Percutaneous absorption type preparation and process for preparing the same
This is a continuation of application Ser. No. 07/336,149 filed Apr. 11, 1989 now abandoned. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a percutaneous absorption type preparation and a process for preparing the same. More particularly, the present invention relates to a percutaneous absorption type preparation comprising an adhesive layer which comprises a pressure-sensitive adhesive and a percutaneous absorption type drug present in the adhesive layer in an amount greater than the saturated solubility in the adhesive, the drug being held in the adhesive layer in a homogeneous and stable state, and a process for preparing the preparation. 
     BACKGROUND OF THE INVENTION 
     It is already known to administer a percutaneous absorption type drug through the skin by, for example, adhering to the skin or mucosa a polymer containing a percutaneous absorption type drug, and many methods thereof have been proposed in various patents, literatures, etc. The typical method comprises forming on a suitable backing an adhesive layer comprising a polymer which comprises a rubber or acrylic resin based pressure-sensitive adhesive admixed with a percutaneous absorption type drug. 
     The actual concentrations of the percutaneous absorption type drugs present in the adhesives have been equal to or less than the saturated solubility thereof in the pressure-sensitive adhesives. The reason for this is that even if the drug in excess of the saturated solubility is simply incorporated in the adhesive, large-sized crystal particles thereof are formed and remain in the adhesive layer without being absorbed through the skin. 
     On the other hand, a method has been proposed to absorb a drug through the skin without loss by adding a percutaneous absorption type drug to a pressure-sensitive adhesive in an amount greater than the saturated solubility as disclosed in, for example, U.S. Pat. No. 4,719,226. 
     According to this method, the amount of drug in excess of the solubility is dispersed in the adhesive layer as recrystallized fine particles, thereby allowing the drug to be absorbed through the skin without loss for a predetermined period of time. 
     Besides, it is known that the adhesive strength of the pressure-sensitive adhesive to the skin decreases with the lapse of time in addition to external factors. Therefore, if a pressure-sensitive adhesive having a low viscosity is used, the desired adhesion effect to the skin can be obtained, but there is the disadvantage that part of the adhesive remains on the skin (hereinafter referred to as &#34;adhesive remaining problem&#34;). On the other hand, if a pressure-sensitive adhesive having a high viscosity is used, the adhesive does not remain on the skin, but in some cases, the desired adhesion effect to the skin is obtained only for a short period of time. 
     Under the above circumstance, if the drug in excess amount above the saturated solubility in a pressure-sensitive adhesive is dispersed in the adhesive in the form of recrystallized fine particles, in the event that the pressure-sensitive adhesive has a high visocisity, there are the same disadvantages as described above and the edge peeling of a preparation occurs; and in the event that the adhesive has a low viscosity, since the excess amount of the percutaneous absorption type drug is dispersed in the form of recrystallized fine particles, the drug does not exhibit the function as fillers and the adhesive remaining problem still occurs. 
     SUMMARY OF THE INVENTION 
     Accordingly, one object of the present invention is to provide a percutaneous absorption type preparation, wherein even if the viscosity of a pressure-sensitive adhesive is a low viscosity, by making a percutaneous absorption type drug in an amount greater than its solubility present in the adhesive in the specific form, the drug exhibits a function as fillers, thereby causing no adhesive remaining problem, at the initial stage, and with the lapse of time, the adhesive properties are maintained together with dissolution of the recrystallized drug and the preparation does not peel off. 
     Another object of the present invention is to provide a process for preparing the preparation. 
     The percutaneous absorption type preparation according to the present invention comprises 
     a backing which is substantially impermeable to a percutaneous absorption type drug, and 
     an adhesive layer provided on the surface of the backing, which comprises a pressure-sensitive adhesive and a percutaneous absorption type drug (which is solid at room temperature), wherein the drug is present in the adhesive in an amount greater than its saturated solubility in the adhesive and the drug is present in the adhesive in the form of a continuous recrystallized state and also a substantially network state. 
