Pharmaceutical preparation in the form of a foil having an active substance incorporated therein

© Patent holder(s): Schering Aktiengesellschaft of Berlin and Bergkamen, Federal Republic of Germany.

© Avg.: Ir. Th.AHJ Smulders et al

United Patent Offices Nieuwe Parklaan 107 2587 BP The Hague.

© Application No. 7507785.

© Filed June 30, 1975.

© Priority claimed from July 5, 1974, and October 17, 1974.

© Country(ies) of priority: Federal Republic of Germany (DE).

© Priority application number(s): Nos. P 2432925 and P 2449865.

© Available for inspection 7 January 1976.

© Published June 1, 1990.

© Issued November 1, 1990.

Date: October 2, 1990.

METHOD FOR THE MANUFACTURE OF A FOIL-SHAPED MEDICINAL PREPARATION.

The invention relates to a process for the manufacture of a follicle-shaped medicinal preparation comprising a water-soluble cellulose derivative as a base and one or more medicinal substances evenly distributed therein.

British Patent No. 1,108,837 discloses a follicle-shaped medicinal preparation for use as a local anesthetic. It consists of a foil of film-forming material with an anesthetic active ingredient evenly distributed throughout it. Of the many follicle-forming substances used herein, including methylcellulose, ethylcellulose, and hydroxyalkyl ethers of cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and alkali metal carboxycellulose are preferred. The foil can be formed in any way, but the description and examples only mention formation by pouring and by spreading out the starting solution.

However, such preparations have the disadvantage that the follicle-forming substances used partially enclose the active ingredients and release them only slowly or not at all.

Belgian Patent 637,363 discloses paper films suitable as carriers for active pharmaceutical compounds. These films consist of water-insoluble cellulose fibers and a water-soluble binder. Sodium carboxymethylcellulose is the preferred water-soluble binder. The medicinal compound is incorporated either during the manufacture of the foil, or after the manufacture of the foil it is transferred to the paper foil by dropping it onto it in a dissolved state or sprinkling it on it in a solid state, or by passing the foil through a solution of the medicinal substance. The discontinuous method of preparing the foil and applying the medicinal substance separately (only this method is explained in the examples) has the disadvantage that the dosage accuracy is not particularly good; however, this accuracy is of great importance with today's medicinal substances dosed in low concentrations. Inaccuracies arise not only during the application of the medicinal substance, but also during the preparation and pretreatment of the carrier, as well as from changes in the carrier material during storage. For example, it has been shown that, according to the recipe in the Belgian patent, an even film layer is not formed when using film-drawing machines, and the film shrinks during drying.

From the German Offenlegungsschriften 1.800.580 and 1.931.080 medicinal preparations are known in liquid and ointment form, which only form a solid film after application to the skin.

U.S. Patent No. 3,803,300 discloses ointment-like films (dried oil-in-water emulsions). Unlike the gel-like medicinal preparations and placebos according to the invention, the films according to this U.S. patent contain oils or fats and emulsifiers.

The aim of the invention is to provide a method for manufacturing a medicinal preparation in the form of a film that does not exhibit the aforementioned disadvantages of medicinal films described above. The activity of the active ingredients must be retained in the film, and the film must not change during storage. Finally, the film material must not encapsulate the active ingredients and must fully release them upon use of the preparation.

This objective is now achieved by applying a special method of manufacturing the film and the use of special release agents. The method according to the invention is characterized in that a solution or suspension containing, in addition to the medicinal substance(s),

- 84% by weight solvent or suspending agent,

6-20 wt.% methylcellulose, ethyl cellulose, water-soluble hydroxyalkyl ethers of cellulose or water-soluble methylhydroxyalkyl ethers of cellulose as foeiievormer,

0-30 wt.% fillers and

0.01 - 2 wt.% polyoxyethylene, polyoxypropylene or polyoxyethylene, which is esterified with an acyl group or etherified with an alkyl group at a terminal hydroxyl group, as a release agent, which is drawn out into a film, dried and possibly divided into parts.

