Pharmaceutical preparation in the form of a foil having an active substance incorporated therein
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35 claims: 17 independent, 18 dependent
- 1WHAT IS CLAIMED IS:1. A pharmaceutical preparation in the form of a foil sheet having a uniform dry film thickness of about 0.05-1 mm, wherein the foil incorporates one or more pharmacologically active ingredients and is obtained from a foil forming material or materials consisting essentially of a nonionic, water soluble methyl ether, hydroxyalkyl ether or methylhydroxyalkyl ether of cellulose or poly-N־vinylpyrrolidone.
- 12A preparation as claimed in any one of claims 1 to 11, which is in the form of a two-phase or multi-phase preparation wherein the foil contains different active ingredients and/or different concentrations of active ingredient in different sections or zones of the foil, and or in which one or more sections or zones may contain no active ingredient.
- 32A process as claimed in any one of claims 21 to 31, wherein two or more solutions or suspensions are prepared each containing a different active ingredient and/or different concentrations of active ingredient and in which one or more solutions or suspensions may contain no active ingredient, the solutions or suspensions are drawn on a suitable foil drawing apparatus having doctor means to give a sheet containing in different .sections or zones of the sheet different active ingredients and/or different concentrations of active ingredient (including zero concentration), and the foil is appropriately divided by cutting, perforation or other means to give a two-phase or multi-phase preparation in which unit dosage portions can be readily detached.
Independent claims17
434 paragraphs in 15 sections, as filed
A pharmaceutical preparation in the form
0f a foil having an active substance incorporated therei n
The present invention is concerned with a pharmaceutical preparation in the form of a foil having an active substance incorporated therein, for internal and external use.
Belgian patent specification No. 637,363 describes paper foils coated with active substance suitable for oral use. The foils consist of cellulose fibers insoluble in water and a watersoluble binding agent. As a water-soluble binding agent there is preferably used sodium carboxymethyl-cellulose. The active substance is applied to the paper foil by dropping on it a solution of the active substance, 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 applying the active substance has the disadvantage that the accuracy of the dosage is not very good, which is of great importance as active 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 carrier and owing to variations during storage of the carrier material. Thus, for example, it has been found that in using foil drawing machines as prescribed in the Belgian patent specification non-uniform layers of foil are formed, and that the foil shrinks during drying. However, it is easy to understand that with non-uniform material the take-up of active substance is also not uniform. Moreover, an active substance bound only on the surface can be partially removed during the handling of the foils, for example, during packing. The sodium carboxymethyl = cellulose used as binding agent becomes detached in the stomach and there is liberated carboxymethyl :cel 1 ulose, which includes some of the active substance and liberates it only slowly or not at all.
It has now been found that foils having a constant thickness and a uniform distribution of active substance are obtained by making foils having active substance incorporated therein and using foil formers that are soluble in water or organic solvents. Especially suitable are foil formers that are soluble both in water and in organic solvents.
As foil formers there come into consideration, for example, poly-N-vinyl-pyrrolidone, vlnylpyrrolidone־v*ny! acetate, methyland -ethyl-cel 1ulose, but preferably non-ionic water-soluble hydroxyalkyl ethers of cellulose, such as hydroxypropyl-cel 1ulose, hydroxyethy1-cel 1ulose and methyl hydroxypropyl cel 1ulose.
Fillers and active substances and advantageously a small . amount of a release agent may be added to the foil former.
are
Suitable release agents /1'nter alia, polyoxyethylene(R) polyoxypropylene polymer (PLURONIC F 68' <sup>1</sup>), polyoxyl stearates, alkyl- or acyl-substituted polyaddition products of ethylene oxide, for example, CREMOPHOR EL' ׳, silicones and silicone parting emulsions, glycerine, propylene glycol and metal soaps.
Suitable as fillers are, for example, cellulose, sugars, for example, lactose, dextrose, cane sugar, etc., starches, polyhydric alcohols, for example, mannitol, calciumncarbonate, calcium phosphate, talcum and dyestuffs in soluble form or as pigments. The fillers may be partially or wholly replaced by active substances. When soluble fillers or active substances are used a transparent smooth foil is formed, and when insoluble fillers or active substances are used a white or coloured paper-like foil is formed.
