GB2421431A

GB2421431A - Water-soluble drug delivery system

Info

Publication number: GB2421431A
Application number: GB0428226A
Authority: GB
Inventors: Bruce Michael Drew; Shilpan Patel; Guy Friedman
Original assignee: Aquasol Ltd; PIONEER MEDICA Ltd; Arrow Coated Products Ltd
Current assignee: Aquasol Ltd; PIONEER MEDICA Ltd; Arrow Coated Products Ltd
Priority date: 2004-12-24
Filing date: 2004-12-24
Publication date: 2006-06-28
Anticipated expiration: 2024-12-24
Also published as: GB2421431B; EP1865930A1; GB0428226D0; IL184157A0; WO2006067514A1; US20080038326A1

Abstract

The invention relates to dosing systems, which involve water-soluble products (which term as used herein includes water-dispersible products) containing ingredients embedded within and/or coated upon a water-soluble film which are released at a prescribed rate into an aqueous environment through one or more perforated less readily soluble water-soluble films. It relates especially to the use of such products in delivering pharmaceutical active ingredients externally or internally to a human or animal body. The more soluble film is soluble in cold water and the less soluble film soluble in hot water. The preferred drug is vancomycin dyed to identify the drug-containing film and monitor its use. The system is used preferably for wound dressings.

Description

1 2421431

DOSING SYSTEMS

l'he invention relates to dosing systems, and concerns in particular such systems which involve water-soluble products (which term as used hereinafter includes water-dispersible products) containing ingredients embedded within and/or coated upon a water-soluble film which are released at a prescribed rate into an aqueous environment through one or more perforated less readily soluble water-soluble films. It relates especially to the use of such products in delivering pharmaceutical active ingredients externally or internally to a human or animal body.

BACKGROUND

The ability to implant drug delivery systems within the human or animal body during a surgical intervention has been reliant on various treatments, all of which have had to be removed in a second surgical intervention once the drug(s) has been delivered and done its work. Such medications, whilst providing varying degrees of effectiveness, all share common limitations such as the inability to deliver the drug accurately and reliably to the site of the intervention for the optimum level of time and the need to remove the drug delivery system in a second intervention. Delivering a drug accurately and reliably to the site oi'the intervention br the optimum level of time has advantages compared to alternative methods of drug delivery such as intravenous injection, oral tablets, capsules or suppositories. There are similar difficulties of delivering a drug accurately and reliably to the affected area for the optimum level of time in the treatment of open wounds Ofl the suriace of the body resulting, for example, from burns, scalds or injuries incurred during warfare. Here, the major difticulties are again the need to deliver the drug accurately and reliably to the affected area, in this case an open wound, and again, the removal of the drug delivery system after treatment without damage to the healing tissue.

It is known from the prior art that pharmaceutical active ingredients can be delivered to the site of an open wound by means of a water-soluble delivery system. Amongst other patents which can be cited in this connection are the following: - . I f S a s * - .a - S, S. S S a % S I S... *. Ill S Patent Number Applicant Priority Date GB 2097681A Smith & Nephew Associated 02 May 1981 ______________ Companies Limited EP 111 0546A1 Johnson & Johnson Consumer 23 December 1999 ___________________ Companies Inc. 12 January 2000 CR 680566A5 Lucchini Lab SA 10 July 1990 US 6,175,054 Bristol-Myers Squibb Company 31 October 1996 US 6,072,100 Johnson & Johnson Consumer 28 June 1998 ___________________ Companies Inc. US 4,713,243 Johnson & Johnson Products Inc. 16 June 1986 US 4,540,408 Smith & Nephew Associated 29 April 1982 ___________________ Companies Limited ___________________ US 4,292,299 Teijin Limited 06 November 1979

INVENTION

The present invention is designed to address the limitations highlighted above by proposing a novel form of delivery system that provides a watersoluble or water-dispersible product containing one or more ingredients in which the ingredient is embedded within or coated upon one or more carrier water soluble films, which are protected by less readily water- soluble films on either side, at least one of which is perforated to allow the migration of ingredient through the perforations as soon as the product is placed in contact with an aqueous medium at an appropriate site, thereby allowing the ingredient to be dispensed and the product at least partially dissolved or dispersed over a period of time such that there is no need fhr its subsequent physical removal from the site.

