DK143221B - PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL MEDICINE FOR ORAL OR TOPICAL USE - Google Patents

Description

(11) PUBLICATION OF PRESENTATION 143221 {& I TUSfll \ Ra DENMARK i · »i«, ci. · A · t k 9/70 • (21) Anugnme No. 295 ^ / 75 (22) Filed on 50 · Jun. 1975 (24) Race day 50 · Jun. 1975 (44) The claim presented and. η. -iqO.

the submission inscription rffentBggly made it ^ * 0UX1 xyo1

DIRECTORATE OF

PATENT AND TRADE MARKET (30> Priority honored from it

July 5 1974 «2452925, DE

Oct 17 1974, 2449865, DE

(41) Aim. avail. Jan 6 1976 (7i) SCHERING AKTIENGESELLSCHAFT, Berlin and Bergkamen, Muellerstrasse 1 70-T78, 1 Berlin 65, DE.

(72) Inventor: Peter Fuchs, Uncle Tom Str. 62, 1 Berlin 57, DE: Juergen Hilmann, Ugandas ^ r. 9, 1 Berlin 65, DE.

(74) Plenipotentiary 'agent':

The company Chas. Hude.

(64) Process for preparing a drug 1 film form for oral or topical use.

The invention relates to a process for the preparation of a medicament in foil form for oral or topical use and containing an active substance content of up to 60% by weight of the foil.

From the specification of Danish patent application No. 6755/73, granules, fibers and films are known which are formed by or formed after the extrusion of molten masses. The matrix consists, for example. of the active substance and hydroxypropyl cellulose (G-type) with a molecular weight of 275,000. The drug according to said Danish patent application can only be used locally in body cavities and is used to deliver controlled amounts of active substance at a predetermined rate.

In contrast, the film-formulated drugs of the present invention are suitable for oral and topical use. They are obtained on endless carriers by a continuous film-pulling process. The gelatinous, viscous matrix used therefor is available as a solution or suspension. Water-soluble cellulose derivatives, such as hydroxypropylcellulose (L-type) having a molecular weight of 75,000, which can be used as foil thinners, are responsible for the beneficial properties of the drugs in the form of the invention. They condition the tear strength and flexibility of these foils. They dissolve quickly in water, thus completely releasing the active substance.

From usa. U.S. Patent No. 3,108,043 to spermicidal preparations for vaginal use is known. The paper-like material is prepared by pouring and drying. The matrix consists, for example. of the active substance, sodium carboxymethyl cellulose, glycerol and urea. The solubility of the preparation and the controlled release of the active substance are controlled by the addition of urea. Due to the method of preparation (pouring and drying) and the use of carboxymethyl cellulose, an accurate dosage of the active substance, as it takes place in the drug formulated in the present invention, is not possible.

Belgian Patent No. 637 * 363 discloses paper foils which are coated with active substance and are suitable for oral use. The films consist of water-insoluble cellulose fibers and a water-soluble binder. As a water-soluble binder, sodium carboxymethyl = cellulose is preferably used. The active substance is applied to the paper film by dripping the dissolved active substance, by spraying the solid active substance or by allowing a solution of the active substance to pass through the film. The discontinuous process of separately producing the film and applying the active substance has the disadvantage that the accuracy of the dosage is not very good, which, however, is of great importance in the presently low doses. Inaccuracies occur not only in the application of the active substance, but also in the preparation and pretreatment of the carrier and during changes in the storage of the carrier material. Thus, it has e.g. It has been found that, according to the Belgian patent prescription, no uniform film layer is formed by using film-pulling machines and that the film shrinks upon drying. However, it is readily recognized that in the case of non-uniform material, the uptake of active substance will also be non-uniform. In addition, a surface-only active agent may be used in the handling of the film, e.g. at the packaging, partially detached. The sodium carboxymethyl cellulose used as a binder is dissolved in the stomach, thereby releasing the carboxymethyl cellulose = 3 1A 3 2 2 1 solution which partially encloses and only delays or does not release the active substance at all.

