FI60354B - FOERFARANDE FOER FRAMSTAELLNING AV LAEKEMEDEL I FOLIEFORM - Google Patents

Description

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Ma 1 J (11) UTLÄGGNINGSSKRIFT 60 35 4 C (45) Patent granted 11 01 1932 Patent oeddelat ^ (51) KY.ik.3 / int.a.3 A 61 K 9/70 ENGLISH I - Fl N LAN D ( M) P «M" ttlh «k.mu * - P» t «nt.n» ölcn »n * T51Ö01 (22) Hakamispllvt - Antttknlngidag 17 · 06.7 5 (23) Alkuplivi — Giltl | hcuda (17 · θ6. 75 (41) Interpreters | external - Bllvlt offmtllg 06.01 j6

Patent and Registration Office .... .

. , (44) Date of NihUviksIpanon and the month of publication. - Q,

Patent Office of the Federal Republic of Germany published 30.09.Oi (32) (33) (31) Requested «cuoftais —Begird prlorltet 05.07.7 ^ 17.10.7 ^ Federal Republic of Germany-Republic of Germany -7 »P 2Uk9865.5 (71) Schering Aktiengesellschaft, Berlin / Bergkamen, DE; Mullerstrasse 170-172, 1 Berlin 65 »Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Peter Fuchs, Berlin, Jurgen Hilmann, Berlin, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7 * +) Oy Kolster Ab (5H) Method for the manufacture of a medicinal product in the form of a film - Förfarande för framställning av läkemedel i folieform

The present invention relates to a process for the preparation of a medicament for oral or topical administration in the form of a film having an active ingredient content of about 0 to 60% by weight relative to the total weight of the film.

Belgian patent 637 363 discloses paper films which, when coated with an active ingredient, are suitable for oral administration. The films consist of water-insoluble cellulose fibers and a water-soluble binder. Sodium carboxymethylcellulose is preferably used as the water-soluble binder. The active ingredient is introduced into the paper film by dripping the dissolved active ingredient, scattering the solid active ingredient, or drawing the film through the active ingredient solution. This discontinuous method of manufacturing the film and the application of the active ingredient has the disadvantage that the dosing accuracy is not very good, which, however, is very important with the active ingredients currently being administered. Inaccuracies arise not only during the application of the active ingredient, but also during the preparation and pre-treatment of the carrier and during the storage of the carrier 2 60354. Thus, for example, it has been found that, in accordance with the instructions of this Belgian patent, the use of film-drawing machines does not result in a uniform film layer and that the film shrinks when dried. However, it is easy to see that in the case of non-uniform substances, the acceptability of the active ingredient is not uniform. In addition, only the surface-bound active ingredient may partially detach during handling of the films, such as in the packaging step. The sodium carboxymethylcellulose used as a binder dissolves in the stomach, thereby releasing the carboxymethylcellulose, which partially silences the active substance and only slows down or does not release it at all.

The process according to the invention for obtaining films which retain their thickness and uniform distribution of the active ingredient is characterized in that the active ingredient and optionally a release agent, preferably in an amount of 0.01 to 2% by weight based on the total weight of the solution or suspension, is dissolved or suspended in water and / or one to a solvent or suspending agent consisting of one or more physiologically acceptable organic solvents in an amount of L8-8% by weight based on the total weight of the solution or suspension is added about 6-20% by weight of nonionic, water-soluble cellulose hydroxyalkyl ethers acting as film formers methyl hydroxyalkyl ethers, preferably hydroxypropyl, hydroxyethyl or methylhydroxypropylcellulose, or methyl or ethylcellulose or a mixture of the two, and optionally 0-30% by weight of excipient; optionally homogenized; drawing the solution or suspension on a film-drawing machine into a wet spread with a thickness of 0.1-2 mm and drying the wet spread to obtain a uniform dry film with a thickness of 0.05-1 mm.

Fillers and active ingredients and, suitably, a smaller amount of a release agent may be added to the film formers.

Suitable release agents include e.g. polyoxyethylene polyoxypropylene polymers (PLUB0NIC F 68 ^), polyoxystearates, alkyl- or acyl-substituted polyaddition products of ethylene oxides, for example CREMOPH0R EL'- ', silicones and silicone separation emulsions, glycerol, propylene glycol and metal.