In considering the above invention, the term "aqueous medium" should be taken to mean any water-based liquid or gel environment including the different aqueous fluids of varying pH which are to be found within the body, within the gastro-intestinal tract or within an open wound upon the surface of the body, wherein this term refers to the human or animal body.

The product can, in theory, he of any thickness. In practice, however, products of thickness less than I 5tm are unlikely to be strong enough and those of' thickness greater than 500tni are likely to be too stiff to be applied easily to the site to he treated.

S 5 aSS I $ * 4 5 5 5 5 S I * * S - I m - . I S * a as a 5 * * I SI a S $ a.. . *55 I Where the required ingredient or ingredients are contained within the mass or upon the surface of a water-soluble film hereinafter described as the "carrier" water-soluble film, it is highly desirable that the rate at which the ingredient(s) is released from the carrier watersoluble film should be accurately controlled in order that the ingredient can be dispensed accurately and reliably. This can be achieved by laminating further water-soluble films hereinafter described as "protecting" water-soluble films to either side of the carrier watersoluble film wherein the protecting water-soluble films are less soluble at a given temperature than the carrier water-soluble film and wherein one of protecting water-soluble films is perforated in order to allow the ingredient(s) to seep through the perforations over a prescribed period of time. It will be evident that the rate of release of the ingredient(s) is controlled by the solubility of the carrier water-soluble film and the size and number of perthrations in the perfbraled protecting watersoluble film. The description of the invention is completed by the further lamination of a relatively quickly dissolving water-soluble film described hereinafter as the "adhering" water-soluble film which should be made easily distinguishable from the protecting water-soluble film, in order to avoid the product being applied the wrong way round. A simple way to avoid such confusion, although this is by no means limiting, is for the "adhering" water-soluble film to be an embossed film to distinguish it from the unperforated protecting water-soluble film which is not an embossed film.

Thus, one embodiment of the invention concerns a drug delivery system in the form of a water soluble film, or laminate of two or more such films, or extrusion of one upon another such film, carrying on one or more of its surfaces or within the mass of one or more films comprising the laminate, one or more pharmaceutical active ingredients required to be delivered to an appropriate site such as a surgical intervention, the tongue, vagina, rectum or an open wound and which will self adhere to at least part of the site to be treated and which will be partially or totally dispersed into an aqueous medium present at the site such that there is no need for its subsequent physical removal from that site.

Where more than one active ingredient is required to he delivered, controlled release of different ingredients in stages can be obtained by increasing the number of carrier water- soluble films within the laminated product. In this way, each ingredient becomes available at the appropriate time for optimum treatment.

* S *S* * S * * * S I S S S * * S S S 555 S S S S. I S S S ** I S S S 55 S S S S.. - S 555.

The incorporation of one or more required ingredients into the mass of the carrier water- soluble film as opposed to printing or coating the ingredients on one or both surfaces of the carrier water-soluble film allows slow release presentations to he formulated by selecting lower soluhility polymers from which to manufacture the carrier water-soluble film. By this means, the required active ingredients are made available over a prescribed period of time.

The thickness of the product can also be used to vary the rate of dispensing active ingredients 1. Where the active ingredients are held on the surface of the carrier water-soluble film, the active ingredients may be released at such a rate that the product may disperse in the aqueous medium before the treatment is complete. This can be overcome by making the perforated protecting water-soluble film thicker and/or less soluble than the carrier water- soluble film at any given temperature.

2. Where the active ingredients are incorporated within the mass of the carrier water-soluble film, they are released at a steady rate as the carrier water-soluble film dissolves. The duration of the treatment can therefore be varied by adjusting the rate of solubilisation and the thickness of the carrier water-soluble film.

The presence of an adhering water-soluble film as part of the product causes an immediate adherence to the surface being treated, due to the presence of an aqueous medium at the site to he treated, whether this moisture is present due to bodily or other fluids or has deliberately been applied to the surface in preparation for the application of'the product. The level of adherence can be varied by adjusting the composition and type of adhering water-soluble film; different adhering water-soluble film compositions can be selected for different site conditions. It is important to underline that the adhering water-soluble film being watersoluble will automatically self adhere to moist surfaces due to the solubilisation of its surface producing an adhesive effect. In situations where the quantity of aqueous medium present on the surface is insufficient to soluhilise enough of the surface area of the patch to obtain self- adherence of the patch, then the self adherence may he supplemented or in the limit fully obtained by means of a water-soluble adhesive that has been either applied to the product during its manufacture or applied to the surface immediately prior to the application of the product. This invention can use any composition of adhering water-soluble film provided it * * I.. S S * S S S S I S S I * S S S SIS S I I 5* 4 S S * ** S S S S ** S * S S.. S *5* S forms a suitably adhesive surface with the amount of aqueous medium present at the site of application.

