Privacy Act Statement
`
`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your submission of the
`attached form related to a patent application or patent. Accordingly, pursuant to the requirements of the Act, please be advised
`that: (1) the general authority for the collection of this information is 35 U.S.C. 2(b)(2); (2) furnishing of the information solicited
`is voluntary; and (3) the principal purpose for which the information is used by the U.S. Patent and Trademark Office is to
`process and/or examine your submission related to a patent application or patent. If you do not furnish the requested
`information, the U.S. Patent and Trademark Office may not be able to process and/or examine your submission, which may
`result in termination of proceedings or abandonment of the application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1.
`
`The information on this form will be treated confidentially to the extent allowed under the Freedom of Information Act
`(5 U.S.C. 552) and the Privacy Act (5 U.S.C. 552a). Records from this system of records may be disclosed to the
`Department of Justice to determine whether the Freedom of Information Act requires disclosure of these record s.
`
`2.
`
`A record from this system of records may be disclosed, as a routine use, in the course of presenting evidence to a
`court, magistrate, or administrative tribunal, including disclosures to opposing counsel in the course of settlement
`negotiations.
`
`3.
`
`A record in this system of records may be disclosed, as a routine use, to a Member of Congress submitting a
`request involving an individual, to whom the record pertains, when the individual has requested assistance from the
`Member with respect to the subject matter of the record.
`
`4.
`
`A record in this system of records may be disclosed, as a routine use, to a contractor of the Agency having need for
`the information in order to perform a contract. Recipients of information shall be required to comply with the
`requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C. 552a(m).
`
`5.
`
`A record related to an International Application filed under the Patent Cooperation Treaty in this system of records
`may be disclosed, as a routine use, to the International Bureau of the World Intellectual Property Organization, pursuant
`to the Patent Cooperation Treaty.
`
`6.
`
`A record in this system of records may be disclosed, as a routine use, to another federal agency for purposes of
`National Security review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act (42 U.S.C. 218(c)).
`
`7.
`
`A record from this system of records may be disclosed, as a routine use, to the Administrator, General Services, or
`his/her designee, during an inspection of records conducted by GSA as part of that agency's responsibility to
`recommend improvements in records management practices and programs, under authority of 44 U.S.C. 2904 and
`2906. Such disclosure shall be made in accordance with the GSA regulations governing inspection of records for this
`purpose, and any other relevant (i.e., GSA or Commerce) directive. Such disclosure shall not be used to make
`determinations about individuals.
`
`8.
`
`A record from this system of records may be disclosed, as a routine use, to the public after either publication of
`the application pursuant to 35 U.S.C. 122(b) or issuance of a patent pursuant to 35 U.S.C. 151. Further, a record
`may be disclosed, subject to the limitations of 37 CFR 1.14, as a routine use, to the public if the record was filed in
`an application which became abandoned or in which the proceedings were terminated and which application is
`referenced by either a published application, an application open to public inspections or an issued patent.
`
`9.
`
`A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local law
`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation.
`
`EFS Web 2.1.17
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1026
`
`

`

`PATENT SPECIFICATION (cid:9)
`•
`(21) Application No. 28252/75 (cid:9)
`(22) Filed 4 July 1975
`CZ (31) Convention Application No. 2 432 925
`(32) Filed 5 July 1974
`CZ (31) Convention Application No. 2 449 865
`(32) Filed 17 Oct. 1974 in
`(33) Fed. Rep. of Germany (DE)
`(44) Complete Specification published 17 May 1978
`(51) INT CL2 A61K 9/70, 31/565
`(52) Index at acceptance A5B 240 24Y 38Y 396 753 757 75Y 764
`
`Y
`
`(11) 1 510 999
`
`(54) A PHARMACEUTICAL PREPARATION IN THE FORM OF
`A FOIL HAVING AN ACTIVE SUBSTANCE INCORPORATED
`THEREIN
`
`(71) We, SCHERING AKTIENGESELLSCHAFT, a body corporate
`organised according to the laws of Germany, of Berlin and Bergkamen, Germany,
`do hereby declare the invention, for which we pray that a patent may be granted to
`us, and the method by which it is to be performed, to be particularly described in
`and by the following statement:— (cid:9)
`This 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 Specification No. 637,363 describes paper foils coated with active
`substances suitable for oral use. The foils consist of cellulose fibres insoluble in (cid:9)
`water and a water-soluble binding agent. As water-soluble binding agent there is
`preferably used sodium carboxymethyl-cellulose. The active substance may be
`applied to the paper foil by dropping onto 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 (cid:9)
`the foil and applying the active substance has the disadvantage that the accuracy
`of the dosage is not very good, accuracy being of great importance as active
`substances are generally administered 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 owing to variations during storage of (cid:9)
`the foil material. Thus, for example, it has been found that in using foil drawing
`machines as prescribed in Belgian Specification 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 material the take-up of active substance is also
`not uniform. Moreover, an active substance bound only on the surface can be (cid:9)
`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-cellulose, which includes some
`of the active substance and liberates it only slowly or not at all.
