Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1998-05-20
2004-01-13
Mendez, Manuel (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S501000, C604S093010, C600S380000
Reexamination Certificate
active
06678553
ABSTRACT:
BACKGROUND OF THE INVENTION
1. INTRODUCTION
Most of the efforts currently under way to discover new therapeutic drugs for disorders of the central nervous system (CNS) will also face the problem of delivering them to the brain without impairing the activity or integrity of such substances or compounds, while minimizing systemic adverse effects. And that means finding a way around—or through—the blood brain barrier (BBB), a physiological barrier between bloodstream and brain.
A National Institutes of Mental Health (NIMH) study showed that, in the United States, one out of three individuals suffers from a CNS disorder at some time in life. Approximately two million in the same country have suffered a stroke, which is the third leading cause of death in the United States.
2. IONTOPHORESIS
After the discovery of the electrical nature of nerve impulse by Galvani in 1791, attention focused on the possibility of using electricity as a mode of drug delivery. It has been long known that medicines could be introduced into the human body by way of the skin. The skin has a selective permeability to lipophilic (lipid soluble) substances and acts as a barrier to hydrophilic (water soluble) substances. In 1747, Veratti suggested that hydrophobic drugs might be Introduced to the subcutaneous tissue through human skin by the application of a direct current. This mode has become known as iontophoresis (meaning ion transfer).
In Table 1 we present several examples of drugs introduced through the skin by iontophoresis for some conditions.
Drug
condition
Acetic acid
Myositis ossificans
Aspirin
Rheumatic disease
Dexamethasone and
Tendinitis, bursitis, rheumatoid arthritis
lidocaine
Diclofenac sodium
Scapula-humoral periarthritis, elbow epicondylitis
Iodine
Fibrosis, adhesions, scar tissue, trigger finger
lidocaine
local anesthesia
Morphine
Post-operative analgesia
Pilocarpine
Sweat test (cystic fibrosis)
Pirprophene
Rheumatic diseases
Potassium citrate
Rheumatoid arthritis
Potassium iodide
Scar tissue
Silver
Chronic osteomyelitis
Salicylate
Plantar warts, scar tissue
Sodium fluoride
Tooth hypersensitivity
Table 1: Drugs introduced by iontophoresis for corresponding conditions, substances that can be introduced by iontophoresis.
This is only a small part of different drugs or biologically active substances that can be introduced by iontophoresis. Many lipophilic drugs, such as scopolamine for motion sickness, clonidine for hypertension, and nitroglycerin for the treatment of angina pectoris, can be readily delivered through human skin. With these drugs, the concentration gradient between the drug-loaded reservoir and the body is sufficient enough to deliver the drug through the skin at therapeutic dosage rates. However, this is not the case for hydrophilic drugs.
Because topical application fails to deliver therapeutic dosages of hydrophilic drugs, traditional methods, such as oral or parenteral systemic drug administration, have been favored. However, these methods have several disadvantages.
First, systemic administration may lead to massive inactivation of a drug as a result of the enzymatic action of the liver. Also, oral administration may give rise to incomplete or erratic absorption due to factors like food interaction, inactivation in the gastro-intestinal tract, disease status, and concomitant medication. Furthermore, oral drug administration may give rise to fluctuations in the concentration of a drug in the systemic circulation. This may in turn result in toxic or sub-therapeutic blood levels of the drug.
These problems have been and still are the subject of extensive research and can only partly be dealt with in most cases using different methods including oral administration of pro-drugs and controlled release dosage forms. However, these problems may also be avoided by the use of iontophoresis. Using electric current as an external driving force, hydrophilic, charged drugs can be readily introduced through the epidermal level.
Various types of drugs are potential candidates for iontophoresis. Hydrophilic, charged drugs with relatively low molecular weight are the most suitable for the procedure, although the delivery of some large peptides and hormones by this technique has also proven to be successful.
Direct current, or galvanic current, is the current of choice for iontophoresis. Direct current allows the maximum ion transfer per unit of applied current, because its course is uninterrupted.
According to ohm's law: V=IR,
where V is voltage, I is current, and R is resistance, the voltage generated within the system is therefore dependent on the resistance of the skin or other tissue during the treatment.
It has been suggested by many investigators that penetration of hydrophilic, charged substances occurs mainly by way of sweat ducts, sebaceous glands, and hair follicles and imperfection of the skin (The Shunt Pathway theory).
According to the flip-flop gate mechanism, it has been suggested that permeability of skin may be altered as a result of the application of an electric potential across the skin. Jung et al. in 1983 found that the only structural requirement for pore formation was the presence of alpha-helical polypeptides. When an electric potential is applied across a physiological membrane, a voltage-dependent “flip-flop,’ of the helices occurs. The skin permeability can be enhanced by the formation of “artificial shunts” by the use of direct current as applied during iontophoresis.
The following factors affect iontophoretic skin permeation:
molecular weight,
current density,
skin impedance,
ion conductivity,
pH of the drug solution,
ion valence,
duration of lontophoresis,
concentration of the drug ion in the solution.
In optimal conditions, an organism receives only 10% of the substance on the electrode applied to the skin. In fact, an organism may receive from 1 to 10% of the substance.
Therapeutically, a current density of less than 1 mA per square inch of electrode surface is recommended.
According to Faraday's, First Law of Electrolysis, which states that the mass of a substance liberated at (or dissolved from) an electrode during electrolysis is directly proportional to the quantity of electrolyte.
An electrolyte can be defined as a substance that conducts electric current as a result of dissociation into positively and negatively charged particles called ions, which migrate toward and ordinarily are discharged at the negative and positive electrodes (cathode and anode respectively), of an electric circuit. The most familiar electrolytes are acids, bases, and salts, which ionize when dissolved in such polar solvents as water or alcohol. An essential requirement for solvents to be used is that they conduct electric current and have to possess an electric dipole.
Polar solvents consist of strong dipolar molecules having hydrogen bonding. Water is a very unique polar solvent in that it also has a high dielectric constant, which indicates the effect that a substance has, when it acts as a medium, on the ease with which two oppositely charged ions may be separated. The higher the dielectric constant of a medium, the easier it is to separate two oppositely charged species in that medium, which is an essential requirement for the existence of ionized molecules that may be moved by an electric current, as with iontophoresis.
Table 2 shows some useful polar solvents with their dielectric constants. The values listed are relative to a vacuum which by definition has a dielectric constant of unity.
Solvent
Dielectric constant (&egr; at 20° C.)
water
80
glycerin
46
ethylene glycol
41
methyl alcohol
33
ethyl alcohol
25
n-propyl alcohol
22
The degree of dissolution and subsequent ionization can be improved and regulated by means of the addition of suitable electrolytes forming buffer systems in the selected polar solvent or mixtures thereof.
Siddiqui et al. found that during passive absorption the penetration rate of lidocaine was greatest at the higher pH levels (9.4 and 11.7), where lidocaine is mainly non ionized. On the other hand, lidocaine is mainly in the ioni
Lerner Eduard N.
Lerner Leonid
Intraabrain International NV
Maynard Jennifer
Mendez Manuel
Nixon & Vanderhye P.C.
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