It has now been found that films of uniform thickness and uniform distribution of active substance are obtained when employing a method of the kind mentioned initially, which is peculiar to dissolving or suspending the active substance and optionally a separating agent in a a solvent or suspension agent consisting of water and / or one or more physiologically acceptable organic solvents which introduces a non-ionic, water-soluble hydroxyalkyl ether or methylhydroxyalkyl ether of cellulose, preferably hydroxypropylcellulose, hydroxyethylcellulose or methylhydroxypropyl of two of these, and optionally a filler, optionally homogenizing, iron out the solution or suspension to form a wet layer of 0.1-2 mm layer thickness on a foil coating machine and dry the wet layer to form a uniform, dry film of layer thickness 0 , 05-1 mm. Foil formers which are soluble in both water and organic solvents are particularly suitable.

Fillers and active substances can be added to foil carriers and, as appropriate, a small amount of a separating agent. The separating agent causes the foil to be easily detached from the foil puller carrier.

Suitable separation means include: polyethylene polypropylene polymers ("Pluronic" ® F-68), polyoxystearates, alkyl or acyl-substituted polyaddition products of ethylene oxide, for example "Cremophor" ® EL, Silicon and silicone separation emulsions, glycerol, propylene glycol and metal soaps. - - 4 143221

As fillers, e.g. cellulose, sugar, e.g. lactose, dextrose, cane sugar, etc., starches, polyhydric alcohols, e.g. mannite, calcium carbonate, calcium phosphate, talc and solvents in pigments or as pigments are suitable. The fillers can be completely or partially replaced with active substances. If soluble fillers or active substances are used, a transparent, smooth film is formed, while if insoluble fillers or active substances are used, a white or colored paper-like film is formed.

In the process of the invention, all active substances used in human and veterinary medicine can be used. For internal use, oral administration in particular is discussed. In the external application, in particular, is understood the topical administration on the skin and in body cavities, such as the nose, ear, vagina, etc. Examples of active substances include: progestins, estrogens, mixtures of progestogens and estrogens, sedatives, antidiabetic agents, sulfonamides, antibiotics, trichomonas agents, anti-inflammatory agents, e.g. corticoids, etc.

The active drug may be dissolved or uniformly suspended in the carrier material. The amount of active substance in the foil can amount to 60fo. As single dose (unit) areas are cut or perforated which contain amounts of active substance which are also usually contained in tablets, dragees, ointments, suppositories, etc. Thus, the amount of active substance per single dose, depending on the method of use, be arbitrarily high and range between approx. 1 µg and 0.5 g, whereby the lower and upper doses can be easily under- and over-exceeded, respectively.

In the process of the invention for the preparation of the drug in foil form, the active substance and / or separation agent, the foil former and optionally the filler are dissolved or optionally homogenized, and the solution or suspension is extended to an extruded layer on a foil coating machine. The film obtained by drying the extruded layer is divided into arbitrary sections (units).

143221 5

In the process of the invention, the foil former is suitably used in amounts of 6-20 wt% in the solution or suspension. the filler in amounts of 0-30 wt.% and the separating agent for · - in amounts of 0.01-2 wt.%.

The solvent or suspension is suitably used in amounts of 48-84% by weight, based on the solution or suspension, and the agent consists of water and / or one or more organic solvents. As organic solvents, physiologically acceptable solvents or solvents are considered which, upon drying, can be removed until a physiologically harmless residue. Such solvents are e.g. ethyl alcohol, iso-propanol and methylene chloride and mixtures thereof. Water and ethyl alcohol or mixtures of water and ethyl alcohol are preferably used.

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

The continuous process of preparing the drug in foil form offers the advantage that the active substance is homogeneously and uniformly distributed in the carrier for the active substance. By using the concentration of the active substance in the carrier, the thickness of the foil and the area of the foil, the single dose can be varied very simply.

Also, with an extruded layer, films can be prepared in which different active substances and / or different concentrations of active substance are incorporated next to each other across the film band. With the help of a special, scanning consisting of two or more chambers, different solutions or suspensions can be extended without mixing to a coherent, extruded layer. The width and thickness of the extended layer can be set separately for each chamber. Optionally, zones (stripes) with different active substances or different concentrations can be made visible by different dyes. Upon drying the wet, extruded layer, a foil is obtained which, by appropriate division, e.g. upon perforation, provides units with various active substances and / or concentrations of active substance. Films with different active substances and / or different concentrations of active substance are required for the preparation of multiphase preparations, e.g. for the preparation of prepara- · "'**' Cf.