`The present invention is based on the observation that foils having a constant (cid:9)
`thickness and a uniform distribution of active substance can be obtained by
`making foils having the active substance incorporated therein and using foil
`formers that are soluble in water or certain organic solvents.
`The present invention provides a pharmaceutical preparation in the form of a
`foil (as hereinafter defined), wherein the foil incorporates from a foil forming (cid:9)
`material or materials that is or are soluble in at least one of the following
`solvents:— water, aliphatic alcohols containing up to 6 carbon atoms, chlorinated
`aliphatic hydrocarbons containing up to 8 carbon atoms, aliphatic ketones
`containing from 3 to 7 carbon atoms and mixtures of any two or more of these
`solvents. There are preferably used foil forming materials that are soluble in water, (cid:9)
`ethyl alcohol, isopropanol, acetone or methylene chloride, or in a mixture of any
`two or more of such solvents. Especially suitable are foil forming materials that are
`soluble both in water and in at least one of the organic solvent selected from
`aliphatic alcohols containing up to 6 carbon atoms, chlorinated aliphatic
`hydrocarbons containing up to 6 carbon atoms and aliphatic ketones containing (cid:9)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1027
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`2 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`65 (cid:9)
`
`1,510,999 (cid:9)
`from 3 to 7 carbon atoms, more particularly those that are soluble in mixtures of
`ethyl alcohol and water.
`The term "foil" as used herein includes a lamina strip and a film.
`As foil formers there come into consideration, for example, poly-N-vinyl-
`pyrrolidone, vinylpyrrolidone-vinyl acetate, methyl- and ethyl-cellulose, but
`preferably non-ionic water-soluble hydroxyalkyl ethers of cellulose such, for
`example, as hydroxypropyl-cellulose, hydroxyethyl-cellulose and methylhydroxy-
`propyl-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, inter alia, polyoxyethylene-polyoxypropylene
`polymer (PLURONIC F 68), 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. The terms PLURONIC F 68 and CREMOPHOR EL, are Registered Trade
`Markc.
`As fillers there may be mentioned, for example, cellulose, sugars, for example,
`lactose, dextrose and cane sugar, starches, polyhydric alcohols, for example, mannitol,
`calcium carbonate, calcium phosphate, talcum and dyestuffs in water-soluble form or as
`pigments. The fillers used in the preparations of the invention are generally
`insoluble or only sparingly soluble in water and organic solvents. When fillers and
`active substances are used which are soluble in water or organic solvents a
`transparent smooth foil is formed, and when insoluble fillers, especially cellulose,
`or insoluble 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, for
`example, as the nose, ears and vagina. As active substances there may be
`mentioned, for example: Gestagens, oestrogens, mixtures of g-:stagens and
`oestrogens, tranquillizers, anti-diabetics, sulphonamides, antibiotics, trichomonal
`agents and inflammation inhibitors, for example corticoids.
`The medicaments may be present in the carrier materials in a dissolved or
`uniformly suspended state. The proportion of active substance in the foil may be
`up to 60 per cent by weight of the foil. The surfaces may be cut or perforated to
`form unit dosage portions which can be readily separated and which contain
`quantities of active substance such as are usually present also in tablets, dragies,
`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 from 1 p gram to 0.5
`gram, and the lower and upper dose may easily be smaller or greater.
`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 from 6 to 20 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 2 per
`cent, the percentages being calculated on the total weight of the solution or
`suspension.
`The content of solvent or suspension medium is from 48 to 84 per cent by
`weight and consists of water and/or one or more organic solvents. As organic
`solvents there come into consideration physiologically tolerable solvents or solvents
`that are removed except for a physiologically unobjectionable residue. Such
`solvents are, for example, aliphatic alcohols containing up to 6 carbon atoms,
`chlorinated hydrocarbons, especially chlorinated aliphatic hydrocarbons
`containing up to 6 carbon atoms, aliphatic ketones containing from 3 to 7 carbon
`atoms and mixtures of any two or more of such solvents. There may be mentioned,
`more especially, ethyl alcohol, isopropanol, acetone and methylene chloride, and
`mixturc•> thereof. There are preferably used water and ethyl alcohol or mixtures of
`water and ethyl alcohol.
