USH1160H - Iontophoretic delivery of peptides - Google Patents

Iontophoretic delivery of peptides Download PDF

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Publication number
USH1160H
USH1160H US07/617,824 US61782490A USH1160H US H1160 H USH1160 H US H1160H US 61782490 A US61782490 A US 61782490A US H1160 H USH1160 H US H1160H
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calcitonin
water
patch
iontophoretic
solution
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US07/617,824
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Hawkins V. Maulding
James R. Siverly
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0448—Drug reservoir

Definitions

  • This invention relates to a manner of delivering substances into a mammalian body, and more particulary concerns delivery of polypeptide into a mammalian body.
  • Ionic substances have previously been delivered into body tissue by iontophoretic means.
  • This method for delivering substances normally utilizes direct electrical current in contact with the skin, and drives these substances through intact skin to the interior of the animal body, including the blood stream.
  • Iontophoresis has been shown to be useful in various medical applications and substances such a lidocaine, hydrocortisone and many other drugs have been so administered.
  • iontophoretic devices and systems have been previously described and comprise a source for generating current, a pair of electrodes and the ionic substance to be introduced into the body.
  • the active electrode, the donor electrode that drives the desired substance through the skin, is of the same charge as the substance.
  • the active electrode also physically embrace a source for the drugs, and this can be accomplished by retaining the drug in a compatible matrix, such as a polymeric matrix, e.g. a gel or a solution contained by a semipermable membrane, or even a moist cloth or gauze and water system which will permit flow of electrically charged substance to and through the skin.
  • a compatible matrix such as a polymeric matrix, e.g. a gel or a solution contained by a semipermable membrane, or even a moist cloth or gauze and water system which will permit flow of electrically charged substance to and through the skin.
  • Transdermal patches which contain the drug, a matrix and water are the preferred mode for transdermally administering the active agent to the human or non-human animal patient.
  • European Patent Application 0278 473 discloses a chemical composition and system for iontophoretic transport which comprises a protein, a cosolvent with negative Setschenow constant and water.
  • the protein which may be used includes, but is not limited to, polypeptides having more than about 20 peptide units.
  • the various proteins mentioned include but are not limited to calcitonin and insulin.
  • Iontophoretic transdermal delivery of insulin which is a 51 peptide protein is disclosed by Chien, et al, J. Pharmaceutical Sciences 78, 5, 376-383 May 1989.
  • a further object is the provision of a transdermal device for delivering calcitonin by iontophoresis into animal tissue.
  • the invention is a new system and method for iontophoretically delivering a polypeptide, such as calcitonin, transdermally into animal tissue.
  • a calcitonin such as salmon calcitonin, which is a 32 amino acid polypeptide having a positive charge
  • a calcitonin such as salmon calcitonin, which is a 32 amino acid polypeptide having a positive charge
  • a calcitonin in a matrix consisting essentially of water may be driven through the epidermal layer into the blood stream. This avoids the undesirable complication of also transporting a cosolvent into the transdermal layer or into the blood stream of the human or non-human animal being administered the calcitonin.
  • the levels of calcitonin in the animal blood stream achieved by this method are therapeutic, this being accomplished in short periods of time and without injury or irritation to the epidermal layers.
  • the matrix containing the calcitonin is in the form of an adhesive patch filled with a gel or polymeric substance capable of retaining the water and the calcitonin.
