NO752416L - - Google Patents

Description

Drug carrier.

The present invention relates to pharmaceutical active substance carriers in foil form with incorporated active substance for internal and external use.

Paper foils are known from Belgian patent specification 637-363

which is coated with active ingredient, is suitable for oral use. The foils consist of cellulose fibers that are insoluble in water, and a water-soluble binder. Sodium carboxymethylcellulose is preferably used as a water-soluble binder. The active substance is placed on the paper foil by dripping the dissolved active substance, by sprinkling the solid active substance or by pulling the foil through the active substance solution. The discontinuous method of the separate production of the foil and the application of the active substance has the disadvantage that the dosage accuracy is not particularly good, which is, however, of the greatest importance with the current low-dose active substances. Inaccuracies occur not only in the application of the active substance, but also in the manufacture and pretreatment of the carrier and in changes during storage of the carrier material. thus it has e.g. it has been shown that according to the regulations in the Belgian patent when using foil drawing machines, no uniform foil layer is formed and that the foil shrinks when drying. However, it will be easy to understand that with non-uniform materials, there will also not be a uniform absorption of the active ingredient. An active substance that is only bound on the surface can also, when handling the foil, such as when wrapping, again partially released. The sodium carboxymethylcellulose used as a binder dissolves in the stomach and thereby releases the carboxymethylcellulose which partially encloses the active substance and only delays or does not release it at all.

It has now been shown that foils with a uniform thickness and uniform active substance distribution are obtained when foils with incorporated active substance are produced and foil formers that are soluble in water or in organic solvents are used. Preferably foil-. suitable formers which dissolve both in water and in organic solvents.

As foil formers, e.g. poly-N-vinylpyrrolidone, vinylpyrrolidone-vinyl acetate, methyl- and ethylcellulose, but preferably non-ionic, water-soluble hydroxyalkyl ethers of cellulose,

such as hydroxypropyl cellulose, hydroxyethyl cellulose and methylhydroxypropyl cellulose, in consideration.

Fillers and active ingredients can be added to the foil former and, appropriately, a small amount of a release agent.

Suitable separators are, among other things, polyoxyethylene polyoxypropylene polymers ("PLURONIC F 68"), polyoxyl stearates, alkyl or acyl-substituted polyaddition products of ethylene oxide e.g. "CREMOPHOR EL", silicones and silicone separating emulsions, glycerol, propylene glycol and metal soaps.

As fillers are e.g. cellulose, sugar, such as lactose, dextrose, cane sugar etc., starches, polyhydric alcohols such as mannitol, calcium carbonate, calcium phosphate, talc and dyes in soluble form or as pigments, suitable. The fillers can be partially or completely replaced with active substances. Are soluble fillers used, or active substances, a transparent, smooth foil is formed, and insoluble fillers are used, respectively active substances, a white or coloured, paper-like foil is formed.

According to the invention, all active substances used in human and veterinary medicine can be used. For internal use, oral administration is particularly suitable. Under external application is understood in particular the local administration on the skin and in body cavities such as the nose, ear, vagina, etc. As active substances, e.g. are mentioned: progestogens, oestrogens, mixtures of progestogens and oestrogens, psychosedatives, antidiabetics, sulphonamides, antibiotics, trichomonad agents, anti-inflammatory agents such as e.g. corticoids, etc.

The active pharmaceutical ingredient can be dissolved or uniformly suspended in the carrier material. The proportion of active substance in the foil can amount to approx. 0 - 60%. As a single dose (unit) cut, resp. are perforated, surfaces that contain the amounts of active substance that are usually also found in tablets, dragées, ointments, small sticks, etc. thus the amount of active substance per single dose, depending on the type of application, can be as high as desired and amount to between approx. 1 p.g and 0.5 g, where the lower and upper dose can easily be under or exceeded. Of course, active substance-free carriers (placebos) can also be produced.

When producing the pharmaceuticals according to the invention in foil form, the active ingredient and/or the separating agent is dissolved, or suspended, added to the foil former and optionally the filler, optionally homogenised and the solution, respectively the suspension<t>, drawn out to a layer in a foil drawing machine. The film obtained by drying the coated film is divided into sections (units) as desired.

In the resolution, respectively the suspension, the film former is used in quantities by weight of approx. 6 - 20%, the filler in weight amounts of approx. 0 -

30%, and the separating agent preferably in amounts by weight of 0.01-2%.

Resolution resp. the suspending agent is present in an amount

of approx. 48 - 84% by weight, and consists of water and/or one or more organic solvents. As an organic solvent, physiologically acceptable solvents or such solvents come into consideration, which can be removed by drying to a physiologically harmless residue. Such solvents are e.g. ethyl alcohol, isopropanol, methylene chloride, etc. and mixtures thereof.