`The layer thickness of the wet sheet is generally 0.1 to 2 mm and that of the
`dry foil is from 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
`
`2
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1028
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`3 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`4() (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`60 (cid:9)
`
`1,510,999 (cid:9)
`(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.
`The pharmaceutical preparations of the invention may be in the form of a (cid:9)
`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. Thus, foils can be made with a sheet in which
`different active substances and/or varying concentrations of active substance are (cid:9)
`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 (cid:9)
`concentrations are made visible by different dyestuffs. By drying the wet sheet
`there is obtained a foil, which by being divided in an appropriate way, 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 (cid:9)
`substance are required for making multi-phase preparations, for example, for
`making contraceptive preparations. The possibility of the spatial separation of
`active substances that are incompatible with one another in one foil unit improves
`the stability of the individual active substances. Foils for intravaginal application
`may, for example, also be rolled round an ordinary commercial tampon. (cid:9)
`The invention also provides a process for the manufacture of a
`pharmaceutical preparation in the form of a foil, 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 (cid:9)
`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 (cid:9)
`portions can be readily detached.
`The following Examples 1 to 19 illustrate the invention; with the exception of
`Examples 5 and 15 the preparations described in the Examples are primarily
`suitable for oral administration.
`
`Example 1.
`
`Preparation for 1000 units:
`0.25 gram of d-norgestrel,
`0.05 gram of ethinyl-oestradiol 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-cellulose 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-poIyoxypropylene 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.
`Appearance of the foil: white, paper-like.
`The dry foil has a thickness of about 170 ,um.
`
`3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1029
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`4 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`1,510,999 (cid:9)
`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-cellulose and
`16.50 grams of cellulose.
`
`The suspension so obtained is drawn on a suitable foil drawing apparatus to a (cid:9)
`sheet having a thickness of 500 ,um, 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 (cid:9)
`22.10 mg of hydroxypropyl-cellulose
`16.50 mg of cellulose
`
`40.00 mg
`
`One unit corresponds to an area of about 3 cm2.
`Appearance of the foil: white, paper-like. (cid:9)
`The dry foil has a thickness of about 170 ,um.
`
`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 (cid:9)
`95.00 grams of ethyl alcohol. Into this solution is introduced a powdered
`mixture of
`16.93 grams of hydroxypropyl-cellulose and
`17.20 grams of cellulose.
`
`The suspension so obtained is drawn on a suitable foil drawing apparatus to a (cid:9)
`sheet having a thickness of 500 pm, and is then dried.
`The composition of one unit:
`0.03 mg of d-norgestrel
`0.84 mg of polyoxyl-40-stearate
`16.93 mg of hydroxypropyl-cellulose (cid:9)
`17.20 mg of cellulose
`
`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 ,um. (cid:9)
`
`Example 4.
`A preparation for 1000 units:
`1.10 grams of polyoxyethylene-polyoxypropylene polymer are dissolved in
`152.00 grams of dernineralised water. In this solution is suspended
`0.03 gram of micronised 4-norgestrel, and if necessary homogenised. Into the (cid:9)
`suspension are introduced
`22.10 grams of hydroxypropyl-cellulose 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 um, and is then dried. (cid:9)
`The composition for one unit:
`0.03 mg of d-norgestrel
`1.10 mg of polyoxyethylene-polyoxypropylene polymer
`22.10 mg of hydroxypropyl-cellulose
`16.77 mg of cellulose (cid:9)
`
`40.00 mg
`
`4
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1030
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`5 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`55
`
`1,510,999
`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 ym.
`
`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 (cid:9)
`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 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 pm.
`The foil is suitable for topical use.
`
`Example 6.
`
`A preparation for 1000 units:
`10.00 grams of 7-chloro-2-methylamino-5-pheny1-3H-1,4-benzo-diazepine-4-
`oxide and
`0.84 gram of polyoxyethylene-polyoxypropylene polymer are dissolved in (cid:9)
`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 (cid:9)
`sheet having a thickness of 500 pm, and is then dried.
`The composition of one unit:
`10.00 mg of 7-chloro-2-methylamino-5-pheny1-3H-1,4-benzo-diazepine-4-
`oxide
`0.84 mg of polyoxyethylene-polyoxypropylene polymer (cid:9)
`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: yellow, paper-like.
`The dry foil has a thickness of about 170 ,am.
`
`Example 7.
`
`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
`95.00 grams of ethyl alcohol. Into this solution is introduced a powdered
`mixture of
`16.93 grams of hydroxypropyl-cellulose 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 ,am, and is then dried.
