DE1617845C - Depot medicine in capsule form - Google Patents

Description

dioxide, lecithin, phosphates and others. be added. The gelatine shell of the capsules can be used on normal Solubility adjusted or z. B. be tanned by formalin treatment. In the latter case, will the diffusion of the drug from the sponge-like carrier is further slowed down.

Furthermore, substances can be added to the depot mixture, which trigger the release of the active ingredients control, e.g. B. phosphates, lactose, acids, bases, buffer substances, mucilaginous and gel-forming substances, such as carboxymethyl cellulose and its salts, methyl cellulose, alginic acid and its salts, gel-forming polymeric acrylic acid derivatives, carboxyvinyl polymers, insoluble in acidic medium, in alkaline medium soluble substances such as cellulose acetate phthalate or finely divided silicon dioxide. These substances can also be soluble in gastric juice, such as dicalcium phosphate, and thus the release of the active ingredient especially in the first hour after administration. After the depot body has entered the In the medium of the intestinal tract, no further solution of the dicalcium phosphate occurs, so that the drug is released is slowed down. In this way, a relatively rapid release of an initial dose is achieved. the The rest of the active ingredient is then released more slowly. By adding mucus or gel-forming substances can through their swelling a pore enlargement and loosening of the depot body and thus a controlled release of active ingredients can be achieved.

Come as a carrier medium

a) Liquid, water-soluble or water-miscible substances that can be kept in gelatine capsules Can be filled, such as polyethylene glycols, dioxolanes, glycerin formal, glycofurol, liquid water-soluble or water-miscible alcohols, esters, acid amides and ethers;

b) also substances that are caused by the addition of suitable emulsifiers, solubilizers or other, the miscibility with water-conveying substances with water solutions, suspensions, emulsions or gels, like oils, result in fatty and waxy bodies. Examples for this are:

Peanut oil + polyoxyethylated castor oil,
Neutral oils (triglycerides of fatty acids of medium +5 chain length) + polyoxyethylene sorbitan monooleate,
Castor oil + ethanol,
Castor oil + polyethylene glycol 400,
Paraffin oil + sorbitan trioleate, paraffin oil + polyoxyethylene sorbitan monooleate,

hydrogenated peanut oil + polyoxyethylated castor oil.

55

These combinations can be made according to the definition and purpose given above can be expanded or combined with one another.

Physiologically indifferent natural and / or plastics are suitable as the actual sponge-forming substances, which remain undissolved in water or the digestive juices of the gastrointestinal tract for a long enough time, such as polyvinyl ester, polyvinyl ether, polyvinylidene ester, Polyvinylidene ethers, polyvinyl and polyvinylidene acetals, polyvinyl chloride, polyvinylidene chloride, polycarbonates, Styrene maleic anhydride copolymers and their derivatives, polyethylene maleic anhydride copolymers and their derivatives, alkyl, alkenyl and alkynyl maleic anhydride copolymers and their Derivatives, polystyrene, simple or mixed cellulose ethers and cellulose esters, polyacrylic acid and its derivatives, polymethacrylic acid and its derivatives. Polyterephthalic acid and its derivatives, natural vegetable or animal and synthetic waxes and Resins, montan waxes, gums, shellac, silicone resins and fats, fats, higher fatty acids, their Salts and their derivatives, higher alcohols and their esters and mixtures of the materials mentioned.

The incorporated active ingredients are continuously removed from the depot dosage form described above by diffusion from the microporous sponge body, regardless of the respective pH value of the Digestive juices and released regardless of the enzymatic conditions in the gastrointestinal tract.

About 25% of the depot medicaments according to the invention are converted into about 25% 1 hour after application or the start of the test. , about submitted after 3 hours, about 50% after 6 hours, about 60%, after 8 hours, about 75 ° / ₀ and after 10 hours 100% of the available drugs to the surrounding medium. These data correspond to the requirements placed on modern depot preparations.

The following examples serve to illustrate the process according to the invention. The sponge-like ones Natural or plastics forming depot bodies are each dissolved or in the carrier medium suspended. The active ingredient (s) are then added. The product thus produced is then filled into gelatin capsules in the usual way.

1. 700 g polyethylene glycol 400, 300 g polyvinyl acetate,

100 g ephedine · HCl.

2. 600 g of 2-dimethyl-4-hydroxymethyl-1,3-dioxo-

lan,
400 g polyvinyl maleic anhydride copoly-

mer,

850 g of ethyl lactate, 50 g of ethanol,
100 g procaine · HCl.

3. 700 g of 2-dimethyl-4-hydroxymethyl-1,3-dioxo-

lan,

100 g ethyl cellulose,

100 g styrene-maleic anhydride copolymer, 100 g ethanol,
100 g caffeine.

4. 900 g polyethylene glycol 300, 200 g shellac,

50 g codeine,
100 g mucic acid,
50 g dicalcium phosphate, 10 g sodium carboxymethyl cellulose.

5. 800 g triglyceride mixture (neutral oil), 100 g polyoxyethylated castor oil, 100 g ethyl cellulose,

50 g ethanol,

50 grams of pentobarbital.

6. 100 g polyvinyl butyl ether,

800 g Paraffinium perliquidum DAB 6, 3rd addendum,

100 g sorbitan monooleate,

100 g polyoxyethylene sorbitan monooleate,: 200 g Extractum Crateagi e fruct.

7. 100 g polymethacrylic acid ester, 600 g polyglycol 300,

50 g of ethyl papaverine.