  • a pH of 4-9 is acceptable, preferably a pH of 4.5-6, most preferably 4.5-5.5.
  • the gel may consist of aqueous hydroxypropyl methylcellulose or other neutral gel forming polymers in water.
  • the electrical components of the electrodes usable are also known in the art and preferably are silver/silver chloride electrodes.
  • a convenient configuration for the reservoir containing the calcitonin would a two membrance system whereby the calcitonin, such as salmon calcitonin, in the gel and water matrix would be retained between the two membranes.
  • a two chamber compartment on an adhesive patch is a preferred embodiment of the iontophoretic system of this invention.
  • a current density from about 10 microamps ( ⁇ A) per cm 2 about 300 ⁇ A/cm 2 may be used, higher currents being possible but increasing the chances of damage to the tissued involved.
  • the preferrered current density is about 100-250 ⁇ A/cm 2 .
  • FIG. 1 shows the mean plasma levels of salmon calcitonin with respect to time in the test animals.
  • An iontophoretic device consisting of two patches, one containing a donor gel and a silver wire mesh electrode and the other a return electrode, and a constant current source is used.
  • a tared donor compartment is filled with about 4 ml of 4% hydroxypropyl methylcellulose (Shin-Etsu, Tokyo, Japan) gel containing 12.5 mg of salmon calcitonin/g of gel. The weight of the filled patch is measured to calculate the amount of calcitonin added.
  • the donor compartment is separated from the silver electrode by an anion selective membrane (Raipore #5030H) and the top chamber contains Signa Gel (Parker Labs, West Orange, N.J.). See Sanderson et al, J. Pharm. Sci.
  • the donor gel is contained inside the patch by adhering a Spectra/Por 2 dialysis membrane (molecular weight cut off 12,000 to 14,000 Daltons; Spectrum, Los Angeles, Calif.) to the bottom of the patch.
  • the return patch consists of a silver wire mesh electrode plated with chloride and a chamber filled with Signa Gel. The surface area of each patch exposed to the skin is 10 square cm.
  • the patches of Example 1 are applied to each of three male miniature swine both by iontophoresis and passively in a crossover fashion.
  • two animals receive current while the other is a passive control.
  • animals receive the opposite treatment; see Table I below.
  • the total current applied is 2mA or the equivalent of 200 ⁇ A/cm2.
  • the patches are applied for 12 hours. After that time the current is stopped and all devices are removed.
  • the gel remaining on the skin is recovered for analysis of residual salmon calcitonin not delivered.
  • the amount remaining in the patch is determined by removing the excess gel from the patch, soaking the patch and dissolving the excess gel in pH 5 sodium acetate buffer.
  • Zero time blood samples are drawn the afternoon of the day before the devices are applied. Two ml of plasma from each animal is reserved for the zero sample and the rest pooled for use in the analysis.
  • Blood samples are drawn at 1,2,3,4,6,8,12,24,28,32,48 and 72 hours. For each sample the animal is turned on its back. At least 2 ml of blood is drawn from the vena cava into plastic syringes using an 18 gauge, 1.5 inch needle. The blood sample is transferred into chilled plastic tubes containing lithium heparin. The tubes are centriguged at 4° C. at 3,000 rpm for 10 minutes to isolate the plasma. The plasma is drawn off using a pipette and transferred to a plastic tube labeled with the number of the animal and the sample time. The plasma is stored frozen at -70° C. until all samples are collected. The concentration of calcitonin in each sample is determined by radioimmunoassay.
  • the concentration of salmon calcitonin in the plasma for the two treatments is presented in Tables II and III.
  • the mean plasma levels of the three animals at each sample time are plotted with respect to time in FIG. 1.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Electrotherapy Devices (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention concerns a new system and method for iontophoretically delivering a polypeptide transdermally into animal tissue.

