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Publication numberUS3814097 A
Publication typeGrant
Publication dateJun 4, 1974
Filing dateJan 24, 1973
Priority dateFeb 14, 1972
Also published asDE2305989A1
Publication numberUS 3814097 A, US 3814097A, US-A-3814097, US3814097 A, US3814097A
InventorsD Ganderton, Ainsh J Mc, G Varney
Original AssigneeIci Ltd
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Dressing
US 3814097 A
Abstract
A dressing for administering a drug through the skin of a host comprising a reservoir for the drug and, located between the reservoir and the skin of the host when the dressing is in use, a pad provided with tiny spikes. These tiny spikes augment the absorption of the drug without causing irritation.
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Description  (OCR text may contain errors)

United States Paten 1191 Ganderton et al.

1451 June 4, 1974' DRESSING Inventors: David Ganderton; James McAinsh;

Gordon Varney, all of Macclesfield, England Imperial Chemical Industries Limited, London, England Filed: Jan. 24, 1973 Appl. No.: 326,474

Assignee:

[30] Foreign Application Priority Data Feb. 14, 1972 Great Britain 006692/72 US. Cl 128/268, 128/2 W, 128/260,

I 128/253 Int. Cl. A6" 7/02 Field Search 128/2 W, 260, 268, 253,

References Cited 7 UNlTED STATES PATENTS 3/1962 Baron 128/214 F Kravitz et a1. 128/253 3,062,212 1 1/1962 3,072,122 1/1963 Rosenthul 128/253 R25,637 8/1964 Kravitz et al. 128/253 3,167,073 1/1965 Rosenthal 1. 128/253 3,416,530 12/1968 Ness 128/260 3,545,439 12/1970 Duncan... 128/260 3,565,075 2/1971 Jerry 128/268 3,595,231 7/1971 Pistor 128/253 Primary ExtzminerAldrich F. Medbery Attorney, Agent, or Firm-Cushman, Darby & Cushman ABSTRACT A dressing for administering a drug through the skin of a host comprising a reservoir for the drug and, located between the reservoir and the skin of the host when the dressing is in use. a pad provided with tiny spikes. These tiny spikes augment the absorption of the drug without causingirritution- 10 Claims, 2 Drawing Figures PATENTEDJUN 41914 III HHIIIIIIVIIIIIIILLLL IHIH'HHHHIHHII This invention relates to a dressing for application to the skin. In particular, it relatesto a dressing the primary use of which is not toprotect, or apply medication to, a wound or lesion, but in the administration of a pharmacologically active material to man or an animal.

It is well-known that pharmacologically active materials, including drugs and medicinal products, may be administered to man or animals by a variety of routes of which the most important are by mouth, by injection or topically. However, topical application does not usually result in the pharmacologically active material becoming distributed throughout the body'of the host, and not all pharmacologically active materials may be administered by mouth. Injection is an inconvenient method of administration, especially if it has to be done frequently, and there is a need for an alternative.

It is an object of the present invention to provide a dressing which, on application to the skin, will enable a pharmacologically active material to pass from a reservoir through the stratum corneum and be adsorbed sufficiently to become distributed throughout the body of the host. An essential component of this dressing is a pad or plaster, provided with minute spikes, which is located in contact with the skin.

According to the invention therefore there is provided a pad comprising a sheet of material provided with tiny fibres projecting from at least one face of the sheet, the fibres being sufficiently rigid and projecting sufficiently from one face of the sheet such that upon application of that face of the sheet to the skin of a host, the fibres penetrate the skin to permit a liquid formulation of a pharmacologically active material, when present, to pass into the host and become distributed throughout the body of the host.

The inventionthus provides the basis of a dressing which can be used as an alternative to injection for the administration of a pharmacologically active material.

The number of fibres projecting from a unit area of the sheet may vary widely, but in the preferred embodiments, a multitude of fibres are used. Thus, for example, while some patches may have as few as 4 fibres per cm others may have as many as, or more than, 100 fibres per cm depending upon the diameter of the fibres; it being necessary that the fibres be spaced apart sufficiently to penetrate the skin. Usually, the fibres will be made from material different from that of the sheet,-and in such a case, the fibres are necessarily located within the sheet as well as projecting from a face of the sheet. However, the fibres may be made of the same material as the sheet and simply project from the sheet. I

A wide variety of materials, especially plastics materials, are known which may be used to form the sheet.