The release agent makes it easier to remove the film from the carrier tape during production.

Thanks to the release agent to be used according to the invention, which is absent in the medicinal foils according to British Patent No. 1,108,837 and Belgian Patent No. 637,363, the preparations manufactured according to the invention have a thickness that remains constant over time, while at the same time an even distribution of the medicinal substance over the foil and a complete release of the medicinal substance from the foil are ensured. Among the foeie-forming substances, those substances which are soluble in both water and organic solvents are preferred.

Suitable follicle-forming substances are methyl and ethyl cellulose, but preference is given to ' 2 ' non-ionic, water-soluble hydroxyalkyl ethers or methylhydroxyalkyl ethers of cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose and methylhydroxypropyl cellulose.

Suitable release agents are polyoxyethylenepolyoxypropylene polymers (trademark PLURONIC), polyoxyethylene stearates, and polyaddition products of ethylene oxide, which products are substituted by alkyl or acyl groups, for example the trade mark CREMOPHOR EL.

Suitable fillers include cellulose, sugars 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. When soluble fillers or medicinal substances are used, a transparent smooth film is formed, while when insoluble fillers or medicinal substances are used, a white or coloured papery film is formed.

According to the invention, all medicinal substances administered in human and veterinary medicine can be used. The preparations according to the invention can be applied internally or externally. Oral administration is particularly suitable for internal use. External application refers specifically to topical administration to the skin and in body cavities, such as the nose, ear, vagina, etc. Examples of medicinal substances that can be mentioned are: progestogens, estrogens, tranquilizers, antidiabetics, sulfonamides, antibiotics, antitrichomoniasis agents, anti-inflammatory agents such as corticosteroids, etc.

The active medicinal compound may be present in the carrier material in dissolved or uniformly suspended form. The amount of medicinal substance present in the film can be up to 60%. Dosage units are cut or perforated into sections containing quantities of medicinal substance that are also commonly found in tablets, coated tablets, ointments, and suppositories. In this way, the amount of medicinal substance per dosage unit can be chosen at will depending on the method of application and can be, for example, approximately 1 microgram to 0.5 gram, whereby the stated lower and upper limits can easily be exceeded either upwards or downwards.

To prepare the medicinal preparations in film form according to the invention, the medicinal substance and the release agent are dissolved or suspended in succession, the film-forming substance and, if applicable, the filler are added, if applicable, the mixture is homogenized, and the solution or suspension, respectively, is drawn out on a film-drawing machine to form a film that is still liquid. The foil obtained by drying the liquid film can be cut or otherwise divided into pieces (units) of any desired size.

The film-forming agent is added to the solution or suspension in quantities of 6 - 20% by weight, the filler in quantities of 0 - 30% by weight and the release agent in quantities of 0.01 - 2% by weight.

The solvent or suspending medium is present in an amount of 48-84% (W/W) and consists of water and/or one or more organic solvents. Suitable organic solvents are physiologically acceptable solvents or those that can be removed upon drying down to a residue to which there is no physiological objection. Such solvents include ethanol, isopropanol, methylene chloride, and mixtures thereof. Preferably water, ethanol or mixtures of water and ethanol are used.

The thickness of the wet film is approximately 0.1 to 2 mm and that of the dry film approximately

0.05 to 1 mm, preferably 0.07 to 0.3 mm.

The one-step method for preparing a medicinal preparation in foil form (continuous process) offers the advantage that the medicinal substance is homogeneously and evenly distributed throughout the carrier. By varying the concentration of the medicinal substance in the carrier, the thickness of the foil, and the surface area of the foil, the dosage unit can be easily changed.