     The process for preparing a percutaneous absorption type preparation according to the present invention comprises 
     providing an adhesive layer comprising a pressure-sensitive adhesive containing therein a percutaneous absorption type drug (which is solid at room temperature) in an amount greater than its saturated solubility in the adhesive, on a surface of a backing which is substantially impermeable to the drug, and if desired, simultaneously adhering temporarily a release covering material on the adhesive layer, and 
     applying a stimulation to the adhesive before the excess amount of the drug larger than the saturated solubility in the adhesive is recrystallized, to induce and accelerate the recrystallization of the drug, thereby making the drug present in a continuous crystallized state and also a substantially network state. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The percutaneous absorption type preparation according to the present invention is such that the excess portion of the drug larger than its saturated solubility is continuously recrystallized in a substantially radial state, the continuously recrystallized drug is, although having a directionality as a whole, overlapped in the adhesive layer and shows substantially a network state when observed from the surface, and as a result, the recrystallized drug exhibits a function as fillers to prevent the adhesive remaining on the skin. 
     The state of recrystallized particles of the drug present in the adhesive described above is hereinbefore and hereinafter expressed as &#34;the excess amount of the drug greater than the saturated solubility is present in the adhesive in a continuous crystallized state and also a substantially network state&#34; or the similar phrases. 
     Examples of the backing which can be used include plastic films, composite films or sheets made of synthetic resins such as polyolefin, polyurethane, polyacrylate, polyester, polyvinylchloride, polyvinylidene chloride, polyamide, ethylene-based copolymer and vinyl chloride-vinyl acetate copolymer, porous (micro porous) films or sheets made of rubber and/or synthetic resins, fibrous film or sheets such as nonwoven fabrics, fabrics and paper, metallic foils, and the above films or sheets with metal deposited on the surface thereof. The backing provides a self-supporting property to the percutaneous absorption type preparation and functions to prevent the drug from migrating from the adhesive layer formed on one surface of the backing. 
     The thickness of the backing film is not particularly limited, and can be determined by taking into account a handling property, a feeling to the skin, etc. The thickness thereof is, however, generally in the range of from 5 to 300 μm. 
     The pressure-sensitive adhesive is a polymer (homopolymer or copolymer) having a good pressure-sensitive adhesive property composed only or mainly (at least about 50 wt %) of a rubber and/or synthetic resin which can maintain a percutaneous absorption type drug in an amount greater than the saturated solubility thereof in a continuous recrystallized state and continuously supply the drug to the surface of the skin. The apparent viscosity at room temperature (e.g., 15°-25° C.) of the polymer is 5×10 6  poise or less, preferably from 5×10 3  to 1×10 6  poise. 
     If the apparent viscosity at room temperature is more than 5×10 6  poise, the polymer is so hard that the adhesion to the skin becomes insufficient, and in some cases, the excess drug greater than the saturated solubility does not instantaneously form a continuously recrystallized state in preparing the pharmaceutical preparation. On the other hand, if the apparent viscosity is less than 5×10 3  poise, an adhesive may remain on the skin surface after peeling off the pharmaceutical preparation from the skin. 
     Pressure-sensitive adhesives having apparent viscosity at room temperature of 5×10 6  poise or less are obtained from rubbers such as a styrene-isoprene-styrene block copolymer rubber, a styrene-butadiene rubber, a polybutene rubber, a polyisopropylene rubber, a butyl rubber a silicone rubber, a natural rubber, a synthetic isoprene rubber and the like, and/or from synthetic resins such as poly(meth)acrylate, polyvinyl ether, polyurethane, polyester, polyamide, and ethylene-based copolymers. If desired and necessary, the polymer may contain additives such as a tackifying resin, a liquid rubber, and a softening agent, for example, to control the apparent viscosity of the adhesive at room temperature. 
     The polymers for the adhesives which are preferably used in the practice of the present invention are acrylate copolymers containing at least 50% by weight of acrylic or methacrylic acid alkyl esters where the average number of carbon atoms in the alkyl group is at least 4. The drug is highly soluble in these copolymers, and the copolymers do not irritate the skin or mucosa and maintain the drug in a stable manner. 
     The above acrylate copolymers include copolymers comprising the acrylic or methacrylic acid ester and functional monomers and/or vinyl ester monomers copolymerizable with the ester. The proportion of the functional monomer can range from 0 to about 20% by weight, preferably from 0.5 to 10% by weight, and the proportion of the vinyl ester monomer can range from 0 to about 40% by weight, preferably from 5 to 30% by weight. 
     The above functional monomers can be used to change the coagulation properties of the resulting copolymer depending on the amount of the functional monomer employed and also can be used to change the hydrophilic properties of the resulting copolymer depending on the type thereof. The above vinyl ester monomers can be used to increase the solubility of the drug in the copolymer. 
