JPS58121210A - Manufacture of instantaneous mouth discharging sublingual soft capsule medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has coronary vasoactivity (coronaryac
Instant mouth-release sublingual agent with coronary vasodilatory action containing the compound (4-<2=-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine The present invention relates to a method for producing soft capsules.

A disturbance in the blood circulation of the coronary vessels, which resembles a stroke and is itself clinically determined in the form of a so-called anginal stroke, is a biological sign that requires urgent drug treatment.

Because the time at which such attacks occur is unpredictable, patients suffering from angina must have medication on hand to self-medicate when an attack occurs. The forms of these drugs and preparations must meet all kinds of requirements so that the patients themselves can be treated quickly and reliably. For example: (A) The formulation form of these drugs must be such that it can be reliably and easily taken by the patient despite the patient's limited ability to function during an attack.

(B) Substances useful in the treatment of angina are active drugs that generally require precise dosing, so the form of their preparation must be suitable to ensure adequate dosage. No.

(C) Angina attacks are usually accompanied by intolerable pain and extreme anxiety. Functionally, reduced blood flow to the heart during a stroke can cause permanent damage to the heart muscle, which can lead to death in extreme cases. Therefore, in the treatment of angina pectoris, the drugs used must be sufficiently effective within the shortest possible time (within a few minutes).

The requirements listed in paragraphs (A) to (C) above cannot be achieved by injection solutions that can only be administered parenterally, or solutions that can only be administered orally in the form of intravenous drops. . For unaccustomed patients, self-injection parenterally is difficult and impossible during an attack of angina. The respective dosages of solutions for light administration, which must be taken in the form of drops, cannot be determined precisely enough for patients whose capacity for response is very limited. There is a danger in case of overdosing.

It is already known that 1,4-dihydropyridine derivatives act as coronary vasodilators and can be used in the treatment of the above-mentioned diseases. Compounds belonging to this group are poorly soluble and extremely light-sensitive.

These active ingredients are formulated into tablets or dragees (
(see British Patent No. 1,173,862) have a very slow absorption and therefore do not take effect very quickly, so that the high activity of these compounds cannot be fully exploited.

Therefore, there is an urgent need to provide 1,4-dihydropyridine derivatives in a form that can practically fully exhibit their remarkable coronary vasodilatory action.

It is also known that sublingually administered drugs are rapidly absorbed and highly effective (e.g. nitroglycerin) (Sollman, T., “A Man
ual of pharmacology”W, B,
5undersCO0, philadelphia
, Pa., 1957, p. 631).

Therefore, formulations containing 1,4-dihydropyridine derivatives and designed to be absorbed even when administered sublingually are a major therapeutic advance.

This time, at least the following three components, namely (a) 4-
(2'-nitrophenyl)-2,6-cymethyl-3.
5-Dicarbomethoxy1,4-dihydropyridine 1
parts by weight, (b) 6 to 50 parts by weight, preferably 15 to 35 parts by weight of a polyalkylene glycol having 2 or 3 carbon atoms in the alkylene moiety and having an average molecular weight of 200 to 600, and (C) 2 to 35 parts by weight; Lower alcohol containing 4 carbon atoms and 1 to 3 hydroxyl groups 0.5 to 5f
Only instant oral release sublingual soft capsules with coronary vasodilatory action produced by introducing fl parts of the three ingredients into a capsule with a chewable shell containing at least gelatin are produced by the above-mentioned ( This formulation meets the three requirements of A), (B) and (C), and according to this formulation, the active ingredient is absorbed very quickly and the action of the active ingredient is very rapid. It was found that it appears.

[Instant Oral Release Soft Capsules J (ins-ta)]
nt oral-release 5oft caps
ule) means a soft capsule, generally gelatinous, containing a specific measured amount of a flowable pharmaceutical composition, when the patient bites into the capsule, thereby dissolving the contents of the capsule. is released into the patient's mouth, from where the drug is immediately absorbed into the patient's body.

The chewable capsule shell containing at least gelatin can be filled with the above-mentioned components according to a conventional method. For example, the active ingredient (a) as described above is mixed with the polyalkylene glycol (b) and the lower alcohol (C) in either order, and optionally other conventional formulation auxiliaries are added, and the mixture is mixed with at least gelatin. It is made by filling a chewable capsule shell containing:

4-(2”-nitrophenyl)-2,6-cymethyl-3
, 5-dicarbomethoxy-1,4-dihydropyridine exhibits the following advantages: the capsules can be taken by patients immediately by themselves even in the event of a heart attack; The effect wears off within a few minutes. Also, since the amount of the active ingredient contained in the instant oral release capsule is fixed, there is no danger regarding dosing. Moreover, the administration is extremely simple: administration takes place by sublingual administration, so that there is no need, for example, to first count the number of drops of the infusion containing the active ingredient. Such a formulation is not possible at all in this case since the active ingredient is highly light-sensitive.

