DE2144584A1 - Effervescent preparations for the treatment of heart diseases - Google Patents

Description

Diw.g I37J

Dr. T. Haibach 8 Munich Ϊ

KeuiinflwsU.8.Tel.24O275

UIPHAR S.A. in Lugano (Switzerland)

iJourney for the treatment of heart disease.

The invention relates to a treatment device of certain shapes of heart conditions requiring administration of N-methyl-M-p -Ilydroxyäbhylguanidin O-i / 'hosphab of the formula:

im ^ ^ on

N-CII -CII -0 -? C.
j 2 2 j

CII 0 "Oil

provides.

This connection is in Belgian patent specification 666.891 and is generally called creatinol O-phosphate, It has been shown that creatine oil U-phosphate unexpectedly poor pharmaceutical properties

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according to which its use as a synthetic drug appears particularly suitable. In particular proves this connection in certain pharmacological evaluations extremely useful as an animal tonic, which has no undesirable side effects.

in fact the creatinol phosphate exerts its.; irkunr; en both on the contractility of the heart muscle, as well as on the stimulus distribution in the specific system.

Some properties were evident from the pharmacological ones Try: increasing the action of adrenaline on the ability of the isolated ileron auricle to contract of the rabbit; an increase in the contraction force b cLes isolated rat heart which was working normally or in a state of volume overload; an increase in the ability to contract of the ileus "in situ" of the rabbit, which is endangered by coronary obstruction due to kidney muscle necrosis was.

It has also been shown that the compound in the isolated rabbit heart the restoration of the heating line suppressed by anoxia and the sinus automatism. Furthermore, the compound has proven to be suitable, in the treated animals, the compatibility with the digital to improve. Finally, the compound is able to restore the "effectiveness" of the frog's pull receptors to produce, which are exhausted in their energy deposits. The creatinol O-phosphate has no noteworthy acute and chronic toxicity.

The dose of one g / kg has no significant toxic effects Causes effects (the LO,.. Amounts to intravenous injection

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administration in the mouse 1.2 g / kg, with intraperitoneal administration 3 g / kg and per os 10 g / kg). Chronic administration of the compound in large doses (100 mg / kg) After ύ months, the dog does not reveal any toxic aspects or functional or organic damage to the intestines placed.

The pharmacological results of the effectiveness of creatinol-0-phosphate found their equivalent in clinical practice. It has been shown that oral administration a drug allows the rapid absorption of the active ingredient and its immediate therapeutic effect. The administration of the drug particularly affected the heart failure and certain rhythm and conduction disorders influenced. Some patients with cardiac decompensation is

who were subjected to digital therapy and who were subjected to this Cardiac stimulants not tolerated, could be treated successfully if the effervescent preparation of the Creatinol-0-phosphate was administered.

Favorable effects of treatment with the invention Associations have been made in conditions following coronary disease, both angina and particularly found in the course of the post-heart attack.

The preparation also brings about an improvement in the physical condition of the patient and also contributes to this Reason to that a state of well-being is temporally sustained.

It has also been shown that the administration of an Iirausepreparats of creatinol-0-phosphate with certain vital

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mines, especially vitamin C and J3, the effectiveness; of Means for some forms of heart disease additionally improved, whereby the therapeutic "effects as more complete and reinforced.

The advantages of using the drug according to the invention in Lenschen can be seen from the following table, which summarizes the results of the treatment of a certain number of patients. For four of these patients, the clinical picture is also given below in its main lines. It should be pointed out that Table 1 gives the results of treatment with the anti-freshener based on creatinol phosphate, while Table Z shows the results of treatment with the same preparation, but which is associated with vitamins, especially vitamin C. and 3rd, contains, reproduces.

l) patient E.F., female gender, 56 years old, Diagnosis: Compensatory stenoinsuff iziena.

