MXPA98000267A - Adhesive matrix activable by water containing ametoca - Google Patents

Adhesive matrix activable by water containing ametoca

Info

Publication number
MXPA98000267A
MXPA98000267A MXPA/A/1998/000267A MX9800267A MXPA98000267A MX PA98000267 A MXPA98000267 A MX PA98000267A MX 9800267 A MX9800267 A MX 9800267A MX PA98000267 A MXPA98000267 A MX PA98000267A
Authority
MX
Mexico
Prior art keywords
composition according
water
composition
arnetocaine
adhesive
Prior art date
Application number
MXPA/A/1998/000267A
Other languages
Spanish (es)
Other versions
MX9800267A (en
Inventor
Mccafferty Dermot
David Woolfson Aaron
Original Assignee
Smith & Nephew Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9513742.8A external-priority patent/GB9513742D0/en
Application filed by Smith & Nephew Plc filed Critical Smith & Nephew Plc
Publication of MX9800267A publication Critical patent/MX9800267A/en
Publication of MXPA98000267A publication Critical patent/MXPA98000267A/en

Links

Abstract

An amethocaine composition comprising amethocaine in the form of a free base and a water-activatable adhesive matrix, methods of its manufacture and methods of using it are described.

Description

I RTRIX RDHESIVfl RCTIVRBLE BY RGUR CONTAINING RIIETQCRINfi FIELD OF LR INVENTION This invention relates to pharmaceutical compositions useful for anesthetizing intact human skin. More particularly, it relates to film compositions containing arne + ocaine (2-dinethylaminoethyl-2-dinethylaminoethyl-arninobeneoate).
BACKGROUND OF THE INVENTION Topical compositions containing amethocaine are known in the art to provide effective local anesthesia of intact healthy skin. The local anesthetic must be presented to the surface of the skin substantially in its non-charged lipophilic form, so that it penetrates the lipophilic external barrier of the skin, the stratum corneum, to reach and desensitize the underlying receptors of pain within the structure. of the skin. British Patent No. 2,163,956 discloses aqueous gel compositions containing amethocaine in dispersion as its free base. Under these conditions, the melting point of the amethocaine base is reduced from about 41 ° C to about 30 ° C. Therefore, these compositions undergo a phase change, from solid to an oil liquid dispersion of the drug when applied to human skin, the temperature of which is typically 32 ° C. This phase change is an integral part of the mechanism of action of said compositions, as described in Uoolfson, R.D. and McCafferty, D.F. Percutaneous local anesthesia: Drug relay charactenstics of the amethocaine phase-change system. International Journal ot- Pharmaceutics, volume 94, pages 75-00 (1993). Arnetocaine gel compositions of this type produce sufficient local anesthesia of intact healthy skin to render it insensitive when exposed to needle penetration and other minor surgical surface procedures. These compositions have the following disadvantages with respect to ease of use and susceptibility to chemical degradation of the active ingredient: (1) Since the compositions described are aqueous gels, they need to be spread on the surface of the intact skin at the application site. . This creates a variable area of skin covered with each application. (2) The procedure of spreading the gel on the skin is inconvenient and dirty. (3) These gels are not readily adaptable for self-application, particularly when large areas are to be covered, for example, in the anesthesia of a skin area to be obtained for subsequent use in separate skin graft. (4) The gel compositions should be covered with a suitable separate bandage after applying said gel to the site of the skin. This results in an unpleasant area on the skin during treatment, with the risk of the gel dripping off the sides of the cover bandage and contacting clothes or other areas of the skin. International Patent Application No. PCT / GB92 / 00170, also discloses gel compositions containing arnetocaine and are suitable for percutaneous anesthetic use on intact healthy skin. It is claimed that these compositions have improved stability over those described in British Patent No. 2,163,956, through the provision of a salt component that reduces the solubility of the arnetocaine base in the aqueous gel vehicle, with a concomitant reduction in the alkaline hydrolysis rate of the solution component of the drug. The pH of the drug dispersion is also preferably maintained below 8, generating in situ the free base form of amethocaine from its salt, amethocaine hydrochloride. Patent No. 1,108,837 discloses a sheet-like material of a water-soluble film-forming composition or composition having a local anesthetic agent incorporated therein, more typically of the lidocaine type, but also incorporating the use of anesthetics. local ester type such as amethocaine. Said compound or film-forming composition retains the local anesthetic in solution within the matrix thus formed, or as an extremely phyloidal or colloidal dispersion.An aspect of this invention is that the local lamellar-like anesthetic composition is intended as a alternative for infiltration of the active local anesthetic ingredient by the use of an injection needle.There is no teaching that such compositions can anesthetize the intact skin by the percutaneous route.; The compositions of the invention are intended for application to mucosal epithelium or broken skin, where the barrier of the stratum corneum is not present. In a further aspect of the invention, it is described that said film-forming compound must be water-soluble and the release of the active agent depends on the initial dissolution of the