(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`
`1 September 2005 (01.09.2005)
`
`(10) International Publication Number
`
`WO 2005/079750 A2
`
`(51) International Patent Classification7:
`
`A61K 9/00
`
`(21) International Application Number:
`PCT/GB2005/000615
`
`(22) International Filing Date: 18 February 2005 (18.02.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`04038089
`
`20 February 2004 (20.02.2004)
`
`GB
`
`(71) Applicant (for all designated States except US): BIO-
`PROGRESS TECHNOLOGY LIMITED [GB/GB];
`Hostmoor Avenue, March, Cambridgeshire (GB).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): NOWAK, Edward,
`Zbygniew [GB/GB]; 4 Davey Close, Impington, Cam—
`bridge CB4 9YJ (GB).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`(74) Agent: HILL, Justin, John; McDermott, Will & Emery,
`7 Bishopsgate, London EC2N 3AR (GB).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: FILMS FOR USE AS DOSAGE FORMS
`
`
`
`005/079750A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`films of modified cellulose materials find use as dosage forms. Substances are
`N (57) Abstract: Non gelatin film materials e. g.
`incorporated into the film matrix and films thus prepared may be administered orally, or otherwise internally, or epidermally. The
`administable form may comprise a matrix which contains at least one water soluble polymer in the form of a film, in addition to at
`least one active ingredient, to produce a therapeutic, organoleptic or cosmetic effect.
`
`Page 1
`
`BDSI EXHIBIT 1030
`
`Page 1
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`FIIJMS FOR USE AS DOSAGE FORMS
`
`FIELD OF INVENTION
`
`This invention relates to non gelatin film materials, for example, films of modified
`cellulose materials (or cellulose derivatives), and the incorporation of one or more active
`ingredients.
`
`This invention further relates to film products and methods of preparation thereof and
`includes associated processes for the incorporation of substances into a film matrix.
`
`Films thus prepared may be administered orally or otherwise internally or epidermally,
`or indeed in any manner where it can release one or more active ingredients either
`rapidly or at a controlled rate.
`
`The administrable form may comprise a matrix which contains at least one water-soluble
`polymer in the form of a film; in addition at to least one active ingredient to produce a
`therapeutic, organoleptic or cosmetic effect.
`
`BACKGROUND OF THE INVENTION
`
`As an alternative to tablets and pills, films may be used to carry active ingredients such as
`drugs, pharmaceuticals, and the like. However, historically films and the process of
`making drug delivery systems therefrom have suffered from a number of unfavorable
`characteristics that have not allowed them to be used in practice.
`
`Water-soluble films cast fiorn aqueous solutions containing medications can suffer from
`the aggregation or conglomeration of particles. Self-aggregation of any active ingredient
`Will make the film inherently non-uniform in its composition. If such films were to
`include low dosages of an active ingredient , it is possible that portions of the film may
`be substantially devoid of any e. g. medication.
`
`Furthermore, conventional film casting employs the use the time-consuming drying
`equipment such as a high-temperature air-bath, drying ovens, drying tunnels, vacuum
`driers, or other such drying equipment. The long length of drying time aids in promoting
`the aggregation of the active ingredient and/or other adjuvant. Such process also run the
`risk of exposing the active ingredient, i.e., a drug or vitamin or other components to
`prolonged exposure to moisture and elevated temperatures, which may render it
`ineffective or even harmful.
`
`In an example, Where the film is hot melt extruded, as in the case with HPC, then it could
`be difficult to mix an active ingredient into the film without degrading the active
`ingredient in some way.
`
`Other factors, such as mixing techniques also play a role in the manufacture of films
`containing active ingredients or pharmaceuticals. During film solution preparation air is
`
`Page 2
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 2
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`often trapped in the solution and needs to be removed. This can result in the separation
`of actives which are suspended in the solution (a process commonly known as Froth
`Floatation) which in this instance would be undesirable.
`Additionally if trapped air is not removed then voids are produced in the film during the
`drying stage. The result is non—uniformity in the final film product.