Particularly useful such materials are, for example,

plasticised or unplasticised homopolymeric thermo plastics, for example polyvinylchloride, polyvinylbutyral, polyethylene, polyamides, for example nylon, or cellulosics such as cellulose acetate; plasticised or unplasticised copolymeric thermoplastics, for example ethylene vinyl acetate; cross-linked water soluble polymers, for example polyvinylacetate or polyvinylpyrrolidone; rubbers, both natural and synthetic, for example polyisobutylene or polybutadiene; or foams, for example polyurethane foam, polyester foam or cellulose foam. In this lattercase, the range of materials which may be used is very wide indeed, but care should be taken to choose a foam which is sufficiently rigid to support the fibres and yet sufficiently porous. Preferred plastics materials for the sheet are cellulose acetate or nylon.

The sheet mayalso be made of metal, for example stainless steel, which may either be provided with fibres in the form of fine stainless steel tubes or projections of metal left round the edges of holes punched in the metal sheet. Alternatively a former, for example a naturally spiky material such as a nettle or delphinium leaf may be coated with a metal to give a pad according to the invention, or-a pad prepared from other materials may be coated with metal to strengthen the fibres.

The fibres may be made of any material the surface of which is inert to body tissue and which is sufficiently strong when in the form of tiny fibres to penetrate the stratum corneum under the conditions in which the complete dressing is used. Particularly suitable such materials are, for example, inorganic materials, for example a glass, carbon, alumina, zirconia or silicon nitride; organic materials, for example nylon or polyparabenzamide; or metals, for example stainless steel. Alternatively, a bio-degradable material may be used. The type of material chosen for any particular use will depend upon the site at which the complete dressing is to be applied,the nature of the drug to be administered and any other features associated with that particular use of the complete dressing.

In a preferred use of the pad, a reservoir of pharmacologically active material is arranged'to dispense that material on to that surface of the pad remote from the projecting fibres. In this use, the pad must be permeable to a liquid formulation of a pharmacologically active material. This permeability may be achieved by using fibres in the form of tiny tubes, usually called capillary tubes, by using a sheet of material provided with a number of transverse holes, or by using an intrinsi of the desired liquid formulation. Any method of combination of methods of rendering the pad permeable may be used depending upon whether solid or hollow fibres are used and whether or not an intrinsically'permeable sheet is used, but the use of hollow fibres is considered to be desirable.

The precise diameter of the fibres is not critical provided that they can penetrate the stratum coneum, but it is preferred that the diameter be in the range 8 pm. to pm. unless the ends of thefibres are sharpened in which case, the diameter of the end of the fibre is preferably in the range 8 am. to 100 am. Thelength of fibre which projects from the sheet is, however, important since it must be longenough to penetrate the stratum corneum, but not be so long that serious irritation is caused. In this context, a penetration of at least 20 ,um. is desirable, and a penetration of 1,000 pm. is probably the maximum which can be tolerated, depending upon the site at which the pad is located. The fibres therefore should project from the sheet for a dis tance within the above range, and for preference; within the range 50-500 um. Clearly, the fibres should be aligned so that they project from that face of the 3 as an angle of approximately 45-90 to the face of the sheet. I

It is envisaged-that any liquid formulation of a pharmacologically active material may be used in conjunction with the pad of the invention provided that the formulation has a sufficiently low viscosity to pass through the pad by the means provided. Not only solutions, but suspensions and creams can be used with the appropriate pad. I

A pad according to the invention may be constructed by any suitable method. Thus for the construction of small pads, the fibres may be laid individually on a work base and cemented together using a solution of a plastics material as defined above to form a sheet con-v taining the fibres. Several such sheets may then be joined to form a block which on being sliced normal to the fibres, produces .a sheet containing transverse fibres. On washing the surface of such a sheet with solvent, the fibres can be exposed to any desired length. Alternatively the fibres may be drawn directly on to a drum coated with plastics material and while still on the drum coated with the sameplastics material to give a sheet similar to that produced by hand. Other techniques are the tack-spin process for producing a carpet-like pile of fibres, modified whereby a micro-mesh grid is usedto draw a plastics material in the molten state into a pad of fibres, orthe flock-spraying process for depositing whiskers of organic or inorganic material upon a plastics backing.

