DE1965133A1 - Bile acid and triglyceride absorbing resins - Google Patents

Abstract

Bile acid triglyceride absorbing resins. Compsn. containing at least one synthetic, non-toxic enzyme resistant, cross-linked, ionisable amine polymer having a microporous structure, a swelling capacity below 5 ml/g, a water content below 50% (after equilibration at 25 degrees with H2O satd. air), and a particle size of 0.0001-0.5 mm, are of use as bile acid and triglyceride binders and lipase inhibitors. Preferred cpds. are dialkylaminomethyl subst. polystyrenes with 5-20% cross linkage.

Description

Process for the manufacture of pharmaceutical preparations The invention relates to a process for the production of new pharmaceutical preparations which contain nitrogenous polymers and - among other things - bile acid binding and Have triglyceride binding effects.

Such polymers are known (see e.g. British Patent 929 391) in orally administrable pharmaceutical preparations for binding bile acids Use in the digestive tract and to lower blood cholesterol0 One such preparation is, for example, cholestyramine, a strongly basic ion exchanger in chloride form, used as a treatment for pruritus associated with biliary obstruction is in trade.

BS has been found to be certain synthetic, non-toxic, ionizable Amino group-containing polymers bind bile acids more strongly in an in vitro experiment than the cholestyramine.

In addition, they also show a triglyceride-binding effect, the for which cholestyramine was previously unknown. These polymers, below as "active ingredients" are, in contrast to cholestyramine have one macroporous structure and a swell volume of less than 5 ml / g in water. To Equilibration with air that has 100% relative humidity at 25 °, they have a moisture content of less than 50 %9. Differentiate thereby they differ from the active ingredients of British patent 929 391, which are under the same Conditions show a moisture content higher than G5%.

The active ingredients also inhibit the lipase activity with respect to the bound Triglycerides and lower cholesterol and triglyceride levels in an in vivo experiment of the blood to an adequate extent. As lipase inhibitors, the active ingredients of of particular value if they are incorporated into diet genes for humans or animals, through which weight gain can be controlled. The invention Preparations can therefore be used as remedies against obesity and against other diseases which are associated with excessive fat absorption in the body.

The simultaneous presence of bile acid binding, triglyceride binding and lipase-inhibiting effect is a particular advantage of the active ingredients according to the invention compared to all known similar substances.

The invention relates to a process for the production of pharmaceuticals Preparations, characterized in that at least one synthetic, not toxic, cross-linked, ionizable amino groups that are inert to pre-digestion enzymes containing polymer with a macroporous structure and a swelling volume of less than 5 ml / b in water, which after equilibration with air, which is 100% at 25 ° Relative humidity has a moisture content of less than 50 %, optionally together with at least one solid, liquid or semi-liquid, physiologically harmless auxiliary or carrier and optionally together with at least one other active ingredient in a suitable dosage form brings.

The invention also relates to pharmaceutical preparations which are obtainable by the process according to the invention, and their use to achieve a bile acid-binding, triglyceride-binding, lipase-inhibiting, Cholesterol-lowering and / or triglyceride-lowering effect in living beings.

Preferred active ingredients are polymers based on polystyrene, in particular those with the following schematic basic structure: In this formula, Y is H or CH2Z, and Z is an ionizable amino group. An ionizable amino group is understood to mean an amino group which, when exposed to an acid, forms a substituted ammonium salt and, when exposed to a quaternizing agent, forms a quaternary ammonium salt. The active ingredients can accordingly be in the base form (as primary, secondary or tertiary amines), in the form of ammonium hydroxides or in the form of acid addition or quaternary ammonium salts. The indices a, a and c indicate the proportion 1 of the corresponding monomers in the structure of the active ingredient. The value for a is usually between 1 and 20, that for b between 60 and 94%, and that for c between 5 and 20%.

The index c indicates the Vornetzter content (content of divinylbenzene). It is surprising that polymers of this chemical type with such a high crosslink content show the stated effects as claimed in British Patent 929,391 that crosslinking above about 5% seriously reduces the effectiveness of these resins impair. The index n is a measure of the degree of polymerization, where because of the three-dimensional meshing, precise tooth values for n are not specified can: in any case, n is greater than about 1000.

The group Z can therefore be one of a primary, secondary or tertiary amine derived amino group of the partial formula @ 2 @ - or one of a quaternary Ammonium base derived ammonium group of the partial formula R3N + X- mean, in which the R radicals can be identical or different and are preferably H, alkyl or hydroxyalkyl each with in particular 1 - 5 carbon atoms, especially methyl, ethyl or 2-hydroxyethyl, mean. Active ingredients in which two of the radicals 2 each have a methyl group and the optionally present third radical R is a hydrogen atom or likewise a Mean methyl group are particularly preferred.

