United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,352,457
`
`Jenkins
`
`[45] Date of Patent:
`
`Oct. 4, 1994
`
`USOOS352457A
`
`[54] TRANSDERMAL DEVICE
`
`[75]
`
`Inventor:
`
`Anthony W. Jenkins, Comberton,
`United Kingdom
`
`[73] Assignee: Ethical Pharmaceuticals Limited,
`Ely, United Kingdom
`
`[21] Appl. No.:
`
`30,265
`
`[22] PCT Filed:
`
`Oct. 4, 1991
`
`[86] PCT No.:
`
`PCT/GB9l/01730
`
`§ 371 Date:
`
`Apr. 5, 1993
`
`§ 102(e) Date:
`
`Apr. 5, 1993
`
`[87] PCT Pub. No.: WO92/05811
`
`PCT Pub. Date: Apr. 16, 1992
`
`Foreign Application Priority Data
`[30]
`Oct. 5, 1990 [GB] United Kingdom .............. 9021674.8
`
`
`[51]
`Int. 01.5 .............................................. A61F 13/02
`[52] US. Cl. ....................... 424/448; 424/449
`[5 8] Field of Search ................................ 424/448, 449
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,031,894 9/1986 Urquhart et al.
`................... 128/268
`
`4,746,509
`5/1988 Haggiage et a1.
`.
`...... 424/449
`4,769,028 9/1988 Hoffmann ........................... 424/443
`
`FOREIGN PATENT DOCUMENTS
`
`0013606 7/1980 European Pat. Off.
`0156080 10/1985 European Pat. Off.
`0201828 11/1986 European Pat. Off.
`0209121
`1/1987 European Pat. Off.
`0272562
`6/1988 European Pat. Off.
`0272987 6/1988 European Pat. Off.
`0275716 7/1988 European Pat. Off.
`0279982 8/1988 European Pat. Off.
`0318385
`5/1989 European Pat. Off.
`0328806 8/1989 European Pat. Off.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`'
`
`.
`.
`
`0332010 9/1989 European Pat. Off.
`0371496 6/1990 European Pat. Off.
`2086224
`5/1982 United Kingdom .
`2146526 4/1985 United Kingdom .
`2185187
`7/1987 United Kingdom .
`86/06281 11/1986 World Int. Prop. 0. .
`87/06144 10/1987 World Int. Prop. 0. .
`88/01497 3/1988 World Int. Prop. 0. .
`W08907959 9/1989 World Int. Prop. 0. .
`
`OTHER PUBLICATIONS
`
`Patent Abstracts of Japan, vol. 12, No. 333 (C—526),
`Sep. 8, 1988.
`Patent Abstracts of Japan, vol. 12, No. 159 (C—495),
`May 14, 1988.
`
`Primary Examiner—D. Gabrielle Phelan
`Attorney, Agent, or Firm—Bacon & Thomas
`
`[57]
`
`ABSTRACT
`
`The invention pertains to a method of preparing a de-
`vice for transdermal delivery of an active ingredient
`which is solid at room temperature and in which part or
`all of the active ingredient is present in a saturated or
`supersaturated solution. In the first step, a mixture is
`prepared which includes at least a polymer adhesive, a
`vehicle for the polymer adhesive, an active ingredient
`and a solvent mixture for the active ingredient which
`solvent mixture comprises at least two solvents having
`different boiling points. The mixture is then formed into
`a film and dried. The vehicle for the polymer adhesive
`and at least one of the solvents and the solvent mixture
`have boiling points below the drying temperature of the
`film, while at least one of the solvents in the solvent
`mixture has a boiling point above the drying tempera-
`ture of the film. Thus, at least one of the solvents re—
`mains in the film after drying and the solubility of the
`active ingredient contained in the remaining solvent is
`greater than 10%.
`
`29 Claims, 3 Drawing Sheets
`
`
`k\X\\\\\V 4
`
`  
`
`

 
`
`MYLAN - EXHIBIT 1027
`
`

`

`’ US. Patent
`
`Oct. 4, 1994
`
`Sheet 1 of 3
`
`5,352,457
`
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`
`“4
`
`
`
`

`

`US. Patent
`
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`
`5,352,457
`
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`