Foils can also be manufactured with a still-liquid film, in which various medicinal substances and/or different concentrations of medicinal substances are incorporated alongside each other across the width of the foil strip. Using a special stripping device consisting of two or more chambers, various solutions or suspensions can be drawn out without mixing into a cohesive, still-wet film. The width and thickness of the still-liquid film can be adjusted individually for each chamber. If desired, zones (strips) containing different medicinal substances or with different concentrations can be visualized using different dyes. By drying the wet film a foil is obtained which, when suitably divided, for example by perforation, yields units with different active substances and/or concentrations of medicinal substance or units without active substance. Foils containing different medicinal substances and/or different concentrations of medicinal substances are required for the preparation of multi-phase preparations, for example, for the preparation of contraceptives. The possibility of spatially separating incompatible medicinal substances within a single foil unit improves the stability of the individual medicinal substances. For example, foil for intravaginal use can also be rolled around a standard commercially available tampon.

The invention is further illustrated by means of the following examples, in which, with the exception of Example XII, preparations are described which are primarily suitable for oral administration.

The following specifications can be given for the excipients used in the Examples:

- hydroxyalkylcellulose:

Hydroxypropylcellulose 75000-Klucelfrom Hercules, (p's

Hydroxyethylcellulose HEC-Tylose^ van Hoechst, (R)

Methyl hydroxypropyl cellulose-MethocelM 65 HG from Dow Chemical,

Cr)

Methylcellulose-MethocelMc from Dow Chemical,

- Cellulose:

fR) cellulose fibers - Elcema^ F150 from Degussa,

-Poly-N-vinylpyrrolidone: Kollidon® 25 from BASF,

- Starch:

Maize starch, according to the European Pharmacopoeia: Amylomaydis.

EXAMPLE I

Preparation of 1000 units.

0.25 g D-norgestrel,

0.05 g ethynyloestradiol and

0.84 g of polyoxyethylenepolyoxypropylene polymer (Pluronic F68, a brand name product of Wyandotte) were in

95.00 g of ethyl alcohol is dissolved while stirring, after which a powdery mixture of

16.93 g hydroxypropyl cellulose and

16.93 g of cellulose were added.

The resulting suspension was drawn out on a suitable film drawing device to a still liquid film with a thickness of 500 µm and then dried.

Composition for one unit:

0.25 mg D-norgestrel

0.05 mg ethynyloestradiol

0.84 mg polyoxyethylene polyoxypropylene polymer

16.93 mg hydroxypropyl cellulose

16.93 mg cellulose

35.00 mg

One unit corresponded to an area of about 3 cm²The foil was white and papery in appearance. The dry foil was approximately 170 m thick.

EXAMPLE II

Preparation for 1000 units.

1.10 g Cremophor EL were in

152.00 g of water were dissolved. In this solution 0.25 g of micronized D-norgestrel and

0.05 g micronized ethynyloestradiol suspended and, if necessary, homogenized. The suspension contained

22.10 g hydroxypropyl cellulose and

15.50 g cellulose was added.

The resulting suspension was drawn out on a suitable film drawing device into a film with a thickness of 500 m and then dried.

Composition for one unit:

<td>0.25 mg</td><td>D-norgestrel</td>

<td>0.05 mg</td><td>ethynyloestradiol</td>

<td>1.10 mg</td><td>Cremophor EL</td>

<td>22.10 mg</td><td>hydroxypropyl cellulose</td>

16.50 mg cellulose

40.00 mg

One unit corresponded to an area of about 3 cm²The appearance of the foil was white and papery. The dry foil had a thickness of approximately 170 μm.

The branded product Cremophor EL is a polyaddition product of ethylene oxide and castor oil (40 mol ethylene oxide to 1 mol glyceride).

EXAMPLE III

<td colspan="2">Preparation for 1000 units.</td>

<td>0.03 g</td><td>D-norgestrel and</td>

<td>0.84 g</td><td>polyoxyethylene monostearate-40 were used in</td>

<td>95.00 g</td><td>ethanol dissolved under stirring. In this solution a powdered mixture of</td>

<td>16.93 g</td><td>hydroxypropyl cellulose and</td>

<td>17.20 g</td><td>cellulose brought.</td>

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for one unit:

<td>0.03 mg</td><td>D-norgestrel</td>

<td>20 0.84 mg</td><td>polyoxyethylene monostearate-40</td>

<td>16.93 mg</td><td>hydroxypropyl cellulose</td>

<td>17.20 mg</td><td>cellulose</td>

35.00 mg

One unit corresponded to an area of about 3 cm²The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.