     Examples of suitable acrylic or methacrylic alkyl esters and functional monomers and vinyl ester monomers are shown below. 
     Acrylic or methacrylic alkyl esters: 
     n-butyl acrylate or methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate or methacrylate, nonylacrylate, decyl acrylate or methacrylate, dodecyl acrylate or methacrylate, tridodecyl acrylate or methacrylate, etc. 
     Functional monomers: 
     acrylic or methacrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, methoxyethyl acrylate or methacrylate, ethoxyethyl acrylate or methacrylate, butoxyethyl acrylate, acryl or methacrylamide, dimethylacrylamide, dimethylaminoethyl acrylate or methacrylate,tert-butylaminoethyl acrylate or methacrylate, acrylonitrile, vinyl pyrrolidone, vinyl imidazole, etc. 
     Vinyl ester monomers: 
     vinyl acetate, vinyl propionate, etc. 
     Any percutaneous absorption type drugs can be used in the present invention so long as the drugs can be absorbed through the skin into the body when applied onto the skin and are solid at room temperature. Typical examples of such drugs are shown below. 
     Corticosteroids, analgesic anti-inflammatory agents, hypnotic sedatives, tranquilizers, antihypertensives, antihypertensive diuretics, antibiotics, anesthetics, antimicrobial agents, antifungal agents, vitamins, antiepileptics, coronary vasodilators, antihistaminic agents, antitussive antidepression agents sexual hormone, etc. Representative examples of those drugs are disclosed in, for example, U.S. Pat. No. 4,719,226 (columns 5-6). 
     The amount of the percutaneous absorption type drug added to the pressure-sensitive adhesive is generally about 60% by weight or less based on the weight of the adhesive. It is preferred that the amount of the percutaneous absorption type drug present be controlled such that the amount of the drug is at least 1.2 times, preferably 1.5 to 10 times, the saturated solubility of the drug in the polymer. 
     If the amount of the drug is less than 1.2 times, the amount of the continuous recrystallized particles in the adhesive forming the adhesive layer is too small and the desired lasting drug-releasing effect is difficult to obtain. 
     The percutaneous absorption type drug is added to the pressure-sensitive adhesive having a low viscosity at room temperature in an amount greater than its solubility in the polymer and dissolved therein uniformly in the presence of good solvent, the resulting mixture is applied on a backing and a stimulation is applied thereto, so that an adhesive layer comprising a drug dissolved in the range of its saturated solubility in the adhesive and a redissolvable continuous recrystallized drug present in the adhesive in a continuous recrystallized form and also a network form with a directionality can be obtained. The adhesive layer has adhesive properties conformable to a skin and firmly bonded and fixed on a backing which is substantially impermeable to the drug. 
     By selecting a good solvent, the redissolvable continuous recrystallized drug in the adhesive layer is continuously crystallized and precipitated from its dissolution state in a period of from several minutes to several hours by applying stimulation. 
     Thus, by making the percutaneous absorption type drug in an amount greater than its saturated solubility present in a continuous recrystallized state and also a substantially network state by applying stimulation, the drug exhibits the function as fillers, and the apparent viscosity at room temperature of the adhesive layer increases to a range of 7×10 4  to 6×10 6  poise, which is at least 2 times, preferably 2.5 to 50 times, larger than that of the pressure-sensitive adhesive prior to inclusion of the drug, thereby exhibiting excellent adhesive properties to the skin. 
     The thickness of the adhesive layer is from 5 to 500 μm, preferably from 10 to 300 μm. If the thickness is less than 5 μm, the adhesion to the skin is poor. On the other hand, if the thickness is more than 500 μm, the recrystallized particles are not uniform and no network state is formed due to localized recrystallization. As a result, the drug is not released uniformly. 
     Good solvents for the adhesives and the drugs which can be used to prepare the percutaneous absorption type preparation of the present invention include organic solvents such as ethyl acetate, chloroform, carbontetrachloride, methylene chloride, toluene, xylene, tetrahydrofuran, dioxane or acetone, mixtures of the above organic solvents and alcohols such as methyl alcohol and ethyl alcohol, and mixtures of the above mixtures and a small amount of water. 