`

`US. Patent
`
`Oct. 4, 1994
`
`Sheet 3 of 3
`
`5,352,457
`
`26754
`
`DAYS
`
`200
`
`ISO
`
`|60
`
`I40
`
`IZO 800000
`
`-m‘OVN
`
`'mowd 'IOIGVHLSBO szv1d
`
`

`

`1
`
`5,352,457
`
`TRANSDERMAL DEVICE
`
`,_
`
`The invention relates to a method of preparing a
`device for transdermal delivery of an active ingredient
`and to transdermal devices prepared by that method.
`The administration of drugs through the skin is a
`concept which is now well established and this route
`has several advantages over more conventional forms
`of drug delivery such as injection or oral ingestion. A
`particular advantage is that transdermal drug delivery
`devices can provide a sustained and controlled release
`of the active ingredient over a prolonged period so that
`the resulting blood levels remain constant. This is in
`contrast to other forms of administration where surges
`of the agent occur in the bloodstream immediately after
`administration and then drop away rapidly until the
`next dose is given. In the case of oral administration the
`blood level is further influenced by contents of the
`intestines and therefore difficult
`to control. Trans-
`dermal administration permits direct access to the
`bloodstream without first passage through the gastroin-
`testinal tract and liver and also without the inherent
`problems associated with injection such as risk of infec-
`tion and need for sterile administration equipment.
`Because of the advantage of transdermal administra-
`tion, in recent years a very large number of devices
`have been developed and described for the transdermal
`administration of a variety of pharmaceuticals. The
`devices are usually in the form of a patch or plaster to
`be attached to the skin. Early devices such as for exam-
`ple, that described in US. Pat. No. 3,598,122 comprised
`a reservoir containing the active ingredient, either in
`solid or liquid form. The reservoir walls were com-
`posed of a material permeable to that ingredient and it
`was stuck to the skin by a thin layer of adhesive which
`was also permeable to the active ingredient. The outer
`surface of the reservoir was covered with a backing
`material impermeable to the active ingredient. Such
`devices were bulky and solvents in which the active
`agent was dissolved tended to interfere with the ability
`of the adhesive to stick to the skin.
`With improvements in adhesives available it was soon
`found possible, and indeed preferable, to prepare trans-
`dermal devices in which the adhesive layer itself pro-
`vided the drug reservoir. Thus more modern trans-
`dermal devices usually comprise ‘at least an imperme-
`able backing material, a layer of drug-containing adhe-
`sive attached to the backing material and a release liner
`on the other adhesive surface which is removed for
`application of the device to the skin. Additional mem-
`branes are sometimes included within the device to
`regulate the rate of passage of the active agent from the
`adhesive to the skin.
`Various methods have been used to achieve suitable
`drug/adhesive mixtures in which the active ingredient
`is dispersed in the adhesive without affecting the ability
`of the adhesive to stick to the skin. One of the earliest
`drugs to be administered by a transdermal device was
`nitroglycerin which is used in the treatment of angina
`pectoris and congestive cardiac failure. Nitroglycerin is
`well absorbed by the skin and therefore particularly
`amenable to transdermal administration. Conveniently
`it is a liquid at room temperature and so the approach
`that has been taken is to absorb it on to a solid such as
`lactose which is then dispersed in a polymer adhesive.
`Such devices are described in, for example US. Pat.
`No. 4,776,850, G.B. 2,081,582, and others. One or more
`
`5
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`2
`other “solvents” are sometimes present in the nitroglyc-
`erin adhesive mixtures either as permeation enhancers,
`or for the purpose of “solvent casting” the mixture onto
`a backing layer.
`Where the active ingredient to be incorporated into a
`transdermal device is a solid any solvent for the agent
`must be carefully chosen to be compatible with the
`adhesive. In W086/00814 for example the problem is
`overcome by choosing a single solvent which is both a
`solvent for the drug and a solvent for the adhesive.
`However such a method restricts severely the number
`of different drugs which are compatible with a particu-
`lar adhesive and also the type of adhesive which can be
`used.
`Alternative methods have therefore been used in
`which a drug/adhesive mixture is prepared which in-
`cludes a solvent for the drug and a solvent for the adhe-
`sive. The mixture is spread onto an appropriate backing
`material and then dried to evaporate the solvents leav-
`ing the drug dispersed in the adhesive in particulate
`form. A variation of the method is described in
`W089/0795l in which the solvents for the adhesive are
`evaporated during a drying stage leaving the drug, in
`this case oestrogen, dispersed in particulate form in very
`high boiling point solvents which do not significantly
`evaporate on drying but which have a low capacity for
`the drug.
`While the active ingredient can be taken up by the
`skin from a dispersion of the solid compound, the rate of
`uptake can be far better controlled if the agent is in a
`supersaturated solution, particularly where the solvent
`has an adequate capacity for the active ingredient. As
`the ingredient is taken up by the skin more will become
`dissolved in solution so maintaining a concentration
`gradient over a prolonged period which drives uptake
`through the skin. Transdermal devices are known
`which contain saturated drug solutions. They are de-
`scribed for example in GB. 2,156,215 and US. Pat. No.
`4,201,211. However these documents fail to describe a
`way in which the level of saturation can be precisely
`controlled to produce a supersaturated solution.
`The present invention provides an improved method
`for preparing transdermal devices which contain super-
`saturated solutions of an active ingredient within an
`adhesive layer by use of a carefully selected mixture of
`solvents and selective evaporation of a particular sol-
`vent or solvents by drying at a temperature above the
`boiling points thereof, to influence the final concentra-
`tion of the solution of active ingredient in the device.
`In accordance with the invention a method of prepar-
`ing a device for transdermal delivery of an active ingre-
`dient which is a solid at room temperature and in which
`part or all of the active ingredient is present in a super-
`saturated solution comprises the steps of:
`(a) preparing a mixture comprising at least
`(i) a polymer adhesive
`(ii) a vehicle for the polymer adhesive
`(iii) the active ingredient
`(iv) a solvent mixture for the active ingredient
`which comprises at least two solvents;
`(b) forming the mixture prepared in step (a) into a
`film, and
`(c) drying the film prepared in step (b) wherein the
`vehicle for the polymer adhesive and at least one of
`the solvents in the solvent mixture for the active
`ingredient have boiling points below the drying
`temperature and at least one of the solvents in the
`solvent mixture for the active ingredient has a boil-
`
`

