HU203477B - Process for producing antiflatulant pharmaceutical compositions containing activated poly-dimethyl-siloxane in form of solide dispersion - Google Patents

Abstract

An oral pharmaceutical prepn. against flatulence contains poly-di:methyl siloxane dispersion (dimethicone) as a disperse phase and a water soluble carrier which melts at 40-120 deg. C without decomposition, as a continuous phase. 10-25 wt.% of a pref. molten mixt. is added to the melted carrier. This mixt. contains medically acceptable natural and synthetic bodying, crosslinking and thickening agents pref. polyvinyl chloride, polyvinyl-acetate dextran, micro-crystalline cellulose, polyacrylic acid, poly-vinyl-pyrrolidone and/or an inorganic stabiliser, tricalcium phosphate, calcium-sulphate-hemi hydrate, or calcium-hydrogen-phosphate. 5-30 wt.% activated poly-di:methyl siloxane is added to the prepd. mixt. Cooling and solidification is followed by comminution of the mixt. Other active cpds., excipients and/or additions may also be added for oral admin. of this prod

Description

FIELD OF THE INVENTION The present invention relates to a new type of active pharmaceutical composition containing an activated polydimethylsiloxane with increased activity and antiflatulant activity.

Poly (dimethylsiloxane) (internationally accepted by the World Health Organization as dimethicone; hereinafter referred to as "dimethicone"), which was first produced in U.S. Patent No. 2,441,098. U.S. Pat. No. 5,123,123, is now widely used in the therapeutic treatment of the gastrointestinal tract. Due to its anti-foaming, anti-foaming properties, it can be used effectively to reduce gut bloating and bloating. It is also used as an adjuvant in the treatment of gastric acid neutralization, as well as in gastroscopic and gastrointestinal radiography to reduce the shadows caused by intestinal gases.

To eliminate complaints or general symptoms caused by the presence of increased amounts of gas in the gastrointestinal tract (satiety eating in the abdomen, bloating, occasionally colic-like pains, and sometimes pseudoanginal symptoms due to diaphragmatic depression) At a dose of 20-120 mg.

Dimethicone itself is an oily viscous liquid which is most commonly used as a powder carrier in pharmaceutical formulations. Powdered antacids are often used as powder carriers; the activity of the antacid in such combined formulations is very advantageous, probably due to the fact that due to the foam-reducing effect of dimethicone, the gas bubbles break down and thus the acid-binding agent is more able to mix with and react with the acidic weed.

Thus, combining dimethicone in powder form with the mostly activated form with powdered antacids is beneficial in terms of antacid activity, but it is known and considered a major problem with these combinations that combining with powdered antacids adversely affects the stability of [cf. Rezak, M., J. Pharm. Sci. 55, 538 (1966); Cox, H.L.M., Nijland, G.J .: Pharm. Weekblad 777, 973 (1976); Maxsoud, E etc .: Manuf. Chemist, Aerosol News, 47, 35 (1976)].

To overcome the processing difficulties of liquid viscous dimethicone, U.S. Patent No. 20,573,239. In German patent application, a method is proposed which emulsifies activated dimethicone in a melt of relatively thermostable sugar alcohol in molten sorbitol at a temperature of about 130 ° C and then, after cooling the melt, crushes the solidified solid emulsion. In this way, solid, water-soluble granules containing the activated dimethicone are prepared. While not only advantageous in terms of technological further processing, this solution is rather cumbersome, costly, and energy intensive and risky due to the high temperature required (130 < 0 >C); at such high temperatures, an emulsion with a sufficiently fine dispersion is difficult to produce, and the final product is difficult to grind due to the high strength of the solidified sorbitol melt.

In our studies to overcome these drawbacks of known methods, it has been found that the reduction in the efficiency of activated dimethicone applied to a powder carrier is related to the adsorption of the activated dimethicone in the capillaries of the powder carrier; this adsorption results in a progressive deterioration of the antifoaming effect. Thus, the addition of activated dimethicone impregnated on porous filter paper into a foamed system did not result in any foam reduction effect, even if the chunks of paper impregnated with activated dimethicone were reduced to a very As size.