Description

BACKGROUND OF THE INVENTION
This invention relates to a manner of delivering substances into a mammalian body, and more particulary concerns delivery of polypeptide into a mammalian body.
Ionic substances have previously been delivered into body tissue by iontophoretic means. This method for delivering substances such as chemicals or drugs normally utilizes direct electrical current in contact with the skin, and drives these substances through intact skin to the interior of the animal body, including the blood stream. Iontophoresis has been shown to be useful in various medical applications and substances such a lidocaine, hydrocortisone and many other drugs have been so administered.
Various iontophoretic devices and systems have been previously described and comprise a source for generating current, a pair of electrodes and the ionic substance to be introduced into the body. The active electrode, the donor electrode that drives the desired substance through the skin, is of the same charge as the substance.
It is preferable that the active electrode also physically embrace a source for the drugs, and this can be accomplished by retaining the drug in a compatible matrix, such as a polymeric matrix, e.g. a gel or a solution contained by a semipermable membrane, or even a moist cloth or gauze and water system which will permit flow of electrically charged substance to and through the skin. Transdermal patches which contain the drug, a matrix and water are the preferred mode for transdermally administering the active agent to the human or non-human animal patient.
European Patent Application 0278 473 discloses a chemical composition and system for iontophoretic transport which comprises a protein, a cosolvent with negative Setschenow constant and water. The protein which may be used includes, but is not limited to, polypeptides having more than about 20 peptide units. The various proteins mentioned include but are not limited to calcitonin and insulin.
Iontophoretic transdermal delivery of insulin, which is a 51 peptide protein is disclosed by Chien, et al, J. Pharmaceutical Sciences 78, 5, 376-383 May 1989.
It is an object of the present invention to provide a means for iontophoretically delivering transdermally calcitonin, especially salmon calcitonin, into animal tissue.
It is a further object to provide a method for delivering calcitonin by iontophoretic transdermal means to a human or a non-human patient without the use of a cosolvent in the drug reservoir.
A further object is the provision of a transdermal device for delivering calcitonin by iontophoresis into animal tissue.
SUMMARY OF THE INVENTION
The invention is a new system and method for iontophoretically delivering a polypeptide, such as calcitonin, transdermally into animal tissue.
DESCRIPTION OF THE INVENTION
It has now been surprisingly found that a calcitonin, such as salmon calcitonin, which is a 32 amino acid polypeptide having a positive charge, may be iontophoretically introduced transdermally into mammalian tissue by means of continuous application of a voltage difference less than about ten volts with a simple aqueous electrode system. No need for cosolvent is required. Instead, a quantity of a calcitonin in a matrix consisting essentially of water may be driven through the epidermal layer into the blood stream. This avoids the undesirable complication of also transporting a cosolvent into the transdermal layer or into the blood stream of the human or non-human animal being administered the calcitonin.
The levels of calcitonin in the animal blood stream achieved by this method are therapeutic, this being accomplished in short periods of time and without injury or irritation to the epidermal layers.
Generally the matrix containing the calcitonin is in the form of an adhesive patch filled with a gel or polymeric substance capable of retaining the water and the calcitonin. A pH of 4-9 is acceptable, preferably a pH of 4.5-6, most preferably 4.5-5.5. The gel may consist of aqueous hydroxypropyl methylcellulose or other neutral gel forming polymers in water.
The electrical components of the electrodes usable are also known in the art and preferably are silver/silver chloride electrodes.
A convenient configuration for the reservoir containing the calcitonin would a two membrance system whereby the calcitonin, such as salmon calcitonin, in the gel and water matrix would be retained between the two membranes. A two chamber compartment on an adhesive patch, is a preferred embodiment of the iontophoretic system of this invention.