It is preferable, in the case where the moist surface to be treated ibrms part of the human or animal body, that the product is made from watersoluble films that have been approved for ingestion or absorption into body tissues. At the present time, hydroxy propyl methyl cellulose (HPMC), pullulan, or starch based films arc preferred. 1-lowever, these materials are by no means limiting. Whether for medical use or for other applications, other water-soluble materials can be used, as they are approved, including those films based upon polyvinyl alcohol (P VOl 1), polyethylene oxide, modified celluloses such as carboxy-methyl cellulose (CMC), dextrin, guar gum, gelatine and their derivatives. In the case where one or more films are based upon PVOH, their solubility at a given temperature may be adjusted by selecting a grade with a specific molecular weight and a specific % hydrolysis. By way of example, to obtain solubilisation in an aqueous medium at a temperature at or above 60 C, the PVOH should preferably be 90-99% hydrolysed, and to obtain solubilisation in an aqueous medium at a temperature of 25 C and below, the PVOH should preferably be 80-90% hydrolysed.

When the adhering water-soluble film is based upon PVOFI, it is possible to increase its level of tack or stickiness by using film made from a lower molecular weight of PVOH than would otherwise he used. Additives like guar gum, dextrin, starch and gelatine compositions can he added to increase the relative tack value of the adhering water-soluble film. This may be important where the amount of aqueous medium at the site is low. Similarly, it is possible to increase the flexibility of the product in order to provide increased contact with the moist surface by using a water-soluble film with a higher water content than the range of 4.0-8.0% Ibund within most commercially available water-soluble films. Using different kinds of plasticisers can also affect the flexibility of the product as well as the relative tack value of the adhering water-soluble film. Various plasticisers can be used including, but by no means limited to, glycerol, sorbitol, polyethylene glycols and polypropylene glycols of various molecular weights, castor oil, and fish oil.

In the specific case of pharmaceutical active ingredients, the product may be applied to an external surface lesion such as a burn or scald, an ulcer, to an internal wound, or alternatively to the mouth, vagina or rectum, by which delivery system the active ingredient is slowly released into the area being treated while the product itself disintegrates under the influence of * S SeS S S * S S * S S S S S * * S S **S S * S S. 4 S S S 55 5 S * I S 55 5 5 S S.. - S *SS S its host environment, such that there is no need for its subsequent removal. Where nutraceutical ingredients are incorporated into the product, application via the mouth is preferred. Where sexual stimulants are incorporated into the product, application via the vagina is preferred.

Although the treatment of burns varies from hospital to hospital and from country to country, it is essential to prevent infection or if infection is already present, to bring this under control as rapidly as possible. This often involves the use of an anti-bacterial or an anti-fungal or an antibiotic composition. Among recommended active ingredients for the treatment of such infections are chlorhexidjne, bacitracin, neomycin and polymixin, although these are by no means limiting. One of the many methods recommended for the treatment of burns is to apply a cream containing chiorhexidine and lignocaine which cream has the double advantage of being both antiseptic and pain relieving. Typically, for surface wounds, the dressing is left on for four or five days befOre being changed unless the wound becomes painful or there is any evidence of infection such as redness, swelling, or pain, when the dressing should be immediately changed. The use of this invention will facilitate observation of the area being treated since the product, unlike that of a typical dressing, will normally be almost transparent. However, where it is desirable to make the product opaque, any one or more of the watersoluble films comprising the product may be rendered opaque by loading with a filler such as a United States Pharmacopoeia (USP) grade of calcium carbonate.

In certain applications of the product described by this invention, it may be useful or indeed essential fOr air to reach the site being treated. In such cases, the product may be perfOrated throughout its entire thickness to a greater or lesser extent depending upon the desired amount of the surface requiring exposure to air.

