CA1067407A

CA1067407A - Pharmaceutical preparation in the form of a foil having an active substance incorporated therein

Info

Publication number: CA1067407A
Application number: CA230,802A
Authority: CA
Inventors: Peter Fuchs; Jurgen Hilmann
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1974-07-05
Filing date: 1975-07-04
Publication date: 1979-12-04
Also published as: DD122196A5; JPS5129218A; DK143221C; IE42604B1; GB1510999A; AU8252775A; SE413285B; FR2276811A1; FI751801A7; SE7507659L; IN142428B; RO68836A; FI60354B; NL7507785A; DK295075A; NL186294C; PH18973A; IL47573A0; IL47573A; CH625704A5

Abstract

ABSTRACT OF THE DISCLOSURE
A pharmaceutical preparation for internal or external use includes a foil incorporating one or more pharmacologically active ingredients, the material forming the foil being soluble in water or organic solvents. The foil forming material may be poly-N-vinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate, methyl- and ethyl-cellulose, hydroxypropyl-cellulose, hydroxyethyl-cellulose or methylhydroxypropyl-cellulose. The active ingredient may be a gestagen, oestrogen, mixture of a gestagen and an oestrogen, a tranquillizer, an anti-diabetic, sulphonamide, antibiotic, a trichomonal agent or an inflammation inhibitor.

Description

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This invention relates to a pharmaceutical prepaxation in the form of a foil having an active substance incorporated the~ein, for internal and external use.
Belgian Patent No. 637,363 describes paper foils coated with active substances suitabLe for oral use. The foils consist of cellulose fibres insoluble in water and a water-soluble binding agent. The water-soluble binding agent i9 preferably sodium carb-oxymethyl-cellulose. The active substance may be applied to the paper foil by dropping a solution of the active substance onto the foil, by spreading the solid active substance on the foil or by drawing the foil through a solution of the active substance.
The discontinuous process of separately making the foil and apply-ing the active substance has the disadvantage that the accuracy of the dosage is not very good which is of great importance because acti~e substances are generally used in small doses at the present time. Inaccuracies arise not only in applying the active substance, but also in the manufacture and pretreatment of the foil and because of variations during storage of the foil material. Thus, for example, it has been found that in using foil drawing machines as prescribed in Belgian Patent No. 637,363, non-uniform layers of foil are formed, and that the foil shrinks during drying.
However, it is easy to understand that with non-uniform ma~erial the take-up of active substance is also not uniform. Moreover, an active substance bound only on the surface can be partially removed during handling of the foils, for example, during packing.
The sodium carboxymethyl-ceIlulose used as binding agent becomes detached in the stomach and there is liberated carbo~ymethyl-cellulose, which includes some of the active substance and liber-ates it only slowly or not at all.
The present invention is based on the observation that foils having a constant thickness and a uniform distribution of active substance can be obtained by making foils having the active - 1 - ~