     The adhesive and drug are uniformly dissolved in such a good solvent so that the amount of the drug is at least about 1.2 times the saturated solubility thereof in the adhesive to thereby prepare a solution having a solids content of from 10 to 40% by weight, preferably from 15 to 30% by weight, for preparation of an adhesive layer. This solution is coated on a backing in a dry thickness of from 5 to 500 μm, preferably from 10 to 300 μm, and dried at 20° to 180° C. for 0.5 to 30 minutes. If necessary and required, a releasing film (a film coated with a releasing agent) is temporarily adhered to the adhesive layer. A physical stimulation is applied to the adhesive layer containing the drug in an amount greater than its saturated solubility in the adhesive to induce and accelerate recrystallization of the drug, and as a result, a percutaneous absorption type preparation wherein the recrystallized drug is dispersed in a continuous recrystallized state and a substantially network state can be obtained. 
     A method of applying a physical stimulation to the adhesive layer is, for example, a method of giving a shearing and impactive stimulation to the adhesive layer. For instance, a perforation treatment by a needle-like material or a cylindrical material is applied to give a stimulation to the adhesive. 
     The excess drug in the adhesive to which a stimulation has been applied by the perforation treatment is such that the recrystallization thereof is induced and accelerated from the perforation portion to proceed in a continuous crystallized state and a substantially network state with a directionality, and connects the crystallized state which is proceeded from the neighboring perforation portion, and the whole recrystallization is completed. 
     Another stimulation applying method is a method wherein in obtaining a percutaneous absorption type preparation containing the drug in an amount designed from the preparation base sheet (e.g., a preparation sheet before cutting) comprising a backing and a percutaneous absorption type drug-containing adhesive layer, a stimulation is applied simultaneously when the base sheet is cut with a punching blade or a rotary blade. In this case, the crystals of the drug in a continuous recrystallized state and a substantially network state proceed inwardly from the edges of the preparation. 
     If desired, the adhesive layer may contain fillers such as fine silica powder, titanium white and calcium carbonate; absorption accelerating agents such as polyhydric alcohols, sulfoxides, amides, adipates, sebacates, laurates, salicylic acid, urea and allantoin; vehicles such as milk sugar, cyclodextrin and cellulose powder (which are generally mixed with the drug in advance); and compounding agents such as softening agents and anti-itch agents within the range of about 30% by weight or less for the purpose of increasing the volume, accelerating absorption or shape formability. 
     The percutaneous absorption type preparation of the present invention is designed in such a manner that an amount of the percutaneous absorption type drug in excess of the saturated solubility thereof in the pressure-sensitive adhesive is present in the pressure-sensitive adhesive in a continuous recrystallized state and a substantially network state. As a result, the percutaneous absorption type preparation of the present invention has the characteristic feature that the drug sufficiently exhibits a filler-like function to the pressure-sensitive adhesive having a low viscosity dissolution of the crystals with the lapse of time, resulting in decrease of the filler-like function thereof, ensures a good adhesion to the skin without presenting the problem of adhesive remaining. 
     Another characteristic feature is that since the continuous recrystallized particles of the drug are absorbed to the skin by sequential redissolving of the crystals starting from the region of the adhesive layer close to the skin, the preparation of the present invention has an excellent releasability over a long period of time. 
     In the process for producing the preparation, the system is uniformly dissolved using a good solvent, the resulting solution is applied on the backing, followed by drying, and a stimulation is applied thereto to form a continuous recrystallized state. Therefore, the recrystallization proceeds uniformly and there is no irregularity of recrystallization. As a result, a preparation having a stable releasability can be obtained. 
     Further, in applying a stimulation, use of cutting blade or perforation treatment can apply the stimulation to each portion simultaneously. Therefore, there is no irregularity of recrystallization in the preparation. 
     The present invention is described in greater detail by reference to the following non-limiting examples. All parts are by weight unless otherwise indicated. 
     EXAMPLE 1 
     The blend having the following components was polymerized in conventional manner to obtain a pressure-sensitive adhesive solution having an apparent viscosity at room temperature of 5×10 4  poise. 
     
         ______________________________________                                    
2-Ethylhexyl acrylate  97 parts                                           
Acrylic acid            3 parts                                           
Azobisisobutyronitrile  0.2 parts                                         
Ethyl acetate          42.9 parts                                         
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     To 100 parts (calculated on a solid basis) of the solution was added 100 parts of ethyl acetate which was a good solvent for the above-prepared adhesive and a drug, in which 25 parts of isosorbide dinitrate (the saturated solubility thereof in the above pressure-sensitive adhesive: about 8% by weight) had been uniformly dissolved, and the mixture was then stirred to prepare a solution for an adhesive layer. 