In addition, the anti-foaming effect is related to the effect of the anti-foaming meshes on the interfacial tension and also to the degree of dispersion that may be available; this is also shown by our experience that the finer the dispersion of activated dimethicone, the better the anti-foaming effect is, as shown by the results of the modified Rezak foam test (shown in more detail below). Activated dimethicone (prepared as in Example 3), used in fine dispersion in stabilized form, has a significantly higher foam-reducing activity than activated dimethicone directly adsorbed on the powder, both at 10-10% concentration with aluminum hydroxide powder.

A fine dispersion emulsion can be very difficult to form in aqueous systems without the use of an emulsifier. However, the surfactant emulsifiers act in the opposite direction to that of dimethicone Avan. Therefore, it appears that with the conventional type of active compound, activated dimethicone applied to a solid carrier, the delivery of Avan fine dispersion emulsion into the gastrointestinal tract and the maintenance of the unchanged potency of the activated dimethicone in pharmaceutical formulations cannot be achieved.

However, in our experiments, the surprising and novel result was that both difficulties can be eliminated and the cited 20 57 239. These drawbacks of the process of the German patent application can also be overcome by mixing the activated dimethicone in a melt of a water-soluble carrier which is solid at room temperature but can be melted at 40 ° C to 120 ° C without decomposition. The resulting mixture is cooled to a solid emulsion upon cooling, the active dispersed phase of which is the activated dimethicone and the outer continuous phase of the solidified carrier. Suitable carriers for this purpose are organic or inorganic materials which meet the above physical conditions

They are active in the melt of which the activated dimethicone is well emulsifiable and which are biologically inactive at any given dose and do not exert any undesirable biological effect. Examples of suitable materials suitable melting polyethylene glycols, urea, and hydrous crystalline inorganic salts such Najs ^ lO ^ O, MgSO ₄ * 7H ₂ O and / or A ^ SO ^ ieHjO mentioned.

However, in order to form a finely dispersed emulsion of dimethicone in the molten state of these materials, which retains this fine dispersion after cooling and solidification, it is added to the melt of the outer phase carrier, a cross-linking hydrophilic polymer, or a high molecular weight material such as polyvinyl chloride, polyvinylpyrrolidone, dextran or the like. This additive, due to its physical or chemical properties, for example through cross-linking between macromolecules, forms a framework in the solidifying melt of the carrier that provides a gelatinous structure and a certain degree of solidity of the solid outer phase formed without interrupting the melt phase.

Thereafter, when the activated melting mixture is thoroughly homogenized by mixing the melt mixture thus obtained in an appropriate amount and the molten mixture is cooled and solidified, a finely dispersed solid emulsion is obtained in which a greater amount of the as in conventional dimethicone formulations known hitherto, while maintaining the stability of efficacy over time, as illustrated by the results of the modified Rezak foam test in Figure 1.

The present invention thus provides a novel antiflatulant oral pharmaceutical composition comprising a new type of activated polydimethylsiloxane (dimethicone) as a dispersed phase and a water-soluble carrier which is a meltable, water-soluble carrier in a solid dispersion, characterized in that 10-20% by weight of a solid, water-soluble, preferably pre-melted, water soluble carrier, preferably at 40 ° C to 120 ° C, of a pharmaceutically acceptable natural or synthetic skeletonizing and / or crosslinking, viscosity enhancing macromolecular excipient, preferably polyvinyl chloride; polyvinyl acetate, dextran, microcrystalline cellulose, polyacrylic acid, polyvinylpyrrolidone and / or inorganic solidifying agents, e.g. bentonite, tricalcium phosphate, calcium sulfate hemihydrate or calcium hydrogen phosphate are mixed and the molten mixture is mixed with 5-30% by weight of activated polydimethylsiloxane to form a fine dispersion, which is cooled and solidified and then formulated for oral administration.

Activated dimethicone used as an active ingredient in the pharmaceutical compositions of the present invention is a liquid polydimethylsiloxane having a viscosity of at least 3 · 10 · ⁴ m ² / s and containing 4 to 7% by weight of fine silica (cf. Martindale, Extra Pharmacopoeia, 28th Ed. ., The Pharmaceutical Press, London, 1982,1068).

In the process of the present invention, it has been observed with respect to excipients admixed to the molten outer phase for solidification or crosslinking, that these solids, when incorporated into the molten phase in the prescribed manner prior to emulsification of activated dimethicone, when incorporated into the melt phase, the melt fills their capillary cavities so that they are no longer able to absorb the activated dimethicone.