~7 substance inco~porated therein and using foil formers that are soluble in water or or~anic solvents.
The present invention provides a pharmaceut~cal preparation in the form of a foil, wherein the foil incorporates one or more pharmacologicall~ active ingredi.en-ts and is obtained from a foil forming material or materials soluble in water or organic sol~ents. Especially suitable are foil forming materials soluble both in water and organic solYents.
Suitable foil formers there include poly-N-vinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate, methyl- and ethyl-cellulose, but preferably non-ionic water-soluble hydroxyalkyl ethers of cellulose such as, ~or example, hydroxypropyl-cellulose, hydroxyethyl-cellulose and methylhydroxypropyl-cellulose.
In addition to the active substance or substances, the foil may contain fillers and advantageously a small amount of a release agent.
Suitable release agents are, polyoxyethylene-polyoxy-propylene polymer (PLURaNIC F 68 ~?, polyoxyl stearates, alkyl-or acyl-substituted polyaddition product~ of ethylene oxide, for example, CR~MOPHOR EL ~ , silicones and silicone parting emulsions, glycerine, propylene glycol and metal soaps.
The fillers include cellulose, sugars, for example, lactose, dextrose and cane sugar, starches, polyhydric alc.ohols, for example, m-nnitol, calcium carbonate, calcium phosphate, talcum and dyestuffs in soluble form or as pigments. When soluble fillers and soluble active substances are used, a transparent smooth foil is formed, and when insoluble flllers or insoluble active substances are used a white or coloured paper-like foil is formed.
A11 acti~e substances used in human and veterinary medicine can be used in accordance with the invention. ~or internal use there comes into consideration especially oral administration. As external use there is to be understood, more especially, topical administration on the sk:in and in body cavi-ties such, for example, as the nose, ears and vagina. The active substances may be, for example, gestayens, oestrogens, mixtures of gestagens and oestrogens, tranqui:llizers, anti.-diabetics, sulphonamides, antibioticsl trichomonal agents and inflammation inhibitors, for example,: corticoids.
The medicaments may be present in the car~ier materials in a dissol~ed or uniformly .suspended state. The proportion of acti.ve substance in the foil may be from 0 to 60 per cent. The suraces may be cut or perforated to form single doses (units), which contain quantities o~ active substance such as are usually present in tablets, dragées, salves and suppositories. Thus, the quantity of active substance per single dose may be as high as desired depending on the mode of; use and between about 1 ~g and 0.5 g, and the lower and upper dose may easily be smaller or greater. It is, of course, possible also to make carriers free from active substance (placebos).
For the production of the medicinal preparations in foil form of the invention the active substance and/or parting compound is disso.lved or suspended, the foil former and optionally the filler is introduced, optionally homogenized, and the solution or suspension is drawn out on a foil drawing machine to a sheet.
The foil obtained by drying the sheet is divided into sections (units).
Into the solution or suspension are introduced the foil former in a proportion by weight of about 6 to 7.0 per cent, the filler in a proportion by weight of up to 30 per cent and the release agent preferably in a proportion by weight of 0.01 to per cent are introduced into the solution or suspension.
The content of solvent or suspension medium is about ~8 to 8~ per cent by weight and consists of water and/or one or 1~i7~0~

moxe organic solvents. The organic solvents are physiologically tolerable solvents or solvents that are removed except for a physiologically unobjectionable residue. ~uch solvents axe, for example, ethyl alcohol, isopropanol and methylene chIoride, and mixtures thereof. Water and ethyl alcohol or mixtures of water and ethyl alcohol are preferably used.
The layer thickness of the wet sheet is about 0.1 to

2 mm and that of the dry foil is about 0.05 to 1 mm, and prefer-ably 0.07 to 0.3 mm.
The process of making the medicinal preparation in foil form in one operation (a continuous process) has the advantage that the active substance is homogeneously and uniformly distri-buted in the medicament carrier. By varying the concentration of the~active substance in the carrier, the thickness of the foil and the area of the foil the unit dose can be varied in a very simple manner.
Foils can also be made with a sheet in which different active substances and/or varying concentrations of active substance are incorpoxated side by side over the width of the web of foil.
Zo ` By means of a special doctor, which consists of two or more compartments, different solutions or suspensions can be drawn out without mixing to form a coherent sheet. The width and thickness of the sheet is separateIy adjustable for each compartment. If desired, zones (strips) having different active substances or different concentrations are made visible by different dyestuffs.
By drying the wet sheet there is obtained a foil, which by being divided in an appropriate manner, for example, by perforation, yields units containing different active substances and/or concentrations of active substance or units containing no active substance. Foils containing different active substances and/or different concentrations of active substance are required for making multi-phase preparations, for example, for making ~L~7~(37 contraceptive preparations~ The possibility o;E the spatial separation of active substances that are incompatible with one another i~ one foil unit improves the stability oE the individ-ual active substances. ~oils for intravaginal application may, for example, also be rolled round an ordinary commercial tampon.
The following examples illustrate the invention; with the exception of Examples 5 and 16, the preparations described in the examples are primarily suitable for oral administration.
Example 1 Preparation for 1000 units:
0.25 g of d-norgestrel, 0.05 g of ethinyl-oestradiol and 0.84 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 95.00 g of ethyl alcohol while stirring, and into this is introduced a powdered mixture of 16.93 g of hydroxypropyl-ceIlulose and 16.93 g of cellulose.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ~m, and is then dried.
The composition of one unit:
0.25 mg of d-norgestrel 0.05 mg of ethinyl-oestradiol 0.84 mg of polyoxyethylene-polyoxypropylene polymer 16.93 mg of hydroxypropyl-cellulose 16.93 mg of cellulose _. .
35.00 mg One unit corresponds to an area of about 3 cm2.
~ppearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.