`

`3
`ing point above the drying temperature and
`wherein the solubility of the active ingredient in
`the said solvent or solvents having a boiling point
`above the drying temperature is greater than 10%.
`The above method provides a very precise way of 5
`preparing an adhesive/active ingredient mixture which
`contains a supersaturated solution of the ingredient after
`drying.
`It is to be understood herein that the term “active
`ingredien ” is intended to mean a single active agent or
`a combination of more than one active agent.
`Dissolving the active ingredient in a mixture of sol-
`vents and then drying at a temperature which facilitates
`the evaporation of the vehicle for the adhesive and one
`of the solvents for the active ingredient, because it is
`above their boiling points, leaves the active ingredient
`in a supersaturated solution in the solvent or solvents
`that remain. Supersaturated solutions are particularly
`advantageous from the point of View of transdermal
`administration because they assist in controlling the rate
`of migration of the active ingredient through the skin as
`previously mentioned.
`The choice of particular solvents, adhesives and dry—
`ing temperatures is dictated by the solubility of the
`particular active ingredient in the solvent or solvents
`remaining in the device after drying. Thus with careful
`selection of all the components the method of the inven-
`tion can provide transdermal devices which can admin-
`ister a very wide range of drugs. The solubility of the
`active ingredient in the solvent or solvents having a
`boiling point above the drying temperature needs to be
`greater than 10%.
`The polymer adhesive may be a polyisobutylene or
`silicone adhesive although acrylate polymer adhesives
`are particularly preferred. Suitable vehicles for the
`acrylate adhesives are for example methanol, ethanol,
`industrial methylated spirits (IMS),
`isopropanol and
`water. Suitable vehicles which may be used with poly—
`isobutylene are toluene, xylene and methylene chloride.
`Suitable vehicles for silicone adhesives are chloro-
`fluorocarbons such as, for example, trichlorotrifluoro-
`ethane. For acrylate adhesives aqueous dispersions are
`preferred. In this latter case drying temperatures used in
`drying the film must always be in excess of 100° C. at
`normal atmospheric pressures. Where the vehicle for
`the adhesive is a lower boiling solvent such as methanol
`(bp 65° C.), ethanol (bp 785" C.) or isopropanol (bp
`82.4° C.), a lower drying temperature may be used pro-
`viding it is above the boiling point of the low boiling
`solvent included in the solvent mixture for the active
`ingredient.
`'
`In one embodiment of the invention the vehicle for
`the adhesive and the solvent to be evaporated during
`drying from the solvent mixture for the active ingredi-
`ent both are chosen to have a boiling point below that of 55
`ethanol. A drying temperature can thus be chosen
`which allows the ethanol to be maintained within the
`device. This is advantageous because ethanol is a useful
`skin permeation enhancer for some drugs. For acrylate
`systems a suitable solvent which may be evaporated
`while ethanol is retained is methanol. For non-aqueous
`systems ether or chlorofluorocarbons may be used.
`In another embodiment of the invention the solvent in
`the solvent mixture for the active ingredient which is
`evaporated on drying may be ethanol,
`isopropanol,
`industrial methylated spirits (IMS) or water.
`High boiling point solvents suitable for forming the
`saturated or supersaturated solutions of the active ingre-