`The composition for one unit:
`1.00 mg of norethisterone acetate
`0.03 mg of ethinyl-oestradiol
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1031
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`6 (cid:9)
`
`5
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`1,510,999 (cid:9)
`
`0.84 mg of polyoxyethylene-polyoxypropylene polymer
`16.93 mg of hydroxypropyl-cellulose
`16.20 mg of cellulose
`
`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 ,um.
`
`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-cellulose
`8.47 grams of hydroxyethyl-cellulose 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 sum, 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 propylene glycol
`8.47 mg of hydroxypropyl-cellulose
`16.19 mg of cellulose
`
`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 turn.
`
`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 (cid:9)
`101.60 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-cellulose and
`16.20 grams of starch. (cid:9)
`
`The suspension so obtained is drawn on a suitable foil drawing apparatus to a
`sheet having a thickness of 500 ,um, 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 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 ,um.
`
`6
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1032
`
`(cid:9)
`

`

`7 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`1,510,999 (cid:9)
`Example 10.
`
`A preparation for 1000 units:
`1.00 gram of norethisterone acetate
`0.03 gram of ethinyl-oestradiol 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-cellulose
`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 jam, and is then dried.
`The composition for one unit:
`1.0 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: white, paper-like.
`The dry foil has a thickness of about 170 urn.
`Example 11.
`
`A preparation for 1000 units:
`1.00 gram of norethisterone (17a-ethinyl-19-nor-testosterone)
`0.03 gram of ethinyl-oestradiol and
`0.22 gram 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-cellulose 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 yin and then dried.
`The composition for one unit:
`1.00 mg of norethisterone (17a-ethiny1-19-nor-testosterone)
`0.03 mg of ethinyl-oestradiol
`0.22 mg of polyoxyethylene-polyoxypropylene polymer
`16.00 mg of hydroxypropyl-cellulose
`16.00 mg of cellulose
`
`33.25 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 approx. 230 urn.
`
`Example 12.
`A preparation for 1000 units:
`4.00 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-cellulose and
`15.1 grams of calcium carbonate.
`
`7
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55 (cid:9)
`
`The suspension so obtained is drawn on a suitable foil drawing apparatus to a (cid:9)
`sheet having a thickness of 500 ktm and dried.
`
`55
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1033
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`8 (cid:9)
`
`5
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30 (cid:9)
`
`35 (cid:9)
`
`40
`
`45 (cid:9)
`
`50 (cid:9)
`
`55 (cid:9)
`
`1,510,999 (cid:9)
`The composition for one unit:
`4.00 mg of glisoxepide *
`0.90 mg of polyoxyl-40-sLearate
`15.00 mg of hydroxyethyl-cellulose
`15.00 mg of calcium 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 ,um.
`* 4 - 14 - [p - (5 - methyl - isoxazol - 3 - carboxamido) - ethyl] - benzosulphonyll- (cid:9)
`1,1 - hexamethylene - semicarbazide.
`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
`0.840 gram of silicone oil
`6.930 grams of methyl-cellulose 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 jam and dried.
`The composition of one unit:
`0.030 mg of d-norgestrel
`0.840 mg of silicone oil
`6.930 mg of methyl-cellulose
`10.000 mg of poly-N-vinyl-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 ktm.
`Example 14.
`
`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-cellulose,
`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 (cid:9)
`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 (cid:9)
`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.
`
`8
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 1034
`
`

`

`1,510,999 (cid:9)
`Example 15.
`Foils for intravaginal application:
`The foil is prepared in accordance with Example 11.
`The composition of one unit:
`100.0 mg of 5-morph olin omethy1-3-(5-nitro-l-methyl-2-imidazoly1)- (cid:9)
`methyleneamino-2-oxazolidone. HC1
`8.4 mg of Cremophor 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 foil (1 unit) is either rolled round an ordinary commercial tampon or is
`itself rolled to form a narrow tube.
`Example 16.
`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-cellulose 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-cellulose and
`14.91 grams of cellulose, and if necessary homogenised.
`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 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 2 (free from
`active substance)
`
`14.91 mg
`14.91 mg
`
`0.18 mg
`30.00 mg
`
`9 (cid:9)
`
`5 (cid:9)
`
`10 (cid:9)
`
`15 (cid:9)
`
`20 (cid:9)
`
`25 (cid:9)
`
`30
`
`35 (cid:9)
`
`40 (cid:9)
`
`45 (cid:9)
`
`50 (cid:9)
`
`Part 1 (containing active substance)
`0.25 mg of d-no