This light-sensitivity is due to the gelatin-containing capsule shell.
This can be particularly addressed if a white or colored opacifying agent and, more preferably, in addition to the opacifying agent, a non-toxic dye that absorbs light in the wavelength range of 250 to 460 nm is included.

The active ingredient contained in the capsule according to the invention is the well-known formula % dropyridine (UK Patent Specification No. 1 173 862).
(see issue).

The polyalkylene glycols used according to the invention are likewise known. They have an average molecular weight of 200-600. Polyethylene glycol and/or polypropylene glycol having an average molecular weight of 300 to 600 [e.g. bo'), j')s-)I, r
(Hoechst) ,)Ltho-)Lt9■(L
utrol 9■) (BASF>, polydiol (p
olydiols■>(1-1i1S>, Carbowax■) (Unio
It is preferable to use n Carbide).

Among them, polyethylene glycol is particularly preferred.

The lower alcohols with 2 to 4 carbon atoms and 1 to 3 hydroxyl groups used according to the invention are likewise known. Preference is given to using glycerin, propylene glycol or butylene glycol. Among them, glycerin is preferred.

Furthermore, the following can be used as formulation auxiliaries that can be incorporated as necessary: flavoring agents (fragrances), essential oils, preferably peppermint oil, medicinal oil, aniline oil, caraway oil, lemon oil or Eucalyptus oil; sweeteners such as saccharin or saccharin sodium (soluble saccharin) nigericyrrhizinate ammonium salt, etc.

The liquid contents of the capsules according to the invention may also contain small amounts of water.

The capsule shell used in the present invention is in a ready-made state (re
ady-to-use 5tate) te54 to 80
% noceratin, 1 to 36% glycerin (or sorbitol) and 7 to 15% water, and optionally 0.5 to 5% opacifiers such as titanium dioxide: yellow iron oxide, red Contains iron oxides such as iron oxide, brown iron oxide, black iron oxide: or calcium carbonate, preferably titanium dioxide. Such opacifiers can be present in the capsule shell alone, or in combination of two or more.

Furthermore, the capsule shell may contain 250 to 46
It is also possible to include pharmaceutically acceptable dyes that absorb light at wavelengths within the range of 0n-, preferably from 280 to 420n-. As such dyes it is possible to use, for example, food dyes such as Gelbu Orange-S or tartrazine.

Therefore, gelatin compositions for capsule shells can be prepared by, for example,
It is produced by mixing 40-66% pure gelatin with 8-36% glycerin (or sorbitol) and 22-34% water and allowing the mixture to swell for a period of time. Thereafter, if desired, the composition is melted at 60° C. until bubble-free and added with an opaque agent, a clarifying agent and optionally a dye “Gelbe Orange-S”.
(Color Index No. 15985) and optionally further preservatives (eg p-7 minobenzoic acid, rubic acid, benzyl alcohol, etc.) can be incorporated homogeneously into the composition.

Preparation of the formulation for filling the capsule shells described above is as follows:
-(2''-nitrophenyl)-2,6-cymethyl-3,
5-dicarbomethoxy 1,4-dihydropyridine,
This is carried out by dissolving the polyalkylene glycol and a lower alcohol, preferably glycerin, with gentle heating and stirring. The gelatin capsule shells can be filled using known methods such as SCHER
ER), liner (LE INER), two-tone (N
ORTON> or ACCOGEL machine. After filling, capsule.

It can be used immediately after drying.

The glycerin that may be present in the capsule shell may partially migrate into the liquid content of the capsule, and therefore the amount of glycerin in the liquid content of the capsule after preparation is more than 5 parts by weight. Sometimes.

The instant oral release capsules of the present invention are preferably used for sublingual absorption.

The accompanying graph shows the very rapid onset of action of the active ingredient contained in the capsules of the invention, particularly in tragacanth, due to sublingual absorption, when compared to dab administration.

The graph shows the active ingredient, 4, when dosed in various ways to an anesthetized dog with a catheter inserted into the coronary sinus.
-(2'-di-a-phenylene-2゜6-dimethyl-3,
This figure shows the action of 5-dicarbomethoxy-1°4-dihydropyridine.