143221 6 Rates of Pregnancy Prevention. By means of the possibility of the spatial separation of incompatible active substances in a foil unit, the stability of the individual active substances is improved. Foils for. intravaginal administration may e.g. also rolled into a commercial tampon.

With the exception of Examples 5 and 13, the exemplary compositions described are preferably suitable for oral administration.

Example 1

Manufacture of 1000 units; Dissolve 0.25 g of D-Norgestrel 0.05 g of ethynyl oestradiol and 0.8½ g of polyoxyethylene polyoxypropylene polymer in 95 g of g of ethyl alcohol with stirring and introduce into this solution a powder mixture consisting of 16.93 g of hydroxypropyl cellulose and 16.93 g of cellulose.

The resulting suspension is stretched onto a suitable foil coating apparatus to an extruded layer having a coating thickness of 500 µm and then dried.

Composition of a unit; 0.25 mg D-Norgestrel 0.05 mg ethynyl estradiol 0.8½ mg polyoxyethylene polyoxypropylene polymer 16.93 mg hydroxypropyl cellulose 16.93 mg cellulose 35.00 mg o 2

One unit corresponds to an area of approx. 3 era. Appearance of the foil: white, pear-like. The dry film has a thickness of approx. 170 yams.

7 143221

Example 2

Preparation of 1000 units: 1.10 g of Cremophor®EL is dissolved% 152.00 g of water. In this solution 0.25 g of micronized D-Norgestrel and 0.05 g of micronized ethynyl estradiol are suspended and homogenized evenly. 22.10 g of hydroxypropyl cellulose and 16.50 g of cellulose are introduced into the suspension.

The resulting suspension is wiped off on a suitable foil xa & cage putty to an extruded layer with a layer thickness of 500 μηι and then dried.

Composition for one unit: 0.25 mg D-Norgestrel * 0.05 mg ethynyl oestradiol

1.10 mg of "Cremophor" ®EL

22.10 mg hydroxypropyl cellulose 16.50 mg cellulose WOjOO mg 2

This unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of oa. 170 pm.

Example 3

Preparation of 1000 units: 0.03 g of D-Norgestrel and 0.8 * + g of polyoxyl-2 O stearate are dissolved in 95.00 g of ethyl alcohol with stirring.

In this solution, a powder mixture consisting of 16.93 g of hydroxypropyl cellulose and 17.20 g of cellulose is introduced.

The resulting suspension is wiped on a suitable foil drying apparatus to an extruded layer having a layer thickness of 500 µm and then dried.

Composition of a unit: 0.03 mg D-Norgestrel 0, $ + mg polyoxyl - ^ - O-stearate 16.93 mg hydroxypropyl cellulose 17.20 mg cellulose 35.00 mg o 2

One unit corresponds to a surface of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. 170 μηι.

Example b

Preparation of 1000 units: 1.10 g polyoxyethylene polyoxypropylene polymer is dissolved in 152.00 g demineralized water. In this solution, 0.03 g of micronized D-Norgestrel is suspended and optionally homogenized. 22.10 g of hydroxypropyl cellulose and 1 7, 77 g of cellulose are introduced into the suspension.

The resulting suspension is wiped on a suitable foil peeler to an extruded layer of 500 µm layer thickness and then dried.

9 143221

Composition of a unit: 0.03 mg D-Norgestrel 1) 10 mg polyoxyethylene polyoxypropylene polymer 22.10 mg hydroxypropyl cellulose 16.77 mg cellulose * + 0.00 mg 2

One unit corresponds to an area of approx. 3 cm · The appearance of the foil: white, papery. The dry film has a thickness of approx. 170 pm.

Example 5

Preparation of 1000 units: 0.025 g of fluocortolone trimethyl acetate and 0.183 g of glycerol are dissolved in 30,000 g of ethyl alcohol. Into this solution are introduced 7.292 g of hydroxypropyl cellulose.