It should also be understood that it is preferred that no other ions of like charge to the drug be present in the transdermal patch. Preservative to prevent microbiological contamination is also useful. To avoid driving this preservative into the tissue, it is also understood that it should be neutral or negatively charged.
A current density from about 10 microamps (μA) per cm2 about 300 μA/cm2 may be used, higher currents being possible but increasing the chances of damage to the tissued involved. The preferrered current density is about 100-250 μA/cm2.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the mean plasma levels of salmon calcitonin with respect to time in the test animals.
EXAMPLE 1
An iontophoretic device consisting of two patches, one containing a donor gel and a silver wire mesh electrode and the other a return electrode, and a constant current source is used. A tared donor compartment is filled with about 4 ml of 4% hydroxypropyl methylcellulose (Shin-Etsu, Tokyo, Japan) gel containing 12.5 mg of salmon calcitonin/g of gel. The weight of the filled patch is measured to calculate the amount of calcitonin added. The donor compartment is separated from the silver electrode by an anion selective membrane (Raipore #5030H) and the top chamber contains Signa Gel (Parker Labs, West Orange, N.J.). See Sanderson et al, J. Pharm. Sci. 76,215 (1987) and Parsi U.S. Pat. No. 4,731,049 respecting anion selective membranes. The donor gel is contained inside the patch by adhering a Spectra/Por 2 dialysis membrane (molecular weight cut off 12,000 to 14,000 Daltons; Spectrum, Los Angeles, Calif.) to the bottom of the patch. The return patch consists of a silver wire mesh electrode plated with chloride and a chamber filled with Signa Gel. The surface area of each patch exposed to the skin is 10 square cm.
EXAMPLE 2
The patches of Example 1 are applied to each of three male miniature swine both by iontophoresis and passively in a crossover fashion. In the first part of the study, two animals receive current while the other is a passive control. For the second phase of the study, animals receive the opposite treatment; see Table I below. The total current applied is 2mA or the equivalent of 200 μA/cm2. The patches are applied for 12 hours. After that time the current is stopped and all devices are removed. The gel remaining on the skin is recovered for analysis of residual salmon calcitonin not delivered. The amount remaining in the patch is determined by removing the excess gel from the patch, soaking the patch and dissolving the excess gel in pH 5 sodium acetate buffer.
Zero time blood samples are drawn the afternoon of the day before the devices are applied. Two ml of plasma from each animal is reserved for the zero sample and the rest pooled for use in the analysis.
Blood samples are drawn at 1,2,3,4,6,8,12,24,28,32,48 and 72 hours. For each sample the animal is turned on its back. At least 2 ml of blood is drawn from the vena cava into plastic syringes using an 18 gauge, 1.5 inch needle. The blood sample is transferred into chilled plastic tubes containing lithium heparin. The tubes are centriguged at 4° C. at 3,000 rpm for 10 minutes to isolate the plasma. The plasma is drawn off using a pipette and transferred to a plastic tube labeled with the number of the animal and the sample time. The plasma is stored frozen at -70° C. until all samples are collected. The concentration of calcitonin in each sample is determined by radioimmunoassay.
Results
The concentration of salmon calcitonin in the plasma for the two treatments is presented in Tables II and III. The mean plasma levels of the three animals at each sample time are plotted with respect to time in FIG. 1. Animal #149-5 aside, there was on average from 20 to 1000 times greater calcitonin concentrations with iontophoresis than with no current.
              TABLE I                                                     
______________________________________                                    
EXPERIMENTAL DESIGN                                                       
Animal #      Part I       Part II                                        
______________________________________                                    
149-1         Iontophoresis                                               
                           Passive                                        
149-4         Iontophoresis                                               
                           Passive                                        
149-5         Passive      Iontophoresis                                  
______________________________________                                    

