MXPA98004007A - Device for increasing the release of biologically active substances and compounds in an organi - Google Patents

Abstract

Many of the efforts that are currently underway to discover new therapeutic drugs for central nervous system (CNS) disorders will also face the problem of getting them to the brain without impairing the activity or integrity of such substances or compounds, while minimizing the effects adverse of the system. And that means finding a way around - or through - the brain blood barrier (BSB), a physiological barrier between the bloodstream and the brain. A study by the National Institute of Mental Health (INSM) shows that, in the United States, one out of every three individuals suffers from some CNS disorder at some point in their lives. Approximately two million in the same country have suffered an attack, which is the third leading cause of death in the United States [17, 1

Description

DEVICE FOR INCREASING THE RELEASE OF BIOLOGICAL ACTIVE SUBSTANCES AND COMPOUNDS IN AN AGENCY DESCRIPTION OF THE INVENTION Currently, most efforts on the way to discover new therapeutic drugs for central nervous system (CNS) disorders will also confront the problem of releasing them to the brain without harming the activity or integrity of such substances or compounds, while the systematic adverse effects are minimized. And that means finding a way around or through the blood brain barrier (BBB), a physiological barrier between the bloodstream and the brain. A study by the National Institute of Mental Health (NIMH) shows that, in the United States, one of three individuals suffers from central nervous system disorder at some stage of their life. Approximately two million in the same country have suffered a stroke, which is the third leading cause of death in the United States [17, 18]. 2. IONTOPHORESIS After the discovery of the electrical nature of the nervous impulse by Galvani in 1791, attention is focused on the possibility of using electricity as a mode of drug release. Galvani provided a major stimulus to Volta to discover a source of electricity from direct current, voltaic battery or battery, and new research on the effects of direct current (DC) on animal tissues broadens the scientific basis for the total subject of electrophysiology . It has been known for a long time that medicines can be introduced into the human body through the skin. The skin has a selective permeability for lipophilic substances (soluble to lipids) and acts as a barrier for hydrophilic substances (soluble in water). In 1747, Veratti suggests that hydrophilic drugs can be introduced into the subcutaneous tissue through human skin by the application of direct current [5]. This mode has come to be known as iontophoresis (which means ion transfer). Table 1 shows several examples of drugs introduced through the skin by iontophoresis for some conditions. Drug Condition 1. Acetic acid Ossifying myositis 2. Aspirin Rheumatic diseases 3. Dexamethasone and lidocaine Tendinitis, bursitis, rheumatoid arthritis 4. Diclofenac sodium Scapulahumeral periarthritis, elbow epicondylitis 5. Iodine Fibrosis, adhesions, scar tissue, burst finger • f 6. Lidocaine Local anesthesia 7. Lithium Arthritis couty 8. Morphine Postoperative analgesia 9. Pilocarpine Sweat test (cystic fibrosis) 10. Pirprofen Rheumatic diseases 11. Potassium citrate Rheumatoid arthritis 12. Potassium iodide Scar tissue 13. Silver Chronic osteomyelitis 14. Salicylate Plantar warts, scar tissue 15. Sodium fluoride Hypersensitivity of teeth Table 1: Drugs introduced by iontophoresis for corresponding conditions. This is only a small part of different drugs or biologically active substances that can be introduced by iontophoresis. The skin is a multi-component, multifunctional organ that is involved in the body's interactions with, and adaptation to, the environment. This is composed of the dermis and epidermis. The thickness of the dermis varies from 1 mm on the leather to 4 mm on the part later. The blood vessels, the lymphatic vessels, the nerve endings, the hair follicles, the sebaceous glands, the sweat glands, are all located in the dermis. The epidermis is in the range of 0.075 to 0.15 mm in # thickness, except in the palm and in the plant, up to where it can be up to 0.6 mm thick. Many lipophilic drugs, such as scopolamine for motion sickness, clonicide for hypertension, and nitroglycerin for the treatment of angina can easily be released through human skin. With these drugs, the concentration gradient between the depot loaded with drugs and the body is sufficient to release the drug through the skin in therapeutic dose ratios. However, this is not the case for hydrophilic drugs [20]. Since topical application fails to deliver therapeutic doses of hydrophilic drugs, traditional methods, such as the administration of systematic, oral or parenteral drugs, have been favored. Without However, these methods have several disadvantages. B First, systematic administration can lead to mass 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 such as food interaction, inactivation in the gastrointestinal tract, disease status, and concomitant medication. Additionally, the oral administration of drugs can give rise to fluctuations in the concentration of a drug in the systematic circulation. This can your result in toxic or subtherapeutic blood levels of the drugs. These problems have been and are the subject of prolonged investigation and can be partially only conducted in the majority of cases using different methods that include the oral administration of pro-drugs and controlled-release dosage forms. However, these problems can also be avoided by the use of iontophoresis. Using electric current as a force of * external impulse, hydrophilic drugs can be easily introduced through the epidermal level. Several types of drugs are potential candidates for iontophoresis. Hydrophilic drugs with relatively low molecular weight are the most suitable for the procedure, although the release of some large peptides and hormones by this technique has also proved successful [5, 3, 6]. Direct current or galvanic current is the current of choice for iontophoresis. Direct current allows the maximum transfer of ions per unit of current applied, due to its course that is uninterrupted [7]. According to Ohm's law: V = IR, where V is the voltage, I is the current, R is resistance, the voltage generated within the system is therefore dependent on the resistance of the skin or other tissue during the treatment. Many researchers have suggested that the penetration of hydrophilic substances occurs mainly by the form of the sweat ducts, sebaceous glands, hair follicles and the imperfection of the skin (The Shunt Pathway theory [3, 10, 23, 4].) According to the scale gate mechanism, * has suggested that the permeability of the skin can be altered as a result of the application of an electric potential between the skin [5, 6]. Jung et al., In 1983 found that only the structural requirement for pore formation is the presence of alpha helical polypeptides [12]. When an electric potential is applied between a physiological membrane, the "scale" effect depends on the voltage of the propellers. The permeability of the skin can be increased by the formation of "artificial closures" by the use of direct current as applied during iontophoresis [5, 6]. The following factors affect the permeation of the iontophoretic skin: - molecular weight, - current density, - impedance of the skin, - ion conductivity, 25 - pH of the drug solution. - valence of the ion, - duration of iontophoresis, - concentration of the ion of the drug in the solution. Under optimal conditions, an organism receives only 10% of the substance when applying the electrode to the skin. In fact, an organism can receive from 1 to 10% of the substance. Therapeutically, a current density of less than 1 mA per square inch of the electrode surface is recommended [7]. According to the first Law of Electrolysis of Faraday, which states that the mass of a substance released in (or dissolved from) an electrode during electrolysis is directly proportional to the amount of the 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 to and are ordinarily discharged into the negative and positive electrodes (cathode and anode respectively), of an electrical circuit. The most familiar electrolytes are acids, bases and salts, which ionize when they dissolve in such polar solvents as water and alcohol. An essential requirement for the solvents to be used is that they conduct electric current and that they must have an electric dipole. Polar solvents consist of strong dipole molecules that have a hydrogen bond. Water is a very unique polar solvent, since it 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 can be separated. The higher dielectric constant of the medium, it is easier to separate two oppositely charged species in that medium, which is an essential requirement for the existence of ionized molecules that can be moved by an electric current, as with iontophoresis. Table 2 shows some useful polar solvents with their dielectric constants. The values listed are related to the vacuum in which by definition it has a dielectric constant of one. Solvent Dielectric constant (e) (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. they form buffer systems in the selected polar solvent or mixtures thereof. Seddiqui et al [22 [found that during passive absorption the penetration rate is greater in 5 when pH levels are higher (9.4 and 11.7), where lidocaine is mainly un-ionized. On the other hand, lidocaine is mainly in the ionized form at pH 3.4 and 5.2. ? During iontophoresis, the drugs do not penetrate a large depth. After applying a current of 5 mA on the right side and 0 mA on the left side for 20 minutes, dexamethasone radioradio is detected at a maximum depth of 1.7 cm on the right side, which is the location of the joint capsule of the hip of the monkey (Glass et to [9]). MjL For electrophoresis, not only can direct (galvanic) current be used but also other different impulse currents, as well as direct polarity and alternating polarity in a rectified regime (diadynamic, sinusoidal, fluctuation, etc.). It is possible to use or combine different types of energy. For example, iontophoresis can be combined with ultrasound, magnetic field, temperature increase, etc. 25 When a polarity is chosen, it is necessary to take into account that the ions of all metals, of local anesthetic drugs, of most alkaloids, and of antibiotics all have a positive charge. Therefore, these must be introduced from an anode. On the other hand, the ions of all metalloids and acid radicals have a negative charge and must be introduced from the cathode. There have been a number of interesting results that Do they prove a successful introduction of drugs and other W chemical substances in the brain of animals through the iontophoresis [15, 1]. 3. PHARMACOKINETICS 3.1 Physicochemical factors in the transfer of drugs between membranes. The absorption, distribution, biotransformation and Excretion of a drug involves its passage between the JK-cellular membranes. The important characteristics of a drug are its size and molecular shape, degree of ionization, relative lipid solubility of its ionized and non-ionized forms. Passive processes 20 Drugs cross the membranes by either passive processes or by mechanisms that involve the participation of membrane components. Both the non-polar lipid soluble compounds and polar water soluble substances, which retain sufficient lipid solubility, can cross the lipid portion of the membrane by passive diffusion. Such a transfer is directly proportional to the concentration gradient between the membrane. As long as the partition coefficient is higher, the concentration of the drug in the membrane is greater and its diffusion is faster. The volume flow 5 of water carries with it any water-soluble molecule that is small enough to pass through the channels. Filtration is a common mechanism for the transfer of many small polar and non-polar substances, soluble in water. 10 Capillar endothelial cells have large channels (40A), and molecules as large as albumin can pass to a limited degree from the plasma to the extracellular fluid. In contrast, the channels in the intestinal epithelium and most cell membranes have approximately 4Á in diameter and allow the passage only of water, urea, and other small molecules, soluble in water. Substances do not generally pass through channels in cell membranes, if their molecular mass is greater than 100 to 200. Most inorganic ions are sufficiently small to penetrate the membrane channels, but its concentration gradient between the cell membrane is generally determined by the potential of the transmembrane. Weak Electrolytes and Influence of pH. Most drugs are weak acids or bases and are present in solution as well as non-ionized and ionized species. The non-ionized portion is usually soluble in lipids and can diffuse easily between the cell membrane. In contrast, the ionized fraction is often unable to penetrate the lipid membrane due to its low lipid solubility, or to pass the membrane channels due to its size. If the ionized portion of a weak electrolyte can pass through the channels or through the membrane, it will be distributed according to the transmembrane potential in the same way as an inorganic ion. 10 Membrane mediated active transport by carrier. Passive processes do not explain the passage of all drugs between cell membranes. Active transport is responsible for the rapid transfer of many organic acids and bases between the renal tubule, the choroid plexus, and the liver cells. The transported substance is transferred against an electrochemical gradient. The transcellular fluxes are formed by the active transport of Na + between the epithelial cells. Proteins and other macromolecules slowly cross epithelial cells for pinocytosis, a form of vesicular transport. 3.2 ABSORPTION OF DRUGS It is of practical importance to know the way in which drugs are absorbed. The absorption ratio influences the time course of the drug effect, and this is an important factor in determining the dose of the drug.