`
`An alternative to casting film solutions containing active ingredients is to surface coat the
`active ingredient onto a film substrate. This can result in a hetrogenous system where the
`active is poorly associated with the film surface resulting in an oily or powdery surface
`layer prone to abrasion and simply being wiped off during conversion or handling.
`
`SUMIVIARY OF THE INVENTION
`
`One object of the present invention relates to production of films containing active
`ingredients using novel processes.
`
`A active ingredient can be conveniently transported through the surface of a film via a
`liquid formulation applied on one or more surfaces of the film.
`
`In accordance with one aspect of the present invention, by way of example only, a active
`ingredient may be dissolved in a hydrophilic, organic system to form a homogeneous
`solution or dispersion. This solution or dispersion can be then applied to one or more
`surfaces of a non gelatin polymeric film, e.g. a dry cellulose ether film, resulting in the
`active ingredient and/or liquid carrier phase being transported through the surface of the
`‘dry’ film resulting in a new film composition.
`
`This new film composition may or may not contain all the components of the film and
`solution. It may have the active ingredient absorbed to a varying degree in the film
`substrate, for example, the active ingredient may be absorbed evenly within the film
`substrate or it may be absorbed only near the surface of the film substrate. Variation
`between these 2 physical states are envisaged. Patterns or bands in the films are
`contemplated.
`
`The film substrate may remain completely intact or relatively physically unchanged
`immediately following the incorporation process, and can be converted to any size or
`shape of unit dosage form. Alternatively, the film substrate may liquefy or dissolve partly
`or fully, during the incorporation process, but nevertherless finally forming a single
`discrete film, after curing.
`
`Films according to the present invention are typically made up of one or more soluble
`polymers or polymers which will otherwise degrade e.g. at the intended site of release of
`
`Page 3
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 3
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`the active ingredient, e. g. in the mouth. Non readily soluble films are also contemplated ,
`as there are situations where this could also be a possible advantage, for example in the
`controlled release of a medicament.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`One aspect of the invention relates to non gelatin films and in particular films made fiom
`cellulose ethers.
`
`the way in which such films incorporating one or more active
`More particularly,
`ingredients can be produced is herein described.
`
`Such films are useful for delivering a variety of agents to humans and other animals to
`produce a therapeutic, organoleptic or cosmetic effect.
`
`Selective deposition of active ingredients about or within dosage forms according to the
`present invention may result in superior storage qualities (e.g. no exposed active) of a
`dosage form or superior active ingredient release characteristics (favourable zonal
`depositiona of actives. The selective/accurate deposition of actives may also result in less
`wastage of active ingredient, during the manufacture of the dosage form. This may also
`result in less wastage of other materials such as film forming polymers etc.
`
`Typically, cellulose ether films can be prepared by casting an aqueous solution of the
`cellulose ether onto a heated plate which drives off the water and other fiagitive solvents
`to leave a solid thin film.
`
`Suitable cellulose ethers include hydroxypropyl methylcellulose (HPMC), hydroxy
`propyl cellulose (HPC), Hydroxy ethyl methyl cellulose (HEMC), Hydroxy ethyl
`cellulose (I-IEC), methyl cellulose (MC), carboxy methylcellulose (CMC) (including
`sodium carboxy methylcellulose) and salts and derivatives of all aforesaid.
`
`Enteric materials that also may be suitable include cellulose Acetate phthalate (CAP),
`Hydroxy Propyl methyl cellulose phthalate (HPMC-P), Hydroxy propyl methyl cellulose
`acetate succinate (HPMC-AC), and also , Ethyl Cellulose (EC), Carboxymethyl
`hydroxyethyl cellulose (CMHEC), and sodium salt of above Wa—CMHEC)
`(the Na salt would not be regarded as enteric)
`
`The invention is not limited to utilization of cellulose ethers for film formation nor to a
`
`film for use in connection with only treating animals or humans, but is intended to utilize
`any suitable non gelatin film, made in accordance with the method of the present
`invention, which can release an active ingredient.