The associated anion X- means CH- or an anion of any physiologically harmless acid. Usually the active ingredients are called chlorides administered. However, it is also possible, for example, to use the corresponding sulfates, phosphates, e.g. primary (dihydric), secondary (monohydrogen) or tertiary phosphates, bicarbonates, Carbonates, formates, acetates, propionates, malonates, succinates, malates, tartrates, Citrates, maleates, fumarates, ascorbates or with the anions of succharin or of Use amino acids such as aspartic acid, glutamic acid loaded polymers.

The active ingredients present in quaternary form are particularly suitable the chlorides. If these are administered in very high doses, however, they can Hyperchloremic acidoses occur, with the concentration of chloride ions in the serum increases, the concentration of bicarbonate ions in the serum decreases, an increased Excretion of chloride ions in the urine occurs and the pH of the urine decreases will. These undesirable phenomena can be reduced to a minimum, if, if active ingredients are administered in very high doses, quaternary Chlorides used in a mixture with other quaternary salts, e.g. together with bicarbonates, Phosphates or citrates.

The active ingredients are produced by conventional polymerization, with a relatively high crosslinker content (0 to 20, preferably G to 8 percent by weight) and works in the presence of inert substances that affect the macroporous structure of the polymers cause.

One of the basic anion exchangers available on the market basically all those as active ingredients that have a macroporous structure own. For example, those protected under the following can be used Products available under commercial names: Amberlite IRA-68, Amberlite IRA-93, Amberlite IRA-401, Amberlite IRA 401-S, Amberlite IRA-900, Amberlite IRA-904, Amberlite IRA-910, Amberlite IRA-911, Amberlite XE-233, Amberlyst A-21, Amberlyst A-26, Amberlyst A-27, Amberlyst A-29, De-Acidite FFIP, De-Acidite HJP, De-Acidite KMP, De-Acidite MJP, De-Acidite NIP, De-Acidite PIP, Duolite A 101 D, Duolite A 101 D Hi, Duolite A 102 D, Lewatit MP 60, Lewatit MP 62, Lewatit MP 64, Lewatit MP 500, Lewatit MP 600.

These commercial products are not expedient in the form in which they are commercially available, used according to the invention, but in washed, optionally dried and optionally ground form, so that some of the original key figures specified by the manufacturer (e.g. water content, bulk weight, Grain size, capacity) no longer apply.

In particular, two commercial preparations have proven to be active ingredients, which are hereinafter referred to as "Active ingredient A" and "Active ingredient B" and whose properties (characteristics) compared to those of cholestyramine are summarized in the following overview: Cholestyramine active substance A active substance B Amine type quaternary tertiary quaternary Content of ver 2%>5%> 5% Netzer (Divinylbenzene) Capacity (dry) 2.9 mew / g 4.2 mew / g 3.6 mew / g Source volume in Water 21 ml / g 3.6 ml / g 3.25 ml / g Bulk weight (dry) 440 g / l 230 g / l 275 g / l Water consumption> 63% *) 28% 36% at 25 ° *) according to Brit. U.S. Patent 929,391.

These characteristics were determined as follows: Capacity: a) Polymers of the quaternary amine type: 1 g of the dry polymer is mixed with 5% aqueous X @ OH converted into the OH form until no more chloride can be detected in the filtrate. Man Washed neutral with water, exchanged in a column with 40 ml of 10% NaCl solution the OH anion against the Cl anion and washed with 100 ml of water. Titrate in the filtrate the base content with 0.1 N GCl, with 1 ml of consumed HCl of a capacity of 0.1 milliequivalent (meq) per gram.

b) Tertiary amine-type polymers: 1 g of the dry polymer stirred with 50 ml of 1N XaOH for 30 minutes, then washed alkali-free with water and 10 ml of HCl are added in a volumetric flask. Make up to 100 ml with water, left to stand for 16 hours with occasional shaking and titrated with 0.1 M NaOH against methyl red.

Swelling volume: 1 g of the dry polymer is used with a sufficient Amount (10 - 30 ml) of water left to stand for 2 hours with occasional shaking. The volume is then determined in a measuring cylinder after vibrating for 1 minute of the polymer under water.