* In addition, the choice of the route by which a drug is administered is often influenced by considerations of drug absorption. Factors that Modify Absorption 5 Absorption from all administration sites is dependent on the solubility of the drug. The drugs given in aqueous solution are absorbed more quickly than those given in oily solution, suspension or solid form. For those given in solid form, the dissolution ratio may be a limiting factor in its absorption. Local conditions at the absorption site alter the solubility. In this way, in the low pH of the gastric juice, many acidic drugs are absorbed slowly, since they precipitate in the stomach fluid, and the dissolution occurs very slowly. Highly insoluble substances may not be absorbed from the alimentary tract at all. The concentration of the drug influences its absorption rate. Drugs ingested or injected in solutions of High concentrations are absorbed more quickly than drugs in low concentration solutions. Circulation to the absorption site also affects the absorption of the drug. The increased blood flow, brought about by massage or local application of heat, improves the absorption of a drug. The absorption surface area to which the drug is exposed is one of the important determinants of the absorption rate of the drug. Enteric Administration (Oral) versus Parenteral. Often there is a choice of route by which a therapeutic agent can be given, and a knowledge of the advantages and disadvantages of different routes of administration is then of fundamental importance. Oral ingestion is the oldest method of drug administration. Disadvantages for the oral route include mesis as a result of irritation of the gastrointestinal mucosa, destruction of some drugs by digestive enzymes or low gastric pH, and the formation with food of complexes that can not be absorbed. Drugs absorbed from the gastrointestinal tract can be metabolized for a long time the liver before they gain access to general circulation. Parenteral drug injection has certain distinct advantages over oral administration. In some cases, parenteral administration is essential for the drug to be actively absorbed. The absorption is usually more faster and more predictable than when a drug is given by mouth. In emergency therapy, parenteral administration is particularly helpful. If a patient is unconscious, uncooperative, or unable to retain anything given by mouth, parenteral therapy can be a need. The injection of drugs also has its disadvantages. Strict asepsis must be maintained to avoid infection, an intravascular injection may be presented when it is not proposed, pain may accompany the injection, and it is often difficult for a patient to carry out the same injection if a procedure is necessary. self-medication Parenteral therapy is also more expensive and less safe than oral medication. Oral Ingestion The rate of absorption of the drugs from of the gastrointestinal tract is generally proportional to the lipid solubility of the compound in question. If the drug is a weak acid or base, its non-ionized form is more soluble in lipids, and the pH within the gastrointestinal tract becomes a major determinant. Alcohol, a non-electrolyte, soluble in lipids, it is quickly absorbed into the bloodstream by diffusion between the gastric and intestinal mucosa. Quaternary ammonium compounds and other lipid-insoluble, fully ionized drugs are absorbed more slowly. Other drugs are poorly absorbed since their non-ionic forms are insoluble in lipids. Weak bases, such as quinidine and ephedrine, which are predominantly ionized at the pH of the gastric juice, are poorly absorbed through the gastric mucosa and are absorbed mainly through the intestinal mucosa. Weak acids, such as salicylates and barbiturates, which are predominantly non-ionized in acidic gastric contents, are more easily absorbed from the stomach. If the gastric contents are made composite alkalies, the acids become ionized and can be absorbed more slowly. However, gastric pH also influences the solubility of the drug and dissolution ^^ of the solid dose form. In addition, the net effect of the change in gastric pH may be relatively minor, since the The absorption of most drugs occurs mainly in the intestine due to its greater surface area. For the same reason, the absorption of most drugs is delayed or reduced if gastric emptying is delayed. The absorption through the alimentary tract can be decreased if the ingested drug is unstable in the fluid Gastrointestinal or if it is linked to food or other gastrointestinal contents. The simultaneous ingestion of the food also delays the absorption delaying the gastric emptying. Drugs that are destroyed by gastric juice or that cause gastric irritation, are sometimes administered in dosage form with a coating that prevents dissolution in the gastric contents. However, some enteric coated preparations of a drug may also resist dissolution in the intestine, and very little of the drug can be absorbed.