A pad according to the invention can be'used to assist the absorption of a topically applied formulation of a pharmacologically active material, for example a cream or gel, by being placed over the applied formulation. In this case, of course, the pad need not be permeable. However the principal use envisaged for a pad according to the invention is as part of a dressing for the administration of a pharmacologically active material to man or an animal.

According to a further feature of the invention there is provided a dressing for the administration of a pharmacologically active material to a host comprising a pad as previously defined in accordance with the invention in'which the pad is permeable to a liquid formulation of a pharmacologically active material, and a reservoir fora liquid formulation of a pharmacologically active material so located that the pharmacologically active material, when present, can pass from the reservoir and through the pad.

In order that this aspect of the invention may be clearly understood, two simple embodiments of a dressing according to the invention will now be described with reference to the accompanying drawings of which:

FIG. Iis'a diagrammatic representation of a vertical section of one embodiment I and I FIG. II is a diagrammatic representation of a vertical section of another embodiment. I Referring first to FIG. I, the dressing comprises a relatively rigid case I of metal or hard plastics material in the shape of an inverted shallow dish provided with a rim 2. Across the case 1, approximately in line with the rim 2, is a pad according to the invention in the form of a sheet of plastics material 3, provided with tiny fibres 4 projecting from the lower face of the sheet 3. As illustrated, the projection of the fibres 4 from the sheet 3 is much exaggerated in order'to render it visible. Particular pads which may be in the dressing are illustrated in theaccompanying Example 1-6, and in the event of such a pad not being permeable to a formulation of pharmacologically active material by virtue of the permeability of the sheet or the fibres being hollow, the pad is made permeable by being pierced in 5-10 places. If necessary, such intrinsic permeability is augmented by holes pierced through t h e pad. The space formed between the pad and the case 1 forms a reservoir 5, and .at the upper part of case 1 (the base of the inverted dish) is located a means for filling the reservoir in the form of ahole which is closed by a plug 6, made of relatively soft material, for example'neoprene, which is capable of re-sealing after a needle has been passed through and then withdrawn from the plug. Secured to the case 1 are straps 7 which extend from each side of the case 1. v

I In use, the dressing is secured upon the skin of the host to whom a phannacologically active material is to be administeredby means of the straps 7 so'that the fibres 4, projecting from the sheet 3 are held against the surface of the skin. A liquid formulation of the pharmacologically active materiaL'usually in the form of a solution, is filled into the reservoir 5 through the needle of a hypodermic syringe inserted through the plug 6.

When the reservoir 5 is filled,-the' needle is withdrawn and the plug re-seals. The dressing is .then left in place on the skin of the host until sufficient pharmacolog-' the skin of the host. I I

Referring now to FIG. II, the dressing illustrated is ically active material has been administered through similar to that of FIG. I in that it comprises a relatively I rigid case 1, and a pad, formed from a sheet of plastics material 3 with fibres 4, forming a reservoir 5 which can be filled with a liquid formulation of a pharmacologically active material via a plug 6 located in the side wall of the case 1. The dressing of FIG. II is however provided with means for applying pressure to the formulation of pharmacologically active material, when such is present in the reservoir 5, in the form of a chamher 8 in theupper part of the case 1, separated from the reservoir 5 by a flexible membrane'9, and capable of retaining gas under a pressure greater than atmospheric pressure. In the particular embodiment of FIG. II, the chamber 8 can contain granules of sodium bicarbonate, preferably coated with a polymer, so that on admitting an acidic solution to the chamber 8 via the needle of a hypodermic syringe inserted through the plug 10, carbon dioxide gas is slowly generated and a pressure is exerted on the-membrane 9. I

The embodiment of FIG. II is used in the same way as that of FIG. I, being secured to the host by straps 7.

Clearly the two embodiments illustrated represent.

only particular examples of dressings'according to the invention, and many variations of detail can be envisaged.