In addition, it has been surprising and novel to observe that if the surface of the particles incorporated in the melt is close to a regular spherical surface, e.g. in the case of polyvinyl chloride (Solvic 122) and polyvinyl acetate (Mowilith), the antifoam of the melt-emulsified activated dimethicone is further stored or stored. slightly increased after heat treatment, as shown by the results of our modified Rezak foam test as shown in Figure 2. This phenomenon is probably due to the fact that, at a temperature of about 60-70 ° C in the process of the invention, the dimethicone is significantly distributed on the surface of the solid excipient particles, which further inhibits the adherence of the foam lamellae (cf. Figure 3).

Practical embodiments of the process of the invention are illustrated by the following examples:

Example 1

The following materials are used:

polyethylene glycol 6000 60 g polyvinyl chloride (Solvic 122) 15 g activated dimethicone (Simethicone Q7-2243 LVA Compound,

Dow Corning, USA) 25 g

The required amount of polyethylene glycol is melted at 60-70 ° C. This melt is charged to a high-speed homogenizer and then mixed with the required amount of polyvinyl chloride. To the still warm, densely flowing melt, add about a. Activated dimethicone, preheated to 70-80 'C, and homogenized by stirring for 5 minutes. The emulsion thus prepared is poured onto a still solid surface. In this way, after solidification, a crushable solid mass is obtained. After shredding, it is sieved through a 1 mm mesh sieve and, after mixing with suitable pharmaceutical excipients (binder, lubricant), filled into hard gelatin capsules or tabletted so that the amount of activated dimethicone is 20-120 mg per dosage unit.

HU 203 477 Β

Example 2

The following materials are used:

sodium sulfate crystal (Na 2 SO ₄ »10H ₂ O), 60 g tricalcium phosphate, 15 g of activated dimethicone 25g

The crystalline sodium sulfate is carefully melted, the melt is charged to a high speed mixer, and tricalcium phosphate [Ca ₃ (PO 4) ₂ ] is added immediately in small portions. activated dimethicone and homogenize for 5 minutes. In the following, the procedure of Example 1 is followed.

Example 3

The following materials are used:

sodium sulfate, crystalline 70 g microcrystalline cellulose (Avicel PH 101) 25 g activated dimethicone 5 g

The preparation was carried out as described in Example 2 except that Avicel PH 101 microcrystalline cellulose was used instead of tricalcium phosphate.

Example 4

The following materials are used:

sodium sulfate, crystalline 47 g urea 10 g polyacrylic acid (Carbopol 934) 15 g activated dimethicone 28 g

The preparation was carried out as in Example 2, except that polyacrylic acid (Carbopol 934; Serva Feinbiochemica, Heildelberg) was added to the melt mixture instead of tricalcium phosphate.

Example 5

The following materials are used:

sodium sulfate, 33 g crystalline magnesium sulfate crystals (MgSO ₄ '7H ₂ O) 30 g Dextran 12 g, 25 g of activated dimethicone

The mixture of sodium sulfate and magnesium sulfate is carefully melted by heating and immediately homogenized in the hot melt with the prescribed amount of dextran. In the still hot melt mixture, the activated dimethicone, preheated to 70-80 ° C, is emulsified with stirring for 5 minutes. In the following, the procedure of Example 1 is followed.

Example 6

The following materials are used:

sodium sulfate, crystalline 30 g of magnesium sulfate, crystalline 30 g of polyvinylpyrrolidone 15 g of activated dimethicone 25 g

The preparation was carried out as in Example 5, except that polyvinylpyrrolidone was used instead of dextran.

To prepare the compositions of the Examples, VH. Urea, crystalline sodium sulfate, crystalline magnesium sulfate, polyvinylpyrrolidone, U.S.P.-N.F. XVI. of tricalcium phosphate according to the standard. dextran (Ch. 41, molecular weight: 70-100,000) produced by Biogal Pharmaceuticals was used.