All active substances used in human and veterinary medicine can be used in accordance with the invention. For internal use there comes into consideration especially oral administration. As external use there is to be understood, more especially, topical administration on the skin and in body cavities such as the nose, ears, vagina, etc. As active substances there maybe mentioned, for example: Gestagens, oestrogens, mixtures of gestagens and oestrogens, tranquillizers, anti-diabetics, sulphonamides, -־ antibiotics, trichomona! agents, inflammation inhibitors, for example, corticoids, etc.
The medicaments may be present in the carrier material in a dissolved or uniformly suspended state. The proportion of active substance in the foil may be about 0 to 60 per cent. The surfaces are cut or perforated to form single doses (units), which contain of quantities/active substance such as are usually present also in tablets, dragees, salves, suppositories, etc. 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 ugram and 0.5 gram, 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 dissolved or suspended, the foil former and optionally the filler-« is introduced, optionally homogenised, 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 20 per cent., the filler in a proportion by weight of about 0 to 30 per cent, and the parting compound preferably in a proportion by weight of 0.01 to 2 per cent.
The content of solvent or suspension medium is about 48 to a.l'ο η έ <or ׳Η n <sup>4</sup> Co'nrb i n a t i 0 rf with per cent. (W/W) and consists of water/and/er one or more organic sol vents.
As organic solvents there come into consideration physiologically tolerable solvents or solvents that arejremoved except for a physiologically unobjectionable residue. Such solvents are, for example, ethyl alcohol, isopropanol, methylene chloride, etc.
־ and mixtures thereof. There are preferably used water and ethyl alcohol or mixtures of water and ethyl alcohol.
The layer thickness of the wet sheet is about 0.1 to 2 mm and that of the dry toil is about 0.05 to 1 mm, and preferably 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 distributed 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 incorporated side by side over the width of the web of foil. 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 separately 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 appropriately divided, 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 preparations for contraception. The possibility of the spatial separation of active substances that are incompatible with one another in one foil unit improves the stability of the individua! active substances. Foils for 1 nt.ravaginal application may, for example, also be rolled round an ordinary commercial tampon.
The invention also includes the use of foil formers that are soluble in water and/or organic solvents for making carriers for medicinal substances, and especially the use of non-ionic watersoluble hydroxyalkyl ethers of cellulose such as hydroxypropylcellulose, hydroxyethyl-cellulose and/or methyl hydroxypropyl־ cellulose.
With the exception of Examples 5 and 16 the preparations described by way of example are preponderantly suitable for oral administration. EXAMPLE 1 Preparation for 1000 units
0.25 gram of d-norgestrel,
0.05 gram of ethinyl-oestradi01 and
0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in
95.00 grams of ethyl alcohol while stirring, and into this is introduced a powdered mixture of
16.93 grams of hydroxypropyl-cel 1ulose and
16.93 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm, 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-cel 1ulose
16.93 mg of cellulose
35.00 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 pm.
EXAMPLE 2
A preparation for 1000 units
1.10 grams of Cremophor EL' are dissolved in
152.00 grams of water. In this solution are suspended
0.25 gram of micronised d-norgestrel and
0.05 gram of micronised ethinyl-oestradiol and if necessary homogenised. Into the suspension are introduced
22.10 grams of hydroxypropyl-cel 1ulose and
16.50 gram of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm, and is then dried.
The composition for one unit:
0.25 mg of d-norgestrel
0.05 mg of ethinyl-oestradiol
1.10 mg of Cremophor EL^<sup>R</sup>^
22.10 mg of hydroxypropyl-cel 1ulose
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 the thickness of about 170 pm. EXAMPLE 3
A preparation for 1000 units
0.03 gram of d-norgestrel and
0.84 gram of polyoxyl-40-stearate are dissolved, while stirring, in
95.00 grams of ethyl alcohol, Into this solution is introduced a powdered mixture of
16.93 grams of hydroxypropyl-cel 1ulose and
17.20 grams of cellulose.
*
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm, and is then dri ed.
