DE1123437B - Process for the manufacture of drug forms - Google Patents

Description

The invention relates to a method for producing pharmaceutical forms for oral applications using synthetic resins as the active substance release retarding embedding compound, whereby Irritant effects of the active ingredients on the stomach are largely avoided and a steady release the active ingredient is safely guaranteed over a longer period of time. So far one has these problems are solved in such a way that the active ingredients are coated with more or less sparingly soluble coatings provided. One group of these coatings are the enteral coatings, which oppose the acidic gastric secretions are resistant and only dissolve in the alkaline intestinal secretions to prevent z. B. acid sensitive Active ingredients against gastric secretions or the stomach against active ingredients with an irritant effect on the To protect gastric mucosa (see Swiss patent 283 585).

Another group are the coatings, which take a long time from the gastrointestinal Liquids are destroyed and with which a depot effect of the enclosed active ingredient is achieved shall be.

To achieve a steady release of the active ingredient over a longer period of time, According to a further variant, the active ingredients were coated with coatings of different thickness or solubility Mistake. The release of the active ingredient took place in all these cases by the fact that the coatings under exposure to the gastrointestinal fluids were destroyed or at least burst in which they were have been mined or swelled. As a result, such coatings could be used for the production of such coatings only those synthetic resins or synthetic resin mixtures are used that are in the gastrointestinal Liquids showed the necessary solubility and / or swelling capacity.

However, the observation was made that, in particular with coatings with which a depot effect of the active ingredient is to be achieved, the desired effect cannot always be guaranteed because the coatings are matched to an average composition of the gastrointestinal fluids and with a longer residence time in the Gastrointestinal tract the individual differences in the gastrointestinal fluids have a stronger effect, so that in the worst case the coating bursts prematurely and the active ingredient is released prematurely. It has been found that these difficulties in the drug forms with delayed release of active ingredient can be safely avoided by using an art method of production
of drug forms

Applicant:

Rohm & Haas Company,
Philadelphia, Pa. (V. St. A.)

Representative: Dr. G. W. Lotterhos

and Dr.-Ing. H. W. Lotterhos, patent attorneys,

Frankfurt / M., Lichtensteinstr. 3

Claimed priority:
V. St. v. America 9 September 1955 (No. 533 504)

Charles Louis Levesque, Philadelphia, Pa.

(V. St. A.),
has been named as the inventor

resins used such polymer substances that, in contrast to the synthetic resins used for the various types of coatings, the gastrointestinal Liquids are resistant to, do not swell in them, but are permeable to these liquids and from these polymer substances, together with the active ingredients, form a solid body that contains the active ingredient contains in even distribution, which is then crushed and possibly in a known manner into drug forms, how tablets etc. are processed.

As active ingredients can compounds or combinations of compounds that are in aqueous Liquids dissolve at least to some extent, but those that dissolve in water solve quickly, preference is given. Some examples are methamphetamine salts, p-aminobenzoic acid, Ephedrine, mannitol, amphetamine, erythromycin, penicillin, atropine, theophylline, sex hormones, Hydantoine, vitamins B and C and / or toluidine blue 0. As polymer substances are suitable for the method of the invention includes all polymers that are resistant to gastrointestinal fluids

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and are permeable, but do not swell in them otherwise, the diffusion and leaching rate and at the temperatures occurring during storage of the active ingredient can be regulated in a simple manner and to the temperatures neither sinter nor set to a block existing conditions,
melt. The polymer substances can be rubbery, but the hard polymers, ie the method claimed, consists in that of those which are present in glassy active substance in one or more liquid mono- or crystalline state at ordinary temperature Because of the mers dispersed, the mass obtained is given preference to a solid easier processing. Body polymerized and given the desired shape

Some examples from the large number of poly and size shredded. According to a variant, you can

mers and copolymers that meet this requirement in the liquid monomer or the liquid monomer

and according to the invention use are mixed polyfunctional monomers are added

are for polymers that are in the crystalline state those that are capable of the polymerization process

present: polyethylene, for polymers that form in amorphous cross-links that form the polymer substance

State present, tert. Butyl acrylate, making various insoluble in most solvents. at

Methacrylic acid esters, e.g. B. the methyl, ethyl, 15 application of this process technology can be used as

Isopropyl and isobutyl esters, mixed polymers of monomers also those that are usually very hydro-