              TABLE II                                                    
______________________________________                                    
SALMON CALCITONIN PLASMA LEVELS                                           
FOLLOWING IONTOPHORESIS (mIU/ml)                                          
Pig Number                                                                
Time   149-1     149-4   149-5   Mean  SEM                                
______________________________________                                    
0      0.000     0.000   0.000   0.000 0.000                              
1      2.210     1.466   0.372   1.349 0.534                              
2      3.139     4.057   0.099   2.432 1.196                              
3      3.070     4.840   0.222   2.711 1.345                              
4      6.955     4.582   0.022   3.853 2.034                              
6      7.825     5.890   0.000   4.572 2.353                              
8      8.627     8.542   0.000   5.723 2.862                              
12     13.160    13.940  11.070  12.723                                   
                                       0.857                              
24     1.527     1.368   0.733   1.209 0.243                              
28     0.295     0.302   0.092   0.230 0.069                              
32     0.258     0.404   0.168   0.277 0.069                              
48     0.289     0.149   0.107   0.182 0.055                              
72     0.149     0.169   0.060   0.126 0.034                              
______________________________________                                    

              TABLE III                                                   
______________________________________                                    
SALMON CALCITONIN LEVELS FOLLOWING                                        
PASSIVE ADMINISTRATION (mIU/ml)                                           
Pig Number                                                                
Time   149-1     149-4  149-5   Mean  SEM                                 
______________________________________                                    
0      0         0      0       0     0                                   
1      0.020     0.086  0.031   0.045 0.020                               
2      0         0.115  0.182   0.099 0.053                               
3      0.027     0.055  0.261   0.114 0.073                               
4      0         0      0.295   0.098 0.098                               
6      0.064     0.032  0.431   0.175 0.128                               
8      0.061     0.077  0.579   0.239 0.170                               
12     0         0.035  0.510   0.181 0.164                               
24     0.111     0.695  0.075   0.293 0.200                               
28     0         0.089  0.084   0.090 0.004                               
32     0         0.068  0.103   0.057 0.030                               
48     0.032     0.058  0.065   0.051 0.010                               
72     0         0.053  0       0.017 0.017                               
______________________________________
The amount of calcitonin placed in each patch, the residual calcitonin recovered from the patch and the estimate of the amount of calcitonin transported, calculated from the difference between the amount applied and the amount recovered, are shown in Table IV.
              TABLE IV                                                    
______________________________________                                    
SALMON CALCITONIN DELIVERED                                               
Iontophoresis                                                             
             149-1       149-4  149-5                                     
______________________________________                                    
Mg Applied   38.4        43.7   39.1                                      
Mg Recovered 12.4        30.8   35.3                                      
Mg Delivered 26.0        12.9    3.8                                      
______________________________________

Claims (8)

We claim:
1. A device for transdermal transport of a chemical into animal tissue by electrolytic means comprising a calcitonin and water in a reservoir usable for iontophoretic administration.
2. A transdermal patch for delivering a calcitonin into the blood stream of a patient having in an electrode thereof a solution consisting essentially of a calcitonin and water.
3. A transdermal patch according to claim 2 wherein said calcitonin is salmon calcitonin.
4. A transdermal patch according to claim 3 wherein the solution additionally contains a preservative.
5. A method for transdermally transporting a calcitonin into animal tissue which comprises use of a device according to claims 1 or 2.
6. A method according to claim 5 wherein the solution additionally contains a neutral or anionic preservative.
7. A method for transporting salmon calcitonin into the blood stream of a patient which comprises using an iontophoretic patch containing in a donor electrode a solution of salmon calcitonin and water.
8. A method according to claim 7 wherein the donor electrode solution consists essentially of salmon calcitonin and water.
US07/617,824 1990-11-26 1990-11-26 Iontophoretic delivery of peptides Abandoned USH1160H (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0732122A1 (en) * 1995-03-17 1996-09-18 Takeda Chemical Industries, Ltd. Stabilized interface for iontophoresis
EP0732121A1 (en) * 1995-03-17 1996-09-18 Takeda Chemical Industries, Ltd. Transdermal drug delivery process
US5747453A (en) * 1995-06-06 1998-05-05 Alza Corporation Method for increasing the electrotransport flux of polypeptides
US6333189B1 (en) 1996-06-06 2001-12-25 Alza Corporation Method of making an electrotransport device
US20060121104A1 (en) * 2002-10-31 2006-06-08 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications
US20060233871A1 (en) * 2002-10-31 2006-10-19 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications
US20070078096A1 (en) * 1997-11-12 2007-04-05 Cormier Michel J Buffered drug formulations for transdermal electrotransport delivery
US20070082040A1 (en) * 2002-10-31 2007-04-12 Meir Stern Transdermal delivery system for dried particulate or lyophilized peptides and polypeptides
US20090137480A1 (en) * 2002-10-31 2009-05-28 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications

Citations (8)

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US4640689A (en) 1983-08-18 1987-02-03 Drug Delivery Systems Inc. Transdermal drug applicator and electrodes therefor
US4702732A (en) 1984-12-24 1987-10-27 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation and transdermal delivery of pharmacologically active ligands
US4708716A (en) 1983-08-18 1987-11-24 Drug Delivery Systems Inc. Transdermal drug applicator
US4786277A (en) 1986-11-21 1988-11-22 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation
US4842577A (en) 1986-10-20 1989-06-27 Yamanouchi Pharmaceutical Co., Ltd. Plaster structural assembly for iontophoresis
US4919648A (en) 1983-08-18 1990-04-24 Drug Delivery Systems Inc. High tack drug patch
US4921475A (en) 1983-08-18 1990-05-01 Drug Delivery Systems Inc. Transdermal drug patch with microtubes
US4942883A (en) 1987-09-29 1990-07-24 Newman Martin H Drug delivery device

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4640689A (en) 1983-08-18 1987-02-03 Drug Delivery Systems Inc. Transdermal drug applicator and electrodes therefor
US4708716A (en) 1983-08-18 1987-11-24 Drug Delivery Systems Inc. Transdermal drug applicator
US4919648A (en) 1983-08-18 1990-04-24 Drug Delivery Systems Inc. High tack drug patch
US4921475A (en) 1983-08-18 1990-05-01 Drug Delivery Systems Inc. Transdermal drug patch with microtubes
US4702732A (en) 1984-12-24 1987-10-27 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation and transdermal delivery of pharmacologically active ligands
US4842577A (en) 1986-10-20 1989-06-27 Yamanouchi Pharmaceutical Co., Ltd. Plaster structural assembly for iontophoresis
US4786277A (en) 1986-11-21 1988-11-22 Trustees Of Boston University Electrodes, electrode assemblies, methods, and systems for tissue stimulation
US4942883A (en) 1987-09-29 1990-07-24 Newman Martin H Drug delivery device

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0732122A1 (en) * 1995-03-17 1996-09-18 Takeda Chemical Industries, Ltd. Stabilized interface for iontophoresis
EP0732121A1 (en) * 1995-03-17 1996-09-18 Takeda Chemical Industries, Ltd. Transdermal drug delivery process
US5700481A (en) * 1995-03-17 1997-12-23 Takeda Chemical Industries, Ltd. Transdermal drug delivery process
US5837281A (en) * 1995-03-17 1998-11-17 Takeda Chemical Industries, Ltd. Stabilized interface for iontophoresis
US5747453A (en) * 1995-06-06 1998-05-05 Alza Corporation Method for increasing the electrotransport flux of polypeptides
US6313092B1 (en) 1995-06-06 2001-11-06 Alza Corporation Method for increasing the electrotransport flux of polypeptides
US6333189B1 (en) 1996-06-06 2001-12-25 Alza Corporation Method of making an electrotransport device
US20070078096A1 (en) * 1997-11-12 2007-04-05 Cormier Michel J Buffered drug formulations for transdermal electrotransport delivery
US20060233871A1 (en) * 2002-10-31 2006-10-19 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications
US20060121104A1 (en) * 2002-10-31 2006-06-08 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications
US20070082040A1 (en) * 2002-10-31 2007-04-12 Meir Stern Transdermal delivery system for dried particulate or lyophilized peptides and polypeptides
US7363075B2 (en) * 2002-10-31 2008-04-22 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized medications
US7383084B2 (en) * 2002-10-31 2008-06-03 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized medications
US20090137480A1 (en) * 2002-10-31 2009-05-28 Meir Stern Transdermal delivery system for dried particulate or lyophilized medications
US7662404B2 (en) 2002-10-31 2010-02-16 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized peptides and polypeptides
US8133505B2 (en) 2002-10-31 2012-03-13 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized medications

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