The resulting solution is wiped on a suitable foil wrap to an extruded layer having a layer thickness of 500 µm and then dried.

Composition of a unit: 0.025 mg fluocortolone trimethyl acetate 0.183 mg glycerol 7.292 mg hydroxypropyl cellulose 7.500 mg 2

One unit corresponds to an area of approx. 1 cm. The appearance of the foil: transparent. The dry film has a thickness of approx. 70 μη.

This film is suitable for topical application.

143221 ίο

Example 6

Preparation of 1000 units: 10.00 g of 7-chloro-2-methylamino-5-phenyl-3H-1,1 + -benzodiaze = pin-β-oxide and 0.8½ g of polyoxyethylene polyoxypropylene polymer are dissolved in 95} 00 g of ethyl alcohol. Into this solution is introduced a powder mixture consisting of 16.93 g of hydroxypropyl cellulose and 7} 23 g of cellulose.

The resulting suspension is wiped onto a suitable foil wrap & wrap to an extruded layer with a layer thickness of 500 μηι and then dried.

Composition of a unit: 10.00 mg of 7-chloro-2-methylamino-5-phenyl-3H-1,1 + - benzodia3e = pin-1-oxide 0.8½ mg polyoxyethylene polyoxypropylene polymer 16.93 mg hydroxypropyl cellulose 7.23 mg cellulose 35.00 mg 2

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: yellow, papery. The dry film has a thickness of approx. 170 yams.

Example 7

Preparation of 1000 units: 1.00 g of Worethisteronaeetate 0.03 g of ethynyl estradiol and 0.8½ g of polyoxyethylene polyoxypropylene polymer are dissolved in 95.00 g of ethyl alcohol. Into this solution is introduced a powder mixture consisting of 11.9 g of hydroxypropyl cellulose and 16.20 g of cellulose.

The resulting suspension is wiped on a suitable foil puller to an extruded layer with a layer thickness of 500 µ® and then dried.

Composition of a unit: 1.00 mg Norethisterone acetate 0.03 mg ethynyl estradiol 0.8 * + mg polyoxyethylene polyoxypropylene polymer 16.93 mg hydroxypropyl cellulose 16.20 mg cellulose 35.00 mg 2

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. 170 μιη.

Example 8

Preparation of 1000 units: 1.00 g of norethisterone acetate 0.03 g of ethynyl estradiol and 0.8½ g of propylene glycol are dissolved in a mixture of 101.60 g of methylene chloride and 26.0 g of ethyl alcohol. Into this solution is introduced a powder mixture of 8.7 g of hydroxypropyl cellulose 8.1 + 7 g of hydroxyethyl cellulose and 16.19 g of cellulose.

The resulting suspension is wiped onto a suitable film-pressing machine to an extruded layer having a layer thickness of 500 µm and then dried.

12 143221

Composition of a unit: 1.00 mg Norethisterone acetate 0.03 mg ethynyl estradiol 0.8¼ mg propylene glyeol 8, * + 7 mg hydroxypropyl cellulose 8, 7 mg hydroxyethyl cellulose 16.19 mg cellulose 35.00 mg o 2

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. 170 pm.

Example 9

Preparation of 1000 units: 1.00 g of norethisterone acetate 0.03 g of ethynyl estradiol and 0.8¼ g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 101.60 g of methylene chloride and 25 bo of g of ethyl alcohol. Into this solution is introduced a powder mixture of 16.93 g of hydroxyethyl cellulose and 16.20 g of starch.

The resulting suspension is wiped on a suitable film extruder to an extruded layer having a layer thickness of 500 µm and then dried.

Composition of a unit: 1.00 mg Forethisterone acetate 0.03 mg Ethynyl estradiol 0.8¼ mg polyoxyethylene polyoxypropylene polymer 16.93 mg hydroxyethyl cellulose and 16.20 mg starch 35.00 mg 13 143221 2

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. 170 prn.

Example 10

Preparation of 1000 units: 1.00 g of Norethisterone acetate 0.03 g of ethynyl oestradiol and 0.8½ g of polyoxyl-t-O stearate are dissolved in 95.00 g of ethyl alcohol. Into this solution is introduced a powder mixture of 16.93 g of hydroxypropyl cellulose 8.10 g of lactose and 8.10 g of corn starch.