Suitable fillers are, for example, cellulose, sugar, such as lactose, dextrose, cane sugar, etc., starches, polyhydric alcohols, such as mannitol, calcium carbonate, calcium phosphate, talc and colorants in soluble form or as pigments. Fillers may be partially or completely replaced by active ingredients. If soluble fillers or 3 60354 active ingredients are used, transparent, smooth films are formed; if insoluble fillers or active ingredients are used, a white or colored, paper-like film is formed.

According to the invention, all active ingredients used in human and veterinary medicine can be used. For internal use, oral administration in particular comes into question. Topical use is to be understood here as topical application to the skin and body cavities, such as the nose, ear, vagina, etc. Examples of active ingredients are: pregnancy agents, estrogens, mixtures of pregnancy agents and estrogen, tranquilizers, antidiabetics, sulfonamides, sulphonamides , Trichomonas, anti-inflammatory agents such as corticoids, etc.

The active drug may be dissolved or uniformly suspended in a carrier. The proportion of active substance in the film may be about 0-60 #. Surfaces containing the same amounts of active ingredient as tablets, granules, ointments, suppositories, etc. are cut or perforated into a single dose. Thus, depending on the application, the amount of active ingredient per single dose can be freely selected and from about 1 to 0.5 g. limits can easily be exceeded or exceeded. Of course, active ingredient-free carriers (Placebos) can also be prepared.

A film former of about 6-20% by weight, a filler of about 0-30% by weight and a release agent, preferably 0.01% by weight, are added to the solution or suspension.

The solvent or suspending agent is about h8-8h by weight and consists of water and / or one or more organic solvents. Suitable organic solvents are physiologically tolerable solvents or solvents which, on drying, can be removed to a physiologically harmless level. Such solvents include, for example, ethyl alcohol, isopropanol, methylene chloride, etc., and mixtures thereof. Preferably water and ethyl alcohol or mixtures of water and ethyl alcohol are used.

The layer thickness of the wet application is about 0.1-2 mm and that of the dry film about 0.05-1 mm, preferably 0.07-0.3 mm.

After drying, the film is cut into sections (units) of the desired size.

The method of preparing the drug in the form of a film in one operation (continuous method) offers the advantage that the area of action is evenly and uniformly distributed in the active ingredient carrier. With the concentration of active ingredient in the carrier, the thickness of the film and the surface area of the film, the unit dose can be varied very simply.

Brushed films can also be produced in which there are different active ingredients and / or different active ingredient concentrations side by side over the entire width of the film web. By means of a special applicator with two or more compartments, different solutions or suspensions, without mixing with each other, can be applied as a cohesive application. The width and thickness of the spreader are individually adjustable for each tray. If desired, zones (stripes) with different active ingredients or different concentrations can be visibly distinguished by different dyes. By drying the wet spread, a film is obtained which, when divided accordingly, for example by perforation, gives units with different active ingredients and / or active ingredient concentrations or units without active ingredient. Films with different active ingredients and / or different active ingredient concentrations are needed for the preparation of multi-substance preparations, for example for the preparation of contraceptives. The possibility of separating incompatible active ingredients in the same membrane unit in this way improves the stability of the individual active ingredients. For example, membranes for intravaginal use can be wrapped around ordinary commercial tampons.

With the exception of Examples 5 and 16, the formulations described as examples are primarily suitable for oral use.

Example 1 Preparation of 1000 units 0.25 g of D-Norgestrel, 0.05 g of ethinyl estradiol and 0.8 U g of polyoxyethylene polyoxypropylene polymers are dissolved in 95.00 g of ethyl alcohol with stirring; to this solution is added a powder mixture of 16.93 g of hydroxypropylcellulose and 16.93 g of cellulose.

The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 yxa and then dried. Composition of one unit: 0.25 mg D-Norgestrel 0.05 mg ethinyl estradiol 0.8 U mg polyoxyethylene polyoxypropylene polymers 16.93 mg hydroxypropylcellulose 16.93 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm, 5 60354

Appearance of the film: white, paper-like.

The thickness of the dry film is about 170 yum.