Jeginn to the treatment, the patient presented dikes of tacli3 ^r arrhythmic ivongestionsdekompensation (shortness of breath, edema, lung and liver stasis, oliguria) According to atrial fibrillation, electrocardiographic signs of heart enlargement and JiventrikelttberbelastunfV on.

The treatment is started with Pigitoxin (1 ¹ drop - 0.3 mg) twice a day for 1 days and then 1 1 drop per day, with a partial improvement in the circulatory conditions being observed: due to the occurrence of vomiting, too much and electrocardiographic signs of digital accumulation, therapy must be interrupted. ; <acii some i'agon

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the i; igit out therapy with the same doses again added, with creatinol-rhosphate in the form of an i3rausenibels (3 tablets of each;> ÜO mg ./iricstoff per lag) added will. j) The treatment is tolerated well and a complete orc compensation is achieved.

.;) rabient V.N., male gender, 30 years old: ijisproteinänie due to lipoid nephrosis; exiergetic dynamic cardiac muscle insufficiency.

/ Ai ieginn the iehandlung, the patient nautwassersucht, ilypercholesterinämie, I) LsproteinSinLc, SCIU / eratmig: eit at Ansurenrrungen, enlargement of the heart and a typical electrocardiographic 'IILD with such extension of the electrical systole, that the boundaries of the mechanical systole be exceeded.

although treatment with corticosteroids and amino acids decidedly improved nephrosic disproteinemic symptoms, she only slightly influenced the electrocardiographic image, which, however, after treatment with kreabinol 0-i'hosphab in the form of: Jrausemibtels (j l'abletten per day) became almost normal.

3 ) Patient G.> i., Female gender, 6 years old:

Intermittent left tubercle block myocardiosclerosis.

The patient's 2KG shows in continuous alternating periods with a normal course of the litter and loden with complete lock of the left tavern. i> io trade with Ki'eatinol ü-Phospliat in the form of a; Rausemitbels (J'i'abbben per day) has the lead Oiiblau'-. Ho's left tavern Ls cursingly normalized.

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4) patient G.T., male, 51 years old; chronic coronary insufficiency.

During the day, the patient indicates both in: aihe and frequent angina crises on and consumed even after exertion daily 7 ~ S tablets iiitroglycerin, although he intensive therapy with conventional drugs against angina (Prenilam Limit rate with long-lasting Effectiveness) is subject. The subsequent gain of creatinol O-phosphate in the form of an anti-inflammatory agent has the frequency and intensity of the Aiigina attacks considerably degraded.

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TABLE 1

Trap treated with creatinol O-phosphate in the form of an effervescent agent

1 U
• β *? diagnosis α
ω art / Il ■ P
> -4 I. duration ■ ige 1 5
V4
0)
> Symptoms and
Signs ahead
the
treatment State • igen I.
I.
!
I. ω j case no. Age / yes
Ueschlecii chronic pain I.
S.
I.
0
> mouth Dose (tab:
th / day treatment Simultaneously Yes Heavy weight after
the treatment Mebenwohlui H
• Η
9
I.
1 5ό Ο decompensation lich Il Days energy 2 f 3 XU Edema Well Atrial fibrillation Heavy weight extraventricular JMB> Days energy Compensation he I. Myocarditis 3 10 Oliguria enough disappearing no Well j that of the extra ⁵ V Angina pectoris
syndrome Days typical systole Myoka rdischXmie 3 15th angina reduced crime no Well 4th - Morgagni- frequency 46 0 Atrial yentricular
rer block at * age Adams
Stokes Reducing the Heart . 3 15th Crises complete atrie-ven-
tricular blocks. no Well 5 Yes and atrio-ventricular 80 <? Congestion Decree Days Heavy weight large block from 10th compensation 3 IS energy
Oliguria Circulatory accom- no Well 6th ⁶³ * Kongestionedekom- * a Heavy weight compensation o ⁷¹ pensation consequences v. Days ode Rejoining 7th Myocardial infarction 3 IS - me, oliguri sation no Well ό6 ο Agina pecfcris
syndrome Days the following
anginOse 3 10 Crises Reducing the
Frequency of no Well -7- Crises Mk - » Il Il Il Il