`
`It is contemplated that such films however may have particular application in the
`treatment of animals and humans and perhaps more particularly to the production and use
`of a film that is suited to ingestion or application otherwise to a human or other animal.
`
`Page 4
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 4
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`In one preferred embodiment of the invention, a film produced by the method in
`accordance with the present invention is provided, such film containing a active
`ingredient suitable for human or animal ingestion.
`
`In an aspect of the invention there is provided a film that is an effective and convenient
`topical or intra-cavity drug delivery system for applying and delivering controlled
`dosages of therapeutic agents e.g. onto or into skin or the body.
`
`Controlled drug delivery via the skin, (e. g. in skin care or cosmetics), gynaecological,
`vaginal, cranial, abdominal, otic, uterine, nasal, sinus, rectal, buccal, oral, ophthalmic,
`and wound care applications can also be achieved by the use of the product according to
`the present invention.
`
`The film can be utilized for the delivery of a wide range of pharmaceutically active
`ingredients. Some therapeutic agents exhibit absoption problems due to solubility,
`degradation (e.g. in the gastro-intestinal tract), or reduction by extensive metabolism.
`
`Without limiting the invention, examples oftherapeutic agents include hypnotics,
`sedatives, anti-epileptics, awakening agents, psychoneurotropic agents, neuromuscular
`blocking agents, antispasmodic agents, antihistaminics, atiallergenics, cardiotonics,
`antiarrhymics, diuretics, hypotensives, vasopressors, antitussive expectorants, thyroid
`hormones, sexual hormones, antidiabetics, anti tumor agents, antibiotics and
`chemotherapeutics and narcotics.
`
`Cosmetically active compounds may include breath freshening agents like menthol, or
`other flavours of fragrances used for oral hygiene and or actives used for dental and/or
`oral cleansing like quaternary or ammonium bases. The effect of flavours may be
`enhanced using flavour enhancers like tartaric acid, citric acid, vanillin, and the like.
`
`A particularly suitable cellulose ether is HPMC. To facilitate processing of the films and
`to increase the apparent flexibility, at least one plasticizer maybe added, such as an edible
`plasticiser for an oral film. Plasticisers commonly used are polyols, glycols, acetins,
`carboxylic acids and the esters of these acids, for example polyethylene glycol, glycerin,
`triacetin, citric acid and triethylcitrate respectively. The plasticisers maybe used
`individually or in combination and maybe present in any desired amount, particularly
`from 0 to about 40 percent of the solid film and more particularly from 0 to 20 percent.
`
`Optional ingredients may be added including, without limitation, colourants, emulsifiers,
`humectants, defoamers and anti block agents. Such optional components are typically
`added in minor amounts, to aid the processing of the film and typically are less than 10%
`total by weight based upon the weight of the cellulose ether component.
`
`Page 5
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 5
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`The base films may be made by a variety of processes, for example by dissolving or
`dispersing the film components in water or other solvents and drying into film form.
`Alternatively the film resins could be hot-melt extruded. Additionally a dispersion or
`solution maybe directly coated or sprayed onto another edible product, such as a tablet or
`foodstuff and dried to form an edible film. The preferred technique is to have film
`solution cast and dried to produce a sheet of flexible, thin film.
`
`The base of a film so produced can be seen to act as a ‘building block’ from which the
`final
`film product is produced (product film). The ‘building block’ film may be
`considered as a part-formed film, and the product film may be considered as a
`homogenous film or a film formed from one or more bands, at least one band being
`derived from the building block. The’ building block’ film according to the present
`invention may be considered as only a part-formed film because further mass is added
`later as an inevitable result of the method according to the present invention,
`
`A uniform, flat film is found to be suitable to serve as a ‘building block’ film. Such films
`can be used to form tablets or monoliths, which may comprise many such films.
`
`The next stage in the process according to the present invention is the application of a
`fluid, e.g. a liquid, to the film. The liquid may be applied by many methods including
`ink-jet type application. In one embodiment, the ink-jet type apparatus may be modified
`to apply active(s) and a film forming polymer or polymers and in this way, accurate
`patterns of doses in the dosage form can be realized.