Example 2 Preparation of 1000 units (r) 1.10 g of Cremophor Eli 'are dissolved in 152.00 g of water * 0.25 g of micronized D-Norgestrel and 0.05 g of micronized ethinyl estradiol are suspended in this solution and homogenized. 22.10 g of micronized ethinyl estradiol are introduced into the suspension and homogenized. 22.10 g of hydroxypropylcellulose and 16.50 g of cellulose are introduced into the suspension.

The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 μm and then dried.

Unit composition: 0.25 mg D-Norgestrel 0.05 mg ethinyl estradiol 1.10 mg Cremophor El / ^ 22.10 mg hydroxypropylcellulose 16.50 mg cellulose 40.00 mg 2

One unit corresponds to an area of about 5 cm.

Appearance of the film: white, paper-like.

The thickness of the dried film is about 170 yum.

Example 3 Preparation of 1000 units 0.03 g of D-Norgestrel and 0.84 g of polyoxyl 40 stearate are dissolved in 95.00 g of ethyl alcohol with stirring. To this solution is introduced a powder mixture of 16.93 g of hydroxypropylcellulose and 17.20 g of cellulose.

The resulting suspension is applied with a suitable film-drawing device to an application having a layer thickness of 500 μm and then dried.

Composition of one unit: 0.03 mg D-Norgestrel 0.84 mg polyoxyl 40 stearate 16.93 mg hydroxypropylcellulose 17.20 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The dry film has a thickness of about 170.

Example 4 Preparation of 1000 units 6 60354 1.10 g of polyoxyethylene polyoxypropylene polymers are dissolved in 152.00 g of demineralized water. 0.05 g of micronized D-Norgestrel are suspended in this solution and homogenized if necessary. 22.10 g of hydroxypropylcellulose and 16.77 g of cellulose are introduced into the suspension.

The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 μm and then dried.

Composition of one unit: 0.03 mg D-Norgestrel 1.10 mg polyoxyethylene polyoxypropylene polymers 22.10 mg hydroxypropylcellulose 16.77 mg cellulose 40.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dried film is about 170 yum.

Example 5 Preparation of 1000 units 0.025 g of fluorocortolont trimethyl acetate and 0.183 g of glycerol are taken up in 30,000 g of ethyl alcohol. 7.292 g of hydroxypropylcellulose are introduced into this solution.

The resulting solution is drawn with a suitable film-drawing device into an application having a layer thickness of 500 μm and then dried.

Composition of one unit: 0.025 mg fluorocortolont trimethyl acetate 0.163 mg glycerol 7.292 mg hydroxypropylcellulose 7,500 mg 2

One unit corresponds to an area of about 1 cm.

Film appearance: translucent.

The thickness of the dried film is about 70 yum.

The film is suitable for topical use.

Example 6 Preparation of 1000 units 10.00 g of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzolazepine-4-oxide and 0.84 g of polyoxyethylene polyoxypropylene polymers are dissolved in 95.00 g of ethyl alcohol. To this solution is introduced a powder mixture of 16.93 g of hydroxypropylcellulose and 7.23 g of cellulose.

7 60354

The resulting suspension is drawn with a suitable film-drawing device into a spread having a film thickness of 500 μm and then dried.

Composition of one unit: 10.00 mg 7-chloro-2-methylamino-5-phenyl-4H-1,4-benzodiazepine-4-oxide 0.84 mg polyoxyethylene polyoxypropylene polymers 16.93 g g hydroxypropylcellulose 7.23 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: yellow, paper-like.

The thickness of the dry film is about 170 yum.

Example 7 Preparation of 1000 units 1.00 g of norethisterone acetate, 0.03 g of ethinyl estradiol and 0.84 g of polyoxyethylene polyoxypropylene polymers are dissolved in 95.00 g of ethyl alcohol. To this solution is introduced a powder mixture of 16.93 g of hydroxypropylcellulose and 16.20 g of cellulose.

The resulting suspension is drawn by a suitable film-drawing device into a spread having a layer thickness of 500 μm and then dried.

Composition of one unit: 1.00 mg norethisterone acetate 0.03 mg ethinyl estradiol 16.93 mg hydroxypropylcellulose 0.84 mg polyoxyethylene polyoxypropylene polymers 16.20 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The dry film has a thickness of about 170.