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Exam~le 2 A preparation for 1000 units:
1.10 g of Cremophor EL ~ are dissol~ed in 152.00 g of water. In this solution are suspended 0.25 g of micronized d-norgestrel and 0.05 g of micronized ethinyl-oestradiol and if necessary homogenizea. Into the suspension are introduced 22.10 g of hydroxypropyl-ceIlulose and 16.50 g of cellulose.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ~m, and is then dried.
The com,position for one unit:
0.25 mg of d-norgestrel 0.05 mg of ethinyl-oestradiol 1.10 mg of Cremophor EL ~
22.10 mg of hydroxypropyl-cellulose 16.50 mg of cellulose 40.00 mg One unit corresponds to an area of about 3 cm .
Appearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
'Ex'ample 3 A preparation for 1000 units:
0.03 ~ of d-norgestrel and 0.84 g of polyoxyl-40-stearate are dissolved, while stirring, in 95.00 g of ethyl alcohol. Into this solution is introduced a powdered mixture of 16.93 ~ of hydroxypropyl-ceIlulose and 17.20 g of cellulose.

~ ~7~q The suspension thus obtained .is drawn on a sultable ~oil drawing apparatus to a sheet having a thickness of 500 ~m, and is then dried~
The composition of one.unit:
0.03 mg o~ d-norgestrel 0.84 mg of polyoxyl-40-stearate 16.93 mg of hydroxypropyl-ceIlulose 17.20 mg of cell.ulose ..35.00 mg One unit corresponds to an area of about 3 cm2.
Appearance of the foil: ~hi.tel paper-like.
The dry foil has a thickness of about 170 ~m.
Example 4 A preparation for 1000 units:
1.10 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 152.00 g of demineralized water. In this solution is suspended 0.03 g of microized d-norgestrel, and if necessary homogenized. Into the suspension are introduced.
22..10 g of hydroxypropyl-cellulose and 16.77 g of cellulose.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of.500 ~m, and is then dried.
The composition for one unit:
0O03 mg of d-norgestrel 1.10 mg of polyoxyethylene-polyoxypropylene polymer 22.10 mg of hydroxypropyl-cellulose 16.77 mg of cellulose -40.00 mg One unit corxesponds to an area of about 3 cm2.
Appearance of the.foil: white, paper-like.
The dry foil has a thickness of about 170 ~m, Exam_le.5 A preparation for 1000..units 0~025 g of fluocortolone trimethylacetate and 0.183 ~ of gylcerine are dissolved in .30.000 g of ethy.l alcohol. Into this solution are introduced 7.292 g of hydroxypropyl-cellulose~
The solution thus obtained is draw on a suitable foil drawing apparatus to a sheet having a thickness to.500 ~m, and is then dried.
The composition of one unit:
0.025 mg fluocortolone trimethylacetate 0..183 mg of glycerine - 7:.292 mg of hydroxypropyl-cellulose 7.500 mg One unit corresponds to an area of about 1 cm2.
Appearance of the foil: transparent.
The dry foil has a thickness of about 70 ~m.
The foil is suitable for topical use.
Examp:le 6 A preparation for 1000 units:
10.00 g of 7-chloro,2-methylamino-5-phenyl-3~-1,4-benzo-diazepine-4-oxide and 0.84 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 95.00 g of ethyl alcohol. Into this solution is introduced a powdered mixture of 16.93 g of hydroxypropyl-cellulose and 7.23 g of cellulose.

