DE1908946A1 - Pharmaceutical preparations and processes for making the same - Google Patents

Description

A b s_cjiri ft

N.V. Philips'Gloeilampenfabrieken, Eindhoven / Holland

"Pharmaceutical Preparations and Processes for Manufacture

the same"

The invention relates to pharmaceutical preparations, in relation to the even delivery of the .effective Constituent to the body have favorable properties.

The production of salts of therapeutically active substances with ion exchangers based on sulfonated * polystyrene resins is known. These connections have in the ver. equal to other salts have the advantage that the "active ingredient is gradually entered into the gastrointestinal tract, causing the effect of the therapeutic agent is prolonged and undesired side effects are reduced (British Patent 824,337).

It has now been found that some of these are sulfonated Polystyrene preparations release the remedy too quickly, regardless of the particle size, the degree of crosslinking or the relationship between the therapeutic ^ "" effective ingredient and the ion exchange resin.

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Thereby the effect of "a uniform release of the" Remedy practically not achieved, it has been shown that the speed of delivery of the effective Rather, one component in such combinations has exponential than a ΐί-order curve.

According to the invention, "a therapeutic preparation with improved even delivery of the effective. Substance during at least the first hours after the departure obtain. - C /; -

The invention relates to an oral, the efficacious; Component of a gradually releasing therapeutic preparation, the grains of an ion exchanger and one on the same; ■ absorbed therapeutically active agent 'contains ^ which grains with a thin layer of a non-toxic Material that is practically insoluble in gastric juice and that swells in the gastrointestinal tract, thanks to the outer layer of swellable material, the release of the medicinal product takes place over a relatively long period Period. Because the outer layer is only in the intestines swells, the drug is mainly delivered in the gut.

In connection with the manner in which the outer layer is applied, regularities of the layer thicknesses per granule occur in the case of some granules, while the average layer thickness also varies for each granule. BxeJe ^ Ef ^ kt ^; can be increased by the fact that Gramtlen intentionally

which the thickness of the resin layer is different.

It should be evident that the -Pjpäjgs ^ - ^ according to the invention compared to a preparation ^ i ^^ with one made from sugar or

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Gelatin existing outer layer have advantages (see British Patent 1 085 739), -. because, to a particular Point in time for granules for which the release of the active ingredient has already begun this levy Txird gradually continued, while with other granules the submission at this point in time or at a later date Points in time. '

This is explained in more detail with reference to FIG. 1. In this figure, curve 1 shows the release effect of a resin granule containing only the medicinal product; curves 2 and 3 relate to the release effect of the same granules, which are now surrounded by a thin or a thick layer, respectively. Finally, curve 4 shows the uniform release effect of a preparation which consists of a mixture of granules coated with thin and thick layers. Since there are many granules, each with a different strength, a more even total delivery is achieved than is shown in the figure.

This system v / eist the advantage that fast a certain level of remedies content in blood reaches v <? May lems, which can then -'erden maintained over a period of I ⁷ "Ftund ^ n.

like that.

Different remedies are rendered ineffective in the body at different ^ velocities' or scissors-c j & sn. Kech ^ dir ^ Ffinding can speed the delivery of the ν ^ ΓΚ337ηβη ~ 3 ^ ε * β ¥ ΜΪ +? 11_οε ^ urch

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SAD

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The invention is described in more detail below with reference to the following three ^{7 points:}

1. The material for the outer layer to be applied;

2. the ion exchanger and

J5. the therapeutically effective component. '·'.

Particularly, suitable fabrics for the outer layer are Cellulose ethers and cellulose esters or mixtures thereof.

In the cellulose esters, which are preferably used, a ' or several hydroxyl groups of the cellulose molecule with one k polycarboxylic acid esterified such that at least one The carboxy group of the acid remains unesterified. Suitable acids are citric acid, phthalic acid and maleic acid. Others Hydroxy groups of the cellulose molecule can be mixed with V aliphatic carboxylic acids, e.g. B. acetic acid, bituric acid,> Propionic acid and maleic acid.