Example Θ Preparation of 1000 units 1.00 g of norethisterone acetate, 0.03 g of ethinyl estradiol and 0.84 g of propylene glycol are dissolved in a mixture of 101.60 g of methylene chloride and 26.40 g of ethyl alcohol. To this solution is introduced a powder mixture of 8.47 g of hydroxypropylcellulose, 8.47 g of hydroxyethylcellulose and 16.19 g of cellulose.

The resulting suspension is drawn with a suitable film-pulling device into a spread with a layer thickness of 500 μm and then dried.

60354

Composition of the unit: 1.00 mg norethisterone acetate 0.03 mg ethinyl estradiol 0.84 mg propylene glycol 8.47 mg hydroxypropylcellulose 8.47 mg hydroxyethylcellulose 16.19 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film is about 170 yum.

Example 9 Preparation of 1000 units 1.00 g of norethisterone acetate, 0.03 g of ethinyl estradiol and 0.84 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 101.60 g of methylene chloride and 25-40 g of ethyl alcohol. To this solution is introduced a powder mixture of 16.93 g of hydroxyethylcellulose and 16.20 g of starch.

The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 μm and then dried.

Unit composition: 1.00 mg norethisterone acetate 0.03 mg ethinyl estradiol 0.84 mg polyoxyethylene polyoxypropylene polymers 16.93 mg hydroxyethylcellulose and 16.20 mg starch 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The dry film has a thickness of about 170.

Example 10 Preparation of 1000 units 1.00 g of norethisterone acetate, 0.03 g of ethinyl estradiol and 0.84 g of polyocylyl 40 stearate are dissolved in 95.00 g of ethyl alcohol. To this solution is introduced a powder mixture of 16.93 g of hydroxypropylcellulose, 8.10 g of lactose and 8.10 g of corn starch. The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 μm and then dried.

9 60354

Unit composition: 1.00 mg norethisterone acetate 0.03 mg ethinyl estradiol 0.84 mg polyoxyl 40 stearate 16.93 mg hydroxypropylcellulose 8.10 mg lactose 8.10 mg corn starch 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film is about 170 yum.

Example 11 Preparation of 1COC unit 1.00 g of norethisterone (17α-ethynyl-19-nor-testosterone), 0.03 g of ethinyl estradiol and 0.22 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 84.75 g of ethyl alcohol and 4.00 g of water. A powder mixture containing 16.00 g of hydroxypropylcellulose and 16.00 g of cellulose is introduced into this solution, optionally homogenizing.

The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 600 and dried.

Unit composition: 1.00 mg norethisterone (17α-ethynyl-19-nor-testoeterone) 0.03 mg ethinyl estradiol 0.22 mg polyoxyethylene polyoxypropylene polymers 16.00 mg hydroxypropylcellulose 16.00 mg cellulose 33.25 mg 2

Area per unit: about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film is about 230 yum.

Example 12 Preparation of 1000 units: 4.0 g of glisoxepid (4- [4- [β- (5'-methylisoxazole-3-carboxamide) ethyl] benzenesulfonyl] -1,1-hexamethylene semicarbazide) in micronized form are dissolved in 0, 9 g of polyoxyl 40 stearate, suspended in 152.0 g of water and homogenized. 15.0 g of hydroxyethylcellulose and 15.1 g of calcium carbonate are introduced into the suspension.

The resulting suspension is drawn with a suitable film-drawing device into a spread with a layer thickness of 500 μm and dried.

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Unit composition: 4.00 mg Glisoxepid (4- [4- [p- (5-methylisoxazole-5-carboxamide) ethyl] benzenesulfonyl} -1,1-hexamethylene semicarbazide) 0.90 mg polyoxyl 40-stearate 15.00 mg hydroxyethylcellulose 15.10 mg calcium carbonate 35.00 mg 3

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dried film is about 170 yum.

Example 13 Preparation of 1000 units 0.030 g of D-Norgestrel is dissolved in 40,000 g * of methylene chloride and 55,000 g of ethanol. To this solution are introduced 0.840 g of silicone oil, 6.930 g of methylcellulose and 10,000 g of poly-N-vinylpyrrolidone and 17.200 g of starch, possibly homogenizing.

