AU1006899A - Transdermal drug delivery system - Google Patents

Description

I Peml~3 1 A USYRAL[A.

Pairent s Act, 19.90

ORIGINAL.

COMPLETE SPECIFICATION STANDARD PATENT *.invention Title: Transderweal drug delivery The fol .lowing statrament is atuil description of this Invention, Including the best method of perlorming it known to us: IKSDEMAL DRUG DEM IRY iYSE F eld o ,pr. This invention relates, to a tranaderical. drug -delivery system,' andwror -e paiticu-larly, to a drug delivery system, il. which .druag-gaue are encapsulated' within material which controls ,-he release over time of an active ingredient'.. in accordance with the invention, the active ingrediezzt. As released into a water retaining matrix.

-Backqround of the Invention3 Devices and meth ~s have been developed for the administration of pharmalceuticals at- desired. sustained levels by absorption through, the- skin. Transdeirtal delivery systems are available,-,or have beer. proposed,for many pharmaceutical- agents. -Typically5 devices used in such techniqjieS LeE ten referred to. as "patches") are attached to the skin of a patient,. usually adhesively.

The active agent is caused to diffuse from. the device through the skin for -absorption ifito the bloodstream.

Upon absorption into the bloodtreamt the agefit is carried, throughout the body of the patient.

-2- Nurnerouj techniques have been preposed to control the rate of release of pharmaceutical agents in transdermal delivery systems, For example,, in U.S.

Patents Nos. 4,314,557, and 4,460,472, systems are S disclosed which control the rate of release of an agent by the rate of which a drug solute phase dissolves in a polymer- matrir phase. In U.S. Patent No., 4,379,454,a drug and an absorption enhancer are said to be contained in a solid, semi-solid or gel matrix phase.

U.S. Patent No. 4,409,206 describes a transdermal -release system using a kin-compatible poiyacrylate," which swells with water and may contain a hydrophilic component to regulate the rate of release.

U. S. Patent go. 4,624,665 suggests sealing the skin with an occlusive layer, and transportn eie dosage of *An active agent across the layer from a rate controlling system.

U. S. .iatent No. 4,.645,502 discloses an 'ncapsulated pe ietion enhancer amand'-a dry, active agent Vithis an aqueous gelled reservoir.

PaetNo. 49083discloses an active -pharmaceutical dispersed in a polymeric material to form, by cross-linking, a matrix./ As an alternative, a solution of the active pharmacelatial. may be dispersed in the matrix prior to cros-s-_knkin5t in which case, the patent -says, umicro reservoirs": the drug are formed in the -3matrix. A suggestion is also made in thspatent of the; possibility Of incorporating a buffe-Ciflg agent into the;, matrix.

U.S. Patent S,149,5381 dis3cl~oses inclusionl, i:n a S tadral delivery system- for C-Pioids. of an encapsulated antagoniSt. as a control on -thertef delivery Of the opioid.

fthe drug delivery system of the present inventionl takes the form of an occlusive patch, which can be applied to a clean sectio~n of sk1 Th cluSiOn entraps sweat which. in turn serves to hydrate the skir, (specifically, the stratM11 2prnpUm), _thus fatcilitating drug penetration across the skin. The pntrapped sweat -can.

also saturate a matrix in which ,a specific drug is dispersed in microeflcapsulated form. The matrixC is formulated from gums and gelling agents,. so .that itabsorbs several times its own weight in moisture.

Drug release from the microcaj sules into the matrix depends on the relative ease withl which water. 'I froll *the entrapped sweat is able to penetrat-e he~ microcapsules',coat to dissolve drug in the ipner core.- This process can be closely controlled by selection of the coating material for the drug. or by manipulating the constituents- of the coating material.

2, For example,' the hydrophilic and hydrophobic elements of rua~ c OC--Y :i i.

rr.

trrr.-* -4the coating material can be designed to affect the water permeability of the coating. Dissolved drug then leaches into the matrix and is delivered through the skin to exert the desired effect.