The composition of one unit:
0.03 mg of d-norgestrel
0.84 mg of polyoxyl-40-stearate
16.93 mg of hydroxypropyl-cel 1ulose
17.20 mg of cellulose
35.00 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 pm. EXAMPLE 4
A preparation for 1000 units
1.10 grams of polyoxyethylene-polyoxypropylene polymer are dissolved in
152.00 grams of demineralised water. In this solution is suspended 0.03 gram of mfcronised d-norgestrel, and if necessary homogenised.
Into the suspension are introduced
22.10 grams of hydroxypropyl-cel 1ulose and
16.77 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 μm, and is then dried.
The composition for one unit:
0.03 mg of d-norgestrel
1.10 mg of polyoxyethylene-polyoxypropylene polymer
22.10 mg of hydroxypropyl-cel 1ulose
16.77 mg of cel 1ulose
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 pm.
EXAMPLE 5
A preparation for 1000 units
0.025 gram of fluocortolone trimethylacetate and
0.183 gram of glycerine are dissolved in
30.000 grams of ethyl alcohol. Into this solution are introduced
7.292 grams of hydroxypropyl-cellulose.
The solution so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm, and is then dried.
The composition of one unit:
0.025 mg of fluocortolone trimethylacetate
0.183 mg of glycerine
7.292 mg of hydroxypropyl-cellulose
7.500 2 One unit corresponds to an area of about 1 cm .
Appearance of the foil; transparent.
The dry foil has a thickness of about 70 pm.
The foil is suitable for topical use.
EXAMPLE 6
A preparation for 1000 units
10.00 grams of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide and
0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in
95.00 grams of ethyl alcohol. Into this solution is introduced a powdered mixture of
16.93 grams of hydroxypropyl-cellulose and
7.23 grams of cellulose.
The suspension so 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:
10.00 mg of 7-ch1oro2־-methylamino-5-phenyl-3H-l ,4-benzodi azepi ne-4-oxi de at
0.84 mg of polyoxyethylene-polyoxypropylene polymer
16.93 mg of hydroxypropyl-cel 1ulose
7.23 mg of cellulose
35.00
One unit corresponds to an area of about 3 cm . Appearance of the foil: yellow, paper-like.
The dry foil has a thickness of about 170 pm.
EXAMPLE 7
A preparation for 1000 units
1.00.gram of norethisterone acetate,
0.03 gram of ethinyl-oestradi01 and
0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in
95.90 grams of ethyl alcohol. Into this solution is introduced a powdered mixture of
16.93 grams of hydroxypropyl-cel 1ulose and
16.20 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ym, 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-cel 1ulose
16.20 mg of cellulose
35.00
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 ym.
EXAMPLE 8
A preparation for 1000 units:
1.00 gram of norethisterone acetate
0.03 gram of ethinyl-oestradiol and
0.84 gram of propylene glycol are dissolved in a mixture of
101.60 grams of methylene chloride and
26.40 grams of ethyl alcohol. Into this solution is introduced a powdered mixture of
8.47 grams of hydroxypropyl-cel 1ulose,
8.47 grams of hydroxyethyl-cel 1ulose and
16.19 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm, 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 glycol
8.47 mg of hydroxypropyl-cel 1ulose
8.47 mg of hydroxyethyl-cel 1ulose
16.19 mg of cellulose
35.00 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 pm. EXAMPLE 9
A preparation for 1000 units:
1.00 gram of norethisterone acetate,
0.03 gram of ethinyl-oestradiol and
0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in
60.וסו grams of methylene chloride and
25.40 grams of ethyl alcohol. Into this solution is introduced a powdered mixture of
16.93 grams of hydroxyethyl-cel 1ulose and
16.20 grams of starch.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ym, and is then dried.
The composition for one unit:
1.00 mg of norethisterone acetate
0.03 mg of ethinyl-oestradi01
0.84 mg of polyoxyethylene-polyoxypropylene polymer
16.93 mg of hydroxyethyl-cel 1ulose and
16.20 mg of starch
35.00 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 ym.