The resulting suspension is drawn with a suitable film-pulling device into a spread with a film thickness of 500 μm and dried.

Unit composition: 0.030 mg D-Norgestrel 0.840 mg silicone oil 6.930 mg methylcellulose 10,000 mg poly-N-vinylpyrrolidone il, 200 mg starch 35,000 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film was about 170 μm.

Example 14 Preparation of 1000 units 0.84 g of polyoxyethylene polyoxypropylene polymers are dissolved with stirring in 95.00 g of ethyl alcohol, and a powder mixture of 17.08 g of hydroxypropylcellulose and 17.08 g of cellulose is introduced into this solution.

The resulting suspension is drawn with a suitable film applicator into a spread having a film thickness of 500 μm and then dried.

Unit composition: 0.84 mg polyoxyethylene polyoxypropylene polymers 17.08 mg hydroxypropylcellulose 17.06 mg cellulose 35.00 mg 11 60354

Example 15 Preparation of 1000 units: 0.04 g of saccharin, 0.04 g of cream essence and 0.40 g of polyoxyethylene-polyoxypropylene polymers are dissolved in a mixture of 79 * 00 g of ethyl alcohol and 4 * 00 g of water. To this solution are introduced 50.00 g of iron (II) Fumarate, 15 * 00 g of hydroxypropylcellulose, 5 * 52 g of cocoa and 4 * 00 g of cellulose, possibly homogenizing.

From the suspension thus obtained, a spread with a layer thickness of 0.5 mm is drawn with a suitable film-drawing device and then dried.

Unit composition · 50.00 mg iron (II) fumarate 15 * 00 mg hydroxypropylcellulose 0.40 mg polyoxyethylene polyoxypropylene polymers 5.52 mg cocoa 0.04 mg saccharin 0.04 mg cream essence 55 * 00 mg per unit weight.

2

One unit corresponds to an area of about 5 cm.

Film appearance: light reddish brown.

Example 16

Membranes for vaginal use:

The films are prepared according to Example 11.

Composition of one unit: 100.0 mg 5 “morpholinomethyl-5- (5-nitro-1-methyl-2-imidiazolyl) methyleneamino-2-oxazolidone * HCl 8.4 mg Cremophor 169.2 mg methylhydroxypropylcellulose 72.4 mg cellulose 550.0 mg weight of one unit.

One unit corresponds to an area of about 8x4 cm.

Appearance of the film: light yellow.

The film (l unit) is wrapped either around a commercial tampon or around itself on a tight roll.

Example 17 Binary preparation

Part 1: containing 21 units of active substance Part 2: 7 units without active substance Preparation of part 1 5000 units: 12 6 0 3 5 4 O »75 g of D-Norgestrel, 0.15 g of ethinyl estradiol and 0.54 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture, with 237.00 g of ethyl alcohol and 12.00 g of water. To this solution are introduced 44-28 g of hydroxypropylcellulose and 44.28 g of cellulose, possibly homogenizing.

Preparation of Part 2 1000 units: 0.18 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 79.00 g of ethyl alcohol and 4.00 g of water. 14.91 g of hydroxypropylcellulose and 14.91 g of cellulose are introduced into this solution, optionally homogenizing.

The suspensions thus obtained are drawn with a suitable film-drawing device which sweeps in two parts (widths: 1 = 54 mm; 2 = 18 mm) into a spread having a thickness of 5.5 mm and then dried. By corresponding division into units of 18 x 18 mm, for example by perforation, three units with active ingredient and one active ingredient-free unit can be obtained across the width of the film. The film web can now be cut into desired sections with three units with active ingredient and one unit without active ingredient.

Unit composition:

Part 1 (active substance) Part 2 (without active substance) 0.25 mg D-Norgestrel 0.05 mg ethinyl estradiol 14.76 mg hydroxypropylcellulose 14.91 mg 14.76 mg cellulose 14.91 mg 0.18 mg polyoxyethylene polyoxypropylene polymers 0.18 mg 30.00 mg unit weight 30.00 mg 2

Unit area: about 3 cm.

Appearance: white.