The present invention also includes a visible indicator, for example, microencapsulated color change indicator, which can be designed, through its formulation, to effect a visible change at significant time points in the lifetime of the patch. Since the mechanism effecting the visible change has a commonality or interrelatedness to that responsible for the release of drug, the manufacture of the indicator can be tailored to represent the status of drug release from the microcapsules. For example, the release of sufficient drug quantity to exert 15 a therapeutic action can be associated with one visible change, and the near exhaustion of drug reserves from the microencapsulated core can be associated with a second visible change. This second feature, in particular, can serve as an indication to the user that a replacement 20 patch should be applied. At present, only drugs intended for a prolonged duration of action those requiring a sustained release profile) are administered via the transdermal route. This may be due, in part, to the inability to define precisely the quantity and extent of transdermal drug delivery in the short and intermediate terms. The use of indicators with transdermal drug delivery systems in accordance with the present invention, broadens the utility of drug delivery through the skin by allowing precise accurate indication and evaluation of the process of drug release, and thus the subsequent link to o- I r o r r p ~r .II- R1 the desired therapeutic activity.

therefore, facilitates exploitation of route, where drugs are to be administered for short or intermediate durations of controlled release.

This invention, the transdermal through the skin action, or in -r The above-mentioned visible indicator preferably comprises, for example, a layer of microencapsulated colored material visible through the backing of the patch.

The indicator may advantageously be designed as a system of multiple colored indicators, to represent the significant time points in the process of drug release from the microcapsules. For example, one indicator can be engineered to change color when a sufficient quantity of drug, determined to be necessary to initiate therapeutic 15 action, has been released from the micrctapsules. In a different embodiment, the indicator can be engineered to change color when the drug reserves in the microcapsules have been depleted, thus providing an easily interpreted visual, cue to the useful lifetime of the patch. The design of the indicator makes it a particularly suitable model for the process of drug release, since the mechanism responsible for the drug release over time can be engineered to be the same as the release rate responsible for the indicator's visible change.

At the present time, only drugs intended for a prolonged duration of action those requiring a sustained release profile) are administered via the transdermal route. This limitation may be due in part, to -a l~b3~C -iy I L the inability to precisely track and evaluate transdermal drug delivery in the short and intermediate terms. The design of the indicator in this invention provides the ability to define and signify the quantity and extent of drug release for short or intermediate durations of action, or in controlled release, therefore broadening the utility of transdermal therapeutic systems.

The present transdermal drug delivery system may be useful and advantageous in several settings: In a preferred embodiment, a system in accordance with this invention can be used to deliver drugs such as, for example, quinine derivatives or S pyrimethamine, in chemoprophylaxis against malaria.

Children, for example, may prefer transdermal tedication to the alternative of regular oral medication, and the effectiveness of transdermal medication is not compromised by the presence of concomitant illnesses and symptoms such as vomiting or diarrhea. Moreover, the present system can be engineered to release an antimalarial drug in a "zero 20 order" fashion so that a constant, stable blood concentration can be maintained, thus reducing the likelihood of "breakthrough" infection from fluctuations in blood antimalarial concentration. The useful lifetime of the patch can readily be assessed, since the color indicator will change as drug is exhausted.

In another preferred embodiment, the system of this invention can.be used to deliver analgesic drugs for example, in peri-operative and post-operative analgesia.

-V

-7- The medical literature has shown that the need for postoperative pain relief is diminished when analqezics are administered to patients in the pre- or peni-operative period. Analgesics (for example, members of the class of S non-steroidal anti-inflamumatory drugs, such as flurbiprofen) may be formulated into a transdermal patch for application immnediately prior to simple surgical or dental procedures- These patches will- be left on the patient for continuing pain relief after the procedure.

'0 Such an application reduces the need for parenterally or orally administered pain relief- -Furthermore, transdermal absorption of the analgesic agent will be unaffected by post operative vomriting, or by the absence of food in the gastrointestinal tract (for example, if the patient should have to undergo a preoperative fast). Further uses could I nclude long-term use for chronic and sub-chronic painful i nd inflammatory conditions.

In yet another preferred embodiment, the svyqten of this invention can be. used to deliver topical doses of lo-cal anesthetic agents prior to minbr surgical procedures or before the insertion of intravenous -cannulae. Local anesthesia in this manner may be of particular advantage where subcftsneous intradermal. injections are a relative contraindication (for example, where such 25 injections wil~l distort the srcueo neligt~u and lead to an irncrease in scarringl. In such a setting, patches can be applied by the patient, a relative or friend, or by a healt-h professional in advaznce of the procedure,. Multiple, color indicators can then be designed to Ichange with significant time laadmark's. For example, ore ndcator may be used to Signify when1 quantities of loCat aneastheti.c should have been to effect pain relief, and anothIer indicator_ may when rmost of the d ose has been delivered from the adecruate released sigonif~y patch In still another preferred embodim..ent, the system of this invention is jseful where constant levels of an antibiotic drugc are desirable to prevent or treat recurrent-or persistent infectioris; for example, for the delivery of anti-tuberculouS arugs where sustaine d therapy is indi cated. A pa c oaining a drug such as.