     This solution was coated on a 12 μm thick polyester film in a dry thickness of 40 μm and dried at 100° C. for 4 minutes. A releasing film coated with a releasing agent was then temporarily provided on the above-prepared adhesive layer, and the percutaneous absorption type preparation was punched out therefrom using a cutting blade 5 cm square. 
     By the visual examination of the preparation obtained, it was found that the crystals of the drug were continuous in the shape of cedar leaves and dispersed in a substantially network state. 
     EXAMPLE 2 
     The base sheet of the preparation obtained in Example 1 was subjected to a perforation treatment using a blade planted with needles lengthwise and breadthwise at the interval of 5 mm, and, thereafter, the preparation of a predetermined size was obtained. 
     It was found that the crystallization of the drug was started from the perforation area and joined roughly at midpoints between perforations. 
     The concentrations in blood of Examples 1 and 2 are shown in Table 1 below. 
     
                       TABLE 1                                                     
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Example  Concentration in Blood (ng/ml)                                   
No.      12 hrs  24 hrs      36 hrs                                       
                                   48 hrs                                 
______________________________________                                    
1        310     290         250   200                                    
2        260     270         240   220                                    
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     COMPARATIVE EXAMPLE 1 
     The solution obtained in Example 1 was coated on a 12 μm thick polyester film in a dry thickness of 40 μm and dried at 90° C. for 5 minutes. A releasing film was provided thereon temporarily and the laminate was aged at room temperature for 48 hours to prepare a percutaneous absorption type preparation containing recrystallized fine particles having a mean particle diameter of about 5 μm. 
     COMPARATIVE EXAMPLE 2 
     The blend having the following components was polymerized in conventional manner to obtain a pressure-sensitive adhesive solution having an apparent viscosity at room temperature of 7×10 5  poise. 
     
         ______________________________________                                    
2-Ethylhexyl acrylate  94 parts                                           
Acrylic acid            6 parts                                           
Azobisisobutyronitrile  0.2 parts                                         
Ethyl acetate          42.9 parts                                         
______________________________________                                    
 
    
     This solution was treated in the same manner as in comparative Example 1 to obtain a percutaneous absorption type preparation containing recrystallized fine particles having a mean particle diameter of about 5 μm. 
     The evaluation results of Examples 1 and 2 and Comparative Examples 1 and 2 with regard to adhesion to the skin and adhesive remaining with the lapse of time are shown in Table 2 below. 
     
                       TABLE 2                                                     
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       Adhesion to skin   Adhesive                                        
       with the lapse of time                                             
                          remaining                                       
       12 hrs                                                             
             24 hrs  36 hrs  48 hrs after removal                         
______________________________________                                    
Example 1                                                                 
         good    good    good  good   none                                
Example 2                                                                 
         good    good    good  good   none                                
Comparative                                                               
         good    good    good  good   periphery                           
Example 1                                                                 
Comparative                                                               
         good    part    part  periphery                                  
                                      none                                
Example 2                                                                 
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     Measurement Methods 
     Apparent Viscosity at room temperature: 
     This viscosity was measured using a creep-shear viscometer. A sample (10 mm in width and 20 mm in length) was adhered to a Bakelite panel, and the distance of movement of the sample in a very short time under a given load was read. The following equation gives the viscosity: ##EQU1## wherein W: Load (g) 
     l: Thickness of the sample (cm) 
     A: Contact area (cm 2 ) 
     dx: Distance of movement in dt second (cm) 
     Adhesion to the skin with the lapse of time: 
     Sample sheets (5 cm×5 cm) were adhered to the breast of a male adult, and the adhesion was observed after 12, 24, 36 and 48 hours, respectively, based on the rating indicated below. After 48 hours, the sheet was peeled off and the state of adhesive remaining was evaluated on the basis of the rating indicated below. 
     Adhesion with the lapse of time: 
     Good: No peeling 
     Part: Partial peeling on the periphery 
     Periphery: Almost all area on the periphery was peeled off 
     Half: Half the area of sheet was peeled off 
     Remaining adhesive: 
     None: Adhesive remaining was not observed 
     Part: Adhesive remained partially on the periphery 
     Periphery: Adhesive remained on the whole periphery 
     Remarkable: Adhesive remained on the whole area 
     Concentration in blood: 
     Sample sheets (6 cm in diameter) were adhered to the back of a rabbit where the hair had been removed. After 12, 24, 36 and 48 hours, the blood was taken and the concentration of the drug in the blood was measured using gas chromatography. 