Example 18

Ternary preparation (two-step preparation)

Lot 1: 11 units containing 0.05 mg of D-Norgestrel 0.05 mg of ethinyl estradiol

Lot 2: 10 units with 0.125 mg D-Norgestrel 0.050 mg ethinyl estradiol

Part 3: 7 units without active substance

Preparation of Part 1 1100 units: 0.055 g of D-Norgestrel, 0.055 g of ethinyl estradiol and 0.190 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 15 60354 86.900 g of ethyl alcohol and 4-400 g of water. 16.346 g of hydroxypropylcellulose and 16.346 g of cellulose are introduced into this solution, optionally homogenizing.

Preparation of Part 2 1000 units: 0.125 g of D-Norgestrel, 0.050 g of ethinyl estradiol and 0.180 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 79,000 g of ethyl alcohol and 4,000 g of water. 14.823 g of hydroxypropylcellulose and 14.822 g of cellulose are introduced into this solution, optionally homogenizing.

„Preparation of 3,700 units: 0.189 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 82,950 g of ethyl alcohol and 4,200 g of water. To this solution is introduced 15.656 g of hydroxypropylcellulose and 15.655 S of cellulose, possibly homogenizing.

The suspensions thus obtained are drawn into a spread with a suitable three-compartment film-drawing device (compartment width 18 mm) and dried. By corresponding division, for example by perforation, into 18 x 18 mm units for part 1, 18 x 19.8 mm for part 2 and 18 x 28 mm for part 3, three units with different effects can be obtained across the width of the film web. solids content. Preparations with 11 units of part 1, 10 units of part 2 and 7 units of part three can be separated from the film strip.

Unit composition:

Part 1 Part 2 Part 3 Ingredients 0.050 mg 0.125 mg - D-Norgestrel 0.050 mg 0.050 mg · * ethinyl estradiol 0.180 mg 0.160 mg 0.270 mg polyoxyethylene polyoxypropylene polymers 14.860 mg 14.823 mg 22.366 mg hydroxypropylcellulose 14.860 mg 14.822 mg cellulose 30.364 mg mg unit weight 2 2 2 approx. 3 cm approx. 3.5 cm approx. 5 cm unit area white white white appearance

Example 19

Ternary preparation

Lot 1: 11 units containing 0.05 mg of D-Norgestrel 0.05 mg of ethinyl estradiol

Lot 2: 10 units with 0.125 mg D-Norgestrel 0.050 mg ethinyl estradiol 14 60354

Part 3 '7 units with 50.00 mg of iron (II) fumarate

Preparation of 1100 units of part: 0.066 g of "Lebensmittelgelb no. 2" (Tartrazin E 102) is dissolved in 4,400 g of water and then taken up in 86,900 g of ethyl alcohol.

To this solution are dissolved 0.055 g of D-Norgestrel, 0.055 g of ethinyl estradiol and 0.198 g of polyoxyethylene polyoxypropylene polymers. 16.313 g of hydroxypropylcellulose and 16.3.15 g of cellulose are introduced into this solution, optionally homogenizing.

Preparation of part 2 1000 units: C, 65 g of "Lebensmittelorange no. 2" (Sunsetyellow: E 110) are dissolved in 4,000 g of water and then mixed with 79,000 g of ethyl alcohol. and 0.180 g of polyoxyethylene polyoxypropylene polymers 14.790 g of hydroxypropylcellulose and 14.79 g of cellulose are introduced into this solution, optionally homogenizing.

Preparation of 3,700 units: 0.042 g of saccharin, 0.042 g of cream essence and 0.406 g of polyoxyethylene polyoxypropylene polymers are dissolved in a mixture of 55.300 g of ethyl alcohol and 2.800 g of water. 35,000 g of iron (II) fumarate, 17,500 g of hydroxypropylcellulose, 5,950 g of cocoa and 4,060 g of cellulose are introduced into this solution, optionally homogenizing.

The suspensions thus obtained are drawn into a spread with a suitable three-compartment film puller (compartment width 18 mm) and then dried. By corresponding division, for example by perforation, into 18 x 18 mm units for part 1, 18 x 19.8 mm for part 2 and 18 x 28 mm for part 3, three units can be obtained across the width of the film web, with has a different active substance content. Preparations with 11 units of part 1, 10 units of part 2 and 7 units of part 3 # can be separated from the membrane tape.