EXAMPLE 10
A preparation for 1000 units:
1.00 gram of norethisterone acetate,
0.03 gram of ethinyl-oestradi01 and
0.84 gram of polyoxyl-40-stearate are dissolved in
95.00 grams of ethyl alcohol. Into this solution is introduced a powdered mixture of
16.93 grams of hydroxypropyl-cel 1ulose,
8.10 grams of lactose and
8.10 grams of maize starch.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 ym, 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 polyoxyl-40-stearate
16.93 mg of hydroxypropyl-cel 1ulose
8.10 mg of 1actose
8.10 mg of maize starch
35.00
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 pm.
EXAMPLE 11
A preparation for 1000 units:
1.00 grams of norethisterone (17<sub>a</sub>-ethinyl-19-nor-testosterone)
0.03 grams of ethinyl-oestradi01 and
0.22 grams of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
84.75 grams of ethyl alcohol and
4.00 grams of water. Into this solution is introduced a powdered mixture of
16.00 grams of hydroxypropyl-cel 1uloee and
16.00 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 600 pm and then dried.
The composition for one unit:
1.00 mg of norethisterone (17<sub>a</sub>-ethinyl-19-nor-testosterone)
0.03 mg of ethinyl-oestradi01
0.22 mg of polyoxyethylene-polyoxypropylene polymer
16.00 mg of h-ydroxypropyl-cel 1 ul ose
16.00 mg of cellulose
33.25 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 approx. 230 pm.
EXAMPLE 12
A preparation for 1000 units:
4.0 grams of glisoxepide *)in micronised form are suspended in
0.9 gram of polyoxyl-40-stearate dissolved in
152.0 grams of water, and if necessary homogenised. Into the suspension are introduced
15.0 grams of hydroxyethyl-cel 1ulose and
15.1 grams of calcium carbonate.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 μ m and dried.
The composition for one unit:
4.00 mg of glisoxepide ί)
0.90 mg of polyoxyl-40-stearate
15.00 mg of hydroxyethyl-cel 1ulose
15.10 mg of calcium carbonate
35.00 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 ym.
EXAMPLE 13
A preparation for 1000 units:
0.030 gram of d-norgestrel are dissolved in
40.000 grams of methylene chloride and
55.000 grams of ethanol. Into this solution are introduced *)
4-0-[g-(5-methyl - i soxazol - 3-carboxami do)-ethyl ]benzolsulfonyl}-1,1-hexamethylen-semicarbazi de.
0.840 gram of silicone oil
6.930 grams of methyl-cel 1ulose and
10.000 grams of poly^N-vinyl-pyrrolidone and
17.200 grams of starch, and if necessary homogenised.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 pm and dried.
The composition of one unit:
0.030 mg of d-norgestrel
0.840 mg of silicone oil
6.930 mg of methyl-cel 1ulose
10.000 mg of poly-N-vinyl-pyrrol 1 done
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 <sub>u</sub>m.
EXAMPLE 14 (PLACEBO)
A preparation for 1000 units:
0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in
95.00 grams of ethyl alcohol while stirring, and into this solution is introduced a powdered mixture of
17.08 grams of hydroxypropyl-cel 1ulose and
17.08 grams of cellulose.
The suspension so obtained is drawn on a suitable foil drawing apparatus to a sheet having a thickness of 500 <sub>p</sub>m and then dried.
The composition for one unit:
0.84 mg of polyoxyethylene-polyoxypropylene polymer
17.08 mg of hydroxypropyl-cel 1ulose
17.08 mg of cellulose
35.00 mg
EXAMPLE 15
A preparation for 1000 units:
0.04 gram of saccharin,
0.04 gram of cream essence and
0.40 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
79.00 grams of ethyl alcohol and
4.00 grams of water. Into this solution are introduced
30.00 grams of iron(II) fumarate,
15.00 grams of hydroxypropyl-cel 1ulose,
5.52 grams of cocoa and
4.00 grams of cellulose, and if necessary homogenised.
The suspension so 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-cel 1ulose
4.00 mg of cellulose
0.40 mg of polyoxyethylene-polyoxypropylene polymer
5.52 mg of cocoa
0.04 mg of saccharin
0,04 mg of cream essence
55.00 mg Weight per unit.
One unit corresponds to an area of about 3 cm .