Cellulose acetate phthalate with 1? - 20 % by weight of acetate groups and 30 % by weight of phthalate groups are used. This mixed ester is not transformed in the stomach, which promotes an even release of the medicinal product over a longer period. . ! ~ V

0) Furthermore v.-urden with cellulose butyrate phthalate and with cellulose acetate butyrate achieved satisfactory results. "· - ■; ..

The outer layer is on the granules of the remedy containing ion exchanger attached in that the Grenillen are placed in a coating pan or pan, which is then rotated, after which the granules of the ion exchanger containing the medicinal product from time to time r 1 + - a solution of the material can be splashed. When using cellulose

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BAD ORlGIWAL

Acetate-phthalate can be converted into acetone with up to the latter 50% by volume of ethanol can be dissolved.

Other methods can of course also be used provided that a uniform layer can be obtained by these methods on the outer surface of the separate particles of the base material containing a medicinal product. ^v

For example, the material can be applied to a river bed. a Medicinal-containing ion exchanger are injected.

The amount of material to use to apply an outer layer depends on the desired uniform release effect, the swelling properties of this substance and the Particle size of the same dependent. A uniform release effect over 12 hours was obtained when 1000 g a combination of an active ingredient with Zerolite 225 with a solution of 5-50g cellulose acetate phthalate (Eastman S-3) was treated. In general, an amount of 0.5-5% by weight of coating material is used has achieved acceptable results with respect to dry ion exchange resin containing a medicinal agent.

Any non-toxic ion exchange resin can be used as the ion exchanger. These resins are usually not soluble in gastrointestinal tract juices. Medicinal products with basic groups, such as amines and quaternary ammonium compounds, are combined with cation exchange resins, while acidic compounds, e.g. B. sulfonic acid or carboxylic acid groups, with anion exchange resins combined v ground ^r.

Particularly satisfactory results were achieved when Amine-type remedies on ration exchangers »dated

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'Sulphonic acids or carboxylic acid resin type are adsorbed. In general, strong cation exchangers have yielded compounds with a greater amount of curative ingredient than can be obtained with weak cation exchangers. Therefore, the combination of the amine type medicinal agent with a sulfonic acid type resin is particularly suitable when a relatively large dose of medicinal agent must be administered in a small volume. Such a sulfonic acid resin in the form of a granule or ball can be prepared by copolymerizing unsaturated materials such as styrene and diphenylbenzene, followed by sulfonation. Examples of suitable sulfonic acid resin type ion exchange materials are: Zeo-Karb 225, Zerolite 225 (Permutit), Amberlite IR-120 (Rohm and Haas), Dowex 50 (Dow Chemical).

The sulfonic acid resins preferably used are with between 2 and 17% diphenylbenzene (DVB) and preferably between 4 and 10% DVB crosslinked while the particle size is between 0.1 and 1 mm. Most commercially available resin types have a particle size of between 10 and 80 mesh (USP sieve), which is a medium one Size of zvfisehen 150 and 840 / U corresponds.

In general, the preparations which gradually release the medicinal product and which have a strong cation exchanger core are more resistant to gastric juices than preparations based on a weak cation exchanger. Therefore, when describing one of the known processes for the production of this type of preparation, the advice is given not to use resins of the carboxylic acid type (patent specification). ■

An advantage of the present invention is that the Carboxylic acid type resins applied without risk of dissolution

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• Can be because the resin with one in gastric juices

insoluble layer is coated. When using a ·; Carboxylic acid resin are grains of a polymer from

Acrylic resin type, e.g. B. Ambeflite IRC-50 or Zeo-Karb 226,

preferred. .

■ "■ / ■ -

The invention has the further advantage that instead of sulfonated polystyrene ion exchangers with carboxylic acid groups can be used. It is known that the salt of a base and a carboxylic acid resin will completely release the active component when it comes into contact with the gastric juices as a result of the reaction of the strongly acidic HCl with the weakly acidic carboxylic acid groups. If the resin granules are prevented from coming into contact with gastric juices, weakly acidic resins can be used. Dar-type resins have particular additional advantages "because" these substances generally have a higher degree of purity. They are not changed by oxidation during storage and do not hydrolyze compounds that are sensitive to strong acids.