Various static and dynamic foam tests have been used to investigate the antifoaming properties of formulations containing activated dimethicone. For the study of the antifoam-reducing activity of the high-potency stabilized formulations in the examples above, Rezak, M., 1966, J. Pharm. Sci. 55, 539 (1966)], using the following procedure:

100 ml of a 0.2% sodium lauryl sulphate solution are poured into a 250 ml measuring cylinder with an internal diameter of 3.2 cm. This solution is shaken until the upper level of the foam formed reaches 150 ml, i.e. 50 ml of foam is formed. The sample containing the antifoam substance to be tested is then added and the measuring cylinder is rotated 5 times in a rotation of 180, such that each inversion takes 1 to 1 second. Flips (not shakes!) Should follow each other continuously without waiting time. After the fifth inversion, wait 15 seconds, then invert the measuring cylinder again and read the foam volume without delay. This value is considered as the "O" time of the test. Thereafter, the decrease in foam volume as a function of time is recorded.

The following examples illustrate the preparation of formulations containing the active compounds which are usually administered together with activated dimethicone.

Example 7 aluminum hydroxide 200 g magnesium oxide 150 g Carboxymethylcellulose sodium 5g 1% aqueous carboxymethyl cellulose -sodium hydroxide 100 ml activated dimethicone dispersion (as in Example 1) 100 g potato starch 25g talc 12g magnesium stearate 7g

HU 203 477 Β

Aluminum hydroxide and magnesium oxide were sieved through a 0.32 mm mesh sieve, mixed and kneaded with 1% carboxymethylcellulose sodium solution.

The wet mass was granulated by passing through a 2.0 mm mesh sieve, then dried and granulated through a 0.80 mm mesh sieve.

To the product so granulated, containing the antacid active ingredients, the required amount of the 0.64-1.00 mm mesh fraction of the dispersion prepared in Example 1 is added together with the disintegrating starch and lubricants (talc and magnesium stearate). and then compressed into tablets weighing 05 g. The tablet formulation thus prepared contains 25 mg of activated dimethicone per tablet with antacid agents.

Example 8

Avicel PH 101 400 g Pancreatin 150 g Activated Dimethicone Dispersion (Example 5) 300 g

The powdered ingredients (Avicel PH 101, pancreatin) were sieved through a 0.32 mm mesh sieve and then mixed with a 0.64-1.00 mm particle size dispersion containing activated dimethicone and pressed to 0.85 g weight. The dragee kernels are converted by spraying several times with a 1% acetone solution of cellulose acetate phthalate in an enteric coated dragee-resistant dragee. The enteric solvent dragee thus prepared contains, in addition to 75 mg of activated dimethicone, an antiflatulant containing 150 mg of pancreatin per tablet. digestive enhancer with a combination of active ingredients.

Example 9 Phenolphthalein 150 g Papaverinium chloride 40 g

1.5% aqueous solution of carboxymethylcellulose sodium in 35 ml of activated dimethicone dispersion (as in Example 5) 160 g menthol 7.5 g anise oil 1.6 g lemon oil 1.2 g lavender oil 1.2 g sage oil 1 , 0 g clove oil 1.0 g talc 7.0 g magnesium stearate 4.0 g

Phenolphthalein and papaverinium chloride were sieved through a 0.32 mm mesh sieve, mixed, kneaded with 15% carboxymethylcellulose sodium solution and passed through a 2.0 mm mesh sieve. The wet granulate was dried and regranulated on a 1.0 mm mesh sieve and mixed with the activated dimethicone dispersion prepared in Example 5. Menthol is dissolved in a mixture of vegetable essential oils and sprayed onto the solid mixture in small portions while stirring. Finally, the lubricants passed through a 0.32 mm mesh sieve are added to the mixture, and the homogeneous mixture is filled into hard gelatin capsules of appropriate size such that one capsule contains 0.375 g of the mixture. The resulting drug capsule is a combined preparation containing 40 mg of activated dimethicone per capsule and other laxative, gallbladder, antispasmodic and mild antiseptic agents.

An in vivo study of the efficacy of activated dimethicone in animals has been developed (Sátory, E., Plachy, J., Szentmiklósi, P., and Rácz, I. Acta Pharm. Hung. 53: 25-27 (1983)].

Rats of both sexes fed a normal diet are dosed orally with 2 ml of 25% Tween 20 solution and then injected with 5 ml of air into the animals via a syringe. Half, one, one and a half hours and two hours after the treatment, the animals are sacrificed by cephalic slaughter. The abdominal cavity is inoculated, the stomach and intestine are stretched and the progress of the gas bubbles is measured in cm. One group of animals was administered orally 15 minutes after treatment with 0.4 ml of 0.1% activated dimethicone emulsion, and the other group with 0.4 ml of 0.1% activated dimethicone emulsion stabilized according to Example 3 of the invention, and killing the animals at the same time as the control group treated with Tween 20 alone; saturation of the gastrointestinal tract with gas bubbles is recorded in the same way in cm.