`
`According to an aspect of the invention,, by way of example, application of a solution,
`suspension or micro-emulsion containing the active ingredient (hereinafter referred to as
`liquid), onto to one or more surfaces of the ‘building block’ film to produces a new film
`or product film.
`
`In one aspect of the invention the product film may serve as a dosage form in its own
`right
`
`In another aspect of the invention the product film may be used to form other dosage
`forms, e.g. by forming a tablet or monolith composed of many layers of the product film.
`The product films used may be the same or different, and any range of a combination of
`different product films. The films may simply be bonded together forming laminate
`dosage forms of many discrete layers or the product films may be fused or welded
`together , forming a single mass of material, albeit perhaps with regional zones with
`varying properties, such as zones with different drugs or drugs in higher concentrations
`or zones of polymers of differing strengths or solubilities. In one process for producing a
`tablet or monolith, the product film (5) may not be allowed to be fully cured, and , for
`example, the liquid deposited about the building block film, is not let to ‘set’ or go into
`solid form, and another building block film is (immediately) applied to form a
`‘sandwich’, and the liquid can/may be taken up by both building block films (perhaps
`taking up active also), e. g. to form a tri-layer (fused) film. This can process can be
`
`Page 6
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 6
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`repeated many times to form multilayer films, e. g. which may be fused. The process also
`has the advantage that there is no need for any additional bonding agent, glue or other
`process to attach the films together, as the liquid used to form the product film has also
`performed this function of bonding. This process has applications in conveniently
`producing robust multilayer dosage forms such as monoliths or tablets.
`
`In an aspect of the present invention, complete homogeneity is achieved in the product
`film.
`
`In another aspect of the present invention, a product film having variations in physical
`quality and/or chemical composition is produced, 6.g. the active may be preferentially
`distributed in a favourable manner within the film.
`
`The result achieved depends on the chemicals and conditions used in the process
`according to the present invention.
`
`In an example, one or more surfaces of a ‘dry’ cellulose ether film are coated.
`
`In one embodiment of the invention, for e. g. ease of processing, application of the liquid
`to one side of the film is sufficient, because, the active ingredient, once transported into
`the film, can form part of the complete film composition. Such method of application of
`an active ingredient can result in film products which have beneficial gradations in
`concentration of the active ingredient in the final film product. Also, such application
`may well inevitably result in a robust film containing active ingredient(s) and which is
`suitable for a variety of applications. Films produced by such a method are physically one
`single film, and may comprise 2 or more ‘bands’ or ‘areas’ in actual fact, such bands or
`areas having a degree of polymeric interaction with the film and or one another.
`
`liquid with the building block film, and subsequent
`The association of the fluid, e. g.
`curing, as necessary, forms the product film.
`
`In one aspect of the invention , the product film comprises a single homogenous polymer
`with the active ingredient evenly dispersed throughout the film , or in a concentration
`gradient Within the film.
`
`In another aspect of the invention, the product film comprises 2 or more bands
`associated with one another to a greater or lesser degree, with the active ingredient
`dispersed within particular band(s) only, or, to an extent, deposited on the surface
`(internal or external) of one or more bands in the product film.
`
`It is to be understood that in this aspect of the invenyion the product film is comprises a
`single physical film. Such product film being robust for both storage and application, and
`which maintains sufficient integrity as such, for commercially viable use.
`
`Page 7
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 7
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`In this aspect of the invention, the product film does not comprise 2 or more discrete
`films simply adhered or bonded together.
`
`The fluid and the building block film associate with one another to an extent where the
`association results in more than adhesion.
`
`To described the product film in another way, the association of liquid and film results in
`a product film which, because of its own physical properties, cannot be physically split
`back into the original physical components from which it was formed i.e. the liquid (or
`cured result thereof) and the building block film. under normal conditions, such films
`resulting fiom bands in the product film. Therefore, the product film always possesses a
`degree of structural homogeneity between at least 2 bands in the film, if those bands,
`indeed exist at all.