EXAMPLE IV

Preparation for 1000 units.

1.10 g of polyoxyethylenepolyoxypropylene polymer (Pluronic F88, a brand name product of Wyandotte) was dissolved in 152.00 g of demineralized water.

In this solution,

0.03 g micronized D-norgestrel suspended and, if necessary, homogenized.

In the suspension were

22.10 g hydroxypropyl cellulose and

16.77 g cellulose brought.

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and subsequently worn.

Composition for one unit:

0.03 mg D-norgestrel

1.10 mg polyoxyethylene polyoxypropylene polymer

22.10 mg hydroxypropyl cellulose

16.77 mg cellulose

40.00 mg

One unit corresponded to an area of about 3 cm²The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.

EXAMPLE V

Preparation for 1000 units.

10.0 g of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo-diazepine-4-oxide and 0.84 g of polyoxyethylene polyoxypropylene polymer (Pluronic F68) were added to

95.00 g of ethanol dissolved.

In this solution a powdered mixture of

16.93 g hydroxypropyl cellulose and

7.23 g cellulose added.

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for one unit:

10.00 mg 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo-diazepine-4-oxide

0.84 mg polyoxyethylene polyoxypropylene polymer

16.93 mg hydroxypropyl cellulose

7.23 mg cellulose

35.00 mg

One unit corresponded to an area of about 3 cm².

The appearance of the mace was yellow and papery.

The dry foil had a thickness of about 170 m.

EXAMPLE VI

<td>Preparation</td><td>for 1000 units.</td>

<td>1.00 g</td><td>Norethisterone acetate,</td>

<td>0.03 g</td><td>ethnylestradiol and</td>

<td>0.84 g</td><td>polyoxyethylene polyoxypropylene polymer (Pluronic F68) were used in</td>

<td>95.00 g</td><td>ethanol dissolved.</td>

<td colspan="2">In this solution a powdered mixture of</td>

<td>16.93 g</td><td>hydroxypropyl cellulose and</td>

<td>16.20 g</td><td>cellulose brought.</td>

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for one unit:

<td> 1,00</td><td>mg</td><td>Norethisterone acetate</td>

<td> 0,03</td><td>mg</td><td>ethynyloestradiol</td>

<td> 0,84</td><td>mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td> 16,93</td><td>mg</td><td>hydroxypropyl cellulose</td>

<td> 16,20</td><td>mg</td><td>cellulose</td>

35.00 mg

One unit corresponded to an area of about 3 cm²The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.

EXAMPLE VII

Preparation for 1000 units:

<td>1.00 g '</td><td>Norethisterone acetate,</td>

<td>0.03 g</td><td>ethynylestradiol and</td>

<td>0.84 g</td><td>polyoxyethylenepolyoxypropylene polymer (Pluronic F127, a brand name product of Wyandotte) in a mixture of</td>

<td>101.60 g</td><td>methylene chloride and</td>

<td>25.40 g</td><td>ethanol dissolved. In this solution a powdered mixture of</td>

<td>16.93 g</td><td>hydroxyethylcellulose and</td>

<td>16.20 g</td><td>brought corn starch.</td>

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for one unit:

1.00 mg Norethisterone acetate

0.03 mg ethynyloestradiol

0.84 mg polyoxyethylene polyoxypropylene polymer

16.93 mg hydroxyethylcellulose and

16.20 mg corn starch

35.00 mg

One unit corresponded to an area of about 3 cm².

The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.