The resulting suspension is wiped onto a suitable film-wrapping machine to an extruded layer with a layer thickness of 500 µm and then dried.

Composition of a unit: 1.00 mg Norethisterone acetate 0.03 mg ethynyl estradiol 0.8½ mg polyoxyl ^ O stearate 16.93 mg hydroxypropyl cellulose 8.10 mg lactose 8.10 mg corn starch 35.00 mg

One unit corresponds to an area of approx. 3 cm2. Appearance of the foil: white, papery. The dry film has a thickness of approx. 170 pm.

Example 11

Preparation of 1000 units: 1.00 g of Norethisterone (17a-ethynyl-19-nor-testosterone) 0.03 g of ethynyl estradiol and 0.22 g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 14, 212 g, 75 g of ethyl alcohol and 1 +, 00 g of water. Into this solution, optionally homogenized, a powder mixture of 16.00 g of hydroxypropyl cellulose and 16.00 g of cellulose is introduced.

The resulting suspension is wiped on a suitable foil peeler to an extruded layer having a layer thickness of 600 µm and dried.

Composition of a unit: 1.00 mg Norethisterone (17a-ethynyl-19-nor-testosterone) 0.03 mg ethynyl estradiol 0.22 mg polyoxyethylene polyoxypropylene polymer 16.00 mg hydroxypropyl cellulose 16.00 mg cellulose 33 »25 mg o

Area per unit: approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. 230 ye.

Example 12

Preparation of 1000 units: * +, 0 g of glyoxide (β - β - / (3- (5-methyl-isoxazole-3-carboxamido) -ethylZ-benzenesulfonyl} -1,1-hexamethylene-semi = carbazide ) in micronized form is suspended in 0.9 g of polyoxyl-O-stearate dissolved in 152.0 g of water and optionally homogenized, with 15.0 g of hydroxyethyl cellulose and 15.1 g of calcium carbonate being introduced.

The resulting suspension is wiped onto a suitable film-wrap to an extruded layer having a layer thickness of 500 µm and dried.

Composition of a unit: 15 143221 +, 00 mg glyisoxepide 0.90 mg polyoxyl-U stearate 15.00 mg hydroxyethyl cellulose 15.10 mg calcium carbonate 35.00 mg 2

One unit corresponds to an area of ea. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of approx. I70 μπι.

Example 13

Foils for intravaginal administration.

The film is prepared according to Example 11.

Composition of a unit: 100.0 mg of 5-morpholinomethyl-3- (5-nitro-1-methyl-2-imidazolyl> methyleneamino-2-oxazolidinone, HCl 8, k mg mg of cellulose 350.0 mg weight per unit

One unit corresponds to an area of approx. 8 x k cm. Appearance of the foil: light yellow. The foil (1 unit) is either rolled around a commercially available tampon or by itself into a narrow tube.

Example 14

Two-phase.

Part 1:21 active substance units.

Part 2: 7 units without active substance.

Preparation of 3000 units Part 1: 16 g of U-2121 0.75 g of D-Norgestrel, 0.15 g of ethynyl estradiol and 0.5½ g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 237.00 g of ethyl alcohol and 12.00 g of water. * 44.28 g of hydroxypropyl cellulose and * 44.28 g of cellulose are introduced and optionally homogenized in this solution.

Preparation of 1000 units Part 2: 0.18 g of polyoxyethylene polyoxypropylene polymer is dissolved in a mixture of 79.00 g of ethyl alcohol and * 4.00 g of water. Into this solution are introduced and optionally homogenized 1 * 4.91 g of hydroxypropyl cellulose and 1 * 4.91 g of cellulose.

The suspensions thus obtained are ironed onto a suitable foil film apparatus with a two-chamber special blade (width of the chambers: 1-5 * 4 mm; 2 = 18 mm) to form an extruded layer of 0.5 mm and then dried. By appropriate division into units of 18 x 18 mm, e.g. by perforation, three units of active substance and one unit without active substance content can be divided over the width of the film. If the foil strip is 18 x Z mm long, Z sections can be divided, which can again be divided into three units with active substance and one unit without active substance.

