gelatinized starch paste is added that the granules are bound and held together. The resulting mixture is pressed through a perforated sieve with a mesh size of about 1.3 mm, ^{dried at 50 °} C. and then passed through a perforated sieve with a mesh size of about 0.8 mm. After the resulting granules have been tested for the concentration of the active ingredients, they are compressed on a conventional tablet machine. The normal dose of the resulting tablets is 1 to 3 tablets.

Example 2

Tablets are made with the following ingredients contain:

l-p-chlorobenzhydryl-4-p- (tert.-

butyl) benzylpiperazine 6.25 mg

p-acetamol 500 mg

Codeine Phosphate 7.5 mg

The tablets are prepared as described in Example 1 with the difference that the codeine phosphate with the l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine and dried granules containing N-acetyl-p-aminophenol and the resulting mixture is tabletted. The following test result was obtained from the Treatment of patients suffering from migraines with the tablets prepared according to Example 2 obtained. In each case 2 tablets were given as a dose per administration, followed by five observations Cases of significant improvement or decrease

experiencing migraine symptoms.

The following table summarizes pharmaceutical preparations according to the invention, with the preparations 1 to 5 in the presented Rpknieion

2. suspension

Codeine phosphate and l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine dihydrochloride are dissolved in distilled water. N-acetyl-p-aminophenol in a finely powdered state is mixed with a further portion of water in which a sufficient amount of a suitable suspending agent is dissolved. To a different proportion Any colorants, protective substances, buffering agents and flavorings can be added to the water. All Portions of water are then mixed together and produce the desired amount of liquid.

3. Syrup

p-Acetamol is dissolved in the required amount of propylene glycol and glycerin. Codeine phosphate andl-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine dihydrochloride are dissolved in the required amount of water. These two amounts of liquid are mixed with one another, the proportions being selected so that the solids remain dissolved in the solvents available for this purpose. Protective substances, flavorings, buffering agents and dyes are then added in aqueous solution, and this mixture as a whole constitutes the the desired amount of liquid.

4. Hard capsules

l-p-Chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine dihydrochloride and codeine phosphate are finely ground together with N-acetyl-p-aminophenol. A suitable lubricant such as magnesium stearate is added and mixed therewith. The entire amount is then passed through a sieve with fine mesh openings and mixed again. The resulting powder is then put into hard gelatin capsules on a conventional encapsulation machine filled.

example 1

There will be tablets containing 1-p-chlorobenzhydryl

4-p- (tert-butyl) -benzylpiperazine (as dichlorohydride and N-acetyl-p-aminophenol in the after The following table contains prepared quantities.

35

40 preparation

No.

1-p-Chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine per tablet

(mg)

N-acetylp-aminophenol per tablet

(mg)

6.25
5

3.75
10

500 500 500 500

For the preparation of the tablets there is l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine dihydrochloride with powdered starch to one free

grind flowing powder. The resulting powder is mixed in the appropriate proportionate quantities with the N-acetyl-p-aminophenol, and the Ge The mixture is passed through a sieve with a mesh size of 0.21 mm. Water is mixed in

and then enough gelatinized starch paste is added that the granules are bound to hold together. The resulting mixture win through a perforated sieve with a mesh size vo; about 1.3 mm pressed through, ^{dried at 50 0} C and then passed through a perforated sieve with a clear mesh of about 0.8 mm. After the resulting granules have been tested for the concentration of the active ingredients, they are compressed on a conventional tablet machine. The normal dose of the resulting tablets is 1 to 3 tablets.

5. Soft gelatin capsules

The active ingredients are needed in powder form along with protective substances, buffering agents Amount of oil binding agent added, which is sufficient as a mixture of a hydrogenated oil and beeswax contains that the powder is suspended. The entire amount is then passed through an appropriate one Given to the mill and mixed again. Then the mixture is vented and finally on one conventional encapsulation machine.

6. Suppositories

55

The active ingredients present in finely powdered form are added to the corresponding amount of suppository base, which is previously heated to a temperature just above its melting point has been added. The powder is melted using a suitable stirrer Well distributed base. It may be necessary to then put the melted mass through a grinder admit. This depends on the particle size. The suppository mass is then suitably shaped Filled with suppository forms.

The invention is illustrated in more detail in the following examples.

Example 2

Tablets are produced that contain the following ingredients:

l-p-chlorobenzhydryl-4-p- (tert.-

butyl) benzyl piperazine 6.25 mg

p-acetamol 500 mg

Codeine Phosphate 7.5 mg

The tablets are prepared as described in Example 1, with the difference that the Codeinphos | phat with the l-p-chlorobenzhydryl-4-p- (tert-butyl benzylpiperazine and N-acetyl-p-aminophenol en containing dried granules and grind de resulting mixture is tabletted.