Water absorption: 4 g of the at 60 ° under reduced pressure to constant weight dried polymers are placed on a watch glass in a desiccator at 25 ° a exposed to a water-saturated atmosphere until no further weight gain occurs. The water absorption is given as a percentage of the total weight.

Compared to cholestyramine, active ingredient = k shows twice as large, active ingredient B a 30% higher lipoid binding in vitro. ("Lipoids" are understood here to mean the sum of those substances which are bound by the polymers made from a mixture of triglycerides and ox bile according to the test methodology given below). The bile acid binding of active ingredient A in vitro is about the same as that of cholestyramine; the bile acid binding of active ingredient B is increased by about 50-60% compared to that of cholestyramine. Eggstein and Kreutz, Klinische Wochenschrift, 44, 262-267 (1966)) were the following cholesterol or. Triglyceride level reductions achieved: Cholesterol triglycerides % Decrease% decrease Cholestyramine 19 6 Active ingredient A 22 21 It was also found that the active ingredients have a favorable effect on the lipid content of the liver. After homogenization of the frozen liver samples and extraction with chloroform / methanol (methodology cf. Sperry, Methods of Biochemical Analyzes, 2, 83 (1955)), the total cholesterol and triglyceride content was determined determined by the above methods. With active ingredient A, the cholesterol content was reduced by 21% and the triglyceride content by 36%.

;) The substances described here have two biological points of attack. They intervene in the enterohepatic cycle of gallic acid and reduce it their reabsorption. This process is secondary exactly as with cholestyramine to a reduction in the cholesterol level. In contrast to cholestyramine you can but they are of the same order of magnitude as triglycerides in the in vivo model Bind cholesterol directly and prevent it from being absorbed. This leads to a reduction the triglyceride level of the blood and is of great importance for lipid metabolism in the liver.

It has also been found that the effectiveness of the active ingredients is crucial depends on their grain size. The smaller this is, the greater the lipoid binding capacity; the ability to bind bile acids, on the other hand, is less dependent on the grain size. It is therefore possible according to the invention by using a certain grain size the ratio of lipoid binding to bile acid binding to a desired level to adjust. For the in vivo experiment, this means that the Verjiäl tuis of Cholesterol lowering to triglyceride lowering within certain limits can vary or adjust, depending on the grain size for the to be administered Selects preparation.

The grain size is expediently less than 0.1 mm; usually be Active ingredients with particle sizes between 0.0001 and 0.5 mm, preferably between 0.001 and 0.2 mm.

Active ingredients that contain larger grain sizes than O, o are also used effective according to the invention, but generally weaker than the active ingredient of smaller particle sizes.

The influence of the grain size can be seen, for example, when using different degrees of fineness of the active ingredient A: grain size (mm) 0.2 - 0.36 0.125 - 0.2 0.024 - 0.125 Lipoid binding 0.35 1.22 2.12 (g lipoids per g active ingredient) Bile acid binding 0.33 0.55 0.56 (g bile acid per g active ingredient) Lipase inhibition (%) 15% 61% 63% These activities were determined as follows: Lipoid binding: 2 g of triglyceride mixture (olive oil) are emulsified in 80 ml of water with the addition of 1 g of ox bile (Fel tauri) while stirring vigorously. 1 g of active ingredient is then left in the emulsion for 30 minutes with gentle stirring, pH 6. It is filtered off with suction, washed with water and dried at 60 ° under reduced pressure to constant weight. The increase in weight corresponds to the total amount of lipids bound by the active ingredient.

Bile acid binding: one works according to the above experimental arrangement, but without the presence of triglycerides.

The weight gain is used as a measure of that bound by the active ingredient Amount of bile acids considered.

Lipase emulsion: 100 mg of olive oil are emulsified in 20 ml of a 0.1 M Borate buffer of pH 8.5, the additional 0.3% albumin, 0.2% sodium deoxycholate and contains 0.2% CaCl2. 100 mg of active ingredient are added. The reaction is 0.1 mg lipase from porcine pancreas is started and runs with constant stirring at 30 ° away.

After 1.2 and 4 hours, 5 ml each are titrated to PLT 11.0.

A blind test that does not contain any active substance is running at the same time.

From the comparison of the results of the inhibition test and the blind test the percentage inhibition is calculated.

The lipase inhibition is also dependent on the concentration ratio Active ingredient: triglyceride. It can, if larger amounts of active ingredient are added, also achieve higher values. So with 50, 200 or 400 (instead of 100) mg of active ingredient A (grain size 0.125 - 0.2 mm) according to the specified method, inhibitions of 48, 93 or 94 o 'achieved.