The manufacture of the carrier water-soluble film with active ingredients embedded within or coated upon it follows the same principles as in the current practice of incorporating fillers.

Those ingredients that are not water sensitive and any other additives such as plaslicisers are mixed into the aqueous solution made from one or more selected water-soluble resins and then the resulting solution or suspension is cast upon a heated drum, upon a conveyor belt or upon a detachable liner, and then progressively dried to produce what is hereinafter described as a cast film.

* * S., * S * S S S S S S S * * S * S *eS S S S 5 5 S ** 5 8 * S 55 I. S S *5* S I (a Ingredients that are water sensitive can he embedded into what is hereinafter described as an extruded film, whether blown or die cast, by mixing the active ingredients into the pre-melted resin pellets prior to extrusion in the same way as are other additives such as plasticisers and slip agents.

Tn the case of heat sensitive ingredients, the cast film rnanufcturing process is preferred, whilst in the case of water-sensitive active ingredients, the extruded film manufacturing process is preferred.

Ingredients can be applied to the surface of the water-soluble carrier film either as an overall coating, or as a specific pattern by any of the current coating or printing methods used to print films. These ingredients may be applied to the carrier water-soluble film as solutions or dispersions iii water or in any alternative liquid medium which will adhere to the water- soluble carrier film when dry and which is not detrimental to the film or the active ingredients is or to the site to be treated.

An indicator may be strategically placed on or within the product to indicate the precise location of the ingredient within the product. This may be done either by incorporating an indicator such as a colour marker (although this type of marker is by no means limiting) within the product in admixture with the ingredient or upon the product in an suitable ink which is then applied by printing the location of the ingredient on the detachable liner of Figure or on the unperibrated protecting watersoluble film in Figures 1, 2 or 3. It will be appreciated that where either of these alternatives provide an indication visible to the naked eye, the product can subsequently be accurately positioned at the site so that the ingredient is accurately targeted to the affected area. In this way, wastage of what may be expensive ingredient(s) can be significantly reduced.

Tn a second aspect relating to the treatment of open wounds or other sites visible to the naked eye, an indicator such as a colour marker (although this type of marker is by no means limiting) may be incorporated within the product in admixture with the ingredient, and then used to measure the rate at which the ingredient is being dispensed. For example, in the case of a colour marker, the intensity of the colour will reduce as the ingredient is dispensed. By this means, the indicator, whether indicating by colour or by other means, can inform the S.. S - . S S $ $ S $ * * S.$S * * - 5$ S $5 * S S S * 5** 5 5 *55 5 patient or the operator that this stage of treatment is complete, allowing application of further product to be made at the appropriate time, if required.

Although the product is initially prepared as a web of material, the product can subsequently either he presented as small, patch like, portions or slit into smaller convenient rolls of material. These presentations are, however, not limiting and other presentations may he considered. The web of material may he cut and processed either into rolls or into patches by any of the current methods used lbr producing paper, filmic or woven labels. The resulting patches can be of any shape or size and can be produced as individual pre-cut units or produced at the time of application by cutting to required size from a roll or sheet of product using, for example, a pair of scissors. The pre-cut form may be most suited to those surfaces that are similar in size, for example, surfiuces within the mouth, vagina or rectum, and the sheet or roll form may he more suited for internal or external wound or burn sites that may vary considerably in size. Similarly, whilst the most convenient shape would be round or oval, it will be readily appreciated that whether pre- cut or cut from roll or sheet form, any shape of patch can be used, the only differences being those of convenience. The product is then applied to the site to be treated.

As an example of how the product may be used on an open wound, a roll is unwound and wrapped around an open wound or burn with the adhering watersoluble film facing the wound or burn. In this example, the product serves two purposes. It administers the active ingredient to the required area of open wound during a prescribed period of time by selecting a certain material for the carrier water-soluble film and a certain design of perforated protecting water-soluble film, and it excludes air from the wound helping to reduce the risk of infection. In comparison with the present method of application by cream or gel preparations, the dose rate provided in this example is uniform across the open wound and the weight of active ingredient can he adjusted to minimise any pain associated with its application. As the water-soluble film is absorbed over time into the wound, any surplus product is removed by cutting with a pair of scissors or other methods and fresh him is applied to the wound without the need to disturb previous applications, thereby allowing the wound to heal more quickly.