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The suspension thus o~tained is drawn on a suitable foil dra~ing appaxatus to a sheet having a thickness o~ 500 ~m, and is then dried.
The composition of one unit:
10.00 mg of 7-chloro-2-meth~lamino-5-phenyl-3H-1,4-benzo-diazepine-~-oxide 0.84 mg of polyoxyethylene-polyoxypropylene polymer 16.93 mg of hydroxypropyl-cellulose 7.23 mg of cellulose 35.00 mg One unit corresponds to an area of about 3 cm2.
Appearance of the foil: yello~, paper-like.
The dry foil has a thickness of about 170 ~m.
Example 7 A preparation for 1000 units:
1.00 g of norethisterone acetate, 0.03 g of ethinyl-oestradiol and 0.84 g of polyoxyethylene-polyoxypropylene polymer and dissolved in 95.00 g of ethyl alcohol. Into this solution is introduced a powdered mixture of 16.93 g of hydroxypropyl-cellulose and 16.20 g of cellulose.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ~m, and is then dried.
The composition for one unit:
1.00 mg of norethisterone acetate 0.03 mg of ethinyl-oestradiol 0.84 mg of polyoxyethylene-polyoxypropylene polymer 16.93 mg of hydroxypropyl-cellulose 16.20 mg of cellulose 35.00 mg 4~

One unit corresponds to an area of about 3 cm2.
~ppearance of the ~oil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
Example 8 A preparation for 1000units:
1.00 g of norethisterone acetate 0.03 g of ethinyl-oestradiol 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, Into this so}ution is introduced a powdered mixture of 8.47 g of hydroxypropyl-ceIlulose, 8.47 g of hydroxyethyl-ceIlulose and 16.19 g of cellulose.
The suspension thus obtained is drawn on a suitable fo'il drawing apparatus to a sheet having a thickness of 500 ~m, and is then dried.
The composition fox one unit:
1.00 mg of norethistèrone acetate 0.03 mg of ethinyl-oestradiol 0.84 mg of propylene glycol 8.47 mg of hydroxypropyl-cellulose 8.47 mg of hydroxyethyl-cellulose 16.19 mg of cellulose 35.00 ~g One unit corresponds to an area of about 3 cm2O
Appearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
Example 9 A preparation for 1000 units:
1.00 g of norethisterone aceta-te, 0.03 g of ethinyl-oestradiol and 7~

0.84 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 101.60 g of methylene chloride and 25.40 ~ of ethyl alcohol. Into this solution is introduced a powdered mixture o~
16~93 g o:E hydroxyethyl-cellulose and 16.20 g of starch.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a~hickness of 500 ~m, and is then dried.
The composition for one unit:
1.00 mg o norethisterone acetate 0.03 mg of ethinyl-oestradiol 0.84 mg of polyoxyethylene-polyoxypropylene polymer 15.93 mg of hydroxyethyl-cellulose and 16.20 mg of starch 35.00 mg One unit corresponds to an area of about 3 cm2.
Appearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
Example 10 A preparation for 1000 units:
1.00 g of norethisterone acetate 0.03 g of ethinyl-oestradiol and 0.84 g of polyoxyl-40-stearate are dissol~ed in 95.00 g of ethyl alcohol. Into this solution is introduced a powdered mixture of 16.93 g of hydroxypropyl-cellulose 8.10 g of lactose and 8.10 g of maize starch.
The suspension thus obtained is drawn on a suitable ~ ~ t7~ ~ ~

foil drawing apparatus to a sheet ha~ing a thickness of 500 ~m, and is then dried.
The composition ~or one unit:
1.00 mg of norethisterone acetate 0.03 mg of ethinyl-oestradiol 0.84 mg of polyoxyl-40-stearate 16.93 mg of hydroxypropyl-cellulose 8.10 mg of lactose 8.10 mg of maize starch 35.00 mg One unit corresponds to an area of about 3 cm2.
Appearance of the foil: ~hite, paper-like.
The dry foil has a thickness of about 170 ~m.
Example ll A preparation for 1000 units:
1.00 g of norethisterone~(l7~-ethinyl-19-nor-testosterone) 0.03 g of ethinyl-oestradiol and 0.22 g of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of 84.75 g of ethyl alcohol and 4.00 g of water. Into this solution is introduced a powdered mixture of 16.00 g of hydroxypropyl-cellulose and 16.00 g of cellulose.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 600 ~m and then dried.
The composition for one unit:
1.00 mg of noxethisterone ~17~-ethinyl-l9-nor-testosterone) 0.03 mg o~ ethinyl-oestradiol 0.22 mg of polyoxyethylene-polyoxypropylene polymer 16.00 mg of hydroxypropyl-cellulose ~7~