Examining the efficacy of the fine dispersion emulsion prepared to stabilize the in vitro anti-foaming effect by an in-vitro antifoam test, it was found that the formulation stored at 40 ° C for 6 months maintained its efficacy to the full (see Figure 2). even less than half of its original size on powdered media.

The surprising and novel result observed in the in vitro studies is that not only the physical stability can be increased by the use of fine dispersion solidifying external phase emulsion technology, but also the antifoam activity can be multiplied (see Figure 1), in vivo studies (Table I). The results shown in Table I show that the effect of activated dimethicone is much more pronounced in the stabilized compositions of the present invention; it outperforms the action of an emulsion of activated concentration of activated dimethicone of known concentration in both time and potency. The composition according to the invention acts locally for 15 minutes and has a local effect on the stomach and the stomach. doudenum eliminates bubble bubbles much faster and more perfectly.

HU 203 477 Β

Table I

Gas bubble saturation measurement in rat gastrointestinal tract [n-10] [Acta Pharm. Hung. 53.25 to 27. (1983)]

Time (hours) control Activated dimethicone The 0.1% emulsion stabilized according to the invention (Example 3) is an emulsion containing 0.1% activated dimethicone 05 stomach and 60 cm small intestine full stomach and 70 cm small intestine full stomach and 15 cm intestine is empty, the gut is full 1 stomach and intestines full stomach and 15 cm intestine empty all the way full stomach and 35 cm intestine is empty and full 15 stomach and 30 cm intestine empty, full on stomach and 35 cm intestine empty, full on stomach and 55 cm intestine empty, longer intestine full 2 stomach and 65 cm intestine empty, full on stomach and 65 cm intestine empty, full on stomach and intestine empty throughout

PATENT CLAIMS

Claims (5)

PATENT CLAIMS CLAIMS 1. A process for preparing an antiflatulant oral pharmaceutical composition containing activated polydimethylsiloxane (dimethicone) as a dispersed phase and a water-soluble carrier which is a meltable, water-soluble carrier in a solid dispersion, characterized in that 10-20% by weight of a water-soluble, preferably pre-melted, water-soluble carrier, preferably at or between 'C and 120' C, with a pharmaceutically acceptable natural or synthetic skeletonizing and / or crosslinking, viscosity enhancing macromolecular excipient, preferably polyvinyl chloride, acetate, dextran, microcrystalline cellulose, polyacrylic acid, polyvinylpyrrolidone and / or an inorganic hardener, preferably tricalcium phosphate, calcium sulfate hemihydrate or calcium hydrogen phosphate, and in the molten mixture, 5-30% by weight of activated polydimethylsiloxane is mixed into a fine dispersion, then cooled and solidified, and optionally 40 other active ingredients which can be used in common with polydimethylsiloxane , preferably antacid, laxative, bile expectorant, enzymatic and / or conventional pharmacist. by mixing excipients, preferably a solid carrier and a lubricant, into a 45 formulation for oral administration. 2. A process according to claim 1, wherein the activated polydimethylsiloxane is a liquid poly (dimethylsiloxane) having a viscosity of at least 3 · 10 · ⁴ m ² / s and having a fine particle size of 4 to 7% by weight. dimethylsiloxane). 3. The process of claim 1 wherein the solidified and comminuted dispersion is admixed with a solid carrier and lubricant and filled into a hard gelatin capsule to form an encapsulated composition containing 20120 mg of activated polydimethylsiloxane per capsule. . The process according to claim 1, wherein the solidified and comminuted dispersion is mixed with a solid carrier and / or other pharmaceutical excipient and compressed into tablets containing from 20 to 120 mg of activated polydimethylsiloxane. 5. A process according to claim 1, wherein the solidified and comminuted dispersion is formulated with conventional active ingredients, preferably antacid, laxative, gallbladder, enzyme-acting agents, suitable for use with the polydimethylsiloxane. carrier, sliding, disintegrating excipients in the form of tablets, capsules, flavored granules or any other conventional oral or human agent. veterinary dosage form.