EXAMPLE VIII

Preparation for 1000 units:

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for a unit:

<td>1.00 g</td><td>Norethisterone acetate</td>

<td>0.03 g</td><td>ethynylestradiol and</td>

<td>0.84 g</td><td>polyoxyethylene monostearate-40 were used in</td>

<td>95.00 g</td><td>ethanol dissolved.</td>

<td>In</td><td>this solution became a powdery mixture</td>

<td>16.93 g</td><td>hydroxypropyl cellulose</td>

<td>8.10 g</td><td>lactose and</td>

<td>8.10 g</td><td>corn starch.</td>

<td> 1,00</td><td>mg</td><td>Norethi sterone acetate</td>

<td> 0,03</td><td>mg</td><td>ethynyloestradiol</td>

<td> 0,84</td><td>mg</td><td>polyoxyethylene monostearate-40</td>

<td> 16,93</td><td>mg</td><td>hydroxypropyl cellulose</td>

<td> 8,10</td><td>mg</td><td>lactose</td>

<td> 8,10</td><td>mom</td><td>corn starch</td>

35.00 mg

One unit corresponded to an area of about 3 cm². 20 The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.

EXAMPLE IX

Preparation for 1000 units:

1.00 g Norethisterone (17a-ethynyl-19-nor-testosterone)

0.03 g ethynyloestradiol and

0.22 g of polyoxyethylenepolyoxypropylene polymer (Pluronic F68) was mixed with

84.75 g ethanol and

4.00 g of water was dissolved. In this solution a powdered mixture of

16.00 g hydroxypropyl cellulose and

16.00 g cellulose added and, if necessary, homogenized.

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 600 µm and then dried.

Composition for one unit:

<td>1.00 mg</td><td>Norethisterone (17a-ethynyl-19-nor-testosterone)</td>

<td>0.03 mg</td><td>ethynyloestradiol</td>

<td>0.22 mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td>16.00 mg</td><td>hydroxypropyl cellulose</td>

<td>16.00 mg</td><td>cellulose</td>

<td>33.25 mg</td><td></td>

The unit area was about 3 cm².

The foil had a white, papery appearance. The dry foil was approximately 230 μm thick.

EXAMPLE X

Preparation for 1000 units:

*1

4.0 g of Glisoxepide ' in micronized form were dissolved in 0.9 g of polyoxyethylene monostearate-40, in

152.0 g water suspended and, if necessary, homogenized.

In the suspension were

15.0 g hydroxyethylcellulose and

15.1 g of calcium carbonate was added.

The resulting suspension was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for a unit:

*1

4.00 mg Glisoxepide '

0.90 mg polyoxyethylene monostearate-40

15.00 mg hydroxyethylcellulose

15.10 mg calcium carbonate

35.00 mg

One unit corresponded to an area of about 3 cm².

The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 um.

) 4-^4-[β-(5-Methyl-isoxazole-3-carboxamido)-ethyl]-benzene-sulfonyl^-1,1-hexamethylene-semicarbazide.

EXAMPLE XI

Preparation for 1000 units:

0.04 g Saccharin,

0.04 g room essence and

0.40 g of polyoxyethylenepolyoxypropylene polymer (Pluronic F68) was mixed with

79.00 g ethanol and

4.00 g of water dissolved. In this solution

30.00 g iron(II) fumarate,

15.00 g hydroxypropyl cellulose

5.52 g cocoa and

4.00 g cellulose added and, if necessary, homogenized.

The suspension thus obtained was drawn out on a suitable film drawing device into a film with a thickness of 0.5 mm and then dried.

Composition for a unit:

<td> 30,00</td><td>mg</td><td>Iron(II) fumarate</td>

<td> 15,00</td><td>mg</td><td>hydroxypropyl cellulose</td>

<td> 4,00</td><td>mg</td><td>cellulose</td>

<td> 0,40</td><td>mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td> 5,52</td><td>mg</td><td>cocoa</td>

<td> 0,04</td><td>mg</td><td>saccharin</td>

<td> 0,04</td><td>mg</td><td>room essence</td>

<td colspan="2">55.00 mg</td><td>weight per unit</td>

One unit corresponded to an area of about 3 cm².

The appearance of the mace was light reddish brown.