The ! Active ingredients can be mixed with solid, liquid and / o (ler semi-liquid pharmaceutical carriers as pharmaceuticals in human or veterinary medicine be used. Organic or inorganic substances are used as carrier substances in question, which are suitable for enteral application and with the active ingredients do not react, such as water, Benzyl alcohols, Polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc. For the enteral Suitable for application are tablets, drages, pastilles, capsules, but granulates are better, Powders, jellies, jams, suspensions, syrups, juices. The specified preparations can optionally be sterilized or mixed with auxiliary materials, such as lubricants, Preservatives, stabilizers or wetting agents, emulsifiers, salts for influencing osmotic pressure, buffer substances, coloring, flavoring and / or aromatic substances.

If desired, the active ingredients can also be used in combination with eie or several other active ingredients are administered.

For example, the active ingredients can be constituents of a low-fat Diet or a weight loss diet and together with nutrients e.g. proteins, Carbohydrates, vitamins, e.g.

Vitamin A, B1, B2, B6, B12, C, D2, D3, E, and / or sweeteners, e.g. Saccharin.

The substances are preferably used in dosages of 0.2 to 10 g administered per dosage unit; the daily dose is expediently between 1 and 30 g. stimulation of the low tosicities of the active ingredients can also be significant higher doses, up to about 200 g per day, can be given.

The active ingredients according to the invention are largely odorless and tasteless and thus resemble cholestyramine. Due to their very low swelling capacity However, they can be processed very well galenically and are the cholestyramine clearly superior. So requires the application of the active ingredients according to the invention only a small amount of extra hydration while strong when ingested swelling agents, e.g.

of chloroestyramine, the body supplied significant amounts of fluids Need to become. This is especially important because all these substances are in relatively holrcrr doses have to be taken.

Example A: Processing an almond product as a starting material serves a macroporous commercial product (basic anion exchanger) with spherical Grain shape and the following characteristics: Grain size: 0.3 - 1.0 mm debris weight of the swollen Resin: 600 - 680 g / l Specific load: up to 40 l / h 1 Total capacity 1.8 mEq / ml (swollen resin): Usable capacity: up to 38, under special conditions up to 45 g (CaO / l resin) Temperature resistance: up to 1000 in a wet sieving process of the commercial product, the proportions <0.5 mm are sieved off 100 g of the finer proportions washed in a column with 300 ml of methanol and then quantitatively with 2N HCl converted into the chloride form. It is washed acid-free with doubly distilled water, dried for 48 hours under reduced pressure at 600 and crushed the obtained Product in a mortar (Retsch mill) for 12 hours or more. In a The fractions with 0.024 to 0.125 mm, 0.125 to 0.2 ram and 0.2 to 0.36 mm grain size of the "active ingredient A" obtained.

The following examples are pharmaceutical preparations described according to the invention Example 1: Jam The unit dose is composed as follows: Active ingredient 5 g fruit pulp (pre-dried) 3 g pectin 0.5 g citric acid 0.5 g ascorbic acid 0.1 g preservative (e.g. sorbic acid) 0.1 g cane sugar 10 g water 10.8 g Example 2: Capsules 0.5 g of active ingredient are with 5 mg magnesium stearate mixed. The mixture is filled into capsules that are filled with soft gelatin Coated Example 3: Dragees Each coated tablet contains: Active ingredient 0.2 g of lactose 0.1 g wheat starch 0.25 g talc 0.048 g calcium stearate 0.002 g The coating ordered from a mixture of wheat starch, sugar, talc, finely divided silica and Tragacanth.

Example 4: Tablets are 500 g of active ingredient and 100 g of potato starch mixed, moistened with a solution of 2 ml glycerine in 100 ml 90% ethanol, granulated with 200 ml of aqueous 50% gelatin mucilage and, after adding 50 g talc and 1 g magnesium stearate pressed into tablets of 750 mg each.

Each tablet contains 600 mg of active ingredient.

Example 5: Siru 1Nfan prepares a mixture of active ingredient 20 kg of polyoxyethylene sorbitan fatty acid ester 2 kg cane sugar 35 kg carboxymethyl cellulose 0.5 kg preservative (e.g. mixture of p-hydroxybenzoic acid methyl ester and n-propyl ester) 0.1 kg ascorbic acid 0.5 kg of glycerin 2 kg of flavors and colors as required and filled with distilled Water to 100 liters.

One dose unit (6 ml) contains 1 g of active ingredient.

