Transdermal Iontophoresis of Vitamin B12 Under Three Different Skin Preparations
Condition: Macrocytic Anemia With Vitamin B12 Deficiency
MeSH terms: Anemia, Macrocytic; Vitamin B 12 Deficiency
Study type: Interventional

Summary: 
      STUDY DESIGN: Phase I Clinical Trial The researchers set out to assess the effectiveness of
      transdermal iontophoretic administration of Vitamin B12 (V.B12) under three different skin
      preparatory conditions.

      SETTING: James J. Peters Veterans Affairs Medical Center (Bronx, NY) BACKGROUND: Poor skin
      permeability precludes the use of transdermal route from being used in common clinical
      practice for rapid and precise administration of medications through intact skin that are
      expected to have a systemic effect. The researchers determined the relative effectiveness of
      an unconventional transdermal iontophoresis technique for the administration of Vitamin B12
      (V.B12) under three different skin preparatory conditions.

      METHODS: During this study, Vitamin B12 (V.B12) was administered through the skin of
      volunteer human research subjects. Iontophoresis was used as transdermal medication delivery
      modality after pre-treatment of the skin in 3 different ways. The sequence of skin
      preparations was arranged in a random order for each subject. Method 1 was called "No Prep",
      serving as the control approach; method 2 was called "Oleic Acid" application to the skin for
      40 minutes; and method 3 was hair "Epilation" (e.g. hair removal by plucking). Fifteen
      milligrams of aqueous solution of V.B12 was administered through intact, previously unused
      skin of an anterior thigh during all 3 tests. Chemoluminescence, on an automated laboratory
      reader Advia Centaur-XP, was used to determine the serum concentration of V.B12 prior to and
      after transdermal iontophoretic delivery. All 3 experiments were performed on the same day
      within an hour of each other. The subject's blood was drawn prior and 10 minutes after the
      20-minute long sessions of transdermal V.B12 iontophoresis. We were able to calculate the
      increase in serum V.B12 concentration and based on estimated blood volume, the total quantity
      and percent dose delivered systemically.
    

Detailed description: 
      In order to quantify the changes in skin permeability to drugs delivered by ION under three
      different preparatory conditions, we used V.B12 as a model substance. Its choice was dictated
      by its inherent safety, positive charge and quantification of serum concentration readily
      available through our clinical laboratory. We compared the effects of unprepared skin (No
      Prep), oil-soaked skin [ref. 9-12] (Oleic Acid) and skin from which hair have been plucked
      out of (Epilation), on the serum concentrations of V.B12 before and after administration via
      ION.

      Veterans and non-Veterans without SCI were recruited for the study comparing the three skin
      preparation methods. This prospective, skin preparatory method sequence-randomized study was
      approved by the Institutional Review Board of the James J. Peters VA Medical Center
      (JJPVAMC). The ION equipment used was a standard FDA-approved wired ION controller unit (IBOX
      by Dynatronics) and 4mL ION electrodes by (ionto+ by Richmar). The skin was prepared using 1
      of the 3 techniques, performed in a random order. Each subject was assigned a 2-digit
      sequential number. A random-numbers table was used to assign the sequence of methods to each
      subject. A single positive electrode patch containing 4mL of a water-based solution with 15mg
      of V.B12 was used per experiment. One negative electrode patch was also used to complete the
      circuit. Blood was drawn prior to the first administration. Thirty minutes after the start of
      the ION delivery of the V.B12 through the skin of anterior thigh, the blood was drawn again.
      The blood was centrifuged for 5 minutes and delivered to the clinical laboratory for testing
      without delay. Serum concentration of V.B12 was measured using chemoluminescence on an
      automated laboratory reader Advia Centaur-XP. The experiments were conducted sequentially in
      a timely fashion, performed on the same day and within a span of 3 hours. Blood was drawn for
      a total of 4 times per subject.

      The "No Prep" technique was performed by simply wiping the two skin surfaces on an anterior
      thigh, where the electrodes were later attached, with two-70% isopropyl alcohol prep. pads.
      The skin surface destined for positive electrode application was sprayed with a thin layer of
      20% Benzocaine (Americaine aerosol spray can) and covered with an occlusive plastic film for
      10 minutes. The film was then removed and the skin was cleansed with water-moistened paper
      towel, followed by one alcohol prep. pad.

      The "Oleic Acid" technique involved first wiping the two skin patches and later soaking the
      skin patch, where the positive electrode was going to be placed, with oil called oleic acid
      for 40 minutes. The oil was then wiped off with a paper napkin and an alcohol pad. That same
      skin area was sprayed with a thin layer of 20% Benzocaine (Americaine aerosol spray
      container) and covered with an occlusive plastic film for 10 minutes. The film was then
      removed and the skin was cleansed with water-moistened paper towel, followed by one alcohol
      prep.

      The "Hair Epilation" technique involved first wiping the two skin patches with 2-70%
      isopropyl alcohol skin preps and sprayed with a thin layer of 20% Benzocaine (Americaine
      aerosol spray container) and covered with an occlusive plastic film for 10 minutes. The film
      was removed and the skin was cleansed with de-ionized water followed by alcohol prep. Hair
      removal, using an epilator machine (Remington EP 7030), was performed by clearing an area of
      5x5cm or 2x2 inch square. The epilated area was then covered with a thin layer of 0.2% Sodium
      Lauryl Sulfate (SLS) in de-ionized water.

      After each of the skin preparations and without delay, 15mg of methylcobalamin dissolved in
      4mL of de-ionized water soaked into the anode patch reservoir was applied to the designated
      skin of the proximal anterior thighs. The 7x7cm skin area under the negative electrode was
      wiped with an alcohol pad and 0.5mL of 1% citric acid dissolved in 0.9% normal saline
      solution was applied to the negative electrode's skin contact surface. The return (negative)
      electrode was then attached to the skin 10cm from the positive electrode.

      An elevated room temperature of 73-78 degrees Fahrenheit (25 degrees Celsius) was maintained
      in the room for the purposes of maintaining adequate blood flow in the peripheral dermal
      capillaries. No exclusion criteria for diseases that decrease capillary perfusion such as
      diabetes have been utilized. As a result, 2 of the 10 subjects who participated in this study
      had a diagnosis of Diabetes Mellitus type 2.

      IBOX ION device was attached to the electrodes by way of wire leads and a multimeter was
      attached to the electrodes in parallel in order to record the skin's electrical resistivity
      prior to and after ION. Throughout the 20-minute ION session, voltage exerted by the IBOX was
      recorded at regular intervals. The voltage was automatically adjusted by the IBOX to deliver
      a pre-set constant electrical current of 4mA/minute. Throughout the procedure subjects were
      asked about the presence of any sensations associated with the ION including effects of the
      medication being administered.
    

Intervention name(s): Vitamin B12
Intervention type(s): Dietary Supplement
Intervention description(s): Diffusion of Vitamin B12 through the skin over 20 minutes under the effect of low amount of direct electric current
Other intervention name(s): Iontophoresis
Intervention MeSH terms: Vitamin B 12; Hydroxocobalamin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Transdermal Penetration Enhancers, Iontophoresis, Neostigmine, Glycopyrrolate, Vitamin B12, Methylcobalamin, Cyanocobalamin