The proportion of dissolution of some preparations in the gastrointestinal fluid can be completely irregular due to the variations in the gatrointestinal pH, gastric emptying, intestinal mobility and other physiological factors that influence the absorption of drugs. On the other hand, slow absorption from the gastrointestinal tract is often incomplete and erratic. The drugs given for a "^ brief therapeutic effect should not be in the form of 'synchronized release. Conversely, the preparations of Synchronized releases are not necessary for drugs with a large inherent duration of effect. Also, the synchronized release preparations of some drugs may not be safe. Sublingual Administration 15 Absorption from the oral mucosa is rapid, and - P ^ greater concentration in the blood can be reached by this route than by decreasing absorption in the alimentary tract. This may result, since the metabolism of drugs as a result of passage through the liver is minimized, and that the drug is not subject to possible destruction by gastrointestinal secretions or complex formation with food. However, substances that are unpleasant to taste or that are irritating should not be given by this route. The sublingual administration route allows the rapid absorption of nitroglycerin and other drugs. It is a convenient method when the drug is suitable for such administration. Rectal Administration The rectal route is often useful when avoiding oral ingestion by vomiting or when the patient is unconscious. In addition, the absorbed drug does not pass through the liver before entering the systemic circulation. However, rectal absorption is often irregular and complete and many drugs cause irritation of the mucosa. rectal. The main routes of parenteral administration are intravenous, subcutaneous and intramuscular. Absorption of lipid-soluble drugs from the subcutaneous and intramuscular sites also occurs by simple diffusion through capillary membranes in the blood. 15 Insoluble lipid drugs are absorbed by penetration through relatively large aqueous channels in the endothelial membrane; Large molecules, such as proteins, gain access to circulation via the lymphatic channels, some large molecules and substances microcrystallines are absorbed from these sites by phagocytosis. Certain irritating and hypertonic solutions can only be given in this way. Repeated intravenous injections are dependent on the power of veins. 25 Drugs should not be given in a single vehicle by this route. Subcutaneous injection can only be used for drugs that are not irritating to the tissue. Drugs in aqueous solution are rapidly absorbed after intramuscular injection. Irritants that can not be injected subcutaneously can often be given intramuscularly. Occasionally a drug is injected directly into an artery to localize its effect on a particular tissue or organ. Antineoplastic agents are sometimes given in this way for the treatment of localized tumors. Vaginal administration The vaginal route is sometimes useful when other routes are inconvenient for some reason. Intrathecal Administration The blood-brain barrier and the blood-cerebrospinal fluid barrier often prevent or slow the entry of drugs into the central nervous system (CNS). Therefore, when local and rapid effects of drugs are desired on the meninges or the cerebrospinal axes as in spinal anesthesia or acute CNS infections, the. Drugs are sometimes injected directly into the spinal subarachnoid space. Intraperitoneal Administration The peritoneal cavity offers a large absorbent surface from which drugs enter the circulation rapidly. Intraperitoneal injection is a common laboratory procedure, but it is used clinically at random. The danger of injection and accessions are too great to guarantee the routine use of this route. However, peritoneal dialysis is sometimes a valuable procedure in the treatment of drug poisoning. Pulmonary Administration Gaseous and volatile drugs can be inhaled and absorbed through the lung epithelium and mucous membranes of the respiratory tract. Access to traffic is fast on this route. In addition, drug solutions can be atomized and inhaled fine drops in the air (aerosol). Topical application Mucous membranes. The drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra and urinary bladder, mainly due to their local effects. Occasionally, as in the application of antidiuretic hormone to the nasal mucosa, systematic absorption is the goal. Skin. Few drugs easily penetrate intact skin. The absorption of those that do is proportional to their solubility in lipids because the epidermis behaves as a lipid barrier. 4. BARRIER BLOOD-BRAIN It has been known for a long time that the volume of brain and the spinal cord is surrounded by a fluid especially secreted, clear called cerebrospinal fluid (FCS). Chemicals, such as metabolites, are ? < . move relatively freely from the alimentary canal 'in the blood, but not in the FCS. As a result, the levels in the blood of sugars, amino acids or fatty acids fluctuates over a wide range, while their concentrations in the FCS remain relatively stable. The same is true for hormones, antibodies, certain electrolytes and a variety of drugs. Injected directly into the blood, they act rapidly on the peripheral tissues, such as muscles, heart or glands, but have little or no effect on the central nervous system (S? C). When administered in the FCS, however, the same substances exert a prompt and strong action. The The conclusion is that the substances injected into the blood do not reach the FCS and the brain quickly enough and in effective concentration. The way in which the brain maintains its constant environment is frequently discussed in terms of a blood-brain barrier (BBB).

* Once substances have discovered their path to FCS, they are free to diffuse into brain tissues [13]. The entry of hydrophilic and relatively large molecules into the CNS is restricted by the existence of a BBB [25]. The BBB separates the brain from the bloodstream and is involved in brain homeostasis. The BBB is located in the cerebral microvessels and is composed of several cellular types, such as endothelial cells, astrocytes,? microglial cells, perivascular macrophages, and pericytes. 10 Brain and endothelial cells form the morphological and functional basis of the BBB. NASAL CAVITY AND OLFACTORY SENSE Nasal Cavity External Nose 15 The terms commonly used to describe the external nose ff are the tip or apex, the base (which includes the nares), the root (where) the nasal bones are attached to the brain) , the dorsum (between the root and the tip), and the bridge (the upper part of the dorsum). Only the third upper part 20 of the external nose is bony. The lower two thirds are cartilaginous. Internal Nose On each side of the nose are the anterior and posterior openings called nares. Later nares are also called the coana. The vestibule is the anterior part, aligned to the skin of the nasal cavity. The nasal septa divides the nose into two nostrils. The lateral wall of the nose is an anatomically complicated area. There are four nasal turbinates or shells. Named from the bottom up, there are 5 turbinates lower, middle, upper and supreme. The mucous membrane of the lower turbinate is very rich in blood vessels and is semierectile. The various nasal meaties are named according to the turbinates that rest on them. Above the upper and supreme turbinates is in sphenostoid space, in which sphenoid sinusoidal is opened. The inferior meatus are large blood vessels (skenopalatine branches) under the mucosa of the lateral wall of the inferior meatus. Both the external and internal carotid systems provide blood supply to the nose. The venous drainage is important since part of it, through the angular vein, leads to the inferior ophthalmic vein and eventually to the sinus cavernosa. The majority of the venous drainage, however, is downward through the anterior facial vein. 20 The lymphatic drainage of the nose is prolonged and parallel to the venous drainage. The olfactory area is located in the upper part of the nasal vault above the upper turbinate. Sensory hairs extend from the surface of the olfactory area to cells that are deep in the mucosa.

The nerve fibers that are at the service of the sense of smell have their cells of origin in the mucous membrane of the upper and posterior parts of the nasal cavity. The complete olfactory mucosa covers an area of approximately 2.5 cm. The central processes of the olfactory vilaments are very fine non-honeycomb fibers that converge to form small fascicles entangled by the Schwann cells and pass through the openings in the cribriform plate of the ethmoid bone in the olfactory bulb. The axons of the cells mitral and inclined enter the olfactory tract, which runs along the olfactory cavity of the cribriform plate to the brain. Some fibers are projected to the middle dorsal nucleus of the thalamus and hypothalamus. That olfactory stimuli and emotional stimuli are strongly united is not surprising, in view of their common roots in the lymphatic system [26]. According to Bell [27], the olfactory system has a direct neuro-autonomic and neurophysiological input to the amygdala and eventually to the hippocampus. Therefore it is It is conceivable that chemical stimuli at low levels can trigger limbic dysfunction in patients who have met the descriptive criterion for somatization disorder. It has also been established [29] that there is no blood-brain barrier in the nasal passages, the structure limbic (eg, amygdala, olfactory bulb and hippocampus) ffF can be easily activated. Therefore, the olfactory nerves can transport toxins directly to the limbic system. This can result in symptoms that include memory loss, irritable bowel, and migraine headaches. Shipley has suggested [28, 16] that it is possible to transport substances which make contact with the nasal epithelium to the brain and that this is in this way possible to influence the function of neurons in the brain, which include some which have prolonged projection to broad areas of the central nervous system. 6. OPTICAL NERVE The optic nerve, which mediates vision, is distributed to the ball of the eye. Most of its fibers are afferent and originate in the nerve cells of the ganglionic layer of the retina. Developed, the optic nerves and retinas are part of the brain and their fibers are provided with glias. The optic nerve, approximately 4 cm long, is directed backward and medially through the back of the orbital cavity. This runs through the optical channel in the cranial cavity and attaches to the optimal chiasm. The optic nerve is enclosed in three covers, which are continuous with the membranes of the brain, and are prolonged so away from the back of the eyeball. Therefore, rt - ^ there is a direct connection between the optic nerve and the brain structures. Itaya and Van Hoesen [11] describe the transneuronal retrograde markers of neurons in the superficial layer of the superior colliculus that follows the intraocular injection of horseradish peroxidase, wheat germ agglutinin. This is one of the most comprehensive reports of transneuronal transport of horseradish peroxidase, agglutinin * of wheat germ, which studies the distribution of conjugated in the visual system that follows the intraocular injections in chicken, rat and monkey [8]. 7. THE ORAL CAVITY The oral cavity is previously joined by the lips, later by the anterior facial arch, inferiorly by the base of the mouth and superiorly by the hard and soft palates. The oral cavity is divided into two parts by the upper and lower alveolar processes of the teeth: first the vestibule of the mouth that rests between the lip and. the cheek on one side and the teeth and the alveolar process on the other hand, and second, the oral cavity limited externally by the alveolar processes and the teeth. The tongue fills the oral cavity almost completely when the mouth is closed. The presence of a slight negative pressure in the The oral cavity ensures that the tongue adheres to the soft and hard palate, thus keeping the mouth closed. The following parts of the language are distinguished; the tip, the margins, the body, the base and the ventral surface. The tongue is covered by the mucous membrane that is continuous with the floor of the mouth. Beneath its anterior tip a fold of the mucous membrane forms the brake, which joins the floor of the mouth. Between the floor of the mouth and the tongue is the sublingual space. The sublingual space is joined by the anterior and lateral jaw; the posterior wall is formed by the stiloglossus muscles, the palatoglossus muscles, and the hyoid bone. The root is formed by the mylohyoid muscles. The epithelium that lines the oral cavity consists of stratified non-keratinized squamous epithelium which is thickened at certain points such as the alveolar edges and the hard palate where it is attached to the underlying periosteum. The subepithelial collection of minor salivary glands is located on the oral cavity being more common in some parts than others. The normal palate at birth consists of three portions: hard palate, soft palate, and uvula. These are covered with continuous non-ciliated mucous membrane with that of the alveolus and meets as a raphe (crest) in the midline. The mucous membrane forms the roughness of the oral surface of the hard palate. The soft palate is attached to the posterior margin of the soft palate. With the mouth closed, the soft palate rests on the tongue. And with an open mouth it remains free. The hard palate often supports the floor of the nose and is covered by dense mucosa. Vascular release. The external carotid artery supplies the tongue via the lingual artery, the floor of the mouth via the sublingual artery, the cheek via the facial artery, and the palate via the ascending pharynx and descending palatal arteries. The latter originates from the internal maxillary artery. Venous drainage runs via the veins of the same names to the facial vein, the terigoid venous plexus and the internal jugular vein. There is also a connection to the cavernous sinusoids via the terigoid plexus. The lymph drains via submental regional, submandibular and parotid nodules to the internal jugular chain. The lymphatic drainage of the base of the tongue and the floor of the mouth are on the same side and the opposite side. 8. STRAIGHT The rectum begins where the taeniae coli fuses to form a continuous longitudinal muscle covering. When taking into account the obliquity of the levator ani muscle, the rectum is intimately related laterally to the pararectal space but below and laterally to the pelvic diaphragm and to the apex of the ischiorectal fossa. The pararectal space is formed by the anterior peritoneum, the internal obturator and the lateral walls of the pelvis laterally, by the rectum moderately and by the levator ani muscle. The rectum also follows the curve of the sacrum in its lower two thirds but at the level of the levator ani muscle, where it enters the anal canal, and in turn back abruptly and downward. The posterior relations of the rectum are the sacrum, the * coccyx, puborectal muscles and middle sacral vessels.