Water and ethyl alcohol, respectively mixtures of water and ethyl alcohol are preferably used.

The layer thickness of the wet area is approx. 0.1 - 2 mm, and the thickness of. the dry foil amounts to 0.05 - 1 mm, preferably 0.07 - 0.3 mm'.

The procedure for producing the medicinal product in foil form i

a work operation (continuous method) offers the advantage that the active ingredient is present homogeneously and evenly distributed in the active ingredient carrier. Depending on the concentration of the active substance in the carrier, the thickness of the foil and the surface of the foil, the single dose can be varied very easily. Foils can also be produced with an area in which different active substances and/or different active substance concentrations are incorporated next to each other over the width of the foil band. With the help of a special coating knife, which consists of two or more chambers, different solutions, resp. suspensions, without mixing are applied in a continuous coat. The width and thickness of the coating is separately adjustable for each chamber. Optionally, zones (stripes) with different active substances, resp. different concentrations, are made visible by different dyes. When drying the wet topcoat, a foil is obtained which, by corresponding division, e.g. by perforation, gives units with different active substances and/or active substance concentrations, respectively units without active substance. Foils with different active substances and/or different active substance concentrations are needed for the production of

multiphase preparations, e.g. for the production of preparations for preventing conception. The possibility of spatial separation of active substances that are incompatible with each other in a foil unit improves the stability of the individual active substances. Foils for intravaginal use can e.g. also rolled in a commercially common tampon.

The invention also relates to the use of foil formers soluble in water and/or organic solvents for the production of pharmaceutical active substance carriers, in particular the use of non-ipnogenic, water-soluble hydroxyalkyl ethers of cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose and/or methylhydroxypropyl cellulose.

With the exception of examples 5 and 16, the exemplary preparations described are preferably suitable for oral administration.

Example 1

Production of 1000 units.

The obtained suspension is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm, and then dried.

Composition for one unit:

One unit corresponds to an area of approx. 3 cm<2>.

Appearance of the foil: white, papery.

The dry foil has a thickness of approx. 170 [im.

Example 2

Production of 1000 units:

■ h

The resulting suspension is spread on a suitable film coating device to a layer with a layer thickness of 500 µm and dried

o

so.

Composition for one unit:

One unit corresponds to an area of approx. 3 cm 2.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 \ xm.

Example 3

Production of 1000 units:

The resulting suspension is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2. Appearance of the foil: white, papery. The dried foil has a thickness of approx. 170 |im.

Example 4

Production of lOOO units:

The obtained suspension is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2. Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 |im.

Example 5

Production of 1000 units:

The obtained solution is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm and dried sa.

Composition of a unit:

One unit corresponds to an area of approx. 1 cm 2.

Appearance of the foil: transparent.

The dried foil has a thickness of approx. 70 |im. The film is suitable for local application.

Example 6

Production of 1000 units:

The obtained suspension is drawn on a suitable foil drawing device to a layer with a layer thickness of 500 (im) and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm.

Appearance of the foil: yellow, papery.

The dried foil has a thickness of approx. 170[im.

Example 7

Production of 1000 units:

The resulting suspension is drawn out on a suitable film drawing apparatus to a layer with a layer thickness of 500 µm and dried

o

so.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 [im.

Example 8

Production of 1000 units:

The obtained suspension is drawn out on a suitable foil drawing apparatus to a layer with a layer thickness of 500 (im) and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2,

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 |im.

Example 9

Production of 1000 units:

The resulting suspension is drawn out in a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 (im.

Example 10

Production of 1000 units:

The obtained suspension is drawn out on a suitable foil drawing apparatus to a layer with a layer thickness of 500 (im) and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm 2.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 (im.

Example 11

Production of 1000 units:

The obtained suspension is drawn out on a suitable foil drawing device to a coating with a layer thickness of 600 (im) and dried.

Composition of a unit:

2

Flat per unit: approx. 3 cm. Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 230[im.

Example 12

Production of 1000 units:

The resulting suspension is drawn out in a suitable foil drawing apparatus to a coating with a layer thickness of 500 (im) and dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 (im.

Example 13

Production of 1000 units:

The resulting suspension is drawn out on a suitable foil drawing device to a coating with a layer thickness of 500 (im) and dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm.

Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170 \ xm.

Example 14

Production of lOOO units:

The obtained suspension is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm and then dried.

Composition of a unit:

Example 15

Production of 1000 units:

The thus obtained suspension is drawn out on a suitable foil drawing apparatus to a layer with a layer thickness of 0.5 mm and then dried.

Composition of a unit:

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: light reddish brown.

Example 16

Film for intravaginal administration: The production of the film takes place according to example 11. Composition of a unit:

One unit corresponds to an area of approx. 8 x 4 cm. Appearance of the foil: light yellow.