sheet-like material. British Patent Application No. 9219079.2 discloses unit dose film compositions of amethocaine suitable for producing percutaneous anesthesia of intact human skin. The description encompasses a hydrophilic gel containing arnetocaine that dries to a film consistency. The film must be moistened completely and directly to activate the phase change of amethocaine. Suitable adhesives are known in the art to ensure non-adherent or low adhesion films to human skin. These adhesives are of the pressure sensitive type. Pressure sensitive adhesives can be produced conventionally by mixing an elastomer with a thickener resin, or alternatively using polymers that are inherently pressure sensitive such as polyacrylate and poly vimlester adhesives. A disadvantage of pressure sensitive adhesives is that the adhesion is lost or substantially reduced when the substrate and / or the medium is wetted. The loss of adhesion in these cases is due to the moisture absorbed by the adhesive and its nourishment. Consequently, the film detaches from the surface of the skin. Rdernas, the water acts effectively as a lubricant between the skin and the pressure-sensitive adhesive, preventing the development of full bond strength and leading to immediate or rapid failure of the joint. The properties of conventional pressure sensitive adhesives known in the art can be found in Satas, O (Editor): Handbook of Pressure Sensitive Technology and Technology, Van Nostrand Reinhold, New York, 1982. It will be apparent to the person skilled in the art, therefore, the percutaneous anesthetic compositions of arnetocama that require the presence of water to activate the change of solid-liquid fae, essential for the release of the drug, are essentially incompatible with the use of such pressure-sensitive adhesives for ensure the amethocaine compositions to healthy intact human skin. Water-activated adhesives have been known for some time. These so-called "wet-bonding" adhesives or bioadhesives have been used in the formulation of novel drug delivery systems. Many examples can be found in Park and others (1987), Bioadhesive Hidrogels, in: Peppas (ed) Hydrogels in Medicine and Pharrnacy, vol. III CRC press, Boca Raion, Florida, and also in LOuchene et al., Pharrnaceut cal and Biornedical flspects of Drug Systems for Drug Administration, Drug Development and Industrial Pharrnacy, Volume 14, pages 283-318 (1988). Bioadhesive films for drug release applications have been known in the art for some time. Such drug-laden films are designed primarily for application to the moist epithelium of the mucosa, rather than healthy skin intact. In such cases, the adhesion process includes interaction with a cover layer of rnucin. For adhesion to the skin, rhucine is not present and the adhesion process is substantially different. Conventionally, bioadhesives have the disadvantages of requiring activation with water, as compared to the pressure sensitive type. Thick, aesthetically unacceptable residues often remain when the compositions having acceptable adhesion to the skin are subsequently removed from the skin site. Such compositions tend to retard drug release by their high micro-viscosity. Bioadhesive compositions containing active medicaments, including local anesthetics for the prevention of skin pain, are described in International Patent Application PCT / US92 / 01730 for Mantelle. These compositions require the incorporation of a non-aqueous solvent for the medicaments, so that said medicaments are not so crystalline in nature, it is pointed out that for local anesthetics, it is preferable to include both their water-soluble salt as its water-soluble free base formulation in the compositions. This teaching is contrary to the known and unique mode of action of the arnetocaine phase change system for percutaneous local anesthesia as described in Uoolfson, ft.D. and McCafferty, D.F. , Percutaneous local anesthesia: Drug reléase characteristics of the amethocaine phase-change system, International Journal of Pharnaceutics, Volume 94, pages 75-80 (1993). It is a prerequisite of this system that any solvent other than water is excluded and that amethocaine is substantially present as a solid crystalline dispersion in an aqueous medium to facilitate the phase change from solid to liquid. Later, such "wet-sticking" or bioadhesive adhesives will be referred to as water-activatable adhesives. International Patent Application No. WO-R-8809169 discloses amethocaine compositions in a solid matrix, mainly films of synthetic hydrophilic plastic material that can be applied directly to the skin. However, the films do not possess any adhesive property. Japanese Patent Application No. JP-R-1272521 describes the incorporation, for example, of narcotic materials into adhesive layers, but does not disclose the use of either "wet-bonding" adhesives or physiologically activatable components with water. International Patent Application No. UO 92/16202 discloses a percutaneous anesthetic delivery system comprising a back layer that is comfortable to the skin, a material that carries the ainetocama and a layer that has no or little tendency to absorb the arnetocama, intermediate between the back layer and a layer of the arnetocaine-bearing material. The back layer may be a coating of adhesive so that it can adhere to the skin of a patient, but there is no mention of the use of "wet-sticking" adhesives. European Patent Application EP-P-0223524 describes the use of polycarboxylic acid and / or anhydride of polycarboxylic acid to produce a film-like adhesive material which can have a drug dispersed