The above relationships differ according to sex. In men, the extraperitoneal rectum is related from bottom to top to the prostate, seminal vesicles, vessel and bladder. In women, the infraperitoneal rectum rests immediately behind the posterior vaginal wall. 15 Arterial supply The colon and rectum are supplied from the territory of the superior and inferior mesenteric arteries. The superior mesenteric artery originates from the front of the aorta just below the coeliac axis. The mesenteric artery The lower one originates from the aorta on the lower surface of the third part of the duodenum. The terminal portion of the inferior mesenteric artery continues over the pelvic rim in the mesocolon as well as the superior hemorrhoidal artery and divides into the ramifications right and left before being subdivided into the anterior and posterior terminal arteries supplying the rectum. The middle emorroid artery supplies the third middle part of the rectum. The inferior hemorrhoidal artery supplies the inferior rectus. The thirteen hemorrhoidal vessels 5 form a comprehensive anastomosis in the submucosa of the anal canal and the inferior rectus. Venous drainage Veins of the rectum include the superior hemorrhoid which drains into the portal and mesenteric system inferior, and the middle and lower hemorrhoids, which enters the systematic venous circulation via the internal iliac veins. The superior hemorrhoidal venous plexus rests on the submucosa of the upper part of the anal canal and inferior 2 cm or more of the rectum. Therefore, five or six collecting veins pass up into the wall of the rectum; in the first they run - ^ -, in the submucosa, but gradually penetrate the muscular covering to be in the perirectal fat where they join to form two veins and eventually the individual upper hemorrhoidal trunk. The average hemorrhoidal vein is not important relatively, but the inferior hemorrhoidal vein is connected to the vertebral plexus which surrounds the spinal cord. Therefore, some compounds can get from the lower venous hemorrhoid through the vertebrae of the plexus into the spinal fluid and from there to the spinal cord and into the brain. 25 9. VAGINA The vagina is an elastic fibrovascular canal that extends upward from the vulva at an angle of 60-70 degrees to the horizontal, although it is not linear as is generally assumed, but angled backward. The vagina has a blind upper extremity except that the cervix with its external os projects through its upper anterior wall.

^ The vault of the vagina is divided into four areas of ? according to his relations with the cervix: later fornix the which is very broad, the anterior fornix which is shallow and two lateral fornices. The posterior wall of the vagina is approximately 10 cm, while the anterior wall is approximately 8 cm in length. The introitus is functionally closed by the lips which are in contact with each other. "^ (f If the walls are separated, the vagina of the nulliparous married woman has a diameter of about 4-5 cm at its lower end and is twice as wide as its upper end, but the width and length of the vagina show considerable individual variations. The functional width is determined to a large degree by the tone and contractions of the surrounding muscles. The vagina is lined by the stratified squamous epithelium which also extends to and covers the vaginal cervix as well as external os. Normally, the * surface lacks keratin. The epithelium is multi-stratified, the cuboidal basal cells are the source of continuous production of the anterior squamous cells. 5 The epithelium does not contain glands of any kind. Vaginal secretion consists of tissue fluids, epithelial residues, electrolytes, proteins, and lactic acid.

The amount of the latter is governed by the content of f > glycogen of the epithelium and the presence of bacillus Do derlein 10 but, in the healthy vagina of an adult, it is at a concentration of 0.75 percent. The pH varies with the level of the vagina, which is higher in the upper part due to the mixture of alkaline cervical mucus. It is also estimated that it varies according to the method used for its determination, but figures of 4.0 to 5.5 with an average of 4.5 are accepted. During menstruation, the flow of alkaline blood raises the vaginal pH to levels of 5.8 to 6.8. The vagina not only "secret"; It also absorbs 20 water, electrolytes and low molecular weight substances. It is believed that absorption and re-absorption occurs in the lateral spaces of the lower vagina. The epithelium rests on a subepithelial connective layer, which contains elastic tissue. The outer side 25 of these are muscle coatings in which the fibers are closely arranged in a criss-cross spiral shape. On the outer side of the muscle layers is a strong covering of connective tissue. The vaginal wall itself and the surrounding ones are extremely vascular, therefore they usually bleed easily at the moment of damage and operation. In the vagina of a newborn child (10 to 14 f days) the pH rises to approximately 7 and remains at that level until it reaches puberty, when, with the onset of 10 total ovarian function, the vagina assumes the features already described. During pregnancy the amount of glycogen increases to a maximum and the acidity of the vagina is high (pH 3.5-4.5). After menopause, the epithelium atrophies and loses glycogen. Dó derlein bacilli are found in small and *. ^ V * amounts and the pH rises in a range of 6-8. Therefore, with vaginal iontophoresis should be taken into account the age and vaginal pH of the patient. Vascular connection 20 Arterial. There are: (1) the vaginal artery mainly; (2) ramifications of the uterine artery; (3) ramifications of the internal pudendal artery; (4) small branches from the middle and lower rectal arteries. The vaginal artery is usually a separate branch (or ramifications) of the internal iliac artery, but it becomes detached from the first part of the uterine artery. It passes forward and inward from the broad ligament to reach the lateral vaginal fornix. - In the vaginal wall, this forms the anastomosis with the azygos ramifications of the circular artery of the cervix. The lower vagina is supplied from the middle and lower rectal vessels and by branches from the internal pudendal artery. # Venosa. A plexus of veins around the vagina is connects with those around the bladder and rectum, and finally drains into the internal iliac veins by branches which mainly accompany the corresponding arteries. Veins of the pelvis usually accompany the arteries and have the same names. Sometimes there are two ?, Ft veins to an artery. There are vein plexuses around the bladder, the urethrovesical junction and the anorectal junction and all ultimately drain into the internal iliac veins. Venous return from the rectum and pelvic colon enters the system portal through the inferior mesenteric veins. The plexuses and pelvic veins have communications with the pre-sacral and lumbar channels of the vertebral plexus. This is probably the explanation for the presence of metastatic growths in the spine and brain when the main tumor is in the uterus.