Appearance of the foil: pale red-brown.
EXAMPLE 16
Foils for intravaginal application:
The foil is prepared in accordance with Example 11.
The composition of one unit
100.0 mg of 5-morpholinomethyl-3-(5-nitro-1-methyl-2imidazolyl)-methyleneamino-2-oxazoli di none.HCl
8.4 mg of Cremophor E1J<sup>R</sup>)
169.2 mg of methyl hydroxypropyl-cel 1ul ose
72.4 mg of cellulose
350.0 mg Weight of one unit
One unit corresponds to an area of about 8x4 cm Appearance of the foil: pale yellow.
The foil (1 unit) is either rolled round an ordinary commercial tampon o.r 1s itself rolled to form a narrow 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.gram of d-norgestrel
0.15 gram of ethinyl-oestradiol and
0.54 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
237.00 grams of ethyl alcohol and
12.00 grams of water. Into this solution are introduced
44.28 grams of hydroxypropyl-cel 1ulose and
44.28 grams of cellulose, and if necessary homogenised.
A. preparation for 1000 units, Part 2.
0.18 gram of polyoxyethylene-polyoxypropylene polymer is dissolved in a mixture of
79,00 grams of ethyl alcohol, and
4.00 grams of water. Into this solution are introduced
14.91 grams of hydroxypropyl-cel 1ulose and
14.91 grams of cellulose, and if necessary homogenised.
A׳' The suspensions so obtained are drawn on a suitable foil drawing apparatus having a two compartment special doctor (widths of the compartments: 1 = 54 mm; 2 = 18 mm) to form a sheet of 0.5 mm and then dried. By appropriate division into :units measuring 18x18 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 Part 2 (containing active substance) (free from active substance)
0,25 mg of d-norgestrel
0.05 mg of ethinyl-oestradiol
14.76 mg of hydroxypropyl-cel 1ulose 14.91mg
14.76 mg of cellulose 14.91mg
0.18 mg of polyoxyethylene-polyoxypropylene polymer 0.18mg
30.00 mg weight per unit 30.00 mg
Area per unit: about J cm .
Appearance: white.
EXAMPLE 18
Three phase preparation .(two active substance stage 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 mg of ethinyl-oestradiol.
Part 3: 7 Units without active substance.
A preparation for 1100 units, Part 1:
0.055 gram of d-norgestrel,
0.055 gram of ethinyl-oestradiol and
0.198, gram of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
86.900 grams of ethyl alcohol and
4.400 grams of water. Into this solution are introduced
16.346 grams of hydroxypropyl-cel 1ulose and
16.346 grams of cellulose, and if necessary homogenised.
A preparation for 1000 units, Part 2.
0.125 gram of d-norgestrel,
0.050 gram of ethinyl-oestradiol and
0.180 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
79.000 grams of ethyl alcohol and
4.000 grams of water. Into this solution are introduced
14.823 grams of hydroxypropyl-cel 1ulose and
14.822 grams of cellulose, and if necessary homogenised.
A preparation for 700 units, Part 3:
0.189 gram of polyoxyethylene-polyoxypropylene polymer is dissolved in a mixture of
82.950 grams of ethyl alcohol and
4.200 grams of water. Into this solution are introduced
5.656 grams of hydroxypropyl-cel 1ulose and
15.655 grams of cellulose, and if necessary homogenised.