The foil (1 unit) is either rolled around a normal commercial tampon or rolled separately into a thin tube.

Example 17

Two-phase preparation

Part 1: 21 units of active ingredient

Part 2: 7 units without active substance

Production of 3000 units of part 1:

Production of 1000 units of Part 2:

The suspensions thus obtained are drawn on a suitable foil drawing apparatus with a two-chamber special coating knife (chamber width: 1 = 54 mm; 2 = 18 mm) to a layer of 0.5 mm thickness, and dried. By corresponding division into units of 18 x 18 mm, e.g. by perforation, three units with active substance and one unit without active substance can be separated across the width of the foil. From the foil tape, as many sections as desired can now be produced in the ratio of three units with active substance and one unit without active substance.

Composition of each unit:

2

Flat per unit: approx. 3 cm.

Appearance: white.

Example 18

Three-phase preparation (preparation with two active ingredient stages) Part 1: 11 units with 0.05 mg d-norgestrel

0.05 mg ethinylestradiol Part 2: 10 units with 0.125 mg d-norgestrel

0.050 mg ethinylestradiol Part 3: 7 units without active substance

Production of 1100 units of Part 1:

Production of 1000 units of part 2:

Production of 700 units of Part 3:

The solutions obtained in this way are drawn onto a suitable foil - drawing apparatus with a three-chambered special-best drawing knife (width per chamber 18 mm) into one layer and dried. In case of corresponding sharing, e.g. by perforation, in units of 18 x 18 mm for part 1, 18 x 19.8 mm for part 2 and 18 x 28 mm for part 3, three units with different active ingredient contents can be separated across the width of the foil. Preparations with 11 units of part 1 can be separated from the foil tape,

10 units of part 2 and 7 units of part 3-

Composition per unit:

Example 19

Three-phase preparation:

Part 1: 11 units of 0.05 mg d-norgestrel

0.05 mg ethinylestradiol

Part 2: 10 units with 0.125 mg d-norgestrel

0.050 mg ethinylestradiol

Part 3: 7 units of 50.00 mg of ferrous fumarate

Production of 1100 units of Part 1:

Production of 1000 units of part 2:

Production of 700 units of Part 3:

The thus obtained suspensions are drawn on a suitable foil drawing apparatus with a three-chamber special coating knife (width per chamber 18 mm) to a coat and then dried. In case of corresponding division,

e.g. by perforation, to units of 18 x 18 mm for part 1,

18 x 19.8 mm for part 2 and 18 x 28 mm for part 3, three units with different (active ingredient - content) can be separated across the width of the foil. The foil tape can be used to separate preparations with 11 units of part 1, 10 units of part 2 and 7 units of part 3.

Composition per unit:

Example 20

Production of 1000 units:

The obtained suspension is drawn on a suitable foil drawing apparatus to a layer with a layer thickness of 500 µm and then dried.

Composition of a tablet:

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery.

The dried foil has a thickness of approx. 170[im.

Claims (1)

1. Medicinal substance carrier in film form with incorporated active ingredient, characterized in that it contains film formers which are soluble in water or organic solvents. 2. Medicine according to claim 1, characterized in that the foil former is soluble in water and in organic solvents. 3. Medicine according to claim 1 or 2, characterized in that non-ionic, water-soluble hydroxyalkyl ethers of cellulose are used as film formers. k- Medicine according to claims 1 - 3> characterized in that hydroxypropyl cellulose, hydroxyethyl cellulose and/or methylhydroxypropyl cellulose are used as film formers. 5. Medicine according to claim 1, characterized in that the medicinal active substance in the foil constitutes 0 - 6o%. • 6. Medicine according to claim 1 or 5, characterized in that the medicinal active substance is dissolved or uniformly suspended in the carrier material. 7- Method for the production of a medicinal product in foil form according to claims 1-6, characterized in that one dissolves or suspends the active ingredient and/or the separating agent, introduces a foil former and optionally a filler, optionally homogenises, extracts the solution or suspension on a foil drawing machine for a topcoat and divides the foil obtained by drying the topcoat into pieces (units) of your choice. 8» Method according to claim 7, characterized in that the foil former is used in an amount of 6 - 20%, the filler in an amount of 0 - 30% and the separating agent preferably in an amount of 0.01 - 2%. 9. Method according to claim 7" characterized by the fact that one who dissolves or suspending agent uses water and/or an organic solvent. 10. Method according to claim 7 or 9> characterized in that the dissolution or the suspending agent is present in an amount of 48 - 84%. 11. Method according to claim 7, characterized in that the layer thickness of the coating is 0.1 - 2 mm and that the thickness of the foil is 0.05 1 mm.