`
`4
`dient in the transdermal device are those having boiling
`points in excess of 110° C. Preferred solvent mixtures
`include one or more of diethylene glycol, propylene
`glycol, propylene carbonate, glycerol, lower molecular
`weight polyethylene glycols, propylene glycol esters,
`polyol fatty acid esters, fatty alcohol derivatives, oleic
`acid, iso-octyl stearate, iso-propyl myristate, isopropyl
`palmitate, ethyl oleate, diisopropyl adipate, diethylsuc—
`cinate, hexylaurate, triglycerides of caprylic or capric
`acids, diethyltoluamide, laurocapram, n-methylpyrroli—
`done and diethylene glycol monoether. Also suitable as
`solvents which are not evaporated from the device on
`drying are essential oils such as eucalyptus oil, tea-tree
`oil and lavender oil. Preferably at least one of the sol-
`vents which remains in the device will also act as a
`permeation enhancer to assist uptake by the skin of the
`active ingredient. Preferred solvent systems are propy-
`lene glycol-diethyltoluamide, n-methylpyrrolidone—die-
`thyltoluamide, propylene glycol
`- diethylene glycol
`monoethyl ether and diethyltoluamide-diethylene gly-
`col monoethyl ether - tea tree oil.
`Among the active agents which may be included in
`transdermal devices produced by the method of the
`invention are anti-histamines such as,
`for example,
`clenastine fumarate, steroid hormones such as oes-
`tradiol, progestins
`such as norethisterone acetate,
`norgestrel, ethynodiol diacetate, medroxy progesterone
`acetate, gestodene and desogestrel, vasodilators such as
`nifedipine and diltiazem, antihypertensives such as
`clonidine and propranolol, bronchodilators such as sal-
`butamol and clenbuterol, anti-tumour agents such as
`methotrexate and S-fluouracil, alkaloids such as physo-
`stigmine and analgesics such as fentanyl, sufentanil,
`buprenorphine and hydromorphone. The device may
`contain an active ingredient which is a combination of
`more than one of the above active agents, for example
`an oestrogen with a progestin.
`While the solvents to be used in the method of the
`invention must be selected in order that a supersatu-
`rated solution is produced on drying, solvents may also
`be selected which modify the properties of the adhesive
`so that it possesses the required degree of adhesion and
`tackiness to stick to the skin for the required period,
`which could be several days, but at the same time can be
`easily removed as required. The method of the present
`invention allows polymer adhesives which are normally
`too aggressive to be used in transdermal devices to be
`rendered suitable by choice and incorporation of an
`appropriate solvent mixture.
`The assembly of a transdermal device prepared in
`accordance with the method of the present invention
`will now be described by way of example with refer-
`ence to FIGS. 1 and 2 of the accompanying drawings
`and Examples 1 to 4.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a vertical section through a first embodi-
`ment of the invention without the inclusion of a rate
`control membrane.
`
`FIG. 2 is a vertical section through a second embodi-
`ment of the invention including a rate control mem-
`brane.
`
`FIG. 3 shows mean plasma concentration time curves
`following transdermal administration of norethisterone
`acetate to four post menopausal women using a trans-
`dermal device prepared in accordance with the method
`of the invention ------. results from samplesassayed by
`RIA at Liverpool University. x-----x results from same
`
`5,352,457
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`