Each pelvic viscera drains into a venous plexus around its walls. The vestibular venous, vaginal, and rectal venous plexuses drain into the internal iliac veins bilaterally. On the pelvic floor, the visceral venous plexuses communicate with the external vertebral venous plexus which surrounds the total length of the spine. The external vertebral plexus communicates with the internal vertebral plexus, which by itself receives the blood of the vertebra. Since there are very few valves in this venous system, this provides a possible path for the spread of neoplastic diseases from the pelvic viscera to the vertebrae. In virgins, the hymen is an impediment to vaginal iontophoresis. Hymen The hymen is a delicate incomplete membrane that protects the entrance to the vagina before maturity and sexual experience. This has one or more openings to allow the flow of menstrual blood and, according to its number and shape is described as annular, crescent, septate or cribriform. If another form is not possible for the introduction of the medication, and this has to be done more than once, an incision should be made in the hymen in such a way that the electrodes can be easily introduced into the vagina.

. THE AUTONOMOUS NERVOUS SYSTEM The autonomic nervous system enervates every organ in the body, creating, as Galen suggests, "sympathy" between the various parts of the body. It has such a complex neural organization in the brain, spinal cord and periphery as well as in the somatic nervous system, but remains largely involuntary or automatic. The hypothalamus can be considered the highest level of integration of autonomic function [2]. This remains under the influence of the cortex of the group of structures known as the limbic system, which includes the olfactory areas, the hippocampus and the amygdaloid complex, the cingulate cortex and the septal area. The regions of the brain regulate the hypothalamus and are critical for emotional expression and affective. The hypothalamus is also related to the maintenance of homeostasis against a changing environment. The autonomic nervous system and many metabolic functions are under the control of the limbic system by means of nerve centers, many of which are located in the hypothalamus. The hypothalamus controls the autonomic nervous system in two ways, by means of the pituitary and from here by other endocrine glands and by the direct descendent nerve trajectories. 25 Lerner [14] who used his electroautonomógrafo proves that the pathology of the internal organs can be provoked initially by the dysfunction of autonomic regulation. 11. THE LIMBIC SYSTEM In 1878 the French neurologist and anthropologist, Pierre 5 Paul Broca, paid attention to a ring of tissue that forms the middle wall of each cerebral hemisphere and called it the lower limbic lobe, although it did not suggest any function for it. Approximately 75 years later, in 1952, Paul MacLean suggests that the components of the limbic ovum, along with the The subcortical nucleus to which it is attached is involved in the elaboration and expression of emotions, and uses the term limbic system to refer this functional circuitry. The limbic system includes the following cortical structures: the olfactory cortex, the hippocampal formation, the cingulate gyrus and subcallose gyrus; as well as the following subcortical regions, which are known at that time in which direct cortical connections are shared: the aigdal, septa, hypothalamus, epithalamus, anterior thalamic nucleus, and parts of the basal ganglia. 20 The limbic region of the telencephalon seems to constitute highly interconnected structures that lie between the neocortical association areas, on the other hand, and the hypothalamus on the other. The limbic region can this way, form the gateway for the neocortical cognitive influence of the hypothalamic mechanism associated with motivation and emotion and vice versa. From the point of view of the literature given above, the following is concluded. The limbic system and the autonomic nervous system, the which is in fact a united autonomic limbic system, regulates all the tissues and organs of an organism that includes the cardiovascular system, the gastrointestinal system, the immune systems, the brain and others. Many substances such as metabolic products, 10 drugs, and other substances can not or only to a limited degree limit the BBB of blood to the brain. From the naxal cavity, these substances can penetrate into the brain, since in the area of 2.5 cm2 of the upper posterior part of the nasal cavity, the BBB does not exist. Therefore, the 15 substances introduced in the upper part of the nasal cavity can enter the brain directly. Access to the CNS is also possible through the optic nerve and through the lower part of the rectum. Using the olfactory nerve and the optic nerve it is has found in the present that it is possible in this way to release compounds in the CNS, by deviating the BBB; the compounds enter in this way in all parts of the CNS and of course in the FSC. To increase the release of substances in the CNS 25 it has been found in the present that the lower part of the rectum can be used, since the inferior hemorrhoidal vein is connected to the vertebral vein around the spinal cord. This arrives therefore to the spinal fluid (FSC), and from there to the CNS. An increased non-invasive intravenous release of drugs or other biologically active compounds using the sublingual space path and through the vagina and upper rectum is also suggested. The above methods are related to the non-invasive release of biologically active compounds to the brain (SCN) or blood. Iontophoresis can increase the release of drugs to the body. The present invention relates in a first embodiment to a device for increasing the release of an effective amount of a biologically active compound in an organ or target tissue in a living organism, comprising at least two electrodes, of which at least one can function as an active electrode and one as a passive electrode, the electrodes that are capable of being placed separately apart, in preselected locations of the organism, where the electrons are all connected to a selected energy source, which generates and it maintains an energy field before and during the increase in the release of the compound under the influence of which the compound is driven in a direction from the F-active electrode to the passive and towards the target organ or tissue. Due to the fact that an energy field is generated over an area which includes at least a part of the target organ or tissue, it now seems possible to release the active compound in one direction from the active electrode to the passive electrode. Preferably, the present device comprises an energy source, which is provided with means for internal electrical circuitry, to maintain the power supply in a rest position, which means that it can activate the electrodes in the release position of the device. composed after the connection to the organism. Any type of electric current that includes but is not limited to CD and AC of any waveform, can be used for all variants, which are will describe in this application. It is noted that the pre-selected locations are preferably with respect to the active electrode, provided with the active substance: the nostril, or the bridge over the nose for the electrode without substance, with the substance applied separately in the nostrils; and a supplementary pair of active and passive electrodes applied superficially. It is found that the electrode acting as the active electrode is provided with a means for carrying the active compound in a container of some kind. Such an arrangement has the advantage that the amount of the active compound to be delivered to the target tissue organ from a pre-selected location at some distance from the tissue organism can be supplied as accurate as possible. If, for example, the active electrode, provided with the active substance of choice is placed in the nostril of an animal, or a human being, and the passive electrode is fixed on the back of the head, an electric field is generated which has a current intensity of up to 10 mA, resulting in the almost complete penetration of the active substance into the brain. The duration of iontophoresis is usually up to 60 minutes (sometimes up to several days). In the present invention, the passive electrode can be divided into two or more parts. It will then be possible to increase in the release of the active substance plus ~ ^ P. exactly to the desired organ or tissue, for example by the dividing electrode, fixed in different places of the organism, sequentially. In this regard it is noted that at least one passive electrode should preferably be fixed in the projection on the skin of the living organism, the target organ or tissue, to which the biologically active compound will be delivered. Additionally, it is noted that a device for the delivery of a pharmaceutical agent or drug by means of the iontophoresis, is already known from the United States Patent 5,298,017. This known device is adapted for the release of the transmucosal and transdermal drug and to avoid short circuitry. However, this preferred device is comprised of a plurality of essentially parallel elements, including the counter electrode and the donor electrode, which are indicated in the present invention as the passive electrode and the active electrode respectively. The problem of this known device is still that burning effects can occur, since the intensity of the current used to generate the penetration of the drug must be high. The device according to the invention does not give rise to such short circuit problems. It is further observed that if the electrodes are not connected to the power source, preferably a As the source of electrical energy, the active compound will diffuse and ^ ß will randomly disperse in the organism from the location where the compound is applied. Only by connecting both the active and passive electrodes in the circuit, the active compound will be released directly to the target organ or tissue. With respect to the electrodes, which may be used in the present invention, they are comprised of electrically conductive material, such as a metal such as aluminum, stainless steel, gold, silver, titanium and zinc. Examples of other electrically conductive materials include carbon, graphite, and metallic salts such as silver chloride. The electrodes can be formed of metal sheets, metal meshes, metal deposited or painted on a suitable carrier support, by means of lamination, evaporation of film, or by mixing the electrically conductive material in a polymer binder matrix. Alternatively, the electrodes of a polymer matrix containing a conductive filler such as a metal powder can be formed., powder graphite, carbon fibers, or other known electrically conductive filler material. Polymer-based electrodes can be manufactured by mixing the conductive filler in a polymer matrix, preferably a mixture of hydrophilic and hydrophobic polymers. Hydrophobic polymers provide structural integrity, while hydrophilic polymers can improve ion transport. For example, the metal powder, the carbon powder, carbon fibers and mixtures thereof can be mixed in a hydrophobic polymer matrix. The energy source connected to the electrodes of the present device is preferably a source that provides an electric field, a magnetic field, high energy waves such as laser beams or ultrasonic waves, etc., in a special embodiment. The source of energy can be a combination of these sources. In another mode, the energy source is a -4K source of thermal energy. Such a source can, of course, also be combined as a source as mentioned above. For example, a combination of a source of electrical energy and a source of thermal energy has the advantage that a compound with a relatively high molecular weight can be supplied to the organism, since the supply of thermal energy will allow a better penetration to the tissues, due to the effects of dilation. In a convenient embodiment of a device According to the invention, the energy source is provided with a means for changing the polarity of the electrodes connected to the energy source, in order to avoid irritation or burning sensation in the tissues at the electrode site. The irritation mechanism is related to the intensity and duration of the unidirectional current of ions in tissues, as they are introduced by means of iontophoresis. Electrochemical burns can originate from the hydrogen and hydroxide ions generated by the DC current, where the H + ions accumulate at the anode, and OH- ions at the cathode, leading to pH changes at both sites. These changes cause tissue damage and eventually electrochemical burns. This can be avoided by periodically reversing the polarity of the current in order to neutralize these ions. By temporarily changing the polarity of the electrodes, it will then become possible to solve the potential limitations in the release of the active compound to the target tissue. Changing the polarity of the electrodes will result in a movement of the active compound in the reverse direction with respect to the initial direction. The drug or other biologically active substance or compound can be selected from the Fc following lists, and that are given as examples and without limitation: amino acids, anabolics, analgesics and antagonists, anesthetics, anthelmintics, anti-adrenergic, anti-asthmatic, anti-atherosclerotic, antibacterial, anticolesterolics, anti-coagulants, anti-depressants, antidotes, anti-emetics agents, anti-epileptic drugs, anti-fibrinolytics, anti-inflammatory agents, anti hypertensive, antimetabolites, anti-migraine agents, antifungals, anti-nausea, anti-neoplastic, anti-obesity agent, anti-Parkinson's, anti-protozoal, anti-psychotic, anti-rheumatic, anti-septic, anti-dizziness, anti-viral, appetite stimulants, vaccines bacterial, bioflavonoids, calcium channel blockers, hair stabilizing agents, coagulants, corticosteroids, detoxifying agents for cytostatic treatment, diagnostic agents (such as contrast media and radioisotopes), drugs for the treatment of alcoholism chronic, electrolytes, enzymes, enzymatic inhibitors, * ferments, enzyme inhibitors, gangliosides and ganglioside derivatives, hemostats, hormones, hormone antagonists, hypotonic, immunomodulatory, immunostimulatory, immunosuppressive, mineral, muscle relaxants, 5 neuromodulars, inotropic neurotransmitters, osmotic diuretics, parasympatolytics, parasympathomimetics, peptides, proteins, psychostimulants, respiratory stimulants, sedatives, lipid-lowering agents in serums, relaxing * of smooth muscle, sympatholytics, sympathomimetics, vasodilators, protective vessels, vectors for people, viral vaccines, viruses, vitamins, and each type of neurotropic drugs and other substances. The invention also relates to electrodes for use in a device according to the invention, which comprise an electrically conductive base member which may be connected to the selected energy source, wherein the upper area of the base member is capable of supporting the biologically active compound, and the entire upper area of the base member is covered with an insulating material 20 The electrode should be inserted as deep as possible in the nose due to two reasons. As mentioned above, in the upper part of the nasal cavity, the BBB does not exist and can be derived, and second the lower parts of the nasal cavity contain many capillaries and veins that provide easy access for drugs to the bloodstream. Such an electrode can be placed in a nasal orifice, but it can also be adapted for use in the arteries or veins or in another cavity of the body or organ. The active electrode is then inserted, for example, intra-arterially or intravenously to be placed close to the thrombus by checking with X-rays, while the passive electrode is connected outside the body. The electric energy field then increases the release of The active compound (such as an anticoagulant) completely in the thrombus, to eliminate thrombus or arteriosclerotic plaque, which may be located in the brain, in the heart or in other organs, and thus avoid surgical interventions. Iontophoresis can also be used here to deliver drugs directly to tumors or other morphological disorders in the stomach, in the urinary tract, in the bladder, intraperitoneally, intraracally, etc. In this case, in the present it is inserted the active electrode in one of these organs or cavities, and by means of this active electrode the active compound is delivered directly into the morphological disorder; The passive electrode must be fixed superficially to the body. In this way, the release of the beneficial compound is increased morphological disorder.