Thus the reservoir may be distinct from the pad, for example the walls of the reservoir may be separate from the case and/or the pad. The reservoir could be, for example, a sachet of plastics material permeable to the liquid formulation of the pharmacologically active material and located within the space formed by the case and the pad in the embodiments illustrated, or it could be formed from the case and a permeable .wall extending across the case along, the inside of the pad. Alternatively, it could be in the form of, for example,

a foam in which a solution of the pharmacologically active material can beretained by capillary action; a capsule which can be filled with pharmacologically active material to be pierced with a needle when it is desired to admit that material to the pad; or a piece of wadding which may be impregnated with the desired pharmacologically active'material. As yet a further alternative, the reservoir may be a gel which may be impregnated with pharmacologically active material as desired.

When the dressing is provided with pharmacologically active material and is in use, that material will diffuse from the reservoir to the pad, and the rate at which this takes place isdependent upon the nature of the reservoir wall and its thickness, both of which can be varied as desired. In the cases illustrated where the pad itself forms one wall of the reservoir, the rate of diffusion is dependent upon the pad and its fibres.

The dressing may also be provided with a layer of ma terial between the reservoir and the pad to act as a diffusion layer to control the rate of delivery of the pharmacologically-active material to the pad.

As illustrated in FIG. II, the dressing may also be provided with means whereby pressure is exerted on the formulation of pharmacologically active material toincrease the rate at. which it passes from the reservoir and/or through the pad. Alternatives to the specific means illustrated are, for example, a distendible reservoir which can be filled under pressure; a spring-loaded reservoir which exerts a mechanical or hydrostatic pressure on its contents; or a pressure bandage which is used both to retain the dressing in place and to exert pressure on the contents of the reservoir.

In addition, or as an alternative to, a pressure bandage, the dressing may be secured to the skin of a host by means of adhesive tape or an elasticated net, and such securing means may form part of the dressing itself. As part of the securing means of the dressing, in order to prevent undue leakage of the formulation of pharmacologically active material from the periphery of the area of skin to which the pad is pressed, the area surrounding the pad, for example the rim 2 in the embodiments illustrated or partof the straps 7, may bear an adhesive tosecure that area to the skin of the host.

As indicated above, the rate of diffusion of the liquid formulation of pharmacologically active material from the reservoir to the host is dependent upon the nature of the reservoir and the nature of the pad. Clearly, the total amount of material administered to the host is also dependent upon the surface area of the reservoir and pad. When an extremely potent drug is to be administered, a small surface area only is required, and the pad may have an area of only a few cm Forless potent materials, where administration of a larger amount of material is necessary, a greater surface area is needed and the dressing may be large enough," say to cover the whole of a patients forearm or a major part of the abdomen.

It will be clear that a dressing according to the present invention, as well as being capable of being used to administer pharmacologically active materials normally given by injection, can also be used to administer such materials continuously over an extended period. Such amethod of administration enables the variation in the concentration of a pharmacologically active material in the blood of a host, produced by administration of the material at intervals, to be reduced, and this advantage is not limited to materials which are normally administered by injection.

tides, for example polypeptide hormones and synthetic polypeptides possessing some at least of the pharmacological properties of the hormones, for example insulin,

oxytocin, bradykinin, gastrin, pentagastrin or urogastrone; or prostaglandins.

As a further feature of the invention there is provided a dressing as defined together with aliquid formulation of a pharmacologically active material. 7

Pads according to the invention are illustrated by the following Examples, and such pads may be tested for efficacy by comparing the transfer of a solution containing a pharmacologically active material through skin in the presence of the pad with the transfer effected in its absence. Both in vitro and in vivo methods may be used. The following is an example of such a test:

. A pad, prepared as described in Example 2, was applied to a clipped and shaved area on the back of a rabbit and secured in place by a rubber pad containing a 2 cm. diameter hole in register with the prepared area of the pad. One ml. of a solution of C radio labelled 3-t-butylaminol 5-propionamido-naphthl -yloxy )2- propanol, a B-adre'nergic blocking agent. in water containing 0.74 mg./ml. was applied to the pad uniformly over a period of 5 hours. Blood samples were taken at regular intervals from the ear of the rabbit and the amount of radioactive drug present measured using a scintillation counter. The experiment was repeated in the absence of the pad and again with the stratum corneum of the skin removed by a hand dermatome. The following results were obtained:

Peak blood concentration observed Application to:

Skin less than 2-3 ngJml. Pad prepared as in Ex. 2 l4 ngJml. Skin minus straum corneum 48 ng./ml.