16.00 mg of cellulose .
33.25 mg One unit corresponds to an area of about 3 çm2.
Appear~nce o~ the ~oil: white, paper~like.
The dry foil has a thickness of approx. 230 ~m.
Example 12 A preparation for 1000 uni*s:
4.0 g of glisoxepide.* in micronised form are suspended in 0..9 g of polyoxyl-40-stearate dissolved in .152.0 g of water, and:if necessary homogenized. Into the suspension are introduced 15.0 g of hydxoxyethyl-ceIlulose and 15.1 g of calcium carbonate.
The suspension thus obtained is drawn on a suitable foil drawing appara*us to a sheet having a thickness of.500 ~m and dried.
The composition for one unit:
4.00 mg of glisoxepide.*
0090 mg of polyoxyl-40 stearate 15.00 mg of hydroxyethyl-cellulose 15.10 mg of calc.ium carbonate -.35.00 mg One unit corresponds.to an area of about 3 cm2.
Appearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
4-{~-[~-(5-methyl-isoxazol-3-carboxamido~-ethyl~-benzolsulphonyl}-l,l-hexamethylene-semicarbazide.
Example 13 A preparation for lOOO.units:
0.030 g of d norgestreI are dissolved in 40.000 g of methylene chloride and 55.000 g of ethanol. Into this solution are introduced 0.840 g of silicone oil 6.930 g of methyl-cellulo:se and 10.000 g of poly-N.-vinyl-pyrrolidone and 17.200 g of starch~,and i~ necessary homoyenlzed.
The suspension thus obta:ined is drawn on a :suitable foil drawing apparatus to a sheet having a t:hickness of;500 ~m and dried.
The composition of one~.unit:
Ø.030 mg of d-norgestrel 0.840 mg of silicone oil 6.930 mg of methyl-cellulose 10.000 mg of poly-N-~inyl-pyrrolidone 17:.200 mg of starch .35.000 mg One unit corresponds to an area of about.3 cm .
Appearance of the foil: white, paper-like.
The dry foil has a thickness of about 170 ~m.
Ex'ampl'e''14 A preparation for 1000. units:
0.84 g of polyoxyethylene-polyoxypropylene polymer are dissolved in 95.00 g of ethyl alcohol while stirring, and into this solution is introduced a powdered mixture of 17.08 g of hydroxypropyl-ceIlulose and 17.08 g of cellulose.
The suspension thus obtained is drawn on a suitahle foil dra~ing app~ratus to a sheet having a thickness of 500 ~m and then dried~

~)t;i7~0P7 The compositi.on ~or one unit:
0.84 mg of polyoxyethylene-polyoxypropylene polymer 17.08 mg of hydroxypropyI-ceIlulsoe 17.08 mg of cellulose ..35.00 mg Exampl:e :15`
A preparati.on for 1000 units:
0.04 g of saccharin 0.04 g of cream essence and 0.40 g of polyoxyethylene-polyoxypropyl.ene:polymer are dissolved in a mixture of 79.00 g of ethyl alcohol and 4.00 g of water. Into this solution are introduced .30:.00 g of iron (II? .umarate, .15.00 g of hydroxypropyl-cellulose, 5..52 g of cocoa and 4:.00 g of ceI.lulose, and if necessaxy homogenized.
The suspension thus obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 0.5 mm, and then dried.
The composition for one unit:
30.00 mg of iron (II) :fumarate 15.00 mg of hydroxypropyl-cellulose 4.00 mg of cellulose 0.40 mg of polyoxyethylene-polyoxypropylene polymer 5..52 mg of co.coa 0.04 mg of saccharin 0.04 mg of cream ess~ence 55.00 mg. Weight per unit.
One unit corresponds to an ar~a of about 3 cm2.
Appearance o the foil: pale red-brown.