Acrylic acid nitrile and methacrylic acid nitrile, miscible polymers, such as acrylic acid, are used

polymers of styrene and methylstyrene as well as poly- are,

vinyl chloride and its copolymers. According to a further variant of the method, a

The polymer applied according to the invention 20 active substance even limited water solubility according to the

Substances are intended for gastrointestinal liquid grinding in a latex or aqueous suspension

at least to such an extent the polymer substance is suspended or dissolved,

be permeable that most of the active ingredient, the latex or polymer substance suspension or

which the polymer substance coagulates in an evenly distributed solution to form a solid crumb and from the

contains, optionally the desired one within the normal residence time of the crumb obtained

Drug form in the human body - particle size are sieved out,

is divorced. But you can also use the latex suspension or the

It should be pointed out that poly-aqueous suspensions of the polymer substance, which, like polyethylene, have a relatively desired active ingredient in suspension or solution, have satisfactory water permeability, spray-dry or tumble-dry, give satisfactory results. Grind the product obtained by adding sodium chloride and, if appropriate, or other water-soluble electrolytes forming it, sieve out the desired grain size from it.
Substances can increase the permeability of the polymer. Another variant is to increase the polymer substance. to dissolve the substance in a solvent, the active

The polymer substances can disperse or dissolve in this solution by way of the 35 Bulk, solution, suspension or emulsion the suspension or solution obtained into a film polymerization can be produced. When using the to shed, then to marry and from the last mentioned Method can hold the polymer substance to get the desired grain size out of the grist solid particles are coagulated, which are closed with a sieve.

Active ingredient mixed quickly or which the active ingredient 40 The amount of active ingredient present in the polymer substance

before coagulation is added, which is evenly distributed below, can also be added as desired

is described. within the quantity range for which

In the polymerization process, a pharmacological effect has been found to be useful in individual cases, possibly the amount at which the active ingredient begins to remove the impurities present in one or more stages in a known manner in one or more characteristic properties of the polymer substance. This affects affect, be varied.
z. B. Inhibitors, residual monomers or other The concentration of the active ingredient in the polymer substances with which polymerizations are initiated substance represents another factor with which. besides the water permeability of the polymer substance

The method of the invention can regulate the drug delivery in different 50 and the particle size

Way to be carried out. One possibility can be.

therein, the powdery polymer substance with crystalline The obtained according to the invention, the active ingredient in linear or granular active ingredient thoroughly mixed to even distribution containing polymer body and then a heat and pressure treatment can be subjected to the desired part after comminution, the polymer substance in one 55 particle size is converted into a carrier material for pharmaceutical solids or a solid mass, preparations mixed in, incorporated or thus contains the active ingredient in dispersion. The obtained will be bound. The solid dispersion of the polymer-active ingredient particles is then converted into particles of the medium z. B. processed into tablets,
desired size crushed. 60 Here, however, it must be ensured that

The particle size is of great importance for the depot effect of the pharmaceutical forms obtained under the processing conditions, no change according to the invention, of the particle sizes, for example by coalescence, since the speed at which the melting or caking occurs. Tableting auxiliaries can also be used for this active ingredient, which is leached from the solid polymer substance, and lubricants can be used for smaller particles. With the particles at large. This makes it possible, by using even those in the pharmaceutical industry , to be filled with particles of different sizes and variations of the usual capsules. However , they can also be packaged in dry form in relation to the individual particle sizes and shortly before

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taking in water or any other the particles that make up the active ingredient in the polymer substance

suitable liquid to be suspended. contain, and the lubricants with each other and

The following examples are intended to demonstrate the process of compressing them into tablets, of the invention and the properties of according to

Invention obtained products are described. 5 Example 3

. 75 mg of a solid dispersion made from polyethylene beis pieI 1 particle consists in which 20 percent by weight MeIh-about 50 parts by weight of p-aminobenzoic acid and amphetamine is dispersed into a small one, for which 50 parts by weight of polyethylene are thoroughly mixed with each other by oral administration of suitable hard gelatin capsules mixed and add the mixture to foils from i °.

a thickness between about 0.9 and 1.9 mm, Example 4 by pressing them in layers at about 104 to 126 ⁰ C and

at an average pressure between about a mixture containing 10% methamphetamine and