Unit composition:

Part 1 Part 2 Part 3 Ingredients 0.050 mg 0.125 mg - D-Norgestrel 0.050 mg 0.050 mg - ethinyl estradiol - - 50,000 mg iron (II) fumarate 0.180 mg 0.180 mg 0.580 mg polyoxyethylene polyoxypropylene polymers 0.060 mg - - "Lebensmittelgelb no. 2" - 0.065 mg - "Lebensmittelorange no. 2" 14.830 mg 14.790 mg 25,000 mg hydroxypropylcellulose 15 60354 11 +, 830 mg ll + »790 mg 5.800 mg cellulose 8.500 mg cocoa 0.060 mg saccharin 0.060 mg cream essence 30,000 mg 30,000 mg 90,000 mg unit weight 2 2 . approx. 3 cm approx. 3.5 m approx. 5 cm unit area yellow orange brown appearance

Example 20 Preparation of 1000 units 0.15 g of D-Norgestrel, 0.03 g of ethinyl estradiol and 0.8 U g of polyoxyethylene polyoxypropylene polymers are dissolved in 95.00 g of ethyl alcohol with stirring; to this solution is introduced a powder mixture of 16.99 g of hydroxypropylcellulose and 16.99 g of cellulose.

The resulting suspension is drawn with a suitable film-pulling device into a spread with a film thickness of 500 [mu] m and dried.

Unit composition: 0.15 mg D-Norgestrel 0.03 mg ethinyl estradiol 0.8 t mg polyoxyethylene polyoxypropylene polymers 16.99 mg hydroxypropylcellulose 16.99 mg cellulose 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film is about 170.

Example 21 Manufacture of 10,000 units

Solution A, in which 1.5 g of D-Norgestrel and 0.3 g of ethinyl estradiol are dissolved in ^ 77.7 g of alcohol, and Solution B, in which 1.5 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 23.0 g of water, combined into solution C.

88.1 g of hydroxypropylcellulose and 88.6 g of cellulose are mixed as powders, sieved through a 1.2 mm sieve and the mixture is added to the mixed solution C.

The resulting suspension is drawn with a suitable film-pulling device into a spread having a film thickness of 600 and dried.

Unit composition: 0.15 mg D-Norgestrel 0.03 mg ethinyl estradiol 16 60354 8.81 mg hydroxypropylcellulose 8.86 mg cellulose 0.15 mg polyoxyethylene polyoxypropylene polymer 18.00 mg

Area per unit: 11 + 1 + mm.

Appearance of the film: white, paper-like,

Film thickness: 260-280 ^,

Example 22 Preparation of 1000 units 1.00 g of norethisterone acetate, 0.03 g of ethinyl estradiol and 0.81+ g of polyoxyl 1 + O-stearate are dissolved in 95 * 00 g of ethyl alcohol. To this solution is introduced a powder mixture of 5 * 00 g of ethylcellulose, 11.93 g of hydroxypropyl cellulose, 8.10 g of lactose and 8.10 g of corn starch. The resulting suspension is drawn with a suitable film-drawing device into a spread having a layer thickness of 500 and then dried.

Composition of the unit: 1.00 mg norethisterone acetate 0.03 mg ethinyl estradiol 0.814 mg polyoxyl 1 + O-stearate 5.00 mg ethylcellulose 11.93 mg hydroxypropylcellulose 8.10 mg lactose 8.10 mg corn starch 35.00 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film is about 170 μm.

Example 23 Preparation of 1000 units 0.030 g of D-Norgestrel is dissolved in 1 + 0.000 g of methylene chloride and 55 * 000 g of ethanol. 0.81 + 0 g of silicone oil, 6.930 g of ethylcellulose and 10,000 g of hydroxypropylcellulose and 17.200 g of starch are introduced into this solution, possibly homogenizing.

The resulting suspension is drawn with a suitable film-pulling device into a spread with a film thickness of 500 μm and dried.

Unit composition: 17 60354 0.030 mg D-Norgestrel 0.8i + 0 mg silicone oil 6.930 mg methylcellulose 10,000 mg hydroxypropylcellulose 17.200 mg starch 35,000 mg 2

One unit corresponds to an area of about 3 cm.

Appearance of the film: white, paper-like.

The thickness of the dry film was about 170 μm.