Preferably, the base member of the present electrode has a substantial frustoconical frustum shape. Such form allows facilitated insertion into the nasal orifice; however, any other way can do it too, such as the shape similar to a tube. In a convenient embodiment, such an electrode according to the invention contains at least one hole or , - ^ opening in the area covered with the insulating material - ~ present in the base member. Such an opening will prevent a blockage Full flow of the organ in which the electrode has been inserted, for example a nasal orifice. In this way, it will be possible to continue normal breathing through the nose during the procedure. According to a convenient modality, the electrode according to the invention, is provided with a container J * wm for the active compound to be supplied, which has a safety detection connection with the upper area of the electrode. In this way, it is possible to release a biologically active compound to a certain tissue or organ in the form discontinuous without the need to remove and re-insert the present device. The container can be made of any suitable material or combinations of materials, which meets the relevant criteria with respect to the relevant criteria with regarding compatibility with the drug or other substance or compound of interest and with the biological environment, but also with respect to ease of manufacture, sterilization, re-usability, small environmental impact, flexibility, connectivity, availability and durability. Additionally, the drug container or reservoir must be constructed of any material, in such a way that it adapts to absorb and maintain a sufficient quantity of liquid in order to allow the drug to be transported through its wall by means of iontophoresis. . Optionally, the container must maintain a self-sealing membrane or valve that allows filling in situ with the drug solution, without the need for elimination and re-insertion of the present device. For example, sponges, gauze or pads consisting of cotton or other absorbent fabric, either natural or of synthetic origin, can be used. More preferably, the containers or reservoirs are composed, at least in part, of one or more hydrophilic polymers. The typical preference is for hydrophilic polymers, since water is the preferred ion transport medium, the hydrophilic polymers have a relatively high equilibrium water content. The matrices of the multi-layered solid polymer container are composed, at least in part, of the hydrophilic polymer. Insoluble hydrophilic polymer matrices are preferred over soluble hydrophilic polymers, since the probability of releasing the insoluble polymer by iontophoresis is very low. The container matrix can be crosslinked with the drug components in a place such as a silastic matrix, or the polymers can be prefabricated and sipped with the components from the solutions, for example with sponges or pads made of cellulose or spun fiber. The container may also consist of a gel matrix structure, or be of a conventional reservoir type that holds the liquid. The polymers may already be of the linear or crosslinked type. Examples of suitable hydrophilic polymers include polyethylene glycols, polyacrylates, polyoxyethylene alkyl ethers, polyvidone, poloxamers, polyethylene oxides, alcoholsPolyvinyl, polyacrylamide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copolyester, cyclodextrins, crospovidone, crosslinked dextrans, croscarmellose sodium, natural gums and starch, and mixtures thereof. Optionally, the container matrix can contain a hydrophobic polymer to improve structural integrity.