The adhesion of the amine type medicinal agent to the resin grains can be obtained by the following methods :

. 1st A salt form of the resin is treated with an aqueous solution of a salt of the amine,

2. the resin in the acid form is treated with a solution of the medicinal agent in the amine form.

These two procedures can be detailed in the following ways to be discribed.

Stirred Ad 1. grains of the resin in the Salzform.werden at room temperature in a solution of the amine with a v.'ässrigen ^"5 filled in the SfO.zform Bechergles. A ⁰ U. ^

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BATH ORIGINAL

1908346

A similar procedure is that an aqueous "" solution of the amine salt over a with the / wetted grains of the resin is poured into its salt form filled column. Both methods are relatively cheap, but take a lot of time, and indeed 8 hours while using these procedures more than about $ 80 of the available amine is adsorbed on the resin.

The grains produced in this way have high stability because the ion-exchanging groups which are not occupied by the amine groups of the medicinal agent are in the salt form. The inside of a grain Ψ is therefore neither strongly acid nor strongly alkaline.

AdE, The procedures are the same as those described under 1) nen procedure provided that a solution of the medicinal product in the amine form, e.g. B. in ethanol is used and that the resin is available in the acid form. In the all ^ generally these processes are faster than the processes described under 1), but they are more expensive, while due to the use of the free amine form the remedy is more easily oxidized.

As described above, an ion exchange material ^ is provided with a layer, through which the effect of the simultaneous release of the medicinal substance adsorbed on this material. "tels enlarged independently of the type of remedy, provided that the remedy can be adsorbed in the form of a suitable ion exchange material or absorbed in such a material. ■■" .-, -; - ^:

The possibility of the formation of a bond between the therapeutic agent and the ion exchange material is "conditioned by the" properties of the therapeutic agent and the ion exchange material. In the present invention, it is advanta- "liaft, ^w hen the Bindunpr? .- uf.-B it is ionic reactions' Instead

; 909842/1634 "■" "'" "'.

finds. It is then necessary that both the therapeutic agent and the ion exchange material in one ionogenic form are known. Thus, in practicing the present invention, it is preferred to use a medicinal product of the ionic type used. The following remedies of this type can be mentioned:

Alkaloids, antihistamines, sympatomlmetics, remedies of the phenyl amine type. The invention is particularly important for the manufacture of preparations of the following remedies: Pralidoxime, is'oxuprine, mebeverine, 1- or 2-amino-adamantane and also 1- (4-hydroxy-pheriyl) -2- (2- (4- -äthylamino) -propanol-1.

According to a preferred embodiment of the invention the grains of the ion exchange material have an average size of 0.1 to 1 mm and contain them. therapeutic effective amine in an amount of 2Q - 60 wt.%, while the outer layer of these grains 2 to 10 $ of their weight forms.

Since it is generally desirable that the active ingredient be rapidly absorbed in the body, it can be beneficial be a mixture of grains with and grains without an outer layer or of those with an outer layer Grains and a soluble salt of the active ingredient. ■

According to a further embodiment of the invention, iie grains are worked up into two-layer or core tablets, one layer or the core of which is a vax-like substance, e.g. B. Gl ^ .oryl monostearate contains. -

The preparations according to the invention körinen as such - ^ erd ^ n, ζ. B. Indians, a teaspoon of the after

- 10 - ■

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BATH

Invention treated grains with a glass of water; is taken. The bearing the "cure _grains. Surrounded by an outer layer can be worked aber.auch ■ to pharmaceutical tablets or capsules, for this purpose, the granules in a ,, waxy material, for example · Kärbowax. 4000, added, which is a special type of polyoxyethylene glycol, after which they are worked up into tablets in the usual way.

Example 1 "■..;

1000 g Zeo-Karb 225 SCR9 with a moisture content * from 50 wt.% 500 g isoxuprine-CHl and 5000 ml distilled Water were mixed together and the liquid mixture was stirred at 40 ° C. for 24 hours. Uech The separated resin grains were filtered up to: dried to a moisture content of 10%, and then calibrated. The grains had a total weight of 980 g and contained 45% by weight isoxuprine (calculated as "hydrochloride"). 900 g of this resin was in a coating pan with the dealt with the following solution:.