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Example 16 Foils for intravaginal application;
The foil is prepared in accordance with Example ll.
The co~position of one unit 100.0 mg of S-morpholinomethyl-3-(5-nitro-1-methyl-2-imidazolyl)-methyleneamino-2-oxazoli-done.HCl 8.4 mg of Cremopho~ EL ~
169.2 mg of methylhydroxypropyl-cellulose 72.4 mg of cellulose 350.0 mg. Weight of one unit.
One unit corresponds to an area of about 8 x 4 cm.
Appearance of the foil: pale yellow.
The $oil (1 unit~ is either rolled round an ordinary commercial tampon or is itself rolled to form a naErow tube.
EXample 17 A two phase preparation Part 1: 21 units containing active substance.
Part 2: 7 units without active substance.
A preparation for 3000 units. Part 1.
0.75 g of d-norgestrel 0.15 g of ethinyl-oestradiol and 0.54 g of polyoxethylene-polyoxypropylene polymer are dissol~ed in a mixture of 237.00 g of ethyl alcohol and 12.00 g of water. Into this solution are introduced 44.28 g of hydroxypropyl-cellulose and 44.28 g of cellulose, and if necessary homogenized.
A preparation for 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 14~.91 g of h~droxypropyl-ceIlulose and 14.91 g of cellulose,~ and if necessary homogenized.
The suspensions thus :obtained are drawn on a suitable foil drawing apparatus having a two compartment s~ecial doctor (widths of the compartments: 1 =.54 mmi 2 = 18 mm) to form a sheet of 0..5 mm and then dried. By appropriate division into units measuring 18 x 18 mm, for example, by perforation, the foil can be divided over its width into three units containing active substance and one unit free from active substance. There may be produced in the web of foil any desired number of sections having a ratio of three units containing active substance to one unit containing no active .substance.
The composition of each unit:

Part 1 (containing active :substance) Part 2 (free from . ..... = . . active.. su~stance~

0.25 mg of d-norgestrel 0.05 mg of ethinyl-oestradiol 14.76 mg of hydroxypropyl-cellulose 14.91 mg 2014~76 mg of cellulose 14.91 mg 0.18 mg of polyoxyethylene-polyoxypropylene0.18 mg polymer 30.00 mg weight per unit 30.00 mg Area per unit: about 3 cm .
Appearance: white.
Example 18 Three phase preparation (two acti~e substance stage preparation) Part 1: 11 Units containing 0.05 mg of d-norgestrel diol.
Part 2: 10 Units containing 0.125 mg of d-n~rgestrel 0.050 mg of ethinyl-oestra-diol.

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Part 3: 7 UnitS without active substance.preparation for 1100 units, Part 1:
0.055 g of d-noxgestre~ r 0.055 g of ethinyl-oestradiol and 0.198 g of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of 86.900 g of ethyl alcohol and 4.400 g of water. Into this solution are introduced 16.346 g of hydroxypropyl-ceIlulose and 16.346 g of cellulsoe, and if necessary homogenized.
A preparation for 1000 units t Part 2.
0.125 g of d-norgestreI
0.050 g of ethinyl-oestradiol and 0.180 g of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of 79.000 g of ethyl alcoho~ and 4.000 g of water. Into this solution are introduced 14.823 g of hydroxypropyl-ceIlulose and 14.822 g of cellulose, and if necessary homogenized.
A preparation for 700 units. Part 3:
0.189 g of polyoxyethylene-polyoxypropylene polymer is dissolved in a mixture of 82.950 g of ethyl alcohol and 4.200 g of water. Into this solution are introduced 15.656 g of hydroxypropyl-cellulose and 15.655 g of ceIlulose, and if necessary homogenized.
The suspensions thus obtained are drawn on a suitable foil drawing apparatus having a three compartment special doctor (width per compartment 18 mm~ to a sheet and dried. By appropriate division, or example, by perforationl there can be distributed over the width of the foil three units of 18 x 18 mm for Part 1, of 18 x 19.8 mm for Part 2 and of 18 x 28 for Part 3, having -~(~674~97 different contents of active substance. There can be separated from the foil web preparations having 11 units of Part 1, 10 units of Part 2 and 7 units of Part.3.
The composition per:unit:
Part 1 Part 2. Part.3. . In~redients O.OS0 mg 0.125 mg - d-norgestrel 0.050 m~ O.OS0 mg - ethinyl-oestradiol 0.180 mg 0.180 mg0.270 mg polyoxyethylene-polyoxypropylene polymer 1014.860 mg 14.823 mg23.366 mg hydroxypropyl-cellulose 1-4.860 mg 14.822 mg22.3-64 mg cellulose 30.000 mg 30.000 mg45.000 mg weight per unit about about about

3 cm2 3'5 cm25 cm area per unit ~hite ~hite white appearance . .