`

`5
`
`5,352,457
`
`samples assayed by RIA at Hammersmith HOSpital. 1
`transderrnal patches applied or replaced. 1 transdermal
`patches removed.
`FIG. 4 shows mean plasma concentration time curves
`following transderrnal administration of oestadiol using
`the devices of Example 4 ( .—‘|) and known product
`Estraderm 50 (X—X). The arrows indicate patches
`applied, replaced or removed as above.
`As already described, a mixture is formed which
`comprises a polymer adhesive in a suitable vehicle, the
`active ingredient to be administered, and a solvent mix-
`ture for the active ingredient which comprises at least
`two solvents one of which must have a boiling point
`above the drying temperature and one below. Prefera-
`bly the active ingredient is first dissolved in the solvent
`mixture and the solution slowly added to the adhesive
`polymer previously dispersed in a suitable vehicle. De-
`pending on the coating technique and adhesive used the
`addition of an adhesive thickener may be required. The
`mixture of adhesive polymer and active ingredient is
`formed into a film, preferably by coating onto a flexible
`sheet material. A typical embodiment of a device
`formed in accordance with the method of the invention
`is shown in FIG. 1. The adhesive mixture is formed into
`a layer 4 on a siliconised release paper 2. The layer is
`preferably about 5 to 500 pm thick. The coated release
`paper is dried at the appropriate temperature to drive
`off the necessary solvents and then laminated to a back-
`ing material 6 impermeable to the active ingredient.
`Suitable siliconised release liners are 3M Health Care
`Type 660 or 1360, Daubert HDPE 1642 or L. Stace
`types 635/6. Preferable backing materials include poly-
`ester film laminate (e.g. 3M Health Care Type 1012 or
`1220), metalised polyester laminate (e.g. 3M Health
`Care Type 1109) and co-extruded high barrier films
`either clear (e.g. BXL Plastics Hybar) or skin-tone (e.g.
`Grace- Cryovac MFZOO). Backings having higher oxy-
`gen and water vapour transmission rates are preferred
`for devices intended for treatment for more than 24
`hours. A suitable backing material in these circum-
`stances is Semex polyester-urethane film type MF
`4387-00.
`
`5
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`15
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`30
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`35
`
`6
`The device of FIG. 2 is formed as previously de-
`scribed except that when using conventional coating/d-
`rying equipment the process becomes two stages. The
`backing material 6, coated with adhesive layer 4b is
`laminated to rate control membrane 8. The second stage
`is the lamination of this laminate to the adhesive layer
`4a which has been coated on to the release paper 2.
`Alternative manufacturing methods are possible and
`more than one rate control membrane can be incorpo-
`rated at any location within a multilayer device. Prefer-
`ably all of the above described layers are assembled on
`a single large sheet which is die cut into transderrnal
`devices of the appropriate size.
`EXAMPLE 1
`
`Transdermal Device Containing Norethisterone
`Acetate Without A Rate Control Membrane