Cellulose acetate phthalate 50 g

Diethyl phthalate 125 g

■ Acetone - 800 ml>

Ethanol . '■ / ■' ■ 200 ml '

The treatment was continued until the outer layer was 1 % of the total weight.

The resin granules so treated were given to human volunteers, while another group was given a corresponding one Was taking the preparation, but it had no outer layer. The course of the release of the active substance is shown in Fig. 2; curve 1 shows the dispensing percentages per hour of the one provided with an outer layer; ■ ":

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■ Preparations and curve 2 these percentages for not preparations provided with an outer layer. From these curves you can conclude that the curve 1 The course of the release of the first preparations shown is more uniform than the course shown by curve 2 the delivery of the latter preparations is.

Example 2

1200 g Zeo-Karb SCR 4 with a moisture content of 60% and 400 g of mebeverine HCl were distilled with 5000 ml Waters mixed. · The "obtained product was 24 hours stirred at room temperature, filtered and then up dried to a moisture content of 10%. The dried one Product had a Mebeverin content of ^

Experiments with animals have shown that the rate of elimination of mebeverine in the urine with this product not much different from that of the pure, not in a resin adsorbed component different v / ar.

In a subsequent experiment, this example manufactured granules-with the same solution (and on. same Xfeise) as in example T coated. The history the release of the active ingredient was based on the Excretion measured, satisfactory for the resin treated in this way.

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Claims (14)

Patent claims: 1 / Oral therapeutic preparation that, when administered the active ingredient gradually "releases and the grains", one ion exchange material and one on that material contains adsorbed therapeutically active substance, covered by a 'thin layer of a non-toxic Material are surrounded that is practically insoluble in gastric juice and that comes out of contact with juices the gastrointestinal tract swells. 2. Preparation according to claim 1, characterized in that the grains of a thin layer of a cellulose, ethers and / or esters are surrounded. 3v preparation according to claim 2, characterized in that the thin layer consists of cellulose acetate phthalate. 4. Preparation according to claim 2, characterized in that the thin layer consists of cellulose acetate butyrate. 5. A preparation according to claim 1, characterized in that the ion exchange material from a crosslinked acidic Cation exchange resin consists. 6. A preparation according to claim 1, characterized in that the ion exchange material is a "crosslinked" sulfonic acid or is a "crosslinked" carboxylic acid resin. 7. A preparation according to claim 6, characterized in that the ion uppush material belongs to the class consisting of a sulfonated copolymer of polystyrene with a cross-linking pro :? ent sat ζ between 1 and 2Or 'and a carboxylated polymerized methacrylic acid with a crosslinking percentage of 1 to POfi. 909842/1634 8. A preparation according to claim 6, characterized in that the sulfonic acid type resin from Zeo-Karb 225, Zerolite 225, Amberlite TR-I20 or Dowex 50. 9. A preparation according to claim 6, characterized in that the resin of the carboxylic acid type consists of Amb Erlit e IRC 50 or Zeo-Karb 226. λ .... '"-: ■' .- 10. Preparation according to claims 1 to 9, characterized in that that a therapeutically effective amine on the ion substitute material is adsorbed. · 11. A preparation according to claim 10, characterized in that the therapeutically effective amine from pralidoxime, isoxuprine, Mebeverine, 1-amino-adamantane, 2-amino-adamantane and 1- (4-hydroxyphenyl) -2- (2- (4-hydroxyphenil) -ethylamino) -propanol-1 consists. · · 12. A preparation according to any one of claims 1 to 11, characterized in that a therapeutically active amine in an amount of 20 to 60% by weight is adsorbed on grains with an average size of 0.1 to 1 mm or absorbed in these grains is, which grains are surrounded by a thin layer of a non-toxic material which is practically insoluble in gastric juice and which swells in the gastrointestinal tract, which layer makes up 2 to 10% of the weight of the grains. 13. capsules or tablets made of a waxy material, the one therapeutically effective amount of the granules after one of claims 1 to 12 included. - 14. Pharmaceutical preparations according to one of the preceding Claims, characterized in that the grains used are made from a mixture of grains with outer layers that are more variable Strength exist. -. ■ 2/1634 -IN THE- Blank page