CS199202B2 - Method of producing gelatine capsules to be bitten up - Google Patents

Abstract

The compsns, which are in the form of gelatin capsules opt. contg. opacifying agents contain (1) 1 pt.wt. of the title cpd. (2) 6-50 (pref. 15-35) pts.wt. of a poly-2-3C-alkylene-glycol of mol.wt. 200-400, (3) 0-5 pts. wt. of a 2-8C alcohol contg. 1-3 OH gps. or benzyl alcohol, and opt (4) conventional formulation adjuvants. The capsules are very suitable for administration by the patient himself during attacks of angina pectoris. They are administered perlingually and the active cpd is absorbed very rapidly.

Description

The present invention relates to a process for the production of coronary compositions in a special form, namely a new formulation of coronally active and already known 1,4-dihydropyridine.

Coronary vascular disorders manifested by seizures, referred to clinically as so-called angirpha pectoris, are vital indications that necessitate immediate administration of a suitable drug.

Since the time at which a similar seizure occurs cannot be predetermined, a patient who has had angina has to carry medication that allows him / her to treat himself / herself in the event of a seizure. Such medicaments, or the forms from which they can be prepared, must meet a variety of requirements to allow a quick and secure treatment by the person themselves.

The preparations must be so equipped that the patient can inject themselves without the difficulty of handling, despite the limited ability of their own movements.

Since substances that are therapeutically effective in angina are usually highly effective drugs where precise dosing is required, the product must be provided to ensure adequate dosing.

An angina pectoris usually occurs with unbearable pain and severe anxiety. Purely functionally, a reduction in cardiac blood flow during a seizure may result in permanent damage to the heart muscle, and. this can result in death in extreme cases. Drugs used in the treatment of angina must therefore be fully effective as quickly as possible within a few minutes.

The foregoing claims cannot be met by injectable solutions which can only be administered parenterally, without being met by oral solutions which can be dosed only dropwise. Parenteral self-injection is difficult for the untrained and impossible in an angina attack. Orally administered solutions, which need to be dosed with drops, cannot be dosed accurately with a patient whose responsiveness is already sufficiently limited. There is a risk of overdose.

It is known that 1,4-dihydropyridine derivatives are characterized by coronary artery dilatation and can be used to treat the aforementioned disorder. Substances belonging to this class of compounds are poorly soluble and, in particular, highly sensitive to light. If the substance is exposed to daylight in the dissolved state, the presence of an irreversible decomposition product, ie 2,6-dimethyl-3,5-diacetyl-4- (2'-nitrosophenyl-pyridine), can be detected within a few minutes by UV spectrophotometer. In daylight, the substance decomposes quantitatively in 10 to 20 minutes.

Reducing and oxidizing agents are added to stabilize the extremely labile 1,4-dihydropyridine derivative redox system, as well as redox systems (e.g. Fe ' / Fe ' ⁿ , ascorbic acid / dehydroascorbic acid) cannot withstand rapid decomposition. The storage of the substance and the corresponding solutions in thick-walled, dark brown bottles will delay the decomposition (if exposed to daylight), but the presence of a decomposition product can be detected in as little as an hour to ninety minutes.

Tablets or dragees (British Patent No. 1,173,862) containing such active substances do not act fast enough due to the slow resorption, so that the powerful effect of these substances cannot be exploited. Thus, there is still an urgent need to convert 1,4-dihydropyridine derivatives into one. the use forms to be sufficiently stabilized and, on the other hand, to fully exploit in practice the strong coronary dilatation effects of the substance.

It is further known that rapid resorption and thus a faster manifestation of action occurs with drugs introduced perlingually, such as nitroglycerin, see T. Sollman " A Manual of Pharmacology ", WB Saunders Co., Philadelphia, USA, 1957 , p. 631.

Consequently, formulations containing stabilized 1,4-dihydropyridine derivatives that can be resorbed upon perlingual administration are therapeutic advances.

It has now been found that only the coronary-active 1,4-dihydropyridine derivatives containing 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1, 4-dihydropyridine, up to 50, preferably 15 to 35 parts by weight of a polyalkylene glycol having two to three carbon atoms in the alkylene moieties, and having an average molecular weight of 200 to 4000, up to 10 parts by weight, preferably 5 to 8 parts by weight of the lower alcohol up to eight carbon atoms and one to three hydroxyl groups, and are found in gelatin capsules for chewing, wherein the capsules contain a repeating agent and a light-absorbing dye at wavelengths of 250 to 460 nm, preferably 280 to 420 nm, where they may be additional processing aids are included.

The chewable capsules are prepared by mixing the above-mentioned active ingredient with polyalkylene glycol and lower alcohols in any order, filling the chewing capsules containing the repeating agent and the color "yellow orange S" (Color-Inex 15985), and optionally additional customary processing aids are added.

It should be described as expressly surprising that the solutions coronary. of active 1,4-dihydropyridine, which, even when bottled in brown bottles or ampoules under the influence of daylight, decompose to the greatest extent pharmacologically inactive in the shortest possible time, are in chewable capsules containing titanium dioxide and the usual food color yellow orange S (Color-index 15985), stable for several months.

Furthermore, it should be noted that it is particularly surprising that by using biting capsules with a certain 1,4-dihydropyridine derivative, namely 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine , there is a very fast demonstration of effectiveness. This special 1,4-dihydropyridine derivative is surprisingly particularly important. Unlike other 1,4-dihydropyridine derivatives, it is absorbed very rapidly perlingually, ie by the tongue and skin of the stirrups.

It is further surprising that this relatively poorly soluble substance can be converted into a rapidly resorbable form, i.e. a liquid form in a gelatin capsule for chewing, the capsule itself being quite susceptible to dissolution.