8. 200 g styrene-maleic anhydride copolymer, 700 g 2-dimethyl-4-hydroxymethyl-1,3-dioxolane,

100 g ethanol,
100 g of aminophenazone.

9. 100 g of zein,
100 g shellac,

100 g of polymethacrylic acid derivative, 2 g of cellulose acetate phthalate, 50 g of oxeladine citrate.

. 10. 900 g of polyethylene glycol 300, 100 g of polyvinyl isobutyl ether, 200 g of shellac,
100 g phthalic acid,
50 g dicalcium phosphate,

20 g of finely divided silicon dioxide.

In the example below, the fixed

Substances melted and intimately through heating

ίο each other ι i verrhisbht, 'Then the became flowing

Active ingredient mixed in and the warm liquid mass in Capsules filled.

11. 900 g polyethylene glycol 4000, 100 g polyethylene glycol 400, 100 g beeswax DAB 6,
100 g polyoxyethylated castor oil, 100 g shellac,
150 grams of pyrilamine maleate.

Claims (3)

1 ■, 2 ■ Furthermore, depot drug forms are known in which the patent claims: Active ingredients are bound to substances that are slow in the. Gastrointestinal tract are loosened, e.g. B. 1. Depot drugs in capsule form, consisting of fats, waxes, fatty acids or glycerol esters. From that a substance similar to that of normal or elevated temperature can be liquid or flowable, liquid or flowable solution or suspension, however, they can be in liquid or flowable form one or more active ingredients and the solution never have such a sufficient depot effect or suspension of one or more physiological agents, such as for a satisfactory depot pharmaceutical Indifferent natural and / or plastics in medium is required, since the active ingredients too quickly one that is miscible with water and / or one with io can be released from liquids. At the vorWater immiscible, a water-oil-emulsifying invention are such substances, or a carrier containing auxiliary solvents, provided they are liquid and flowable, as the carrier medium in gelatin capsules. media used. 2. Depot medicament according to claim 1, characterized in that the production of tablets, coated tablets, granules characterized in that the capsule filling is substances 15 etc. with a uniform depot effect from time to time for the controlled release of the active ingredients. difficult because of various factors in the production 3. Depot medicament according to claim 1 or 2, tion are often not kept constant enough characterized in that the capsule can consist of one, e.g. B. the compression pressure when tableting, the gelatine particle size tanned by formalin treatment for granules, the layer thickness for capsule consists. 20 coatings, the moisture content of the depot body. In this way, different active ingredient releases deviating from the optimum can be brought about. the. So far, soft gelatin capsules were with more or 25 less liquid content with depot character is not known. This is because soft gelatin capsules The invention relates to depot medicaments in capsules - normally only with liquid, at least flowing and form, consisting of one with normal or increased pumpable medicinal preparations that can be filled Temperature liquid or flowable solution or nen. The depot preparations, however, were how Suspension of one or more active ingredients and the 30 mentioned above, practically exclusively Solution or suspension of one or more physio- in solid form with a particle size before logically indifferent natural and / or plastics in capsule filling was too high. one miscible with water and / or one with the object of the invention was consequently liquid Water immiscible to achieve a water-oil-emulsifying preparation with a depot effect. This or a carrier medium 35 containing co-solvent. Object is achieved by the present invention in gelatin capsules. the liquid capsule contents when in contact with the In recent years, depot drugs, digestive juices of the gastrointestinal tract have had a minimal in particular forms depot medicament to be administered orally kroporous, sponge-like body from which medium, increasingly important. They are said to be the active ingredient over a relatively long period of time the patient continuously diffuses the drug out in one or two 40, to near ideal Add single doses per day and solved in a simplified way. Application the setting of a constant The depot medicament according to the invention receives Ensure blood levels. Oral depot medicaments by preparing the active ingredient or ingredients and methods for their preparation are together with an in water or digestion, inter alia in Pharm. Ind., 21, p. 298 (1959); 45 juices of the gastrointestinal tract insoluble or only German apoth. Ztg., 99, p. 1175 (1959); Archive, d. slowly soluble material, namely one or Pharm., 293, p. 766 (1960); German apoth. Currently, several physiologically indifferent natural and / or 104, p. 797 (1964), and in the 'German patent plastics dissolves in a suitable carrier medium Writings 1 076 329, 1 123 437 and I 201 950 described or suspended and the liquid or flowable ben. 50 mixture is filled into the capsules, which consist of both soft As molded depot medicaments to be administered orally, they can also consist of hard gelatine. In the event of Medium were previously known as solid preparations: more fluid mixtures can be liquid-pasty Tablets or dragees with coatings that allow the materials to escape slowly at room temperature or the active agent. Represent tablets or liquid masses at elevated temperature. Dragees whose body consists of an indigestible structure, a so-called matrix, which is miscible with water and in which the and / or water-immiscible, water-oil active ingredient is stored, tablets or dragees containing emulsifying or auxiliary solvents Subder bodies from non-digestible or difficult to digest punch are used. ■
Substances, e.g. As soon as the capsule content is embedded with water or the drug, granules with digestive juices of the gastrointestinal tract in coating-like or different thickness coatings, there is a microporous, also spongy one Filled in hard gelatin capsules or similar bodies containing the drug which can be compressed into tablets, tablets; which does not release the active substance all at once, but rather by diffusion through the special nature of the auxiliary substances (e.g. continuous absorption into the surrounding swelling substances), a protracted release of active substance into the medium. The mixture can also be made possible by tablets with two or more layers, commonly used in capsule production, and which, due to their special structure, enable a different active ingredient release in each case or the lubricity in the capsule. machine-increasing substances, such as finely divided silicon