The suspensions so 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, for example, by perforation, there can be distributed over the width of the foil three units of 18x18 mm for Part 1, of 18x19.8 mm for Part 2 and of 18x28 for Part 3, having 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:
<td> Part 1</td><td> Part 2</td><td> Part 3</td><td> Ingredients</td>
<td> 0.050 mg</td><td> 0.125 mg</td><td> -</td><td> d-norgestrel</td>
<td> 0.050 mg</td><td> 0.050 mg</td><td> -</td><td> ethinyl-oestradiol</td>
<td> 0.180 mg</td><td> 0.180 mg</td><td> 0.270 mg</td><td> polyoxyethylene-polyoxypropyl-</td>
<td></td><td></td><td></td><td> ene polymer</td>
<td> 14.860 mg</td><td> 14.823 mg</td><td> 22.366 mg</td><td> hydroxypropyl-cellulose</td>
<td> 14.860 mg</td><td> 14.822</td><td> 22.364 mg</td><td> cel 1ulose</td>
<td> 30.000 mg</td><td> 30.000 mg</td><td> 45.000 mg</td><td> weight per unit</td>
<td> about</td><td> about</td><td> about</td><td></td>
<td><sup>2</sup>י. ר 3 cm</td><td> 0 c <sup>2</sup> 3.5 cm</td><td><sub>c</sub> 2 5 cm</td><td> area per unit</td>
<td> white</td><td> whi te</td><td> whi te</td><td> appearance</td>
EXAMPLE 19
Three phase preparation:
Part 1: 11 Units containing 0.05 mg of d-norgestrel
0.05 mg of ethinyl-oestradi01
Part 2: 10 Units containing 0.125 mg of d-norgestrel
0.050 mg of ethinyl-oestradiol
Part 3: 7 Units containing 50.00 mg of iron(II) fumarate.
A prepration for 1100 units, Part 1:
0.066 gram of food colour yellow No. 2 (tartrazine; E 102) is dissolved in
4,400 gram of water, and then introduced into
86.900 grams of ethyl alcohol. In this solution are dissolved
0.055 gram of d-norgestrel,
0.055 gram of ethinyl-oestradiol and
0.198 gram of polyoxyethylene-polyoxypropylene polymer.
Into this solution are introduced
16.313 grams of hydroxypropyl-cel 1ulose and
16.313 grams of cellulose, and if necessary homogenised.
A preparation for 1000 units, Part 2:
0.065 gram of food colour orange No. 2 (Sunset Yellow;
E 110) is dissolved in
4.000 grams of water, and then introduced into
79.000 grams of ethyl alcohol. In this solution are dissolved
0.125 gram of d-norgestrel ,
0.050 gram of ethiny1-oestradi01 and
0.180 gram of polyoxyethylene-polyoxypropylene polymer.
Into this solution are introduced
14.790 grams of hydroxypropyl-cel 1ulose and
14.790 grams of cellulose, and if necessary homogenised.
A preparation for 700 units, Part 3:
0.042 gram of saccharin,
0.042 gram of cream essence and
0.406 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in a mixture of
55.300 grams of ethyl alcohol and
2.800 grams of water. Into this solution are introduced
35.000 grams of iron(II) fumarate,
7.500 grams of hydroxypropyl-cel 1ulose ,
9.950 grams of cocoa and
4.060 grams of cellulose, and if necessary homogenised.
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 appropriate division, for example, by perforation, there can be distributed over the width of the foil three units of 18x18 mm for Part 1,
21. of 18x19.8 mm for Part 2 and of 18x28 mm for Part 3, having 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:
<td> Part 1</td><td> Part 2</td><td> Part 3</td><td> Ingredients</td>
<td> 0.050 mg</td><td> 0.125 mg</td><td> -</td><td> d-norgestrel</td>
<td> 0.050 mg</td><td> 0.050 mg</td><td> -</td><td> ethinyl-oestradiol</td>
<td></td><td> -</td><td> 50.000 mg</td><td> iron(II) fumarate</td>
<td> 0.180 mg</td><td> 0.180 mg</td><td> 0.580 mg</td><td> polyoxyethylene-polyoxypropylene</td>
<td></td><td></td><td></td><td> polymer</td>
<td> 0.060 mg</td><td> -</td><td> -</td><td> food colour yellow No. 2</td>
<td> -</td><td> 0.065 mg</td><td> -</td><td> food colour orange No. 2</td>
<td> 14.830 mg</td><td> 14.790 mg</td><td> 25.000 mg</td><td> hydroxypropyl-cel 1ulose</td>
<td> 14.830 mg</td><td> 14.790 mg</td><td> 5.800 mg</td><td> cellulose</td>
<td> -</td><td> -</td><td> 8.500 mg</td><td> cocoa</td>
<td> -</td><td> -</td><td> 0.060 mg</td><td> sacchari n</td>
<td> -</td><td> -</td><td> 0.060 mg</td><td> cream essence</td>
<td> 30.000 mg</td><td> 30.000 mg</td><td> 90.000 mg</td><td> weight per unit</td>
<td> about</td><td> about</td><td> about</td><td></td>
<td> 3 cffl2</td><td> 9 3.5 cm</td><td> ״ ש<sub>m</sub>2 5 cm</td><td> area per unit</td>
<td> yellow</td><td> orange</td><td> brown</td><td> appearance</td>
EXAMPLE 20
Preparation for 1000 units
0.15 g of d-norgestrel
0.03 g of ethinyl-oestradi01 and
0.84 g of polyoxethylene-polyoxypropylene polymer are dissolved in
95.00 g of ethyl alcohol while stirring and a powdered mixture of
16.99 g of hydroxypropyl-cellulose and
16.99 g of cellulose is introduced into this solution.