Composition of a unit:

Part 1 (with active substance) - Part 2 (without active substance) 3 units with 1 unit with 0.25 mg D-Norgestrel - 0.05 mg ethynyl estradiol - 14.76 mg hydroxypropyl cellulose 14.91 mg 14.76 mg cellulose 14.91 mg mg ^ Sg? ^ Genp ° ly0Xypr0 = ° .18 mg 30.00 mg wt. unit 30.00 mg 17 143221 2

Area per unit: Approx. 3 cm Appearance: White 21 units with active substance and then 7 units without active substance are collected in a package with the designation "NEOGYNON" ®

Example 15

Three-phase preparation (two-part active ingredient).

Part 1: 11 units with 0.05 mg of D-Norgestrel and 0.05 mg of ethynyl estradiol.

Part 2: 10 units with 0.125 mg of D-Norgestrohl and 0.050 mg of ethynyl estradiol.

Part 3: 7 units without active substance.

Preparation of 1100 units Part 1: 0.055 g of D-Norgestrel, 0.055 g of ethynyl estradiol and 0.198 g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 86,900 g of ethyl alcohol and * + 00 g of water. Into this solution are introduced and optionally homogenized, 16.3 * + 6 g of hydroxypropyl cellulose, and 1β, 3 * + 6 g of cellulose.

Preparation of 1000 units Part 2: 0.125 g of D-Norgestrel, 0.050 g of ethynyl estradiol and 0.180 g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 79,000 g of ethyl alcohol and * +, 000 g of water. Into this solution are introduced and optionally homogenized, 1, 823 g of hydroxypropyl cellulose and 1 * +, 822 g of cellulose.

18 143221

Preparation of 7 ° C units Part 3 0.189 g of polyoxyethylene polyoxypropylene polymer is dissolved in a mixture of 82,950 g of ethyl alcohol and in +, 200 g of water. To this solution 15,656 g of hydroxypropyl cellulose and 15,655 g of cellulose are introduced and optionally homogenized.

The suspensions thus obtained are wiped on a suitable foil dishwasher with a three-chamber special blade (width per chamber 18 mm) to an extruded layer and dried. Yed appropriate division, e.g. For 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, the film over its width can be divided into three units of food different content of active substance. From the foil strip with a width of 3 x 18 mm and a length of 198 mm, preparations can be separated with 11 units part 1 (left strip with width 18 mm) 10 units part 2 (middle strip with width 18 mm) and 7 units part 3 (right strip with width 18 mm) ..

Composition per unit: -. Part 1 _ Part 2_ Ingredient_ 11 units with 10 units with 7 units with 0.050 mg 0.125 mg - D-Norgestrel 0.050 mg 0.050 mg - ethynyl estradiol 0.180 mg 0.180 mg 0.270 mg polyoxyethylene polyoxy = propylene polymer 14.860 mg 14.823 mg 22.366 mg hydroxypropyl mg 364 mg_cellulose______ 30,000 mg 30,000 mg 45,000 mg wt. unit 2 2 2 approx. 3 cm approx. 3.5 cm approx. 5 cm area per unit white white white appearance 19 143221

Example 16

Trefasepræparat.

Part 1: 11 units with 0.05 mg of D-Norgestrel and 0.05 mg of ethynyl estradiol.

Part 2: 10 units with 0.125 mg of D-Norgestrel and 0.050 mg of ethynyl estradiol.

Part 3: 7 units with 50.00 mg iron (II) funiarate.

Preparation of 1100 units Part 1: 0.066 g of Food Yellow # 2 (Tartrazine; E 102) is dissolved in 1+, 1 + 00 g of water and then introduced into 86,900 g of ethyl alcohol. In this solution are dissolved 0.055 g of D-Norgestrel, 0.055 g of ethynyl estradiol and 0.198 g of polyoxyethylene polyoxypropylene polymer. Into this solution are introduced and optionally homogenized 16,313 g of hydroxypropyl cellulose and 16,313 g of cellulose.