`
`It is also to be understood that the association of the liquid with the building block film to
`form a product film results in a single film which may or may not have more than one
`band associated with it. These bands may comprise e.g., differences in polymer chemistry
`or polymer quality or differences in concentration levels of active ingredient. Indeed,
`these bands may consist of any differences or variations occurring within the film as a
`result of carrying out the process according to the present invention, in order to form the
`product film.
`
`Appropriate means of liquid application onto the film substrate includes extrusion, roller
`application, pouring and leveling by doctor blade or knife, spraying, brush painting or
`wiping. As long as the surface application is uniform, the active ingredient is more easily
`evenly applied onto the film substrate. Preferably, but not essentially the liquid
`comprises at least one polymer which is compatible with the ‘building block’ film. The
`final ‘coated’ film composition may be conveniently left at ambient temperature and
`humidity in order to allow the assimulation of the ‘surface layer’, if applicable, to be
`transported into the body of the film substrate. To accelerate the process, the film
`substrate can be heated up to temperatures of 80°C or the complete film transferred into a
`warm oven of similar temperature for a short period of time. A measure of when
`incorporation of active ingredient is complete is when the film surface becomes touch
`dry.
`
`In many cases, where the liquid carrying the active ingredient, contains non-fiugitive
`materials, a new film composition is produced. There may be instances where fugitive
`solvents are used in the liquid carrier but this would primarily be to accelerate the process
`of active ingredient transport.
`
`As a further embodiment of the invention, two or more active ingredients or materials,
`may be selectively transported into the film substrate. In this instance, one active
`ingredient may have an affinity to move into the film substrate and the other may remain
`on the surface of the film, as a descreate band. An example of this would be a liquid
`
`Page 8
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 8
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`formulation containing an active ingredient such as Ibuprofen and excipient such as
`sucrose. The two materials could be dissolved into a liquid formulation, which when
`applied as the transport medium to a film substrate, would result in the Ibuprofen moving
`into the core of the film and the sucrose, which has no affinity to be transported,
`remaining as a distinct surface layer on the film. This selectivity has a number of
`advantages, for example, the application oftaste masking materials to a film surface.
`
`Typical liquid materials which can be used to dissolve active ingredients or other
`compounds and act as selective transport mediums would primarily be polar liquids,
`which are predominantly water soluble or partially water soluble. These are mainly
`organic but inorganic materials such as water could also be used.
`
`For a liquid to function as a suitable transport medium, compounds containing one or
`more of the following functional groups or compounds in its molecular structure, may be
`found suitable:—
`
`Hydroxy
`Carboxy
`Amino
`Carboxamido
`
`Epoxy
`0x0 or keto
`
`Cyano
`Benzyl
`Alkoxy or aryloxy
`Furans, Pyrroles and thiophenes
`Sulfoxide and sulfone
`
`Quaternary nitrogen
`Pyridine
`Anhydrides
`Esters and lactones
`
`With a relatively broad range of polar organic liquid carriers to select from, it is possible
`to choose one or more compounds to act as a transport medium for a active ingredient.
`The active ingredient would ideally need to be soluble in the transport medium to work
`within this invention. Speed of active ingredient transport and end user application are
`controlled by the careful selection of polar liquids. For example fast transport of active
`ingredient into the film can be controlled by the molecular weight and functional groups
`within the liquid transport medium.
`Inevitably choice of liquid carrier is dictated by the
`end user application of the final film product, for example whether it can be safely
`ingested or, for topical applications, its acceptability for use on skin.
`
`There is no limitation as to which type of medicament, drug, active ingredient, flavour,
`fragrance or agent which can be used in this final step of the process. Those skilled in the
`art of formulation science will choose a suitable polar liquid or formulation to work in
`conjunction with suitable cellulose film to achieve the desired application.
`
`Page 9
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 9
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`In another aspect of the present invention there is provided a method for producing a film
`incorporating active ingredients, wherein the one or more active ingredients are not
`exposed to the harsh conditions which may be necessary to produce a film e. g. the
`‘building block’ film. A milder process, according to the present invention is then used to
`introduce the active ingredient to the film, advantageously avoiding subjecting the active
`ingredient to any unfavourable conditions in film production. This then facilitates the use
`of films which would otherwise be unsuitable for incorporating certain active ingredients,
`due to the initial conditions of film production. New usefiil film formulations are
`therefore contemplated.