*
The suspension obtained is drawn out on a suitable foil drawing apparatus.to a very thin foil having a thickness of 500 pm, 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-cel 1ulose
16.99 mg of cellulose
35.00
One unit corresponds to an area of approx. 3 cm Appearance of the foil: white, paper-like
The dry foil has a thickness of approx. 170 pm.
Contents15
44 members in 27 offices
Priority claims8
| Document | Office | Kind | Date |
|---|---|---|---|
| 2432925 | Germany | A | |
| 2432925 | Germany | A | |
| 2449865 | Germany | A | |
| 2449865 | Germany | A | |
| DE19742432925 | – | – | – |
| DE19742449865 | – | – | – |
| P24329257 | – | – | – |
| P24498655 | – | – | – |
Members44
| Document | Office | Kind | |
|---|---|---|---|
| BE831024A | Belgium | A | |
| IE42604L | Ireland | L | |
| DK295075A | Denmark | A | |
| FI751801A | Finland | A | |
| NO752416L | Norway | L | |
| NL7507785A | Netherlands (Kingdom of the) | A | |
| SE7507659L | Sweden | L | |
| DE2432925A1 | Germany | A1 | |
| FR2276811A1 | France | A1 | |
| JPS5129218A | Japan | A | |
| DE2449865A1 | Germany | A1 | |
| ZA754305B | South Africa | B | |
| DD122196A5 | German Democratic Republic (until 1990) | A5 | |
| AU8252775A | Australia | A | |
| ES439159A1 | Spain | A1 | |
| IN142428B | India | B | |
| EG11756A | Egypt | A | |
| ATA513275A | Austria | A | |
| CS181182B2 | Czechoslovakia (until 1993) | B2 | |
| GB1510999A | United Kingdom | A | |
| IL47573AThis record | Israel | A | |
| AT346492B | Austria | B | |
| US4136145A | United States of America | A | |
| US4136162A | United States of America | A | |
| HU173016B | Hungary | B | |
| PL101842B1 | Poland | B1 | |
| US4152159A | United States of America | A | |
| CA1067407A | Canada | A | |
| FR2276811B1 | France | B1 | |
| SE413285B | Sweden | B | |
| RO68836A | Romania | A | |
| IE42604B1 | Ireland | B1 | |
| DE2432925B2 | Germany | B2 | |
| DE2449865B2 | Germany | B2 | |
| DK143221B | Denmark | B | |
| FI60354B | Finland | B | |
| CH625704A5 | Switzerland | A5 | |
| DK143221C | Denmark | C | |
| FI60354C | Finland | C | |
| JPS6028810B2 | Japan | B2 | |
| DE2432925C3 | Germany | C3 | |
| PH18973A | Philippines | A | |
| NL186294B | Netherlands (Kingdom of the) | B | |
| NL186294C | Netherlands (Kingdom of the) | C |
Numbers
- Publication, DOCDB
- 47573
- Publication, EPODOC
- IL47573
- Application
- 47573
- Application, DOCDB
- 4757375
- Application, EPODOC
- IL19750047573
Titles
- English
- PHARMACEUTICAL PREPARATION IN THE FORM OF A FOIL HAVING AN ACTIVE SUBSTANCE INCORPORATED THEREIN
Classification
- CPC, 1
- A61K9/7007
- IPC, 2
- A61K31 57
- A61K9 70