trimethoprim can, also be designe,!d to deliver effective *levels of the drug to prevent the, recurrence of urinary *tatinfections- This principle is also applicable for Protecting susceptible patients (for example, those with a history oft rheumatic heart-disease) from the risk of heart valve damage f rom r ~ogccus s f ollowing surgical or dental instrumentation- In this setting, a patch containing a suitable antibiotici drug will be applied ittrediately before the procedure, and, then maintained for an appropriate length of time afterwards, so that a constant level o XE the drug will be present during the period of risk- Spe cificr design, of the indicator to change color as the :drug -reserves are depleted should minimize the likelihood of sub-optimal drug delivery, and result. in successfua- eradication of the pathcrgeni~c microbes, or proyhylaxis therefrom.designed Pat ientsr in a nother em bodimentj* the system can be aareliable means of del:-veringq drugs tQ treat with central- nervous system- deficits. for exaplethe anit~.-psyhotic drugs or medicatmn- o ang A:-zheimer's disease. The application of a transdermfal therapeutic systen is easily supervised by a family member or a care provider who need not have' a healthcare background- The patch doe* not require the patient to remember special instructions or to undertake complicated procedures for therapy maintenance, and the color indicators will be useful as a means to assess patient compliance and to assure dose delivery. (For example, if -Q the patch is removed from the skin for any length of time, the indicator's color change would not be oboerved at the appointed time, and Should prompt further investiuation.) ~Brief Decrintion of the Dai~ There are shAown in the drawings Forms of the .,inventi ons which are presently, preferred, althou.gh it should be understood that the inventioft1 may be s.erbcdied in ,other specific. forms Without departing, from its essential attributes., Figure I is a schematic side elevation view, in cross-sec .tion 8 showing the structure of a drug delivery svstem, in accordance with the inv;ention.

Figure 2 is a graph depicting the rate of drug release versus time for a: patch designed for sl.ow and sustained release.

Figure 3 is a graph depicting the rate of drug release versus time for a patch designed for rapid drug release.

Figure 4 is a graph depicting the rate of drug release versus time for a patch designed for a combination release characteristic initially rapid, followed by a sustained release profile).

Referring now to the drawings in detail, there is seen in Figure 1 a transdermal patch, designated generally by the reference numeral 10. The patch comprises a translucent water-impermeable shell, or backing layer 12. The shell 12 provides a reservoir 14 for the other components of the system, described below.

In a presently preferred form of the invention, the shell 12 may be made of a plastic composite, formed by any suitable technique. Other suitable materials, generally of plastic polymeric composition, may be used for the shell 12, and will occur to those skilled in the art. The reservoir 14 may be said to have first and second faces 14a and 14b, the purpose of which is explained below.

A layer 16 of suitable pressure-sensitive adhesive material, of a conventional type, is disposed around a flange portion 18 of the shell, and enables the flange portion 18 to be secured to the skin of a user of the patch 10. It will be understood that when the patch is provided to a user, the adhesive layer 16 will 2- -a I -11ordinarily be covered by a disposable protective layer, not shown.

When attached to the skin of a user, the shell 12 provides the above-mentioned occlusive covering, which enhances the hydration of the skin area covered by the patch 10. Hydration of the skin area, as will be explained, fosters release and absorption of the drug associated with the patch Within the reservoir 14 is a matrix, designated generally by the reference numeral 20. The matrix 20 is formulated to absorb several times its own weight in water, and may comprise, for example, guar, acacia or xanthan gum, or a gelling agent or polymer such as carboxypolymethylene, hydroxyethylcellulose or 15 polyacrylamide. In the case of guar gum, for example, the matrix 20 can be made to absorb between five and ten times its own weight.

Within the matrix 20 in the illustrated form of the invention are microencapsulated particles of the drug, 20 The drug microcapsules 22 in the illustrated embodiment include a core or granule 24 of active ingredient or ingredients (drugs), microencapsulated within a coating material 26. The sensitivity of the coating material to the permeation of moisture is controlled by the choice of 25 coating material (for example, acrylate resins, or methylmetacrylic acid co-polymers), or by its formulation (for example, by incorporating different proportions of hydrophilic ethylcellulose derivatives and hydrophobic '4 fr '^i 'k

'I

-12methylcellulose derivatives). Coatings 26 are selected or designed to be more or less susceptible to moisture penetration and subsequent drug core dissolution, according to the desized drug release characteristics. It will be understood that the dissolution of the drug enables it to leach into the matrix 20 for delivery to, and subsequent passage through, the skin of the user.