Alternatively, whilst not disturbing the healing process, excess product can be removed by washing the wound with warm water. Different active ingredients can be applied during the healing period either by means of different rolls of product or by a combination of different ingredients incorporated within a single roll of product.

I 1*8 * II $ I a * I I I **. a I I. * * as a a * * , a a a s a S The following examples, although by no means limiting, will serve as illustrations to describe how the product may be used in surgical interventions.

In general surgery, a surgical wound which appears to be infected is operated in order to clean the area. During surgery, it is customary to treat the area with locally applied antibiotics.

Application during surgery of the product, which is adapted according to the necessary therapeutic dose and duration of treatment, will release antibiotics over an extended period of time and be beneficial to the treatment.

In abdominal surgery, as with appendix flabitis which is usually treated as infected, long term antibiotics are given intravenously. I-lowever, during surgery, the product described in this invention can be inserted in order to improve infiltration of the antibiotics due to the proximity of the product, even when laparoscopy is concerned, requiring not more than three incisions of 1.5 cm each.

In open fracture operations, the treatment is undoubtedly a procedure leading to potential infection. It will be evident that there are clear advantages resulting from use of the product to provide local antibiotic treatment over an extended period of time and which does not require replacement and avoids spreading of the infection from the affected area.

In a further embodiment of the invention, the product is used as a web of material to encapsulate other ingredients in addition to those contained within its mass. According to the selection of the most appropriate machinery to carry out the encapsulation process, one, two or even more webs of product according to this invention are required. Once the capsules have been tilled, whether with powder, granules, gels or liquids, they are sealed by solvent welding, heat welding, radio frequency welding, laser welding or any other commonly used methods for sealing filmic materials. In this way, further alternative drug delivery systems are made possible by means of this invention.

S * S..

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SPECIFIC DESCRIPTION

As will be apparent from the foregoing, the dosing system described herein provides a measured prescribed dose of one or more ingredients to a site at which an aqueous medium is present. l'his will now be illustrated by reference to Figures 1, 2 and 3.

In Figure 1, there is shown an embodiment of the invention in which there is a single carrier water-soluble film (3) within which is enibedded or upon which is coated one or more ingredients to be delivered. On either side of the carrier water-soluble film are laminated protecting watersoluble films (2) and (4). One of the two protecting water-soluble films (2) is perforated in order to allow the ingredients to seep through the perforations. A further adhering water-soluble film (4) is laminated to the perfbrated protecting water-soluble film in order to seal the perforations and also to provide a layer which will adhere to the site as soon as the product is brought into contact with an aqueous medium on the surttce of the site.

In Figure 2, there is shown an embodiment of the invention in which there are two carrier water-soluble films (31) and (32) both capable of delivering one or more ingredients. It will be evident that in this product construction, the size and/or number of perforations in carrier water-soluble film (31) must he larger than those in carrier watersoluble film (3B) in order that the delivery of ingredients to the site is controlled by protecting perforated water-soluble film shown at (32).

In Figure 3, there is shown an embodiment of the invention in which the unperforated protecting water-soluble film (444) has been further laminated to a detachable liner (555), preferably a printed detachable liner, in order that the location of the ingredients within the product is clearly visible to the user and hence the product can be accurately applied to the site so that delivery of the ingredient is optimised.

*. .1. : . I.. , * *45 *

EXAMPLES

Example 1

1. We cast a warm water soluble film (dissolving at between 3 8-48 C, and preferably between 38-43 C) on a polyester film liner (to make sheet A).

2. We perforated sheet A by means of a pertbrating roll to roll machine using various designs of perforation, so as to obtain different rates of drug delivery.

3. We laminated a cold water soluble film to sheet A on the warm water soluble film side (to make sheet B).

4. We removed the polyester film liner from sheet B (to make sheet C) 5. We cast another sheet of warm water soluble film on a detachable liner (to make sheet D) 6. By means of a stencil, we cut an aperture in a clear polyester film and screen printed on the warm water soluble film side of sheet D a formulation of vancomycin powder within an aqueous cold water soluble film forming composition, including a food grade dye within the formulation to identit' the screen printed area containing vancomycin (to make sheet E). By means of the dye, the user is able to position accurately the screen printed area containing the vancomycin on a wound or affected area.