The following test result was used in the treatment of patients suffering from migraines with the tablets prepared according to Example 2 g (j won. In each case, the dose per administration Two tablets were given after which, in five observed cases, a considerable improvement or decrease experiencing migraine symptoms.

In the following table are according to the invention summarized pharmaceutical preparations, whereby the preparations 1 to 5 in the preceding examples |

have already been mentioned. Preparations Nos. 6 to 14 are for administration in the form of tablets provided, of these preparations Nos. 7 to 10 for administration to children in question come. Preparations No. 15 to 19 are for administration in the form of a single administration form suitable. Preparations 20 and 21 are suitable for administration in the form of suspensions, while the preparations 22 to 26 come as a powder or hard gelatin capsules for administration.

Preparation no.

1-p-Chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine

N-acetyl-salicylamide acetylsalicyl-p-ethoxyacet-dextropropoxy-codeine

p-aminophenol acid anilide phen

1 6.25 500 350 50 50 4.0 7.5 2 5.00 500 50 2.5 3 3.75 500 300 4th 10.00 500 10.0 5 6.25 500 2.5 6th 5.00 1000 480 300 2.5 7th 2.5 300 15.0 8th 2.5 300 15.0 9 2.5 650 6.0 10 2.5 300 500 15th 11th 6.25 3.5 12th 6.25 300 13 ' 7.5 14th 7.5 450 500 350 2.0 15th 24 12.5 15th 16 24 500 500 8.0 17th 24 18th 24 19th 24 1000 500 12.0 20th 12th 21 12th 500 22nd 6.25 23 6.25 24 3.75 25th 3.75 26th 3.75

With regard to the addition of codeine or dextropropoxyphene to the invention, in the previous « It should be noted that the pharmaceutical preparations summarized in the table in the table below include as mentioned above, are preferred measures. The actual stated effect is only due to the interaction between component a) and component b).

Codeine is then preferably used when the tablets are taken after already one Migraine attack has started and the patient has headache. The headache symptoms are caused by the codeine suppressed faster.

The following comparative example shows the surprising Effect that is achieved when using the preparations according to the specification.

Comparative example

A number of formulations were prepared which had the active substances given below contained. The formulations were made according to that described in Example 1 of the application documents Method using starch and lactose as common tableting materials to form tablets processed.

1-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine mg mg of N-acetyl-p-aminophenol

mg 1-p-chlorobenzhydryl

4-p- (tert-butyl) -

benzylpiperazine

mg of N-acetyl-p-aminophenol

3.75 mg of 1-p-chlorobenzhydryl

4-p- (tert-butyl) -

benzylpiperazine mg N-acetyl-p-aminophenol

6.25 mg 1-p-chlorobenzhydryl

4-p- (tert-butyl) -benzylpiperazine mg N-acetyl-p-aminophenol

Mixing ratio:

1:20

1: 200

1: 133

1:80

The formulations given above wui administered at various times to a number of 20 subjects suffering from migraines There were usually more than la people. In

609 517/42

Up to 90% of cases were suppressed or eliminated during a migraine attack Symptoms.

In contrast, I had an administration of 1-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine alone under identical conditions does not result in any greater effects than a suggestive substance. Even then when the amount of 1-p-ChlorbenzhydryI-4-p- (tert-butyl) -benzylpiperazine was administered at a dose of 50 mg, it was completely ineffective in the absence of the analgesic component. Formulations, containing the above analgesic component were somewhat more effective than the l-p-ChlorobenzhydryM-p-itert.-butyO-benzylpiperazine alone, however, they had only a slight reduction in intercranial pain with a small number of test persons.

Similar results were obtained when the N-acetyl-p-aminophenol was replaced by acetylsalicylic acid,

p-Ethoxyacetanilide and salicylamide were replaced in equivalent amounts.

It has been shown that formulations containing l-p-chlorobenzhydryl-4-p- (tert-butyl.) - benzylpiperazir contained in an amount of only 2.5 mg and one of the analgesics mentioned above, for treatment of migraines were effective. Formulations containing smaller amounts of l-p-chlorobenzhydryl-4-p- (tert-butyl) -benzylpiperazine contained were not

ίο tests.

In all experiments it was found that no undesirable side effects occurred. This realization stands in sharp contrast to the experience with known and well-established preparations, wii

for example, preparations containing ergot, which ofl result in undesirable side effects such as nausea.

About 90% of the subjects who took part in the tests drew the grains of the invention

ao combinations of the known combinations.