EXAMPLE XII

Foil for intravaginal application:

Preparation for 1000 units:

100.0 g of 5-morpholinomethyl-3-(5-nitro-1-methyl-2-imidazolyl-methyleneamino-2-oxazolidinone.HCl were added to

8.4 g of a polyaddition product of ethylene oxide and castor oil (40 moles of ethylene oxide to 1 mole of glyceride), dissolved in

508.0 g alcohol/water suspended 1/1. In this suspension were

169.2 g methyl hydroxypropyl cell luiose and

72.4 g cellulose absorbed.

The resulting suspension was spread on a film-drawing apparatus to a layer 500 µm thick and dried.

Composition for one unit:

100.0 5-Morpholinomethyl-3-(5-nitro-1-methyl-2-imidazolyl)methyleneamino-2-oxazolidinone . HC1

8.4 mg Cremophor EL

159.2 mg methyl hydroxypropyl cellulose

72.4 mg cellulose

350.0 mg weight per unit.

One unit corresponded to an area of approximately 8 x 4 cm.

The appearance of the mace was light yellow.

The foil (1 unit) was either wrapped around a standard commercially available tampon or rolled up as such into a narrow tube.

EXAMPLE XIII

A two-phase preparation.

Part 1: of this consisted of 21 units with medicinal substance Part 2: consisted of 7 units without medicinal substance.

Preparation for 3000 units (part 1)

0.75 g D-norgestrel,

0.15 g ethynyloestradiol and

0.54 g of polyoxyethylenepolyoxypropylene polymer (Pluronic F87, a brand name product of Wyandotte) was added to a mixture of

237.00 g ethanol and

12.00 g of water dissolved. In this solution were

44.28 g hydroxypropyl cellulose and

44.28 g cellulose added and, if necessary, homogenized.

Preparation for 1000 units (part 2)

0.18 g of polyoxyethylenepolyoxypropylene polymer was added to a mixture of

79.00 g ethanol and

4.00 g of water dissolved. In this solution

14.91 g hydroxypropyl cellulose and

14.91 g cellulose added and possibly homogenized.

The resulting suspensions were drawn out to a 0.5 mm film on a suitable film-drawing device with a two-chamber stripper (chamber width: chamber 1 = 54 mm; chamber 2 = 18 mm) and then dried. By appropriately dividing the film into 18 x 18 mm units, for example, by perforation, three units containing and one unit without the drug could be obtained across the width of the film.

A desired number of pieces could be cut from the foil strip, in the ratio of three units with and one unit without medicinal substance.

Composition for each of the units:

Part 1 (with active ingredient)Part 2 (without active ingredient)

<td>0.25 mg</td><td>D-norgestrel</td><td> -</td>

<td>0.05 mg</td><td>ethylestradiol</td><td> -</td>

<td>14.76 mg</td><td>hydroxypropyl cellulose</td><td>14.91 mg</td>

<td>14.76 mg</td><td>cellulose</td><td>14.91 mg</td>

<td>0.16 mg</td><td>polyoxyethylenepolyoxypropylene polymer</td><td>0.18 mg</td>

<td>30.00 mg</td><td>weight per unit</td><td>30.00 mg</td>

Surface area per unit approximately 3 cm²Appearance: white part 2 consisted of part 3 consisted of 7 units

0.055 g 0.198 g 86.900 g 4.400 g 16.346 g 16.346 g

EXAMPLE XIV

A three-phase preparation (preparation with two therapeutic bridging steps). Part 1 consisted of 11 units of 0.05 mg D-norgestrel.

0.05 mg ethynyloestradiol 10 units with 0.125 mg D-norgestrel

0,050 mg ethynyloestradiol without medicinal compound.

Preparation for 1100 units (part 1):

0.055 g of D-norgestrel, ethynylestradiol, and polyoxyethylenepolyoxypropylene polymer were dissolved in a mixture of ethanol and water. Hydroxypropylcellulose and cellulose were added to this solution and homogenized if necessary.

Preparation for 1000 units (part 2):

0.125 g of D-norgestrel, ethynylestradiol, and polyoxyethylenepolyoxypropylene polymer were dissolved in a mixture of ethanol and water. 14.823 g of hydroxypropylcellulose and cellulose were added to this solution and homogenized if necessary.