therein. There is no mention of the use of arnetocama or the use of "wet-stick" adhesives. Conventional prior art amethocaine formulations may also have the disadvantage that they can not be presented as a unit dose composition, in such a way that an identical amount of the active ingredient is applied in each application. It is known in the art that unit dose compositions offer benefits with respect to patient compliance and patient safety. Therefore, a novel aspect of the present invention is to provide an amethocaine composition in which the arnetocaine is substantially in a crystalline free base form and is dispersed in a water-activatable adhesive matrix. The compositions of the invention are usually not self-adhesive before activating the water-activatable adhesive matrix with water. These compositions are generally in the form of a substantially dry film or a substantially dry film-like shape. Substantially, the term is understood to be sufficiently dry, so that the phase change of arnetocama in the presence of water does not occur. The compositions of the invention generally adhere directly to healthy intact moist human skin and are capable of producing effective percutaneous anesthesia of the treated site. The water-activatable adhesive matrix is preferably not soluble in water. In use, either the patient's skin or the arnetocama composition of the invention alone (or both) can be oyed prior to application of the composition. A further aspect of the present invention is that said amethocaine compositions can be activated before being used with the presence of water on the skin, said activation simultaneously generating the phase change of arnetocaine, an essential prerequisite for drug release and effective clinical performance consistent, and sufficient adhesion in the film composition so that it can be adhered securely to the required site of intact healthy skin.
Alternatively, the composition alone can be moistened before it is applied to the skin. A further aspect of the present invention is that said arnetocame compositions contain at least one film activatable water activatable adhesive polymer. Said water-activatable adhesive polymers should be present in a lower concentration than at which they would retard the release of drug from the water-activated composition, one or more adhesive polymer components substantially not activatable by water. The purpose of the substantially non-water activatable adhesive polymer component is to improve the integrity of the film without affecting release or adhesion of the drug, to allow the location of the water-activatable adhesive layer during a coating manufacturing process and to assist complete the wetting of the arnetocaine composition in use, simultaneously activating the adhesion and drug release mechanisms. Said compositions of arnetocaine may remain securely in place at the site of the skin by means of its water-activated adhesion, but are capable of being easily removed from the skin by a peeling movement, said removal causing a minimum washable residue. with water and aesthetically acceptable on the site. A further aspect of the present invention is that said amethocaine compositions are provided with a water-impermeable backsheet. The water-impermeable back layer in conjunction with the arnetocame composition forms an integrated anesthetic patch percutaneous release system. The purpose of said back layer is, among other things, when in use, to isolate the amethocaine composition activated with water from the medium during clinical use and to prevent the arnetocaine composition from drying out. Said back layer must therefore be impermeable to the penetration of arnetocama to ensure that, during storage, the effective amount of arnetocame dispersed in the water-activatable adhesive matrix is not reduced by gradual migration of arnetocaine to the back layer. A further aspect of the present invention is that said back layer may be laminated with the amethocaine composition. For example, the dorsal layer and the amethocaine composition can be laminated by means of an intermediate transfer adhesive. The intermediate transfer adhesive can be a pressure sensitive adhesive. Said transfer adhesive is not exposed to the skin, but forms an integral part of the overall structure of the patch. A further aspect of the present invention is that said integrated percutaneous anesthetic patch compositions are highly flexible and are substantially thin or ultrathin, which can easily conform to irregular skin surfaces. Also, the patch can be produced in sheets of various shapes and sizes and cut before being used for areas, for example, around the eye or ear. It will be apparent to the person skilled in the art that the invention encompasses a scale of water-activatable adhesive polymers whose properties conform to the specific requirements of the invention, together with a scale of substantially non-water-activatable adhesive polymers whose properties - they also conform to the requirements of the invention. It will also be apparent that the invention also encompasses the use of film modifying components known in the art, such as pharmaceutically acceptable plastifiers. A particularly preferred water-activatable adhesive polymer of the invention is an initial copolymer of rnaleic anhydride and rnetii-vinyl ether, commercially available in a range of types under the tradename Gantrez (Trade Mark) from Gaf Corporation. The components of the substantial adhesive polymer which can not be activated by water, which are particularly preferred in the invention, are sodium hydroxyethylcellulose or carboxymethylcellulose., for example, interlaced sodium carboxymethyl cellulose. A particularly preferred pharmaceutically acceptable plasticizer is glycepne. Therefore, according to the invention, an amethocaine composition is provided in which the arnetocaine is in a crystalline free base form and is dispersed in a matrix comprising a copolymer of rnaleic anhydride and ethyl vinyl ether, eh droxietij cellulose. The composition according to the invention can contain between 1 and 5% w / w, and preferably between 0.5 and 2.5% w / w of substantially water-activatable adhesive polymer component. The compositions may also contain between L and 5% w / w, and preferably between 1.5 and 2.5% w / w of the non-water activatable adhesive polymer component.