It should now be apparent that judicious selection or manipulation of the microcapsule coating material 26 allows control of the rate of drug release from the core 24. A coating 26, that is relatively impervious to moisture, for example, one that is thicker or less permeable because of its physico-chemical properties, or one that contains a higher content of 15 hydrophobic elements in its composition, will result in a more gradual drug release over a sustained period.

Figure 2 depicts in graphical form a drug release profile for a patch designed for slow and sustained release. This type of release characteristic may be desired for maintaining stable concentrations of drugs for a prolongec' duration, for example, in the chemoprophylaxis of malaria.

In contrast, a coating 26 that is relatively permeable to S" water will rapidly release the drug over a short period.

Figure 3 depicts in graphical form a drug release profile 25 for a patch designed for such rapid release. This may be the goal where the patch is intended to deliver a local anesthetic drug, when a rapid onset, and a subsequent rapid discontinuation of the biological effect is desired.

A combination of both release characteristics may be useful in the appropriate setting, for example, in the

I

-13patch for delivering a drug to effect peri- and postoperative analgesia, since the goal here is a rapid onset, followed by a sustained maintenance of pain relief.

Figure 4 depicts in graphical form a drug release profile for a patch of this type. A combination of both the initially rapid release followed by a sustained release profile can be achieved by the incorporation of different "populations" of microcapsules into the patch 10. (For example, microcapsules with coating materials of variable composition and having a variety of water permeability characteristics may be included in the formulation to provide the desired release characteristics).

Also provided within the reservoir 14 adjacent to and operatively associated with the face 14b, and visible through the patch backing, is a microencapsulated color indicator designated generally by the reference numeral 28. This indicator may be designed to change color in response to the presence of water, electrolyte or other secretion, and may be manufactured from inorqanic salts that will change color with hydration (for example, anyhdrous copper sulfate or cobalt chloride).

Alternatively, colorful dyes (like amaranth or mercurochrome) can be microencapsulted to effect a color change when released. The utility of such an indicator is 25 that it exploits the common mechanism for activating both the indicator's color change and the process for drug release, namely, the ease with which water, electrolyte or other secretion penetrates the coating material of the microcapsules.

-14- Commonality or interrelatedness of mechanism enables the color indicator to be tailored to accurately reflect the status of drug release from the microcapsules, either by an appropriate choice of coating material or by manipulation of the components in. the coating. This feature is advantageous in instances where the timing of the onset, peak, and decline of therapeutic effect is an important consideration in the proper use of the drug.

For example, in designing a patch for the delivery of local anesthetic agent, a series of different color indicators can be fabricated to change color at time points corresponding to the time of onset of local anesthesia. the time of peak effect, and the time at which the anesthetic effect begins to wear off. The color 15 changes that will indicate these important "landmarks" in the lifetime of the patch will very closely reflect the true status the quantity and extent) of drug release from the drug microcapsules.

The commonality of mechanism as between the indicator and the drug release, also allows the color change to indicate that successful drug delivery has taken Splace. This feature will be useful in ensuring compliance to dosing instructions, since the color change will not be achieved without continued contact with the skin.

25 Observation, therefore, that a color change did not occur at the expected time can prompt further investigation.

patches in accordance with this invention will have at least one indicator, designed to change color when the drug reserves within the microcapaules are almost jI exhausted, This feature is intended to prompt the user to discard the old patch and to apply a replacement patch, where required.

The above-described patches 10 may be used in conjunction with preparatory skin cleanser, containing, for example, alcohol and a weakly buffered acidic or basic solution. The solvent would serve to remove surface grease to eliminate a barrier to absorption at the skin; and a buffered acidic or basic solution may be selected according to the physical or chemical properties of the particular dug to be administered and to maximize drug stability and enhance transdermal penetration.

This invention includes the description of a.

microencapsulated color change indicator that can be designed, through its formulation, to effect a visible change at significant time points in the lifetime of the patch. Since the dynamics of the mechanism effecting the color change are related to that responsible'for the release of drug, the manufacture of' th color indicator can be tailored to represent the status of drug release from the microcapsules. For example, the release f sufficient drug quantity to exert a therapeutic action can be associated with one color change indicator, and the near exhaustion of drug reserves from the 25 microencapsulated core can be associated with a second color change. This second feature, in particular, will serve as an indicator to the user that a replacement patch should be applied. At present, only drugs intended for a prolonged duration of action those requiring a -16sustained release profile) are administered via the transdermal route. This may be due, in part, to the inability to define precisely the quantity and extent of transdermal drug delivery in the short and intermediate terms. The use of indicators with transdermal therapeutic systems is a novel concept that should considerably broaden the utility of drug delivery through the skin, by allowing accurate indication of the process of drug release, and thus the subsequent link to the desired 10 therapeutic activity. This invention, therefore, facilitates exploitation of the transdermal route, where there is an intent of administering drugs through the skin for short or intermediate durations of action, or in controlled release.