`
`A mixture of acrylate polymer adhesive and the ac-
`tive ingredient norethisterone acetate is formed contain—
`ing the following:
`——_—_
`————_—___
`Component
`Quantity (8)
`Norethisterone acetate (mieronised)
`395
`Propylene glycol
`2125
`Diethyltoluamide
`rooo
`Ethanol (95%) or [MS
`1500
`Primal N560 (acrylate
`44500
`adhesive dispersion in
`water)
`Acrysol ASE 60 (thickener for
`adhesive diluted 50:50)
`Total 50 Kg
`
`
`
`
`480
`
`The norethisterone acetate is dissolved in propylene
`glycol, diethyltoluamide and ethanol by sonication or
`warming. This solution is added slowly to the aqueous
`acrylate adhesive dispersion (Primal N560, Rohm &
`Hass) with mixing. An adhesive thickener (Acrysol
`ASE 60) is then added to the mixture as a 50% solu-
`tion/water mix sufficient to produce a thicker spreading
`solution of around 800 cP (Brookfield) for reverse roll
`
`The reverse manufacturing method is also possible
`and in some cases advantageous i.e. spreading the ad-
`hesive/solvent mixture onto the backing material and
`then laminating it to the release liner.
`FIG. 2 shows a second embodiment of the invention
`in which the adhesive/active ingredient layer is divided
`by a rate control membrane 8. The layer 4a which, in
`use, is in direct contact with the skin provides an initial
`loading dose of the active ingredient. As this migrates
`into the skin the consequent concentration difference
`between layer 4a and 417 causes the layer 40 to be re-
`plenished with active ingredient from the layer 4b at a
`rate dictated by the rate control membrane. Thus the
`inclusion of such a membrane provides a further means
`to control the rate of uptake for a predetermined per-
`iod, firstly by selection of the appropriate membrane
`and secondly by varying the thickness of the layers 4a
`and 46 on either side of the membrane. Suitable materi-
`als for forming the rate control membrane include poly-
`propylene film (e.g. Celgard microporous film), polyvi-
`nyl acetate film (e.g. Mowiol film (Hoechst) and ethyl
`vinyl acetate film (e.g. controlled caliper MSP series
`films obtained from 3M Health Care Speciality Divi-
`sion). The thickness of the layer 40 may be in the range
`5 to 50 um and the thickness of the layer 417 may be in
`the range 50 to 500 pm.
`
`'
`
`(3M
`Health Care Type 1109) at about 100 11.111 wet coating
`thickness and dried at about 105° C. to drive off the
`water and the ethanol or IMS from the acrylate adhe-
`sive. The resulting dried adhesive layer is about 55 pm
`thick. The release liner (Stace type 636) is laminated to
`the adhesive layer. The final sheet is die-cut to form
`transderrnal devices of about 19 or 23.5 cm2 each con-
`taining 1.5 or 2.25 mg norethisterone acetate respec-
`tively, which are packaged individually.
`
`
`
`
`
`55
`
`65
`
`Transdermal Device Containing Oestradiol With Rate
`Control Membrane
`
`A mixture is prepared containing the following:
`
`
`Component
`176 Oestradiol
`Propylene glycol
`Diethyltoluamide
`95% Ethanol or IMS
`Polysorbate 20
`Primal N560 (acrylate
`adhesive dispersion)
`Acrysol ASE 60 (thickener
`for adhesive) 50:50 water
`
`Quantity (g)
`87.5
`400
`100
`100
`12.5
`4262.5
`
`37.5
`
`