Additionally, the compositions may optionally contain between 0.5 and 2%? / P of a pharmaceutically acceptable plasticizer. The compositions may also contain between 0.5% and 5% w / w, but preferably between 1 and 2.5% w / w of the amethocaine base. It will be apparent to the person skilled in the art that the pH of the final film-like composition should be such that there is sufficient arnetocame present in the free base form to allow effective penetration of the skin barrier structure. In accordance with another feature of the invention, there is provided a method of manufacturing an arnetocaine composition as described below, comprising: adjusting the pH of an aqueous dispersion of a water-activatable adhesive polymer to pH greater than 7; add arnetocaine-free base to the dispersion regulated in its pH; and dry the amethocaine composition. The use of amethocaine, for example, arnetocaine free base, is also provided in the manufacture of an arnetocaine composition as described above. A method of percutaneous anesthesia comprising wetting an amethocaine composition or patch system as described above and subsequently adhering the composition or patch to a patient's skin is also envisaged. Alternatively, the percutaneous anesthesia method may comprise first moistening a patient's skin and subsequently adhering the arnetocaine composition or patch, as described above, to the moistened region of the patient's skin. It will be understood that the aforementioned components of the invention are described solely by way of illustration of the invention and are in no way intended to limit its scope. The embodiment of the invention will be illustrated below with reference to Figure 1, which is a cross-sectional view of a patch according to the invention. With reference to Figure 1, a patch (2) comprises a release liner (1) coated with a dry film of amethocaine gel (3) as described above. The dry film (3) is covered with a back layer (5) of a metallized thin sheet strip; this back layer is optionally provided with a pharmaceutical grade transfer adhesive (4) on the dry film side (3) of the < the back (5). The backing layer (5) extends beyond the edge (?) Of the dry film (3) to provide a peeling surface (6).
EXAMPLE 1 Step! •: Preparation of the Gel Gantre copolymer was added;? (Registered Trade Mark) RN-139 to a sufficient quantity of pre-charged water (95-99 ° C) to produce a final polymer concentration of 2% w / w. The water was stirred at a sufficient velocity to produce a fast swirling vortex and the copolymer was slowly sifted in the vortex, so that the powder became wet and dispersed.
The temperature was maintained using a water bath or other suitable heating mechanism. The suspension, maintained at 95-99 ° C, was stirred at high speed until complete dissolution was achieved, indicated by a decrease in viscosity and a change in appearance from milky to transparent white. Any water loss was replaced by evaporation at room temperature with gentle agitation. The resulting solution Gantrez (Trade Mark) had a pH of about 1.5. The previous reaction took approximately 20 minutes until completion. The solution was allowed to cool to room temperature and the pH was then adjusted to pH9 with 30% sodium hydroxide (3.1 ml in 100 g of solution), added slowly and dropwise with continuous stirring. The solution was stirred rapidly while hydroxyethyl elulose (Natrosol (Registered Trade Mark) 250 HHX-Pharrn from Aqualon) was added slowly enough to achieve complete dissolution to produce a final concentration of 1.5% w / w. Then glycerin was added in sufficient quantity to produce a final concentration of 1% w / w. Then it was added to the base solution of ainetocaine (enough to produce a final concentration of 1% w / w) and, by gently heating the reaction vessel, it was allowed to melt in the solution. Once the amethocaine base was completely dissolved, the solution was completely stirred and then allowed to cool to room temperature to produce a pourable amethocaine gel.
Step 2: Film Formation A mold was constructed, which consisted of a glass plate on which a releasing release liner surface was placed upward. An example of a suitable release liner is a commercially available nonwoven fluorinated polyester from 3M Company as Type 9747. This was lightly moistened with water to help adhere the liner to the glass plate. An area was surrounded (for example, 2 cm by 4 cm (ie, to produce 4 patches, each of 4 crn by 3 c)) with a plastic template 3 mrn thick. This template is stuck to the glass plate. The gel from step 1 (10g) was then emptied into the center of the mold, spread evenly and placed under vacuum to remove air-bubbles. The de-aerated gel was allowed to dry in the air under ambient conditions or, alternatively, in a mobile air stream at 60 ° C in a drying tunnel. As an alternative to this process, the gel can be cut directly or