The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. Accordingly, reference should be S made to the appended claims rather than the foregoing specification, as indicating the scope of the invention.

This is a divisional application, being divided from Australian patent application No. 13884195. The entire disclosure of the specification, claims and drawings, as filed in connection with Australian patent application No. 13884/95 is incorporated by reference into this specification.

Claims (11)

1. A drug delivery system for the delivery of a drug across the skin of a user comprising: a shell, said shell providing an occlusive covering on the skin of the user to enhance the hydration of the skin, said shell comprising a reservoir having a first face and a second face, said reservoir having therein a matrix adapted to absorb moisture from the skin and hydrate the skin, whereby the drug penetrates the 10 skin, said reservoir further having therein a plurality of microcapsules, said microcapsules being dispersed within said matrix and having contained therein an effective concentration of the drug; means on said first face of said reservoir for adhering said shell to the skin; and a visible indicator operatively associated with said second face of said reservoir, said indicator comprising a reagent formulated to visibly change in response to the presence of moisture, :electrolytes or other secretions in said matrix.

2. A delivery system in accordance with claim 1, wherein said indicator comprises a color indicator, said indicator having a plurality of microparticles permeable to moisture and having contained therein a chemical intermediate adapted to absorb the moisture in said matrix and to irreversibly change color in response to the moisture level in said matrix.

3. A delivery system in claim 2, wherein said microcapsules dispersed within said matrix. accordance with are uniformly -B I~ ii y a -18-

4. A delivery system in accordance with claim 2 wherein said drug containing-microcapsules are so constructed as to control the rate of release of said drug into said matrix.

5. A delivery system in accordance with claim 4, wherein said chemical intermediate containing- microcapsules are so constructed as to control the rate of absorption of said moisture. A delivery system in accordance with 10 claim 5, wherein said color change is visible to the user of said delivery system.

7. A delivery system in accordance with claim 6, wherein said color change is indicative of the release of said drug from said r.icrocapsules and the 15 depletion of said drug from said microcapsules.

8. A delivery system in accordance with S claim 7, wherein said color change is indicative of the S lifetime of said system.

9. A delivery system in accordance with claim 8, wherein said matrix is adapted to absorb moisture from the skin several times the weight of said matrix. 4, A -19- A delivery system in accordance claim 9, wherein said matrix is selected from the consisting of guar, acacia, xantham gums. wizh group ii. A delivery system in accordanlce with s claim 9; wherein said matrix is selected from the group Consisting of a Selling agent selected from the group consisting of carlboxypolymethylene, hydroxyethylcellulose and polyacrylamide-.

12. A delijvery system in claim 9. where,'if' scaid drug is .hemprophylaxis Ta lia. accordance with adapted for the

13. Adelivery systen in ;accordance with claim 9, wherein gaid drug; cowtprises an analgesic for use in peri-operative ind post-ope rative pain relief. 4 claim 9. delivery

14. A deli.Very system in -accordance with where.;, tsid tsystem i~s -adapted for the topical ~faneathetic aqents. A .delivery systei. in accordance with claimn 9 where in said drug comp rises an antibiotic agent. claim 9, treating -16. A delivery. systei in 1...accordance wherein. said drgcrrge edicatiQn central nervoug system, defi with for A dlivey sste in acacordance with claim 1, wherein said visib!4- ±.ndicator comprises a first indicator and at least a second indicator, said first indicator providing a first visible change indicative of a first event in relation to delivery of said drug, and said second indicator providing a second visible change indicative of a second event in relation to delivery of said drua. 1-30 18;' A delivery system in accordance with claim, 1, wherein said visible indi-cator comprises a first indicator and a. series o'f subsequent Lindicators, said first indicator providing" a first visible change indicative of a first event in relation to delivery of said drug, and- each subsequent indicator providing a visible change indic ative of a respective subsequent event in relation to delivery of said drug. Robert B Royds. John Lim and JolP[ D Ros'en by FrechilIls Patent Attorneys Registered Patent Attorneys for the -Applicants I11 J anuary 199