Preparation for 700 units (part 3):

0.189 g of polyoxyethylenepolyoxypropylene polymer was added to a mixture of

0.050 g 0.180 g 79.000 g 4.000 g 14.823 g 14.822 g

82.950 g ethanol and

4,200 g of water were dissolved. In this solution,

15.655 g hydroxypropyl cellulose and

15.655 g cellulose added and, if necessary, homogenized.

The suspensions thus obtained were drawn out into a film on a suitable film-drawing device equipped with a special three-chamber stripper (width per chamber 18 mm) and then dried. By suitable division, for example by perforation, into 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 contents of medicinal compound could be obtained across the width of the foil.

Preparations containing 11 units (part 1), 10 units (part 2) and 7 units (part 3) could be separated from the foil band.

The composition per unit was:

<td>Part 1</td><td>Part 2</td><td>Part 3</td><td>Incorporated substances</td>

<td>0.050 mg</td><td>0.125 mg</td><td> -</td><td>D-norgestrel</td>

<td>0.050 mg</td><td>0.050 mg</td><td> -</td><td>ethynyloestradiol</td>

<td>0.180 mg</td><td>0.180 mg</td><td>0.270 mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td>14,860 mg</td><td>14,823 mg</td><td>22,366 mg</td><td>hydroxypropyl cellulose</td>

<td>14,860 mg</td><td>14,822 mg</td><td>22,364 mq</td><td>cellulose</td>

<td>30,000 mg</td><td>30,000 mg</td><td>45,000 mg</td><td>weight per unit</td>

<td>approx. 3 cm²</td><td>approx. 3.5 cm²</td><td>approx. 5 cm²</td><td>surface area per unit</td>

<td>white</td><td>white</td><td>white</td><td>appearance</td>

EXAMPLE XV

A three-phase preparation.

Part 1 consisted of 11 units of 0.05 mg D-norgestrel

0.05 mg ethynyloestradiol part 2 consisted of 10 units with 0.125 mg D-norgestrel

0.050 mg ethynyloestradiol part 3 consisted of 7 units with 50.00 mg iron(II) fumarate

<td>Preparation</td><td>for 1100 units (part 1):</td><td></td>

<td>0.066 g</td><td>Food Yellow No. 2 (Tartrazine; E 102) was introduced in</td><td></td>

<td>4,400 g</td><td>dissolved in water and then in</td><td></td>

<td>86,900 g</td><td>ethanol was added. In this solution</td><td></td>

<td>0.055 g</td><td>D-norgestrel,</td><td></td>

<td>0.055 g</td><td>ethynylestradiol and</td><td></td>

<td>0.198 g</td><td>polyoxyethylenepolyoxypropylene polymer dissolved.</td><td></td>

<td colspan="2">In this solution,</td><td></td>

<td>15,313 g</td><td>hydroxypropyl cellulose and</td><td></td>

<td>16,313 g</td><td>cellulose added and possibly homogenized.</td><td></td>

<td>Preparation</td><td>for 1000 units (part 2):</td><td></td>

<td>0.065 g</td><td>Food Orange No. 2 (Sunset Yellow; E 110) was</td><td>in</td>

<td>4,000 g</td><td>dissolved in water and then in</td><td></td>

<td>79,000 g</td><td>ethanol was added. In this solution</td><td></td>

<td>0.125 g</td><td>D-norgestrel,</td><td></td>

<td>0.050 g</td><td>ethynylestradiol and</td><td></td>

<td>0.180 g</td><td>polyoxyethylenepolyoxypropylene polymer dissolved.</td><td></td>

<td colspan="2">In this solution,</td><td></td>

<td>14,790 g</td><td>hydroxypropyl cellulose and</td><td></td>

<td>14,790 g</td><td>cellulose added and possibly homogenized.</td><td></td>

<td>Preparation</td><td>for 700 units (part 3):</td><td></td>

<td>0.042 g</td><td>saccharin,</td><td></td>

<td>0.042 g</td><td>room essence and</td><td></td>

<td>0.406 g</td><td>polyoxyethylenepolyoxypropylene polymer were in a</td><td>mixture of</td>

<td>55,300 g</td><td>ethanol and</td><td></td>

<td>2,800 g</td><td>dissolved in water. In this solution were</td><td></td>

<td>35,000 g</td><td>iron(II) fumarate,</td><td></td>

17,500 g hydroxypropyl cellulose

5,950 g cocoa and

4,060 g cellulose added and, if necessary, homogenized.