Preferably, the hydrophobic polymer is meltable in heat in order to improve the lamination of the container layers. Examples of suitable hydrophobic polymers include, but are not limited to polyethylene, polypropylene, copolymers of ethylene-vinylacetate, polyvinylacetate, polyisobutylenes, polyamides, polyurethanes, polyvinyl chloride, and acrylic or methacrylic resins. The container can be a polymer matrix structure formed by mixing the drug, solvent, electrolyte or other compounds selected with an inert polymer by means of melt mixing, solvent melting, compression or extrusion. The shape of the container can be such that. allow its combination and union or coupling with the electrode active. The shape, size and conformation of the active electrode and its drug container are determined by the physiological environment related to its application and introduction into the body, for example in the nasal orifice, in the blood vessels, in the stomach, in the rectum and in the vagina The connection of the container on the active electrode can be of a permanent or semi-permanent type or of the cartridge type for easy exchange of the containers. The use of suitable adhesives for permanent connection of the container and the active electrode is prevented, while the lock The physical and connecting means such as a slide lock, a luer lock, screw lock are more suitable for semi-permanent connections to allow reciprocating type containers or cartridge. The energy source that a field provides The electric motor is preferably adapted to provide a current of up to 25 mA. Such current seems to be sufficient in practical tests. However, it will be obvious to the skilled person that some deviation from this value may also be used, and will also fall within the scope of the present invention. The invention also relates to the increased release of an effective amount of a drug to the internal target organ or tissue of an organism, such as a mammal, particularly a human being, that is in need of such a Release with such a drug, wherein the release of the compound increases as such in the organ or tissue from a carrier location in the organism body by means of energy-stimulated penetration, generated and maintained by a field between at least two electrodes that can be divided, on the connection with a selected energy source, of which one of the electrodes can function as an active electrode and one as a passive electrode, of which at least one electrode is placed on the outer layer of the organism, and a electrode that has the opposite polarity is places near the place where the active compound is applied. In this regard it is observed that the passive electrode must be fixed in a place on the skin of the organism, which is the projection of the target tissue to be treated with the biologically active compound, for example, when directly administers the active compound to the CNS via the nose, the active electrode is placed in the nose, while the passive electrode is placed on the back of the head. To obtain the desired effects, the passive electrode is moistened with water or hydrogel or an electrically conductive adhesive before it is fixed to the skin, while the active electrode is provided with the active compound before its fixation. However, it is also possible to use a conductive adhesive or hydrogel in the active compound container, for example, in order to allow temporary fixation on the external part of a tumor. For example, a patient with a tumor in the right temporal lobe. In this case, the active electrode with the drug is inserted into the nasal cavity and the passive electrode divided one part is fixed on the back of the head, and the other part is fixed on the right temporal region on the projection of the tumor. Then, the drug is delivered to the brain and the concentration will be much higher in the tumor region. Preferably, the location of the active electrode that holds the drug container is separated from the target tissue by a membrane or tissue having low strength. A direct penetration, for example, from the nasal cavity to the brain, is possible in this way due to the absence of the blood-brain barrier. According to the invention, it also seems possible to increase the release of the biologically active compound from its carrier location in the body to the target organ or tissue, without any substantial distribution in the parts surrounding the organism, for example the bloodstream. According to a preferred embodiment, the release of the active compound increases transnasally to the CNS from the nasal orifice passing the BBB using a current intensity of up to 10 mA between an active electrode introduced into at least one nostril and a fixed passive electrode to the back of the head or other place on the head. According to a variant of this embodiment, compound release is increased transnasally to the CNS using an active electrode fixed externally to the organism's nose, a passive electrode attached to the back of the head, while the active compound is applied intranasally after of the generation of the energy field. Conveniently, the active electrode is divided into two parts, one of which is externally fixed to the nose, and the other that is provided with the active compound is introduced into a nasal orifice. According to a further variant of the invention, the release of the compound in some specific region of the brain is increased using a fixed active electrode intranasally or extranasally and a divided passive electrode, a part of which is externally fixed on the projection of the specific region on the head, and another part is fixed on the back of the head or another place on the head, while the compound has been applied on the nostril. A variant thereof comprises that the passive electrode is divided into two parts, one of which is connected to the back of the head, and the other part is connected to the forehead or other region of the head of the organism, while the Active electrode that carries the active compound connects with the palate in the mouth of the organism. For the release of the active compound, in a certain hemisphere or part of a hemisphere it is necessary to fix the active electrode in one of the nostrils and fix the passive electrode divided on the mastoid, or other place of the body, and on the projection of the tumor. It is noted that one embodiment comprises a kit consisting of two different groups of active and passive electrodes, wherein one group consists of an active electrode which is placed in a nasal orifice and which is provided with a biologically active substance, and a passive electrode which is fixed on the back of the head; and another group consisting of an active electrode, moistened in water, to be fixed in the part of the head opposite the treatment site, and a passive electrode moistened in water to be fixed in the projection of the treatment site, where both groups of electrodes may be connected to two different sources if desired, or to a source, which will also fall within the claimed range of the projection of the present invention. It is further observed that the present type of iontophoresis, (i.e., according to the invention), can be combined with other methods which are suitable for the release of biologically active compounds. Examples of such methods are diathermy, the use of magnetic field, the use of ultrasonic energy, energy beam as a laser, etc., or the use of compounds that provide a dilation effect. These dilatant compounds can either be administered separately via oral or parenteral routes or be combined with the drug delivered via iontophoresis. Diathermy and dilators are preferred when the release of biologically active compounds having a high molecular weight must be increased through some body tissue, for example, by passing the BBB. According to a variant embodiment of the process according to the invention, the compound increases transocularly to the CNS from the eyelid using a current intensity of up to 10 mA between an active electrode fixed on the active compound carried by the eyelid, and an electrode passive fixed to the back of the head or on the body's mastoid.

According to another variant embodiment of the process according to the invention, the compound is supplied to the CNS using an active electrode, putting it in contact with the compound, and both being introduced to the lower part of the rectum of the organism, and a passive electrode, fixed on the spine or another place, using a current of up to 10 mA. According to another variant embodiment of the present invention, the active electrode which is provided with the biologically active compound is placed on the sublingual space and the passive electrode is sub-mandibularly fixed to increase the release of the compound intravenously. According to another variant embodiment of the present invention, the active electrode that is provided with the biologically active compound is placed in the rectum or vagina, and the passive electrode is externally fixed on the spine or elsewhere on the skin of the organism to increase the release of the compound intravenously. According to another variant embodiment of the present invention, the active electrode that is provided with the biologically active compound is introduced into a vein artery, and the passive electrode is fixed on the skin projection of the pathological organ or tissue, for example a thrombus, to which an anticoagulant or fribrinolytic agent is supplied at a high concentration. This can avoid a * systematic effect such as a hemorrhage in the internal organs. According to another variant embodiment of the present invention, the active electrode that is provided with the biologically active compound is placed in the stomach or bladder or intraperitoneally, and the passive electrode is externally fixed on the skin of the organism to increase the release of the compound to the tumor or injury. The present invention is further explained in the following practical modalities. 10 a) It is suggested that iontophoresis is performed according to a first modality, through the nasal cavity. This intracerebral transnasalis method has been called in the present. This method has the following advantage. The mucous membrane of the nasal cavity has a low electrical resistance. Therefore, according to Ohm's law, the current intensity for the same voltage is much higher than the iontophoresis applied through the skin. It is known that the amount of substance introduced by current directly proportional to the current intensity. From here, the proportion of the substance introduced into the body (in the brain) will be greater than if it were done through the skin. The concentration of the substance in the blood introduced by the method herein will be low or absent. In this way, the side effects caused by the introduction of the substance in the systematic circulation will be minimal, in contrast to the intravenous and oral administration. The following method is suggested for this modality. Two electrodes (metal, conductive rubber or other conductive material, as mentioned above) must be introduced into the nostrils. The electrodes have to be covered by cotton or other material moistened in the solution of the necessary drug or compound and touch the nasal mucous membrane. Must be introduced the electrodes as deep as possible, but without provoking feelings of dissatisfaction. The same electrodes should not touch the skin or the membrane of the nasal mucosa, only through the container with the active substance. Another electrode or divided electrode covered with cotton or other material and moistened in the water has to be W 'f. fixed to the mastoid processes or being fixed to the back of the head in the area of cervical vertebra or another place. Depending on the individual tolerance (pressure or some other sense of dissatisfaction), the intensity of the current can be increased up to 10 mA. Subsequently, the current intensity can be decreased until the feeling of dissatisfaction disappears. b) It is suggested that iontophoresis be performed according to a second modality through the oral cavity. HE has called this method in the present transceral * intracerebral. The nasal cavity and pharynx are connected together and together they are called nasopharynx. The oral cavity is connected to the nasal cavity by the upper part of the pharynx. On the other hand, the upper part of the oral cavity, which is the hard and soft palates, is a lower part of the nasal cavity. The hard palate is a thin bone structure, and so also the soft palate is covered on both sides by the epithelium, which is known to have low resistance and easily conduct the current. 10 The following method is suggested in the present for this modality. An electrode (metal, conductive rubber or other conductive material) should be introduced into the mouth and placed in contact with the hard palate. During the procedure the mouth should be closed tightly and the tongue should hold strongly to the hard palate and to the electrode in order to t? Keep it in place. Therefore, the electrode does not need any additional fixation, since its position on the hard palate remains unchanged. The electrode has to be covered by cotton or other material moistened in the solution of the Necessary drug or substance and hold it close to the hard palate. The electrode should be introduced as deep as possible, but without causing feelings of dissatisfaction. The same electrode must touch neither the skin nor the mucous membrane of the oral cavity, only through the container (here cotton wool or other type of cushion) with the active substance. Another divided electrode covered with cotton or other material and moistened in water has to be fixed to the mastoid processes or an individual passive electrode has to be fixed on the back of the head in the area of the cervical vertebra or in any other place of head. Depending on the individual tolerance (pressure or some other sense of discontent), the current can be increased up to 10 mA or more. Subsequently, the intensity of current may be decreased until the feelings of dissatisfaction disappear. The duration of iontophoresis is up to 60 minutes or more, sometimes several days, depending on the dose of a necessary substance, its concentration, the resistance of the epithelium to the hard palate, and other factors. Influenced by the current, a drug or other substance penetrates the nasal cavity and from there through the olfactory structures, to the CNS, without having to pass the BBB. c) It is suggested in the present embodiment of iontophoresis according to the third modality through the eyes. This intracerebral transocularis method has been called in the present. This method has the following advantage. The eyelid skin has a lower resistance than the rest of the surface of the skin and a resistance of the cornea and the sclera is negligible.