The repair of 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,1'-dihydropyridine according to the present invention has the following advantages; a patient who has had a heart attack can inject the substance immediately, with an effect within a few minutes. The dosage is unambiguous because it is given by the amount of active ingredient per capsule to chew. Moreover, administration is simple, perlingually occurring, i.e. without the need to subtract the number of drops of the active ingredient. In this case, such a process is not necessary at all because the active substance is light-sensitive. This light sensitivity can be significantly suppressed if the capsules containing the repeating agent and a non-toxic dye absorbing wavelengths of 250 to 460 nm.

The active ingredient thus treated according to the present invention is the known 4- (2‘-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine (see British Patent 1,173,862) of the formula

The polyalkylene glycols used in the present invention are also known; Preferably, polyethylene glycol and / or polypropylene glycol with an average molecular weight of 300 to 600 are used.

The lower alcohols having two to eight carbon atoms used in the present invention are also known. Preferably, glycerin, propylene glycol or butylene glycol is used.

Flavors or essential oils, preferably peppermint oil, fennel oil, anise oil, caraway oil, lemon oil or eucalyptus oil, sweeteners such as saccharin or saccharin sodium, may be used as further processing aids, cyclamate, ammonium salt of glycirrhizinic acid, etc.

The capsules to be used according to the invention, preferably chewable capsules, are of a gelatin shell which, in the ready-to-use state, contains 54 to 80% gelatin, 10 to 36% glycerin and 7 to 15% water and 0.5 up to 5% of a repeating agent such as titanium dioxide, iron oxides such as yellow iron oxide or red iron oxide, brown iron oxide or calcium carbonate, preferably titanium dioxide, or as a yellow orange-S dye. by first mixing 40-66% pure gelatin with 8-36% glycerin (or sorbitol) and 22-34% water, and allowing the mixture to swell for some time. Then the mass is melted at about 60 ° C, until it is free of bubbles, a repeating agent and yellow orange S (Color Index β) are added.

* 15985), or also a preservative (e.g. ester of p-aminobenzoic acid, sorbic acid, benzyl alcohol) and it is all ^one homogeneously Forge.

The capsule filling of the present invention is prepared by dissolving 4- (2 4--nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydroipyridine with gentle heating and stirring in lower alcohol and polyalkylene glycol. The filling of the gelatin capsules is carried out by known methods, for example using the machinery of Scherer, Leiner, Norton or accogel. After filling, the capsules are dried and ready for use.

The application of the chewing capsules according to the invention is preferably perlingual resorption.

Another illustration shows a very rapid onset of efficacy in perlingual resorption, particularly when comparing the active compound of the invention in a tragacanth.

Comparison of different forms of administration; experiments on narcotized dogs, catetized in the sinus of the heart —--- 1 mg / kg perlingually (capsule to bite *)

..... 1 mg / kg per os (tragacanth) of the mean value in five experiments

The increase in oxygen pressure in coronary blood following perlingual administration of the active compound of the invention at 1 mg / kg as a gelatin capsule content, a mixture of glycerin, polyethylene glycol and water was observed and recorded compared to application of the active compound of the invention into the stomach. fine substance in traganth). These are always mean values of five attempts.

The graph clearly shows that the oral effect of the drug is immediately apparent. In about 5 minutes, the maximum efficacy is approximately attained, while when injected into the stomach • the oxygen pressure rises to the same value only after 60 minutes. Administration of the active ingredient to a solid preparation such as a tablet, dragee or the like. will be even more unfavorable.

The time course of photochemical decomposition of the active substance in ethanolic solution under irradiation with light at 360 nm is given in the table.

8

Table

Time course of photolysis of 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine in ethanol at 360 nm.

Extinction Time Concentration Converters

[seconds] starting materials 0 0.220 4,62.10- ⁵ 10 0.199 4,11.10- ⁵ 25 0.173 3,48.10 ^-5 40 0.151 2,95.10 ^-5 55 0.132 2,49.10 ^-5 70 0,113 2,03.10 ^-5 85 0,098 1,67.10 ^-5 100 ALIGN! 0,086 1,38.10 ^-5 130 0,069 0,97.10 ^-5 Examples of preparation: 1) active substance 1 part propylene glycol 15 Dec parts polyoxyethylene glycol 84 parts 2) active substance 5 parts butylene glycol 3 parts Lutrol 9 ^R 92 parts

decomposition product % 0,10 ^-5 0 0.51 ^-5 11.0 1.14 ^-5 25.7 1,67 ^-s 36.1 2.13 ^-5 46.1 2,59- ⁵ 56.1 2.95 ^-5 63.9 3,24 ^-5 70.1 3.65 ^-5 79.0 3) active substance 3 parts glycerine 5 parts water 5 parts peppermint oil 2 parts polyglycol 85 parts 4) active substance 2 parts benzyl alcohol 3 parts lemon oil 1 part polydiol 200 ^R 94 parts

P R E D Μ £ T

Process for the preparation of gelatin capsules for chewing, comprising mixing, in any order, a weight part of 4- [2'-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine, up to 50, preferably 15 to 15, 35 parts by weight of a polyalkylene glycol having two to three carbon atoms in the alkylene residues and having an average molecular weight of 200 to 4000;

Claims (1)

OF THE INVENTION 1 to 10 parts by weight, preferably 5 to 8 parts by weight of a lower alcohol having two to eight carbon atoms and one to three hydroxyl groups, and optionally also other auxiliaries, and this mixture is filled with a gelatin baking capsule containing a light absorbing colorant a wavelength of 250 to 460 nm, preferably 280 to 420 nm, and a repeating agent