`
`The incorporation of active ingredients in a film in accordance with the invention also
`allows films to be produced which have active ingredients effectively applied and
`incorporated within the film in specific patterns. This also gives rise to the opportunity in
`further treating the film so that e. g. drugs can be release in a timed manner (e. g. parallel
`or sequential timing or both). For example, a film having a certain pattern of drug applied
`to it, can then be folded in a certain manner and fixed that way to produced a dosage
`form, such that certain drugs may be hidden deeper within the dosage form and are
`released later in time than those closer to the surface of the dosage form. In a similar way,
`films may be coiled, compressed and folded in a zig—zag manner or simply set in a multi-
`film ply formation, so form descrete calculated ‘thinking’ dosage forms, which are able
`to release actives in a complex manner, perhaps in accordance with timed release profile
`and/or differing external conditions.
`
`Also contemplated are other dosage forms utilizing film or films made according to the
`present invention. For example a powder slug, tablet may be enrobed by such film or a
`liquid filled pharmaceutical capsule may be made for this film. It is easily contemplated
`e. g that there may be a situation wherein a liquid filled capsule contains a drug which is
`a stomach irritant but unfortunately needs to be release within the stomach. A film
`according to the present invention may be so designed as to incorporate a local
`anaesthetic. A capsule could thus be designed to release a drug (which is a stomach
`irritant) into the stomach, but which before such release, the capsule wall made from the
`film according to the present invention, itself releases a local anaesthetic to reduce the
`pain in the stomach.
`
`Page 10
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 10
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`Examples of the preparation and composition of film material containing medicament are
`as follows:
`
`Example 1
`
`Solution A)
`
`
`
`Hydroxypropyl methylcellulose*
`Glycerin
`Triethyl citrate
`Purified water
`
`*Methocel E50 LV Premium (ex Dow chemicals)
`
`The hydroxypropyl methylcellulose (HPMC) was carefiilly added to the purified water at
`80°C with stirring. This was followed by the addition of glycerin. The solution was
`cooled to 30°C, maintaining agitation to produce a colourless, viscous solution. Triethyl
`citrate was slowly added to the cooled solution with gentle mixing to produce a clear,
`viscous solution.
`
`The solution was allowed to stand for 24 hours to allow it to naturally de-aerate. This
`resulting film forming solution was used to prepare films using an adjustable doctor blade
`CRK. Print Coat Instruments Ltd, Royston, Herts). The gap on the doctor blade was set
`at 1.6mm and used to draw down the solution onto a glass plate, which was then air dried
`for 24 hours at 25°C, 45 % RH.
`
`Once dry this substrate film (film A) had evenly applied to its surface (surface which was
`in contact with the glass plate) a solution B of the following compositions:-
`
`Solution B)
`
`Ibuprofen
`Propylene glycol
`Triacetin
`
`HPMC (Methocel E15 LV Premium)
`
`The I-IPMC was added to propylene glycol heated to 80°C. The mixture was Shirred until
`a solution was formed then the triacetin was added and stirred to form a clear solution.
`This was cooled to 40°C and then Ibuprofen was added. The mixture was Shirred until all
`the Ibuprofen had dissolved resulting in a clear viscous solution. (Solution B). This
`solution, called the selective transport medium will be used in the next stage of the
`process.
`
`Solution B) is evenly applied onto the surface of film A) using a doctor blade knife at a
`rate of 15 grams per sq metre of Solution B to 100 grams per sq metre of film A. This
`
`10
`
`Page 11
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 11
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`results in a total film mass of 115g.s.m. The resulting film is left at room temperature for
`30 minutes until the surface is touch dry and the selective transport medium (STM) and
`ibuprofen has reconstituted itself into the final film (film C).