roller coated onto the release liner before drying. It will be apparent to the person skilled in the art that film formation can be achieved thus by applying a procedure whether continuous or intermittent. The film layer produced has sufficient integrity to be peeled off from the release liner and rolled up again if required. The thickness of this layer was between 30 and 300 μm, but most preferably between 50 and 100 μm. The film was analyzed: Gantrez (Trade Mark) 37% p / p Natrosol (Trade Mark) 27% P / p Glycerin 18% P / p flmetocaine 18% P / p Step 3: Patch Construction The dry atocaine film from step 1 was attached to a suitable transfer adhesive such as the available commercially available sheet acrylic material from the 3M Company sheet as a Co-Tran 9871 Pharmaceutical Grade Transfer Adhesive. Alternatively, the transfer adhesive can be cut or roller coated on the backing layer or on one side of the same film. Once the remaining release layer of the transfer adhesive was united, it was removed and attached to a back layer of metallized sheet. An example of a suitable backing layer is a thin sheet of metallized non-woven polyester, available commercially from 3M Cornpany as Scotchpak Type 1109. An uncoated strip suitable for the back layer can be left as a peeling strip, typically 5 rnm of amplitude. The patch can be cut to any suitable size, depending on the intended clinical application, and can be packaged individually in a thin heat-sealable sheet with an internal liner impenetrable by the drug.
EXAMPLE 2 The percutaneous anesthetic efficiency of an example of an integrated water-activated atocaine patch system prepared according to Example 1 was analyzed according to the pricking method described in Uoolfson, R.D.
McCafferty, D.F., McClelland, K.H. a Boston, V. Concentration-response analysis of percutaneous local anaesthetic forrnulations, Bptish Journal of Anaesthesis, volume 61, pages 589-592 (1988). Eighteen adult volunteers aged between 19 and 33 years old applied the patch to an area of intact healthy skin on the forearm, or near the anterior ulnar fossa-which had previously been moistened. The patch was applied for 30 minutes in each case, after which it was removed, the treated area was delineated and evaluated for anesthesia. All the volunteers reported full anesthesia because of a puncture exposure with a time of occurrence of 44 minutes and a standard deviation of 6.7 minutes.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS
1. An arnetocaine composition in which the arnetocaine is substantially in a crystalline free base form and is dispersed in a water-activatable adhesive matrix.
2. An anechocham composition according to claim 1, characterized in that the water-activatable adhesive matrix comprises at least one adhesive film-forming adhesive.
3. An arnetocaine composition according to claim 2, characterized in that the adhesive polymer is at a concentration lower than that which would retard the release of the drug from a composition activated with water.
4. An arnetocama composition according to claim 2, characterized in that the film-forming polymer also comprises one or more adhesive polymer components substantially not activatable by water.
5. An amethocaine composition according to claim 1, provided with a water impermeable back layer.
6. An amethocaine composition according to claim 5, characterized in that the water-permeable backsheet is laminated with the composition of? 1 arnetocaí na
7. An arnetocaine composition according to claim 6, characterized in that the amethocaine composition and the back layer are laminated by means of an intermediate transfer adhesive.
8. An arnetocaine composition according to claim 7, characterized in that the intermediate transfer adhesive is a pressure sensitive adhesive.
9. An arnetocama composition according to claim 2, characterized in that the film-forming adhesive polymer is a copolymer of maleic anhydride and rilethyl-vinyl ether.
10. An etocaine composition according to claim 4, characterized in that the non-water activatable polymer components are selected from hydroxyethylurea and sodium carboxymethylene cellulose.
11. An arnetocama composition according to claim 1, characterized in that it comprises a plasticizer.
12. An amethocaine composition according to claim 11, characterized in that the plasticizer is glycerin.
13. An amethocaine composition according to claim 1, characterized in that the content of arnetocaine base is 0.5% to 5% w / w. A method of preparing an ainetocaine composition according to claim 1, comprising: adjusting the pH of an aqueous dispersion of a water-activatable adhesive polymer to a pH greater than 7; agr-egar-base Free of arnetocaine to the dispersion regulated in its pH; and dry the amethocham composition. 15. An amethocaine composition according to any of the preceding claims, characterized in that the water-activatable adhesive matrix comprises a copolymer of naleic anhydride and methyl vinyl ether, and hydroxyethylcellulose. 16. A method of percutaneous anesthesia comprising moistening a composition in accordance with the claim 1, and subsequently adhering the composition to a patient's skin or alternatively moistening a patient's skin and applying the composition to the moistened region. 17. The use of arnetocaine in the manufacture of an arnetocaine composition according to claim 1.
MXPA/A/1998/000267A 1995-07-06 1998-01-07 Adhesive matrix activable by water containing ametoca MXPA98000267A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9513742.8 1995-07-06
GBGB9513742.8A GB9513742D0 (en) 1995-07-06 1995-07-06 Compositions