H- I. Thigh blc 6oz H- t, siao ova B. if. Oj ..;. ο do M. r'all jtfr. Next to-
irk-
gene - I U-L / S 1.8 et CD 0 P. -O O fr
P- H . .. et rals I. ker Oil H μ- » H-
0 O Age / year 3eur
haste et
n> φ Cfl
η et age O-i Ski O
pr
oo gender - - - - ■ - "* - ■ nose co henke ο le <■ 0
01 · ■ et H H
■ he
φ Φ φ at 1 O oils H- i Cho P. H-
O
(D O
in et et H
Φ et el P.
P-
H-
φ hias I. riku rikul Diai H-
Oil H QS 43 I- ·· re Ex Oi Φ 0
CQ
ro h ^ et Ul age the Q) I. rage Dose (tablet P CO
P ° I. th / day) P P Treatment (R φ
H B.
H- no 'Φ duration • φ Simultaneous Well ¹ from 1 g ? use of the incomplete 1 from digital Atrioventr
noisy 31oc O
ft Symptoms and 7? H- (N Ί Signs ahead <!
Φ
rs
Oil
ο
S "
H-
P.
s P. Siphon permanent P. I. Q) the treatment No Sxtrasysto Go away State
after
the
öehandlun; H φ no ti5 IH Well Φ P. Well

et H-P O H

When treating heart conditions with creatinol · O-phosphate alone or in combination with vitamins it has been shown that the effective dosage is between 5 and 25 mg / kg body weight per day.

The preferred dosage range is between 5 and 15 ^m g / kg per day. It is preferable to use larger doses at the beginning of the treatment, which can then be reduced considerably for immediate treatment or as maintenance doses. As particularly suitable vitamins to supplement and complete the effect of the agent

Vitamins C and ¹ J have proven themselves.

As already mentioned, it has surprisingly been found that the creatinol · O-phosphate is particularly effective when it is administered in the form of 3rausetabletten, which for the oral administration give very suitable solutions.

These effervescent tablets contain as basic ingredients In addition to the active ingredient, an alkaline bicarbonate or carbonate and an additional amount of tartaric or citric acid. The alkaline bicarbonate and / or carbonate, which is preferably Sodium or potassium carbonate is used for generation the effervescent effect by reacting with the active ingredient, if the tablet is placed in water before ingestion, whereby carbonic acid is released and the corresponding alkali salt of the Active ingredient is formed in solution. The additional addition of tartaric or citric acid has the purpose of the final Solution to give a pleasant sour taste. The effervescent formulation of creatinol-O-phosphate requires Furthermore, a non-hygroscopic base, such as anhydrous corn or grape sugar, and a suitable binding agent.

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The use of crystallized dextrose of high purity has proven particularly suitable. Using this Basis makes it possible to obtain the tablets directly from the mixture of the powder, without regard to Special precautions must be taken to ensure that the machines and rooms are air-conditioned with moisture. As a binder Soluble polysaccharides, such as starch hydrolyzate, have proven particularly useful. As a lubricant For the powder, substances are required that are compatible with the active ingredients and at the same time suitable Possess slip properties and, above all, are completely soluble in water. It has been shown that polyethylene glycols with a molecular weight between 4,000 and 20,000 are appropriate.

The effervescent preparation can also contain a flavoring agent such as microencapsulated mint oil, microencapsulated orange oil, Raspberry flavor and the like., Included. It is also possible to use a coloring agent and a synthetic sweetener such as saccharin and the like.

The effervescent preparation can just as easily be realized in granular form and sold in sealed sachets.