Preparation of 1000 units Part 2: · 0.065 g of Food Orange # 2 (Sunset Yellow; E 110) is dissolved in * +, 000 g of water and then introduced into 79,000 g of ethyl alcohol. This solution dissolves 0.125 g of D-Norgestrel, 0.050 g of ethynyl estradiol and 0.80 g of polyoxyethylene polyoxypropylene polymer. In this solution, li +, 790 g of hydroxypropyl cellulose and 1 7,790 g of cellulose are introduced and optionally homogenized.

Preparation of 700 units Part 3: 20 µg of 0.02 -2 g of saccharin, 0, (Α · 2 g of cream essence and 0.10 g of polyoxyethylene polyoxypropylene polymer are dissolved in a mixture of 55,300 g of ethyl alcohol and 2,800 g of water. optionally, 35,000 g of iron (II) fumarate, 17,500 g of hydroxypropyl cellulose, 5,950 g of cocoa and if 060 g of cellulose are homogenized.

The suspensions thus obtained are wiped on a suitable film-carrying apparatus with a three-chamber special blade (width per chamber 18 mm) to an extruded layer and then dried. By appropriate division, e.g. By means of perforation, in units of 18 x 18 Iran for Part 1, 18 x 19.8 mm for Part 2 and 18 x 28 mm for Part 3, the film over its width can be divided into three units with different active substance content. From the foil strip with a width of 3 x 18 mm and a length of 198 mm, preparations can be separated with 11 units part 1 (left strip with width 18 mm), 10 units part 2 (middle strip with width 18 mm) and 7 units part 3 (right strip with width 18 mm).

Composition per unit:

Part 1 Part 2_pei 3 Ingredient_ 11 unit unit - 7 units containing with me (j 0, -050 mg 0.125 mg - D-Norgestrel 0.050 mg 0.050 mg - ethynyl estradiol 50,000 mg iron (II) fumarate 0, 180 mg 0.180 0.580 mg polyoxyethylene polyoxypropylene polymer 0, Q00 mg - - food yellow # 2 - 0.065 mg - food orange # 2 1, 830 mg l1 *, 790 mg 25,000 mg hydroxypropyl cellulose 1 ^, 830 mg lif, 790 mg 5,800 mg cellulose 21 143221 8,500 rag cocoa 0.06θ mg saccharin 0.060 mg cream essence 30,000 rag 30,000 mg 90,000 rag weight per unit about 3 c no about 3j5 c no about 5 c no area per unit yellow orange brown appearance.

Example 17

Preparation of 1000 units: 0.15 g of D-Norgestrel, 0.03 g of ethynyl estradiol and 0.8U g of polyoxyethylene polyoxypropylene polymer are dissolved in 95.00 g of ethyl alcohol with stirring, and in this solution one powder mixture of 16.99 g of hydroxypropyl cellulose and 16.99 g of cellulose is introduced.

The resulting suspension is wiped on a suitable foil extractor to an extruded layer with a layer thickness of 500 μιη and then dried.

Composition of a unit: 0.15 mg D-Norgestrel 0.03 mg ethynyl estradiol 0.8V mg polyoxyethylene polyoxypropylene polymer 16.99 mg hydroxypropyl cellulose 16.99 mg cellulose 35.00 mg - 2

One unit corresponds to an area of approx. 3 cm. Appearance of the foil: white, papery. The dry film has a thickness of about 170 μηι.

22 143221

Example in a

Manufacture of 10,000 units:

Solution A. Dissolve 1.5 g of D-norgestrel and 0.3 g of ethynyl estradiol in 477 »7 g of alcohol.

Solution B 1.5 g of polyoxyethylene polyoxypropylene polymer is dissolved in 23.0 g of water.

Solution C The solutions A and B are combined.

Suspension B 88.1 g of hydroxypropyl cellulose and 88.6 g of cellulose Mix loosely, pass through a 1.2 mm sieve and introduce, with stirring, into solution C. 600 pm.

Composition of a unit: 0.15 mg D-norgestrel 0.03 mg ethynyl oestradiol 8.81 mg hydroxypropyl cellulose 8.86 mg cellulose 0.15 mg polyoxyethylene polyoxypropylene polymer 18.00 mg p

Area per unit: .144 mm

Appearance of the foil: white, papery bliss of the foil: 260-280 pm.