`
`The final composition of film C, which is a combination of film A and solution B is now:
`%w/w
`
`HPMC
`
`Glycerin
`Triethyl citrate
`Propylene glycol
`Triacetin
`
`Ibuprofen
`
`73 . 1
`
`7.2
`7.2
`7.3
`3.5
`
`l .7
`
`The dry film can be converted into small units for use in oral administration.
`
`Other examples of polar liquids mixtures which can be used to dissolve Ibuprofen and act
`as the selective transport medium are tabulated in table 1 (formulations 1-9). Each of the
`resulting solutions can be applied at the same rate as Solution B) in example 1 to the
`same film A, resulting in a different film composition in each case all contain the
`Ibuprofen as the medicament.
`
`Table 2 demonstrates similar formulations (10-18) but in this case the medicament is a
`simple flavour.
`
`Table 3 illustrates a range of formulations (19-23) based on ascorbic acid (vitamin C) as
`the medicament.
`
`Table 1
`
`
`m” III-Inn"
`
`In_redient
`
`
`
`
`
`
`
`
`
`
`10.0
`----------
`—- 67.5 - ----
`
`
`
`
`ll
`
`Page 12
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 12
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`Pro ylene Glycol
`14 Bu
`olactone
`_
`N Methyl
`P rrolldone
`
`Ethanol
`l
`acetm
`
`Tr
`
`Monoacetm
`
`Lactlc ac1d
`
`_.
`
`2
`
`.
`
`Glamal acet1c a01d
`
`Water
`
`HPMC*
`
`5.4
`
`*Methocel E50 LV Pre
`
`am11
`
`%w.3wD
`
`1m
`
`used
`
`as a VISCOSIty a1
`
`
`695m77..524m
`5.55.
`004(.\
`5.5.5.84
`5.5w4®5.0.5mm4.
`12m00O4...O6
`00mo.6.m27
`050.0.MU...
`OOO0...06
`.1M.0.0.S12m4&
`O14.l2524Ts“
`
`4.15aN4
`
`524
`87.
`
`5.0.5
`
` 1m7O-1m
`
`
`80.
`
`Table 2
`
`760
`
`0..0
`
`
`
`d
`
`m
`
`Formula
`
`In red1ent
`o.
`
`Cherry Flavour +
`Benzyl alcohol
`Isobutanol
`
`Propylene Glycol
`1,4 — But rolactone
`N—Methyl
`P
`ohdone
`
`2._..
`
`Ethanol
`nacetm
`
`T M
`
`onoacet
`
`m
`
`Lact
`
`10 ACld
`
`GlaCIal acetlc aCld
`
`Water
`
`HPMC*
`
` D
`
`+ Cherry flavour ex F
`
`nMW0C
`
`12
`
`Page13
`
`SUBSTITUTE SHEET (RULE 26)
`
`Page 13
`
`
`
`
`

`

`WO 2005/079750
`
`PCT/GB2005/000615
`
`Table 3
`
`Formula
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`Ingredient
`Ascorbic Acid
`
`Lactic acid
`
`428
`
`4
`
`7.5
`
`
`
`
`4.7
`
`
`* Lactic acid provided in the form of a 90% solution ,G’urac PH90 TM, ex Purac
`Biochem)
`
`— *
`
`
`
`
`
`
`
`
`Each Formula (1 to 24) takes a finite time to incorporate and consolidate the medicament
`into a cellulose ether film substrate. Table 4 illustrates the length that each formula takes
`to constitute itself into a HPMC film.
`
`The time value is based on each formula being applied at 25 gsm on a substrate HPMC
`film, 110 micros thick and around 150 gsm in weight. Applications of each liquid
`formulation were performed by means of a doctor blade. Conditioning environment was
`21°C, 45% RH. and the dry point was assessed when the applied surface became touch
`dry.
`
`The resulting films were clear and flee from particulate or crystalline matter.
`
`Formula
`
`Time
`
`Table 4
`
` 1
`
`
`
`Min
`
`3
`
`2 3 4 5
`
`.-
`
`.-
`
`— F
`
`ormulae 1 to 18 were applied to a film of the following composition:
`
`13
`
`P