The effervescent preparation containing creatinol-O-phosphate and vitamins can be formulated in the same way. In addition to the creatinol-phosphate in the doses given above 200-500 mg vitamin C and 25-150 mg vitamin B. Hydrochloride admitted.

The following example recipes give typical formulations of pharmaceutical preparations according to the invention such as

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Formulation 1 - Effervescent tablets based on creatinol-O-phosphate dosed to 500 mg of active ingredient.

g per 100 tablets

anhydrous creatinol O-phosphate 50

Sodium bicarbonate 40

anhydrous sodium carbonate 10

citric acid anhydrous 20

refined crystallized dextrose 211.25

Starch hydrolyzate 10 Polyethylene glycol (molecular weight 4000) 8.75

microencapsulated mint oil as needed.

The ingredients are mixed with one another in a powder mixer until the active ingredient is homogeneously distributed. The powder obtained is then made into tablets in a tablet-making machine with a punch of 35 mm processed.

Formulation 2 - effervescent agent consisting of creatinol-0-phosphate and vitamins.

g per 100 tablets

Creatinol-O-Phosphate 50

Ascorbic acid 30

Vitamin B, hydrochloride 15

Sodium bicarbonate 50

Tartaric acid 3 5

refined crystallized dextrose 153.25

Starch hydrolyzate 8 Polyethylene glycol (molecular weight 6000) 8.75

microencapsulated orange oil as needed.

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/ ι

The ingredients are mixed together in a powder mixer until the active ingredients are homogeneously distributed are. The powder obtained is then made into tablets in a tablet-making machine with a punch of 35 mm processed.

Formulation 3 ~ * Effervescent agent in granular form from creatinol-O-phosphate and vitamin C.

Creatinol-O-Phosphate 400 g

Vitamin C 240 g

Fumaric acid 32Og

Sodium bicarbonate 520 g

Sucrose 2512 g

powdered lemon essence 8 g.

The ingredients are mixed together in a mixing device mixed until the active ingredients are homogeneously distributed. The powder obtained is then placed in a tablet making machine now processed into tablets with a stamp of 33. The tablets obtained are granulated in a granulator until granules of the desired size are obtained.

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Claims (1)

Claims 1. Agent for the treatment of certain forms of heart disease by the oral administration of creatinol-O-phosphate the formula: HN. ^ OH .C-N-CH -CH -0-P> 2 2 II N 'CH O OH 2 j in-Dk Ket-and- ^ Eag .. 2. Means according to claim 1, characterized in that it consists of effervescent tablets with suitable pharmaceutical raw materials and components. 3. Means according to claims 1 and / or 2, characterized in that that it also contains vitamins C and B. 4 · outside agent according to claims 1, 2 or 3 y, characterized in that it is in the form of a granular powder. 5. A method for producing ßrausetabletten according to claim 2, characterized in that the ingredients with refined and crystallized dextrose are mixed together. ü. Method according to claim 5 »characterized in that the effervescent tablets are obtained using sodium or potassium bicarbonate and / or sodium or potassium carbonate will. 2 0 9 8 1 S / 1 7 7 1 21U584 7. The method according to claim 5> characterized in that a polyethylene glycol with a molecular weight between 4,000 and 20,000 is used as a lubricant for the tablets will. -8 -.— -Hej suffer, characterized in that the oral administration of creatinol 0-phosphate Imj ^ siaierungsbe rich between 5 and 15 mg per kg and lay ^ Jja-FoTFm of effervescent tablets, which according to a-io and. -U- 2 0 9 8 15/1771 PATENT LAWYERS DIPL-ING. CURT WALLACH DIPL.-ING. GÜNTHER KOCH DR. TINO HAIBACH s Munich 2, October 25, 1971 OUR MARK: IJ 4l7 - received on ... New version of sub-claim 8 8. Use of the agent according to one or more of the preceding Claims 1 to 4 in the dosage range between 5 to 25 mg, and preferably 5 to 15 mg, per kg of body weight and day. 209815/1771