These results show that the pad increased the absorption of the pharmacologically active'material through the stratum corneum from an extent giving a negligible peak blood concentration to nearly one third of that obtainable when the stratum corneum was absent.

EXAMPLE 1 Fibres, in the form of glass capillary tubes 40 pm. in external diameter and approximately 15 cm. long, were laid individuallyon a glass plate parallel to each other and about 0.5 mm. apart. The ends of the tubes were retained on two strips of double-sided adhesive tape located approximately 13 cm. apart. A solution in acetone of cellulose acetate containing acetyl triethyl citrate as plasticiser was brushed on to the aligned glass tubes and the solvent allowed to evaporate. The process was repeated until a film 0.5l mm. thick had been built up. Several such films were prepared and cut into squares approximately 2.5 cm. X 2.5 cm. The faces of these squares were then brushed with acetone and laid on top of each other with the tubes all pointing in the same direction. Pressure'was applied to the stack of film for several hours, causing the individual squares of film to adhere together to form a cube. This cube was then sliced with a microtomenormal to the axis of alignment of the tubes to produce small sheets of material about 1-2 mm. thick containing glass capillary tubes arranged at 1 mm. intervals across the thickness of the sheet. One face of a small sheet was then etched away by alternately brushing that surface with acetone and then with water until about 100p.m. of glass capillary tube was exposed projecting from the surface of the sheet.This condition usually took some 30-40 applications of acetone and water to achieve and the extent of projection of the tubes was checked by examination of the sheet under a microscope using oblique illumination. In order to avoid blockage of the capillary tubes, air was blown through the pad during the etching process, and this was conveniently achieved by clamping the pad over the surface of a fine ground glass funnel through which air was being blown.

The product was a square of cellulose actate sheet having a centre portion 2 cm. in diameter provided with tiny glass capillarytubes about 0.5 mm. apart extending through the sheet and projecting from one surface by about 100 um.

I g EXAMPLE 2 q The procedure described in Example 1 was repeated except that solid glass fibres'40 pm. in diameter were a. EXA B E:

A platinum crucible was filled with small spheres of E-glass and the whole heated to l,O C. to melt the glass. The crucible was then maintained at l,200 C. for about 2 hours after which the glass was ready tobe drawn into a fibre on a rotating drum. The drum was first coated with a layer of plastics material, usually cellulose acetate, by application of a solution of the plastics material in acetone to the surface of the drum and evaporation of the'acetone. A fibre of glass was then drawn from the tip of the crucible and wound on to the drum through a guide. The drum was rotated, and the guide'wasallowed to traverse the coated surface of the drum at a speed to give the required density of wound fibre, usually 1 fibre/mm. The fibre was then cut, and a coat of plastics material applied to the wound fibre using asolution in acetone. After the acetone had evaporated, the film of plastics material with the glass fibres aligned within it was stripped from the drum. The operation was repeated many times, and then all the sheets so obtained were then interleaved with sheets of the same. plastics material of the same thickness but not containing glass fibres. The sheets were treated with a small amount of acetone and/or methanol as solvent, and by applying pressure to the sheets, a block was built up in which the glass fibres were all aligned in the same direction and evenly spaced apart. The block was then sectioned transverse to the glass fibres to give small sheets of material about 1-2 mm. thick containing glass fibres at approximately 90 to the plane of the sheet and evenly spaced apart. One surface of the sheet was then etched away using a mixture of acetone and methanol, conveniently 60-70 percent v/v of acetone, to leave the glass fibresprojecting from the surface of the sheet. A particularly convenient technique for etching a numberof such sheets was to secure such sheets to the circumference of a wheel and, by rotation of the Plastics Solid or Diameter Projection of Material Hollow glass of fibre i ibrefrmn fibre plastics sheet Cellulose acetate solid pm. 5a 150 urn. containing acetyl V 140-340 1.1m. triethyl citrate 7 66-180 51 as plasticiser (L300 mp 100-300 pm.

I 80-240 ,tm. 120-340 [.Lf'll. 1 10 pin. ca. 150 um. hollow 40-60 [LIT], Ca. 150 um. nylon* solid 40 gm. 3 @400 m.

wheelQallow the sheets to rub against one or more brushes loaded with solvent.