`

`7
`-continued
`
`5,352,457
`
`8
`
`Component
`Quantity (g)
`
`Total
`5000 g
`
`5
`
`The oestradiol is dissolved in the solvent mixture and
`slowly added to the aqueous adhesive to which an
`Acrysol ASE 60 thickener is also added in a similar way
`to Example 1. The mixture is coated onto a siliconised 1
`release liner (3M Health Care Type 660) to give a 50 pm 0
`wet coating which is dried at 105° C. as described
`above. When dried the adhesive layer and liner are
`laminated to a rate control membrane sheet material
`(3M ethyl vinyl acetate membrane, MSP 987192) which
`is then coated with a 250 pm wet coating of the same
`adhesive mixture and dried as before. The adhesive
`layers are then laminated to the clear polyester film
`laminate backing material as described. The sheets are
`cut into 20 cm2 transdermal devices each containing 20
`10.5 mg oestradiol and individually packaged for use.
`EXAMPLE 3
`
`15
`
`Transdermal Device Containing Oestradiol Without A
`Rate Control Membrane
`
`A mixture is prepared containing the following:
`
`
`Component
`Quantity (g)
`1713 oestradiol
`440
`Diethyltoluamide
`2250
`Isopropanol
`60
`47000
`Primal N560
`
`250
`Acrysol ASE 602water (50:50)
`
`Total
`50 Kg
`
`25
`
`30
`
`35
`
`The devices are prepared and assembled as described
`in Example 1. The release liner is coated to a wet-coat
`thickness of 100 pm and after drying and laminating the
`laminate is die cut to 28.5 cm2 devices each containing 40
`2.5 mg oestradiol.
`
`EXAMPLE 4
`
`Transdermal Device Containing Oestradiol Without A
`Rate Control Membrane
`
`A mixture is prepared containing the following:
`
`
`Quantity (g)
`Component
`30
`17-13 Oestradiol (micronised)
`100
`Diethyltoluamide
`3
`Dioctylsodium sulphosuccinate
`2
`lsopropanol/water 50:50
`655
`Primal N560
`200
`Primal N582
`
`10
`q.s
`Acrysol ASE 60:water 50:50
`Total 1000 g
`
`
`
`45
`
`50
`
`55
`
`The devices are prepared and assembled as described
`in Example 1 except that the devices are cut to 20 cm2.
`Results obtained in a 4 subject pharmacokinetic study in
`comparison with an existing product (Estraderm 50) are
`shown in FIG. 4.
`
`Component
`Quantity (g)
`
`Buprenorphine
`42
`Ethanol or IMS
`100
`Diethyltoluamide
`150
`Diethylene‘Glycol Monoethyl ether
`150
`$3311;ng
`32:82
`500
`Pgal N582
`
`50
`Acrysol ASE 50mm, 5050
`5000 g
`
`Total
`
`The devices are prepared and assembled as described
`in Example 1 except that the release liner is coated to a
`wet coat thickness of 150 um and after drying the lami-
`nate is cut to 20 and 50 cm2 devices containing 2.5
`mg/20 cm2 or 6.3 mg/50 cm2 buprenorphine respec-
`tively.
`It is to be noted that the terms Hybar, Cryovac, Cel-
`gard, Mowiol, Contran, Primal, Acrysol, Brookfield,
`Triton and Estraderm, used in the specification are
`Registered Trade Marks.
`I claim:
`
`1. A method of preparing a device for transdermal
`delivery of an active ingredient which is a solid at room
`temperature and in which part or all of the active ingre-
`dient is present in a supersaturated solution comprising
`the steps of:
`(a) preparing a mixture comprising at least:
`(i) a polymer adhesive which is selected from the
`group consisting of acrylate polymer adhesives,
`polyisobutylene adhesives, and silicone adhe-
`s1ves;
`(ii) a vehicle for the polymer adhesive, which vehi-
`cle is selected from the group consisting of wa-
`ter, ethanol, industrial methylated spirits, isopro-
`panol, toluene, xylene, methylene chloride, and
`chlorofluorocarbon;
`(iii) the active ingredient;
`(iv) a solvent mixture for the active ingredient
`which comprises at least two solvents having
`different boiling points;
`(b) forming the mixture prepared in step (a) into a
`film, and
`(c) drying the film prepared in step (b),
`wherein the vehicle for the polymer adhesive and at
`least one of the solvents in the solvent mixture for
`the active ingredient have boiling points below the
`drying temperature, and at least one of the solvents
`in the solvent mixture for the active ingredient has
`a boiling point above the drying temperature, and
`wherein the solubility of the active ingredient in
`the said solvent or solvents having a boiling point
`above the drying temperature is greater than 10%.
`2. A method as claimed in claim 1 wherein the vehicle
`for the polymer adhesive is a solvent having a boiling
`point below that of ethanol.
`3. A method as claimed in claim 2 wherein the vehicle
`for the polymer adhesive is methanol.
`4. A method as claimed in claim 1 wherein the vehicle
`for the polymer adhesive is water.
`5. A method as claimed in claim 1 wherein the solvent
`
`EXAMPLE 5
`
`Transdermal Device Containing Buprenorphine
`Without A Rate Control Membrane
`
`A mixture is prepared containing the following:
`
`65
`
`in the solvent mixture for the active ingredient with a
`boiling point below the drying temperature is selected
`from the group consisting of ethanol, industrial methyl-
`ated spirits, isopropanol and water.
`6. A method as claimed in claim 2 wherein the solvent
`in the solvent mixture for the active ingredient with a
`
`