Example G: Aqueous suspension Mix 30 kg of glycerine with 1 kg Agar-agar, add this Geiuisch to 40 1 water, stir until the mixture is homogeneous, and heated to 500. 20 kg of active ingredient and 150 g of sodium saccharin are then added as well as colorings and flavorings as required and fill up with water to 100 1 on.

One dose unit (5 ml) contains 1 g of active ingredient.

Example 7: Powder A mixture of active ingredient 70 kg of sodium alginate is prepared 4 kg of gum arabic 26 kg and finely powdered. The powder obtained is in unit packages of 5 g each sealed airtight. Shortly before use, a (or are) Open several) pack (s), stir the contents in a liquid or semi-liquid Carrier e.g. in water, fruit juices, vegetable juices, non-alcoholic beverages such as milk, Applesauce, suspended and administered in this form.

Example 89 Granules Dissolve 3 g of flavorings in 100 ml of ethanol, mixes the solution with 797 g of glucose and gives the thus obtained flavored glucose to a mixture of 10 kg of active ingredient, 300 g of sodium alginate and 400 g of polyacrylic acid to. Mix well, granulate, dry in the air and fill in airtight manner sealed polyethylene bags, each containing 4 g of the granulate.

Example 9: Powder - kg of active ingredient are .feinst pulverized and hermetically sealed in linear packs of 5 g each. Shortly before use, a The pack (or several packs are opened), the contents by stirring in one liquid or semi-liquid carriers e.g. in water, fruit juices, vegetable juices, non-alcoholic beverages such as milk, applesauce, suspended and administered in this form.

Example 10: Aqueous suspension 1 kg of active ingredient, 100 g of pectin and 10 g of sorbic acid are stirred with pure water so that the total volume of the Suspension is 10 1.

One dose unit (5 ml) contains 0.5 g of active ingredient.

Claims (10)

Claims 1. Process for the production of pharmaceutical preparations, thereby characterized in that one has at least one synthetic, non-toxic, against digestive enzymes inert, crosslinked polymer containing ionizable amino groups with macroporous Structure and a swell volume of less than 5 ml / g in water that is after equilibration with air that has a 100% relative humidity at 25 °, a moisture content of less than 50 percent by weight, optionally together with at least a solid, liquid or semi-liquid physiologically harmless auxiliary or Carrier and optionally together with at least one further active ingredient into a suitable dosage form. 2. Orally administrable pharmaceutical preparation, marked by containing an effective dose of at least one synthetic, not toxic, cross-linked, ionizable amino groups that are inert to digestive enzymes containing polymers with macroporous structure and a swelling volume of less than 5 ml / g in water, which after equilibration with air, which is 100% at 23 ° Relative humidity has a moisture content of less than 50 Has percent by weight, optionally in addition to at least one solid, liquid or semi-liquid physiologically harmless auxiliary or carrier substance and / or optionally at least one further active ingredient. 3. Pharmaceutical preparation according to claim 2, containing 0.2 to 10 g of active ingredient per dose unit. 4. Pharmaceutical preparation according to claim 2 or 3, characterized in that that a polymer with a grain size between 0.0001 and 0.5 mm is used. 5. Pharmaceutical preparation according to claim 2, 3 or 4, characterized characterized in that a polymer based on polystyrene is used as the active ingredient. 6. Pharmaceutical preparation according to claim 5, characterized in that that a polystyrene containing dialkylaminoethyl groups is used as the active ingredient will. 7. Pharmaceutical preparation according to claim 6, characterized in that that as an active ingredient a polystyrene containing dialkylaminomenthyl groups with a Crosslinker content of 5 to 20, preferably 6 to 8 percent by weight is used. 8. Pharmaceutical preparation according to claim 7, characterized in that that a polystyrene containing dimethylaminoethyl groups is used as the active ingredient that has a swelling volume of 3.2 to 4 ml / g, a crosslinker content of 6 to 8 percent by weight, after equilibration with air, which is 100% relative at 23 ° Humidity, a moisture content of 20 to 40 percent by weight, and has a grain size between 0.0001 and 0.2 mm. 9. Process for achieving a bile acid binding, triglyceride binding, liphase-inhibiting, cholesterol-lowering and / or triglyceride game gel-lowering agents Effect in living beings, characterized in that an effective dose of a Polymers according to claim 1 administered. 10. Use of preparations according to claim 2 to 8 to achieve a gallic acid binding, triglyceride binding, lipase inhibiting, cholesterol level lowering agent and / or triglyceride-lowering effects in living things.