:
Example 19 Three phase preparation:
Part 1: 11 Units containing 0.05 mg of d-norgestrel 0..05 mg of ethinyl-oestradiol Part 2: 10 Units containing 0.125 mg of d-norgestrel 0.050 ~g of ethinyl-oestradiol Part 3: 7 Units containing50.00 mg of iron (II) :fumarate.
A preparation for 1100 units. Part 1:
0.066 g of food colour yeIlow No. 2 (tartrazine; E 102) is dissolved in

4.400 g of water, and then introduced into 86.900 g of ethyl alcohol. In this solution axe dissolved 0.055 g of d-norgestrel 0.055 g of ethinyl-oestradiol and 0.198 g of polyoxyethylene-polyoxypropylene polymer.

Into this solution are in-troduced 16.313 g of hydroxypropyl.-cellulose and 16..313 g of cellulose, and if necessary homogenized.
preparation for lOOO.units. Part 2:
0.065 g of food..colour orange No. 2 (Sunset ~ellow;
E 110~ is disso:lved in 4.000 g o~ water, and then introduced into 79.000 g of ethyl alcohol. In this solution are dissolved 0.125 g of d-norgestr~el 0..050 g of ethinyl-oestradiol and 0.18 g of polyoxyethylene-polyoxypropylene polymer.
Into this solution are:introduced 14.790 ~ of hydroxypropyl-.cellulose and 14.790 g of cellulose, and if necessaxy homo~enized.
A preparation for 700 units. Part.3:
0.042 g of saccharin 0.042 g of cream essence and 0.406 g of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of 55.300 g of ethyl alcohol and 2.800 g of water. Into this solution are introduced .35.000 g of iron (II) .fumarate 17.500 g of hydroxypropyl-.cellulose

5.950 g of cocoa and 4.060 g of cellulose, and if necessary ho~ogenized.
The suspensions so prepared are drawn on a suitable foil drawing apparatus having a three compartment special doctor (width per compartment 18 mm) to a sheet and dried. By appropri-ate division, for example, by perforation, there can be distribu-ted over the width of the foil three units of 18 x 18 mm for Part 1, of 18 x 19.8 mm for Part 2 and of 18 x 28 mm for Part 3, 7~