14.06 and 42.18 kg / cm ² . A sample of 1.9 mm _{containing 90 ° / 0} granulated polyethylene is placed in a

Thickness was ground into pieces 1 cm long and about 15 ball mill and dried. The mixture

Cut 0.2 mm wide. Another sample of is pressurized on a 6x6 Carver press

about 1.9 mm thick was cut into pieces 1 cm long (703.1 kg / cm ² on 25.4 to 6.3 mm plungers at

and cut about 0.5 mm wide. 13O ⁰ C for 2 minutes) to films of varying thickness

Studies of excretions from humans, deformed ^{by 127 mm 2.} Similar samples were found in

the described, about 0.2 mm wide drug- 2 ° the same way using 2O ° / o meth-

form, showed that the time amphetamine with 80% polyethylene and 40% meth-

was required to produce 50% of the drug form amphetamine made with 60% polyethylene. in the

ingested dose of p-aminobenzoic acid in general can be said that the release

divorce, about 2.1 times as long as that, by 50% of the active ingredient from these drug forms

a control dose of the same active ingredient p-amino- 25 concentration of the drug directly and the particle

to excrete benzoic acid. This ratio depends on the size of the material that is

practically independent of the size of the dose. said slides obtained is inversely proportional.

When using the approx. 0.5 mm wide medicament form (1.9 mm x 1 cm), the time required for example 5 is 50% of the dose of p-aminobenzoic acid from 30 A mixture containing 10 Eliminating% methamphetamine and 90% of this composition, 2.8 to 3 times of a 1: 1 interpolymer of methyl methacrylate as long as that containing 50% of the control dose of ester-methyl acrylate, will be thoroughly eliminated. This result confirms the theory that mixed and on the Carver press (see FIG. Beidie particle size play in the release of the active substance 4) at 150 ⁰ C pressed for 3 minutes. Similar proportions of plastic mass, a significant factor of 35, were made in the same manner from 20% methamphetics. The rate of release is amine and 80% of the interpolymer and 40% inversely proportional to the particle size. Methamphetamine and 60% of the mixed polymer produced - The 0.2 mm material (1.9 mm × 1 cm) has about made. The release of the active ingredient from the same weight was almost 2.75 times the surface area particles that had been obtained after comminuting the sample area of the 0.5 mm material (1.9 mm × 1 cm) and 40 the general from it is in water within 6 minutes about the rules that are given in Example 4. 3.1 times as much p-aminobenzoic acid as from the. 0.5mm material released. Example 6

From a 2.54 cm National Rubber Machinery Co.

Example 2 ₄₅ ejection apparatus became a rod at temperatures

After following information tablets are manufacturing between about 140 and 170 ⁰ C ejected. The Ma-

posed, the proportions being based on the material posed a mixture of 40% methamphetamine,

Tablet base refer to: 59% polyethylene and 1% stearic acid. The stick

Methamphetamine 20 weight percent, ™ "* ^{e to kl} * ^{'me r} _A comminuted particle size. From the

embedded in polyethylene particles, ⁵ ° ^ f ^{s Haile product Wurd} _D ^{e the} active ingredient in the same

which put through a sieve with 10 to 16 Ma- ^way ^ as in example 4.

see 75 mg per 2.54 linear cm go Example 7

Lactose 300 mg _TT ..... ....... .. "_"

2Q ° To determine the speed of dissolution of the

j _cc 55 dung-manufactured tablets with such

16 mg are the same, for their production the previously usual

Starch dry 60 mg polymer substances have been used

Magnesium stearate '[[[Y.'. '.'. '.'. '.'. '.'. '.'. '. 4 mg ^fol | _T ^end tests conducted

According to the claimed procedure were

One makes a granulate of lactose with a strength of 60 four different ones, deoxyephedrine hydrochloride as paste, which contains 30 mg starch, and the water. Active ingredient-containing tablets manufactured that are Then you press the mass through a sieve with 4 Ma - mainly differentiated from one another by openings per 2.54 linear cm, it dries and that for variant A, one according to the invention is pressed through a sieve with 16 mesh openings per reversible polymer substance, namely methyl acrylate-2.54 linear cm. Then mix talc, dry starch 65 methyl methacrylate, and for the variants B to D as and magnesium stearate together and gives the mi-polymer substance varying amounts of polyvinyl resin through a 40 mesh screen per acetate. The composition of the 2.54 linear cm. The lactose granules are combined, the tablets are shown in the following table:

Ingredients option A
Amount per tablet Variant B
Amount per tablet Variant C
Amount per tablet Variant D
Amount per tablet Deoxyephedrine · H Cl
Methyl acrylate-methyl methacrylate
Polyvinyl acetate
sugar 15 mg
69.8 mg
24.4 mg
3.4 mg
0.8 mg 15 mg
69.8 mg
24.4 mg
3.4 mg
0.8 mg 15 mg
94.2 mg
3.4 mg
0.8 mg 15 mg
19.8 mg
74.4 mg
3.4 mg
0.8 mg Talc Magnesium stearate

The tablets were manufactured in such a way that the polymer substance is deoxyephedrine hydrochloride the sugar, talc and magnesium stearate passed through a sieve with 30 meshes per 2.54 cm, well mixed and agglomerated, grind the resulting lumps through a sieve with 20 meshes per 2.54 cm, remixed and made into tablets and using a flat beveled 71 144 mm punch were squeezed so that each tablet weighed 114 mg.

The disintegration time of the tablets was determined according to the disintegration test for coating-free tablets (described in US Pharmacopeia, p. 934 [I960]), which gave the following results:

Disintegration time option A perfectly intact
after 8 hours
9 minutes Variant B 1.5 minutes Variant C 5.25 minutes Variant D

30th

Thereafter, the disintegration time of the tablets containing polyvinyl acetate as a polymer substance is less than 9 minutes, while the tablets containing methyl acrylate-methyl methacrylate still after 8 hours were completely intact. It shows that the disintegration of a tablet is accompanied by the release of the active ingredient this comparison; when using polyvinyl acetate, which is under the action of the gastrointestinal If liquid is attacked, the entire active ingredient of a tablet will be used at the latest 9 minutes released while using methyl acrylate methyl methacrylate as the polymer substance A gradual release of the active ingredient is guaranteed even after 8 hours.

Claims (8)

PATENT CLAIMS: 1. A process for the preparation of pharmaceutical forms for oral applications using synthetic resins as the active substance release retarding embedding material, characterized in that a relative to gastro-intestinal fluids resistant, is non-swelling, but permeable for these liquids polymer substance transferred with the active ingredients in a solid dispersion in which the polymer substance forms the continuous phase and the active substance forms the disperse phase and which is then comminuted and optionally processed in a known manner into solid pharmaceutical forms such as tablets. 2. The method according to claim 1, characterized in that the active ingredient in one or dispersed several liquid monomers, the resulting mass polymerized into a solid body and shredded to the desired shape and size. 3. The method according to claim 1, characterized in that the active ingredient in a latex dispersion or an aqueous dispersion of the polymer substance suspends or dissolves the polymer substance Coagulated to a finely divided, firm crumb and optionally from the crumb obtained sifts out the desired size. 4. The method according to claim 3, characterized in that the latex dispersion or the aqueous dispersion of the polymer substance which contains the active ingredient in suspension or solution, spray-dries or dries in a drum, the solid product obtained is ground and optionally sifts out the desired grain size from it. 5. The method according to claim 1, characterized in that the polymer substance in one Solvent dissolves, suspends the active ingredient in this solution or dissolves the suspension obtained or The solution is cast in a known manner to form a film, the film obtained is ground and removed from the obtained film Sift out the regrind to the desired grain size. 6. The method according to claim 1, characterized in that the solid dispersion using by pressure and heat on the mixture of polymer and active ingredient is produced. 7. The method according to claims 1 to 6, characterized in that the polymer substances polyethylene, tert. Butyl acrylate, methacrylic acid ester, such as the methyl, ethyl, fsopropyl or isobutyl ester, Mixed polymers of acrylonitrile and methyl acrylonitrile, mixed polymers of styrene and methyl styrene as well as polyvinyl chloride and its copolymers can be used. 8. The method according to claim 7, characterized in that to increase the permeability of Embedding mass of the polymer substance water-soluble, electrolysis-forming substances, such as sodium chloride, can be added. Considered publications:
German Patent No. 631,201;
Swiss patent specification No. 283 585 A priority document was displayed when the registration was announced. © 209 508/300 1.62