That is, according to the present invention, 11 G/Kg of the above active ingredient was mixed with 1 part by weight of the active ingredient, 1.67 parts by weight of glycerin, 29Ii parts of polyethylene glycol 400, and 1.6 parts by weight of water.
In the form of a liquid composition consisting of 7 parts by weight of a dog (body lF2O ~
The increase in oxygen tension in the blood of the coronary veins after sublingual administration at 25 kQ) was recorded compared to when 111 g/Kg of the active ingredient was applied to the stomach in micronized form in tragacanth. The graph shows the average value of 5 tests each.

The curves in the accompanying graph clearly demonstrate the rapid onset of action following sublingual administration. The oxygen pressure reaches almost the maximum value in just over 5 minutes, while when administered to the helmet, the oxygen pressure after administration is 60%.
It only reaches the same value after a minute.

Administration of the active ingredient as a solid formulation, eg tablets, dragees, etc., exhibits even less desirable values.

The time course of the photochemical decomposition of the ethanol solution of the active ingredient of the poem when exposed to light with a wavelength of 380 rv is shown in the table below.

4-(2'-nitro7enyl)-2,6-dimethino-3,5-dicarbomethoxy-1 at a wavelength of 360 nm
, 4-Dihydropyridine over time in photodecomposition of an ethanol solution Next, examples of formulations of liquid compositions that can be filled into capsules according to the method of the present invention will be shown.

Example 1 4-(2'-nitrophenyl)-2,6-cymethyl-3
゜5-Cycarbomethoxy 1,4-dihydropyridine (
30.0 g (hereinafter referred to as "Nianidibin") was mixed with 60 g of glycerin (without water) while stirring at 40°C.
, Og, water (distilled) 10o, o8 and polyethylene glycol 400 942. Dissolve in the mixture of Og. Then 1.5 g of sodium saccharin and 2.5 g of peppermint oil are added. This mixture can be mixed intimately and then filled into capsule shells at room temperature.

Each capsule contains 0.34 ml of the above filling.

Therefore, each ingredient is present in the following parts by weight: 1 part (30,0 g) glycerin
2 parts (60,0g) water
3.4 parts (100g) saccharin sodium 0.05 parts (1.5g) peppermint oil
0.08 parts (2.5 g) Polyethylene glycol 400 32 parts (942.0 g') A capsule filling having the following composition was prepared in the same manner as in the above example: Example 2 Nianidivine 3 parts Glycerin 5 parts Water 5 parts mint oil
2 parts Polyethylene Glyfur 400 85 g Example 3 Niani Divin 3 parts Propylene glycol 14 parts Polyethylene glycol 300 82 parts Example 4 Niani Divin 5 parts Butylene glycol 3 parts Lutrol 9■
92 parts Example 5 Nianidivine 5 parts Butylene glycol 5 parts Lutrol 9 90 parts Example 6 27 Edipine 1 part Glycerin
20.3 parts Polyethylene glycol 40035.48 Example 7 27 Edipine 3 parts Glycerin
10 parts Water 10 parts Polyethylene Glyfur 400 77 parts The following examples illustrate methods for producing gelatin compositions suitable for producing capsule shells that can be used in the capsules of the present invention.

Example 8 Granulated gelatin 46. First add 20 kg of glycerin in Nigu. OK1? and then moistened with 34°0 kg of water. This mixture was allowed to swell overnight and then melted without bubbles at about 60"C in a heated container with water. This gelatin composition can be used to make gelatin capsule shells. .

Implementation-9 Granulated gelatin was mixed with 24KFI of glycerin and 30% of water.
Kg and moistened in Negoo. The mixture was allowed to swell overnight and then heated to approximately 60° C. without incorporating air bubbles. The gelatin composition obtained can be used for the production of gelatin capsule shells.

Example 10 Granulated Gelatin 46. First add 20 kg of glycerin in Nigu. OK [? Then, it was uniformly moistened with 34°0 kg of water. The mixture was left to swell overnight and then melted at approximately 60°C in a water heated vessel. Titanium dioxide 0
．． 75 Kg and 0.15 Kg of "Gelbu Orange-S" (Color Index No. 15°985) were added to this gelatin composition. This gelatin composition can be used for the production of gelatin capsule shells. Example 11 42.0 kg of granulated gelatin were homogeneously moistened with 13.0 kg of glycerin in a suitable mixer.

A solution of 15.0 Kg sorbitol and 29.0 Kg water was then added to the mixture and stirred until uniformly moistened.

The mixture was allowed to swell for 12-18 hours and then melted without bubbles at about 60-65° C. in vacuo.