having different contents of acti.ve substance. r~here can be separated from the ~oil web preparations having ll..unit o~
Part 1, 10 units of Part.2 and 7 units oE ~art 3.
The composition per.unit:
Part 1 P~rt 2Part 3 In~redients 0.050 mg 0.125 mg - 'd-norgestrel O... OS0 mg 0.050 mg - ethinyl-oestradiol - - 50.000 mg iron ~II) fumarate 0~180 mg a .180 mg 0.580 mg polyoxyethylene-polyoxypropylene polymer 0.060 mg - - food colour yellow No. 2 - 0.065 mg - food colour orange No. 2 14.830 mg 14.790 mg25'.000 mg hydroxypropyl-cellulose 14.830 mg 14.790 mg5.800 mg cellulose - - 8.500 mg cocoa - - 0.060 mg saccharin .. . - - . .. 0.. 06Ømg cream essence .
20 30.000 mg 30.000 mg 90.000 mg weight per unit about about about 3 cm2 3.5 cm2 5 cm2 area per unit yel.low . orange br.own . . .... a.ppe:a.rance .
Exa~ple 20 Preparation for 1000 units 0.15 g of d-norgestreI
0.03 g of ethinyl-oestradiol and 0.84 g of polyoxethylene-polyoxypropylene polymer are dissol~ed in 95.00 g of ethyl alcohol while stirring and a powdered mixture o~
16.99 g of hydroxypropyl-cellulose and 16.99 g of cellulose is introduced into this solution.
The suspension obt~ined is drawn out on a suitable foil drawing apparatus to ~ very thin foil having a thi.ckness of 500 ~m, and is then dried.
The composition of one unit:
0.15 mg of d-norgestrel 0.03 mg of ethinyl-oestradiol 0.84 mg of polyoxyethylene-polyoxypropylene polymer 16.99 mg of hydroxypropyl-cellulose 16.99 mg of cellulose 35.00 One unit corresponds to.an area of approxO 3 cm2 Appearance of the: foil: white, paper-like.
The dry foil has a thickness of approx. 170 ~m.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. In a pharmaceutical composition in unit dosage form for enteral or topical administration and comprising a safe and effective amount of a pharmaceutically active medicament compound and a flexible, water soluble film carrier therefore, the improve-ment wherein the medicament is dissolved or uniformly suspended, together with about 0.01 - 2% by weight of a pharmaceutically acceptable release agent in a film carrier consisting essentially of a non-ionic, water soluble methyl ether or hydroxyalkyl ether of cellulose and the pharmaceutical composition is in the form of a tissue-like sheet, having a uniform dry film thickness of about 0.05 - 1 mm, drawn from a solution of the film carrier containing 0.01 - 2% by weight of a pharmaceutically acceptable release agent, 0 - 30% by weight of a filler and up to 60% by weight of the film carrier of the medicament.

2. A composition according to claim 1, wherein the film carrier is hydroxypropyl-cellulose, hydroxyethyl-cellulose, methyl-hydroxypropylcellulose and mixtures thereof.

3. A composition according to claim 1, wherein the medicament is an estrogen, gestagen or admixture thereof.

4. A composition according to claim 1, wherein the release agent is a polyoxethylene-polyoxypropylene copolymer(s), a polyoxylstearate or an alkyl- or alkanoyl-substituted poly-addition product of ethylene oxide.

5. A composition according to claim 1 wherein the medi-cament or concentration thereof differs in areas thereof defined by strips adjacent to one another along the width of the sheet.

6. A composition according to claim 5, wherein the strips are identified by different dyestuffs.

7. A composition according to claim 1, wherein the sheet is perforated to provide a plurality of single-unit dosages.

8. A composition according to claim 1, wherein the sheet is a transparent and smooth film.

9. A composition according to claim 1 containing a water-insoluble filler uniformly suspended in the film carrier and the film is paper-like.

10. A composition according to claim 9, wherein the filler is cellulose.

11. A composition according to claim 1, wherein the film carrier is methyl cellulose.

12. A composition according to claim 1, wherein the sheet has a thickness of 0.07 - 0.3 mm.

13. A composition according to claim 1, wherein the film carrier is hydroxypropyl-cellulose, hydroxyethyl-cellulose, methylhydroxypropyl-cellulose or a mixture thereof; the medica-ment is an estrogen, gestagen or admixture thereof; the release agent is a polyoxyethylene-polyoxypropylene copolymer, a polyoxyl stearate or an alkyl- or alkanoyl-substituted poly- addition product of ethylene oxide; and the sheet has a thickness of 0.07 -0.3 mm.

14. A process for the production of a pharmaceutical composition in unit dosage form for enteral or topical adminis-tration and comprising a safe and effective amount of a pharma-ceutically active medicament compound and a flexible, water sol-uble film carrier therefore, which process comprises: (a) draw-ing into a sheet having a uniform layer thickness of about 0.1 -2 mm and a dry thickness of about 0.05 - 1 mm, a homogeneous solu-tion or suspension consisting essentially of (1) up to 60% by weight, based on the film carrier, of the medicament, (2) 0 - 30 by weight of a pharmaceutically acceptable filler, (3) a film-forming amount of a water-soluble film-forming polymer, and (4) as solvent or suspending medium, one or both of water and an organic volatile solvent system comprising an organic polar sol-vent miscible in water; and (b) drying the thus-formed sheet to remove the solvent or suspending medium therefrom.