The suspensions thus obtained were drawn out on a suitable film-drawing device with a special stripping device consisting of three chambers (width per chamber 18 mm) to a still-wet film and then dried. By suitable division, for example by perforation, into 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 contents of medicinal compound could be obtained across the width of the foil.

Preparations containing 11 units (part 1), 10 units (part 2) and 7 units (part 3) could be separated from the foil band.

Composition per unit:

<td></td><td>Part 1</td><td>Part 2</td><td>Part 3</td><td>Incorporated compounds</td>

<td> 15</td><td>0.050 mg</td><td>0.125 mg</td><td> -</td><td>D-norgestrel</td>

<td></td><td>0.050 mg</td><td>0.050 mg</td><td> -</td><td>ethynyloestradiol</td>

<td></td><td> -</td><td> -</td><td>50,000 mg</td><td>iron(II) fumarate</td>

<td></td><td>0.180 mg</td><td>0.180 mg</td><td>0.580 mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td></td><td>0.050 mg</td><td> -</td><td> -</td><td>food yellow No. 2</td>

<td> 20</td><td> -</td><td>0.065 mg</td><td> -</td><td>food orange No. 2</td>

<td></td><td>14,830 mg</td><td>14,790 mg</td><td>25,000 mg</td><td>hydroxypropyl cel 1 uiose</td>

<td></td><td>14,830 mg</td><td>14,790 mg</td><td>5,800 mg</td><td>cellulose</td>

<td></td><td> -</td><td> -</td><td>8,500 mg</td><td>cocoa</td>

<td></td><td> -</td><td> -</td><td>0.060 mg</td><td>saccharin</td>

<td> 25</td><td> -</td><td> -</td><td>0.060 mg</td><td>room essence</td>

<td></td><td>30,000 mg</td><td>30,000 mg</td><td>90,000 mg</td><td>weight per unit</td>

<td></td><td>approx. 3 cm²</td><td>approx. 3.5 cm²</td><td>approx. 5 cm²</td><td>surface area per unit</td>

<td></td><td>yellow</td><td>orange</td><td>brown</td><td>onion appearance</td>

<td> 30</td><td colspan="2">EXAMPLE XVI</td><td></td><td></td>

<td></td><td>Preparation</td><td>for 1000 units:</td><td></td><td></td>

<td></td><td>0.15 g</td><td>D-norgestrel,</td><td></td><td></td>

<td></td><td>0.03 g</td><td>ethynylestradiol and</td><td></td><td></td>

<td></td><td>0.84 g</td><td colspan="3">polyoxyethylene polyoxypropylene polymer (Pluronic F68) were used in</td>

<td> 35</td><td>95.00 g</td><td colspan="2">ethanol dissolved under stirring, after which</td><td>in this solution a powdery mixture of</td>

<td></td><td>16.99 g</td><td>hydroxypropyl cellulose</td><td>and</td><td></td>

<td></td><td>16.99 g</td><td colspan="2">cellulose was brought.</td><td></td>

The suspension thus obtained was drawn out on a suitable film drawing device to a film thickness of 500 µm and then dried.

Composition for one unit:

<td>0.15 mg</td><td>D-norgestrel</td>

<td>0.03 mg</td><td>ethynyloestradiol</td>

<td>0.84 mg</td><td>polyoxyethylenepolyoxypropylene polymer</td>

<td>16.99 mg</td><td>hydroxypropyl cellulose</td>

<td>16.99 mg</td><td>cellulose</td>

35.00 mg

One unit corresponded to an area of about 3 cm²The appearance of the mace was white and papery.

The dry foil had a thickness of about 170 µm.