7. We laminated the medicinal side of sheet E to the perforated side of sheet C (to make sheet F).

8. A cut portion of sheet F' containing the screen printed formulation of vancomycin identified by the dye is then placed on the wound or affected area, taking care to ensure that the cold water soluble film side is facing the wound or affected area.

Example 2

1. We cast a warm water soluble film (dissolving at between 38-48 C, and prelérably between 3 8-43 C) on a polyester film liner (to make sheet A).

2. We perforated sheet A by means of a perftrating roll to roll machine using various designs of perforation, so as to obtain different rates of drug delivery.

3. We laminated an embossed cold water soluble film to sheet A on the warm water soluble film side (to make sheet B).

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* *h. : * * * a * * S * 5 4. We removed the polyester film liner from sheet B (to make sheet C) 5. An aqueous cold water soluble film forming composition loaded with neomycin powder within its mass was cast upon the perforated side of sheet C. We sprayed further neomycin powder into the resulting web of material, still in aqueous form, before it entered the dryer (to make sheet D). By this means, we ensured precise embedding of further neomycin powder within the cold water soluble film in addition to the neomycin already present in the aqueous cold water soluble film forming composition prior to casting.

6. After drying, the grams per square metre (GSM) of sheet D was measured with and without the powder embedding step and by difference, we calculated the amount of neomycin powder that had been embedded in the product in addition to that present in the aqueous cold water soluble film forming composition prior to casting.

7. We cast a warm water soluble film on a detachable liner (to make sheet E) 8. We laminated the medicinal side of sheet D to the warm water soluble film side of sheet E arid removed the detachable liner (to make sheet F).

9. A cut portion of sheet F containing the screen printed fhrniulation of vancomycin identified by the dye is then placed on the wound or affected area, taking care to ensure that the embossed cold water soluble film side is facing the wound or affected area. a *

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Claims

I. A waler-soluble or water-dispersible product containing one or more

ingredients in which the ingredient is embedded within or coated upon one or more carrier water soluble films, S which are protected by less readily water soluble films on either side, at least one of which is perforated to allow the migration of ingredient through the perforations as soon as the product is placed in contact with an aqueous medium at an appropriate site, thereby allowing the ingredient to be dispensed and the product at least partially dissolved or dispersed over a period of time such that there is no need for its subsequent physical removal from the site.
2. A product according to claim I in which the product will self adhere to at least a part of the site due to solubilisation of part or all of the adhering water-soluble film following contact with an aqueous medium present at the site.
3. A product aceording to claim 1 in which the product is made of more than one water- soluble material.
4. A product according to claim I in which the product is made by laminating together one or more water-soluble or water-dispersible films.
5. A product according to claim I in which the one or more ingredients are pharmaceutical or nutraceuticaj active ingredients for use in man or in animals.
6. A product according to claims in which the ingredients are an antibacterial or an anti- fiingal or an antibiotic composition or a mixture thereoC
7. A product, according to claim I in which the rate of release of the required ingredients is controlled by the rate of solubilisation of the carrier water-soluble film.
8. A product, according to claim 1 in which the rate of release of the required ingredients is controlled by the size and number of perforations in the perforated protecting waler- soluble film or films.
9. A product according to claim I in which different ingredients are located within the product in such a way that they are released sequentially to the site.
10. A productaccordingtoclaim I admixture with the one or more ingredients in order to identify that part of the product containing the ingredients.
Il.Aproductaccordingtocm I product containing the ingredients.
12. A product according to claim I in which a dye or other indicator is incorporated in admixture with the one or more ingredients in order to monitor the rate at which the one or more ingredients are being dispenset * * * S.. * * S * 2 * ... ? !
13. A product according to claim I in which one or more ingredients are applied in a pattern to the product in order to obtain greater precision of dosage release and reduced wastage of the ingredients.
14. A product according to claim 1 produced in roll form
15. A product as described in claim 12 in which the roll has been coated in whole or in part with a water-soluble or water-dispersible adhesive 1 0
16. A product according to claim 1 produced as discrete patches.
1 7. A product according to claim I in which a printed detachable liner is laminated to the unperfirated protecting water-soluble film.
18. A product according to claim 15 in which the printed detachable release liner identifies that part of the product within which the ingredient or ingredients have been embedded or upon which the ingredient or ingredients have been coated such that the person applying the product shall he able to position the product accurately at the site and then detach the printed release liner. I..

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