     EXAMPLES 3 TO 4 AND COMPARATIVE EXAMPLES 3 TO 6 
     The compositions as shown in Table 3 were used to prepare the preparations in the same manner as in Example 1. 
     
                                           TABLE 3                                 
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             Comparative                                                  
                    Comparative  Comparative                              
                                        Comparative                       
       Example 3                                                          
             Example 3                                                    
                    Example 4                                             
                           Example 4                                      
                                 Example 5                                
                                        Example 6                         
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Composition                                                               
       75 Parts of                                                        
             75 Parts of                                                  
                    60 Parts of                                           
                           85 Parts of                                    
                                 85 Parts of                              
                                        75 Parts of                       
       nonylacryl-                                                        
             nonylacryl-                                                  
                    nonylacryl-                                           
                           2-ethyl-                                       
                                 2-ethyl-                                 
                                        2-ethyl-                          
       ate;  ate;   ate;   hexyl-                                         
                                 hexyl- hexyl-                            
       15 Parts of                                                        
             15 Parts of                                                  
                    20 Parts of                                           
                           acrylate;                                      
                                 acrylate;                                
                                        acrylate;                         
       ethoxy-                                                            
             ethoxy-                                                      
                    ethoxy-                                               
                           15 Parts of                                    
                                 15 Parts of                              
                                        25 Parts of                       
       ethyl-                                                             
             ethyl- ethyl- N-vinyl-                                       
                                 N-vinyl-                                 
                                        N-vinyl-                          
       acrylate;                                                          
             acrylate;                                                    
                    acrylate;                                             
                           2-pyrroli-                                     
                                 2-pyrroli-                               
                                        2-pyrroli-                        
       10 Parts of                                                        
             10 Parts of                                                  
                    20 Parts of                                           
                           done  done   done                              
       vinyl vinyl  vinyl                                                 
       acetate                                                            
             acetate                                                      
                    acetate                                               
Apparent                                                                  
       1 × 10.sup.4                                                 
             1 × 10.sup.4                                           
                    4 × 10.sup.6                                    
                           5 × 10.sup.4                             
                                 5 × 10.sup.4                       
                                        1 × 10.sup.7                
Viscosity                                                                 
(poise)                                                                   
Name of                                                                   
       Flunitra-                                                          
             Flunitra-                                                    
                    Flunitra-                                             
                           Pindolol                                       
                                 Pindolol                                 
                                        Pindolol                          
drug   zepam zepam  zepam                                                 
Saturated                                                                 
         3.5   3.5   4      7     7      6                                
Solubility                                                                
(%)                                                                       
Amount of                                                                 
       10    10     10     15    15     15                                
Drug(parts)                                                               
Adhesion to the skin                                                      
After  Good  Good   Good   Good  Good   Good                              
12 hrs                                                                    
After  Good  Good   Good   Good  Good   Part                              
24 hrs                                                                    
After  Good  Good   Part   Good  Good   Periphery                         
36 hrs                                                                    
After  Good  Good   Half   Good  Good   Half                              
48 hrs                                                                    
Adhesive                                                                  
       None  Remarkable                                                   
                    None   None  Periphery                                
                                        None                              
Remaining                                                                 
Concentration in Blood (mg/ml)                                            
After  28    30     32     50    47     50                                
12 hrs                                                                    
After  40    40     36     45    45     40                                
24 hrs                                                                    
After  35    39     25     41    40     29                                
36 hrs                                                                    
After  30    35     16     37    35     11                                
48 hrs                                                                    
Stimu- Rectan-                                                            
             None   None   *     None   None                              
lation gular (particle                                                    
                    (particle    (particle                                
                                        (particle                         
Applied                                                                   
       punching                                                           
             diameter:                                                    
                    diameter:    diameter:                                
                                        diameter:                         
       blade 3 μm)                                                     
                    2 μm)     4 μm)                                 
                                        4 μm)                          
__________________________________________________________________________
 * Needlelike projections arranged in a lattice form at each distance of  
 12.5 mm                                                                  
 
    
     While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.