Tartrazine (color index No., 19°14
0.0) was dissolved in water and 1.0 Kg of yellow iron oxide (Color Index No. 77.492) was added to this solution with stirring.

After homogeneously mixing the ground dyes and pigments while melting, the gelatin composition was ready to be used for the production of gelatin capsule shells.

Example 12 Gelatin fish grains 41. OKg to Sorbitol 36゜0Kg
and water23. Knead with OKg solution until uniformly moistened,
and - allowed to swell overnight. The mixture is then heated at 60-65°
0.75 kg of calcium carbonate and 0.75 kg of red iron oxide (color index No. 77.491).
After preliminarily stirring 75 kg in 1.5 kg of water to form Pase F, it was added to this melt and treated until it became homogeneous. As soon as the composition was free of air bubbles, it could be used for the production of gelatin capsule shells.

Next, a specific example of the method for producing the instant oral release soft capsule of the present invention will be shown.

Example 13 - So-called dipping method: A suitably shaped dipping mold (pin) is dipped into an air bubble-free gelatin composition having a temperature of about 60°C.

When the dipping mold is removed, the gelatin composition solidifies on the pins to form a rubbery skin. Excess gelatin composition is dripped off. After removing the elastic capsule molds from the pins and suitably cutting the necks of the capsule shells, they are filled with the filler containing the active ingredient by means of a suitable syringe or infusion pump, and the mouth is then filled with a droplet of the gelatin composition. Seal. The filled capsules can be used as is after drying in a circulating air dryer or drying cylinder to a residual moisture content of 7 to 15%. This method can be performed manually or semi- or fully automatically.

Example 14 - Punching method (PunchingPr
oc-Friend: SCHERER and LEIN
In the ER) method, a liquid gelatin composition at about 60°C is
Apply evenly onto a spreader box on several air-cooled cylinders. The gelatin composition is solidified to form two rubbery strips which are fed to a rotary gouer rotating in opposite directions. A pocket-like structure is continuously formed between the rotary and the guide.
The bottom and sides are welded first. The filling containing the active ingredient is introduced under pressure by means of a metering pump, the top of the filled capsule is welded and removed.

After drying in a circulating air dryer or drying cylinder to a residual moisture content of 7 to 15%, the capsules are ready for use.

Example 15 The principle underlying the Norton method is
It is very similar to the principle of Ra law. However, a rotary guide is not used for molding, filling, and punching the capsule, and instead, two plate-like lenses are used.
The difference is that a cular-shaped punching die is used. These punching dies rhythmically press into and apart from each other. Jerk the two gelatin strips from top to bottom in the same rhythm, thus forming, filling and sealing or punching the capsules. Thereafter, the capsules are dried in a conventional manner.

Example 16 The Accogel method is also a rotary gouy method. However, contrary to the shape method, the capsules are manufactured under vacuum.

A gelatin strip is passed over a rotary gouer and drawn by vacuum into individual molds.

The filling is introduced into these cavities corresponding to half of the capsule shell. A second gelatin strip is moved over the contact roller and applied by pressure to the filled half to form the lid of the other capsule shell half and punch the capsule.

As soon as the vacuum is removed after sealing the capsule shell, the bottom half contracts a little, while the top half expands a little. In this way, a capsule is formed which is divided into nearly identical halves by a punched seam. Schierer and/or
In the -ton method, a punching seam separates the capsule shell into exactly equal halves. After drying, the capsules are ready for use.

[Brief explanation of drawings]

The accompanying drawing is a graph comparing the efficacy of various dosage forms of the active ingredient on anesthetized and coronary catheterized dogs. Continuation of page 1 Priority claim @ February 29, 1972 ■West Germany (D
E)■P 2209526.7 Procedural amendment (method) % formula % 3゛, Relationship with the case of the person making the amendment Patent applicant address Leverkusen, Federal Republic of Germany (no street address) Name Bayer Akchengesellschaft 1982
February 22, 2019 (shipment date) 6. Drawing subject to amendment 7. Contents of amendment as attached.

Claims (1)

[Scope of Claims] At least the following three components, namely: (a) 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine 1 weight (b) 6 to 5011 parts of a polyalkylene glycol having 2 or 3 carbon atoms in the alkylene moiety and having an average molecular weight of 200 to 600, and (C) containing 2 to 4 carbon atoms and 1 A coronary vasodilatory effect characterized by introducing three components of 0.5 to 5 parts by weight of a lower alcohol having three hydroxyl groups into a capsule having a chewable shell containing at least gelatin. A method for producing an instantaneous oral release sublingual soft capsule.