Claims (2)

1 2 Discomfort-inducing effect of histamine claims: attributed to the fact that the permeability of the peripheral blood vessels is changed, which is a local an 1. Orally or rectally administrable pharmaceutical swelling causes the tissue. The ent Table preparation for the treatment of migraines, 5 standing pressure acts on the nerve endings, so dal characterized in that it can be identified as certain pain effects Active ingredients in combination a) l-p-chlorobenzhy- In such cases, the on this appearance dryl-4-p- (tert-butyl) -benzylpiperazine and b) nings decreasing pain effects or un N-acetyl-p-aminophenol, p-ethoxyacetanilide, Sa- sensations of well-being through the application of voi contains licylamide or acetylsalicylic acid, with io eliminating histamines, namely because the Ur the active ingredients a) and b) in a relative amount- things of swelling or inflammation be a ratio of 1:20 to 1: 200 is available, and b) be removed. Only in this context is di ( also as a mixture of the analgesics mentioned before- statement of the above-mentioned reference zi can be handled. to understand. All others occurring in the body 2. Preparation according to claim 1, characterized in that the pains that have causes other than the above mentioned that there are also codeine in an amount described cannot be caused by anti from 7.5 to 22.5 ⁰ J ₀₀ or dextropropoxyphene in histamine be alleviated or eliminated. Contains an amount of 12.5 to 37.5V ₀₀ , each based on the previously known sub-amounts of 1 part by weight of active ingredient b). investigations into the use of 1-p-chlorobenzene ao hydryl-4-p- (tert-butyl) -benzylpiperazine no pain reliever properties have been found. The invention is based on the object to provide a pharmaceutical preparation for the treatment of migraine which is non-toxic and which 25 Pain Relief for Migraine Headaches The invention relates to an administered orally or rectally and which can be administered in a timely manner pharmaceutical preparation for the treatment of the occurrence of migraine-related pain of migraines. able to prevent completely. In GB-PS 7 05 979 asymmetrical This object is achieved according to the invention by a 1,4-diaralkylpiperazines, for example 1-p-chlorobenzene-pharmaceutical which can be administered orally or rectally hydryl-4-p- (tert-butyl) -benzylpiperazine. Dissolved preparation of the type mentioned, which thereby It is stated that these compounds are inherently characterized as being active ingredients in combination which characterize an antihistamine ε) l-p-chlorobenzhydryl-4-p- (tert-butyl) -benteristic are, however, also show properties that zylpiperazine and b) N-acetyl-p-aminophenol, p-Äthfür an antihistamine are unusual, for example oxyacetanilide, salicylamide or acetylsalicylic acid increased long-term effect. holds, the active ingredients a) and b) in a relative Antihistamines are mainly used for healing purposes and in proportions of 1:20 to 1: 200 Administered to conditions based on allergies. In b) also available as a mixture of the analgesics mentioned With regard to the presumption that can be due to hand. Food allergies Migraine states produce 40 N-acetyl-p-aminophenol, p-ethoxyacetanilide, SaIi- attempts have already become known, on cylamid and acetylsalicylic acid are known anal- this way Vergetica caused migraines. It was inventively in surprising administration of l-p-chlorobenzhydryl-4-p- (lert.-butyl) - manner found that these special analgesics with benzylpiperazine to alleviate. However, no 1-p-chlorobenzene, which is known as an antihstamine, was achieved resounding success. 45 hydryl-4-p- (tert-butyl) -benzylpiperazine a synergistic In "Pharmaceutical Practice", No. 5 (1969), it is shown to result in the effect of what is caused by migraines P. 97 in the right column stated that a caused stimulus is counteracted or this Pain relief not only through analgesics but blocked. This synergistic effect can also in certain cases can be achieved by substances with other analgesics that have been investigated which among other things cannot be ascertained among the antihistamines. be reckoned. However, this cannot result in the general my conclusion that antihistamines nisse of the active ingredients a) and b) 1:40 to 1: 120 and very generally suitable for relieving pain, in particular 1:70 to 1: 100. are. Antihistamines are generally understood to be the preparation according to the invention mean compounds that produce the effect of 55 in the form of tablets, capsules or suppositories. Weaken or cancel histamine as it is put in and administered. Body due to allergies, anaphylaxis, trauma- The administered amount is chosen such that matic shocks etc. arise. It is only about 2.5 to 24 mg and preferably 8 to 15 mg, knows how to apply antihistamines to the skin, for example 12.5 mg of the 1-p-chlorobenzhydryl To prevent itching caused by insect bites or 60 4-p- (tert-butyl) -benzylpiperazine at the first -bissc are due. By releasing signs of a migraine attack, the body Histamine are available on the basis of the aforementioned disclosure. This amount is beneficial to? symptoms, for example on the basis of allegiances, or even 3 tablets or capsules divided into the a certain discomfort may occur, which should then be taken individually.