`

`5,352,457
`
`9
`boiling point below the drying temperature is a solvent
`having a boiling point below that of ethanol.
`‘ 7. A method as claimed in claim 6 wherein the solvent
`in the solvent mixture for the active ingredient with a
`boiling point below the drying temperature is methanol.
`8. A method as claimed in claim 1 wherein the solvent
`mixture for the active ingredient comprises at least one
`solvent having a boiling point above the drying temper-
`ature selected from the group consisting of diethylene
`glycol, propylene glycol, propylene carbonate, glyc-
`erol,
`lower molecular weight polyethylene glycols,
`propylene glycol esters, polyol fatty acid esters, fatty
`alcohol derivatives, oleic acid, iso-octyl stearate,
`iso-
`propyl myristate, isopropyl palmitate, ethyl oleate, di-
`isopropyl adipate, diethylsuccinate, hexylaurate,
`tri-
`glycerides of caprylic or capric acids, diethyl tolua—
`mide,
`laurocapram, n-methylpyrrolidone, diethylene
`glycol monoethyl ether and essential oils.
`9. A method as claimed in claim 1 wherein the drying
`step (c) is carried out at or above 100° C.
`10. A method as claimed in claim 1 wherein the dry-
`ing step (c) is carried out at a temperature below the
`boiling point of ethanol.
`11. A method as claimed in claim 1 wherein the active
`ingredient comprises at least one active agent selected
`from the categories antihistamines, steroid hormones,
`progestins, vasodilators, antihypertensives, bronchodi-
`lators, anti-tumor agents, alkaloids and analgesics.
`12. A method as claimed in claim 1 wherein the film
`prepared in step (b) is formed by coating the mixture
`prepared in step (a) onto a thin flexible sheet material.
`13. A method as claimed in claim 12 wherein the thin
`flexible sheet material is a siliconised release liner.
`14. A method as claimed in claim 12 wherein the
`flexible sheet material is a backing material imperme-
`able to the active ingredient.
`15. A method as claimed in claim 12 wherein the film
`
`formed in step (b) is between 5 pm and 500 pm thick.
`16. A method as claimed in claim 13 wherein the
`coated surface of the release liner is laminated to a back-
`ing material impermeable to the active ingredient.
`17. A method as claimed in claim 14 wherein the
`coated surface of the impermeable backing material is
`laminated to a siliconised release liner.
`18. A method as claimed in claim 13 wherein the
`coated surface of the release liner is laminated to a rate
`control membrane the free surface of which is further
`coated with the mixture prepared in step (a).
`
`10
`19. A method as claimed in claim 14 wherein the
`coated surface of the backing material is laminated to a
`rate control membrane, the free surface of which is
`further coated with the mixture prepared in step (a).
`20. A method as claimed in claim 18 wherein the
`coated rate control membrane is laminated to a further
`rate control membrane or to a backing material imper-
`meable to the active ingredient.
`21. A method as claimed in claim 18 wherein the
`coated rate control membrane is laminated to a further
`rate control membrane or to a siliconised release liner.
`22. A method as claimed in claim 18 wherein the
`thickness of the adhesive/active ingredient layer on
`either side of the rate control membrane is varied to
`control the rate of migration across the membrane.
`23. A method as claimed in claim 19 wherein the
`thickness of the adhesive/active ingredient layer on
`either side of the rate control membrane is varied to
`control the rate of migration across the membrane.
`24. A method as claimed in claim 18 wherein the
`thickness of the adhesive/active ingredient layer on
`either side of the rate control membrane is varied to
`control the proportion or amount of active ingredient
`immediately available adjacent to the skin for absorp-
`tion.
`25. A method as claimed in claim 19 wherein the
`thickness of the adhesive/active ingredient layer on
`either side of the rate control membrane is varied to
`control the proportion or amount of active ingredient
`immediately available adjacent to the skin for absorp-
`tion.
`26. A method as claimed in claim 14 wherein the
`backing material impermeable to the active ingredient is
`selected from the group consisting of a polyester film
`laminate, metalised polyester laminate co-exh'uded high
`barrier film and an air and water permeable polyure-
`thane.
`27. A method as claimed in claim 18 wherein the rate
`control membrane is selected from the group