In this technique, the diameter of the, drawn fibre could be varied by variation in the speed of rotation of the drawing drum. Thus typically, a drawing'speed of 0.5 metre/sec. produced a fibre of about 40 um. diameter, and a drawing speed of 3 metres/sec. produced a fibre of 15 pm. diameter. 0

Also, the extent of projection of the fibre from the surface of the sheet of plastics material could be varied by controlling the extent of the etching of the plastics material. In any particular pad, the fibres did not all project to the same extent, but nevertheless, a variation in average projection from about pm. to 250 ptm., with individual variation from 50 pm. to 400 um. could be achieved. r

In a variation of the above technique, a glass tube of approximately 1 mm. external diameter was drawn through a heater at 800 C. and wound on to a drum coated with plastics material asabove. By following the above general procedure, sheets of plastics material provided with tiny, projecting hollow glass fibres were produced.

By using the techniques described above. a considerable variety of pads'comprising a sheet of plastics material provided with a multitude of tiny glass fibres projecting from one face, thereof have been preparedjA representative selection of such pads is set out below:

* 1n the case of pads made with nylon as the plastics material. the sheets without glass fibres were obtained by compression moulding instead of by evaporation ofa solution. and the pads were etched with methanol.

. j The procedure described in Ex'amp1e l was repeated using hollow nylon fibres of 50 pan. external diameter or carbon fibres of 10 um. diameter to give pads of cellulose acetate provided with tiny hollow nylon or carbon fibres projecting to about 1.5 pun. from the-surface.

. v.1; EKAMBUQ... V. v

A sheet of EN 58B stainless steel. 26 am. in thickness was cut into discs about 1.5 cm. in diameter and 20 holes punched into each disc by means of a sewing needl mounted in the chuck of a bench drill which was lowereii filfoiifirotatiohIiii'tothe steel'disc to a controlled extent. The holes so produced were 78 pm. in diameter and a burr 104 pm. in length was left projecting from one side of the steel sheet. The net result was a pad, consisting of a sheet of steel provided with tiny fibre-like spikes projecting from one surface, and being permeable to liquid by virtue of the holes.

' EXAMPLE 6 the base, each 200 pm. in diameter. Fine steel tubes 200 pm. in external diameter, 100 pm. in internal diameter were sharpened at one end and then cemented into the holes leaving 150 pm. of sharpened tube projecting from the lower face of the base of the dish. The net result was a pad of stainless steel provided with fibre-like sharpened hollow steel tubes projecting from one surface.

What we claim is:

l. A pad for augmenting the absorption of a liquid formulation of a pharmacologically active material through the skin of a host comprising a sheet of material, a plurality of tiny hollow fibres passing through the sheet and projecting from at least one face of said sheet, said fibres having an external diameter at the end of the fibre in the range 8 pm. to 100 um. and projecting from said sheet from 20 pm. to 1,000 ;.m and a means on one side of said sheet material constituting a means for supplying said liquid material.

2. A pad according to claim 1 wherein the sheet is provided with a multitude of said tiny hollow fibres.

3. A pad according to claim 1 wherein the fibres are composed of glass.

4. A pad according to'claim 3 wherein the sheet is made from cellulose acetate.

5. A dressing for administering a liquid formulation of a pharmacologically active material to a host through the skin of said host, comprising a pad according to claim 1 said supply means comprising a reservoir for receiving a liquid formulation of the phannacologically active material located to permit said liquid formulation, when present, to pass from said reservoir and through said pad to the skin of said host.

6. A dressing according to claim 5 wherein the reservoir comprises a case with the pad forming one wall.

7. A dressing according to claim 5 which additionally includes pressure applying means for increasing the pressure in the reservoir.

8. A dressing according to claim 5 which additionally includes securing means for attaching the dressing to the skin of the host.

9. A dressing according to claim 5 wherein the reservoir contains a plug for the insertion of a means for supplying said liquid formulation of the pharmacologically active material.

10. A dressing according to claim 9 wherein the pharmacologically active material is a polypeptide.

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Classifications
U.S. Classification604/304, 600/556, 423/563
International ClassificationA61K9/70, A61F13/00, A61M37/00
Cooperative ClassificationA61M2037/0023, A61F13/00063, A61K9/0021, A61M2037/0007, A61F13/00068, A61F2013/0017, A61M37/0015
European ClassificationA61M37/00M, A61F13/00B6, A61F13/00B8, A61K9/00M5B