Publications (2)

Publication Number Publication Date
MX9800267A MX9800267A (en) 1998-09-30
MXPA98000267A true MXPA98000267A (en) 1998-11-16

Family

ID=

Similar Documents

Publication Publication Date Title
JP2701951B2 (en) Printed skin permeable drug delivery device
AU746339B2 (en) Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces
US7579019B2 (en) Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces
US5147339A (en) Dressing material for the treatment of wounds, and corpuscles for use in the production thereof
US20050048102A1 (en) Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces
IE52931B1 (en) Bandage for administering beneficial drug
WO2006090782A1 (en) Composition for hydrous adhesive patch for external use and adhesive patch comprising the composition
JP2950613B2 (en) Bioadhesive composition and plaster
JPH0667835B2 (en) Pharmaceutical composition
JP2001506637A (en) Extremely flexible patch having skin action or transdermal action and method for producing the same
EP0874623B1 (en) Water activatable adhesive matrix containing amethocaine
JPH07106978B2 (en) Complex patch preparation
JP3525391B2 (en) Surface stabilized preparations for skin application
MXPA98000267A (en) Adhesive matrix activable by water containing ametoca
KR20050086633A (en) Moisture-activated adhesives for medical applications
JP3496169B2 (en) Plaster and production method thereof
AU744913B2 (en) Water activable adhesive matrix containing amethocaine
JPH09268123A (en) Cataplasm for local anesthesia
JPH07215847A (en) Tape for sleepiness prevention
JP3308628B2 (en) Medical patch
JPH0436133B2 (en)
AU769500B2 (en) Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces
JPH10316825A (en) Adhesive composition
JPH06183956A (en) Stable pharmaceutical preparation for application
JPH0710769B2 (en) Oral formulation