The following method is suggested in the present for this modality. A split active electrode (metal, conductive rubber or other conductive material) must be placed over the eyes. The active electrodes have to be covered by cotton or other material moistened in the solution of the necessary active substance and touch the skin. The same electrodes should not touch the skin, but only through the container (hence the cotton) that stores the active substance. Another division electrode covered by cotton or other material and moistened in water has to be fixed to the mastoid processes or another place or an individual passive electrode has to be fixed on the back of the head in the area of the cervical vertebra or other place. Depending on the individual tolerance (pressure or some other sense of discontent), the intensity of the current can be increased up to 10 mA. Subsequently, the intensity of current can be diminished until feelings of dissatisfaction disappear. This method is called transocular. The variations of this method called transcorneal and transclerotic are performed by applying two special electrodes directly to the cornea and the sclera., respectively. Electrodes placed in contact with the cornea or sclera should release the drug or active substance needed. Another electrode divided or covered by cotton or other material and moistened in water has to be fixed to the mastoid processes or a part of the passive electrode has to be fixed to the back of the head in the area of the cervical vertebra or another place, and another part has to be fixed to the forehead. Depending on the individual tolerance (pressure or some other feelings of dissatisfaction), the current can be increased up to 2 mA or more. d) It is suggested here that iontophoresis is performed according to a fourth modality through the sublingual space of the oral cavity. This method will be called "Intravenous non-invasive release of drugs and other substances". The method of the present has the following advantage. The oral cavity and its part the sublingual space is covered by epithelium, which is known to have low resistance and easily conduct the current. The following method is suggested for this modality. An electrode (metal, conductive rubber, or other conductive material) has to be covered by cotton or other material moistened in the solution of the necessary active compound and must be introduced into the mouth and placed in contact with the mucosa of the sublingual space. During the procedure, the mouth must be closed tightly in order to keep the electrode in place. Therefore, the electrode does not need any additional fixation, since its position in the sublingual space remains unchanged. The electrode has to be covered by cotton or other material moistened in the solution of the drug or necessary substance. The same electrode must not touch the skin or the mucous membrane of the oral cavity, only through the container with the active substance. Another electrode covered by cotton or other material and moistened with water has to be fixed on the skin of the submandibular region. Depending on the individual tolerance (pressure or some other feeling of dissatisfaction), the current can be increased up to 5 mA or more. The duration of this type of iontophoresis is up to 60 minutes or more, depending on the dose of a necessary drug, its concentration, etc. e) It is suggested in the present, the realization of iontophoresis through the rectum or vagina. This method has been called "Non-invasive transrectal delivery" and non-invasive transvaginal intravenous release "of drugs or other substances", respectively. The present method has the following advantage. The rectum and vagina are covered with epithelium, which is known to have low resistance and easily conduct electrical current. According to Ohm's law the current intensity for the same voltage has to be much higher than the iontophoresis made through the skin. It is known that the amount of substance introduced by the current is directly proportional to the current intensity. From here, the proportion of the substance introduced into the body will be greater than if it is made through the skin. In blood, the concentration of the substance introduced by the present method will be the same as intravenous administration. The following method is suggested for this modality. An electrode (metal, conductive rubber, or other conductive material) has to be covered by cotton or other material moistened in the solution of the necessary active compound and must be introduced into the rectum and vagina and put in contact with the mucosa of the space . During the procedure, the rectum should be free of excrement (stool). The electrode does not need any additional fixation, its position in the rectum or in the vagina remains unchanged. Another electrode covered by cotton or other material and moistened in water has to be fixed to the skin of the sacralis or superpubitalis or other space. Depending on individual tolerance (pressure or some other feeling of dissatisfaction), the current can be increased up to 5 mA or more. The duration of this type of iontophoresis is up to 60 minutes or more, depending on the dose of a necessary drug, its concentration, etc.

It is noted that the modalities mentioned above should not be interpreted as limiting. Other modalities, which will be obvious to the skilled person after reading the description and claims, will fall within the scope of the present invention. BRIEF DESCRIPTION OF THE FIGURES The invention will be further explained in the following examples and the attached drawings in which Figure 1 shows a particular embodiment of an electrode according to the invention, while figures 2 to 6 graphically show the results obtained using a device and method according to the invention, while Figures 7a and 7b show the route of transportation of an active substance from the nostril to the brains. In Figure 1, the electrode comprising the conductive base member is represented by 1; this base member preferably has a hollow shape, and is suitably covered with an insulating material, for example a plastic, except the upper areas, which carry the biologically active substance 2. The base member 1 is additionally connected to a current source via 3, connected to the conductive base material. The base member is further provided with one or more perforations 4. Although the electrode as depicted in the figure has a tube-like shape, a substantial frustoconical shape or other shape may be used. In addition, the perforations 5 can have any shape. In Figures 7a and 7b the release of an active compound to the brains is shown schematically. More specifically the compound is applied according to Figure 7a in the nostril by means of the active electrode a. The passive electrode b is fixed on the back of the head. Both electrodes are connected to a source I of energy. After the activation of electrodes a and b the active compound will be driven in the direction from a to b, as indicated by the dashed s f. To increase the release of the active compound in the target tissue e, for example to a tumor, the direction of release of the active substance can be doubled by means of another pair of electrodes, ie the active electrode c and the passive electrode d . These electrodes c and d are connected to a source II of different energy. However, it is possible according to a special embodiment, as shown in FIG. 7b, to use a divided passive electrode, which consists of a passive bl electrode and passive electrode b2, both of which are connected to a power source 1. Also in this case, the direction of the release of the active substance from the nostril to the brains is given by the dashed s f. EXAMPLE 1 Transnasal iontophoresis has been performed in 60 patients and in 20 healthy volunteers in the age of 20 to 40. Forty-five of 60 patients suffer from plant dystonia with sleep disturbances, 40 of which show significant improvement , 4 do not show improvement, and the rest have shown some improvement. These patients are administered with the antidepressant amitripty. The other 15 10 of 60 patients suffer from migraine headaches. These patients are administered with papaverine hydrochloride. Twelve of them have shown significant improvement and 3 show no improvement. The iontophoresis sessions are performed daily for 15-30 minutes, with a total of 20-25 sessions. As a rule, the improvement comes after 3-5 sessions. For healthy volunteers, a piracetam solution is administered. 16 of them show a significant improvement in memorization capabilities and increased activity. Another experiment is carried out in 5 male volunteers at age 20 to 30. The penetrability of benzylpenicilintroduced transnasally into cerebrospinal fluid (FCS) and blood has been investigated herein. At the beginning an endolumbal puncture 25 is carried out with each subject, taking 1 ml of FCS. The needle is left in the puncture site for the duration of the experiment (1.5-2 hours). Then 1 ml of blood is taken from the arm vein. Both fluids are subsequently investigated for the presence of benzylpenicillin by means of a microbiological assay. This analysis was carried out as follows. Three Petri dishes are taken with the culture of streptococci. The first box remains with the culture of streptococci. A second drop of FCS is added to the second. To the third one is added a drop of blood from the vein. The three boxes are subsequently placed on a thermostat to analyze the ability of FCS and blood to destroy streptococci. Then it is covered with a cotton swab moistened in the benzylpenicillin solution (0.2 g [200 000 units] per 5 ml of distilled water). A divided electrode covered by these cotton covers is inserted deep into both nostrils. Another divided electrode covered by cotton moistened in water is fixed in the mastoid processes. The intensity of the galvanic current by iontophoresis is 2.0 mA. The duration of the procedure is 30 minutes. 1.5 hours after the iontophoresis with benzylpenicillin again take 1 ml of FCS and 1 ml of blood. Following the same procedure described above, they are investigated for the presence of benzylpenicillin. It is found that after 1.5 hours of the iontophoresis, the FCS shows significant presence of benzylpenicillin. However, it can not be shown in the blood, since streptococcal lysis does not occur. This is direct evidence that iontophoresis allows benzylpenicillin to enter brain tissue without entering the blood. EXAMPLE 2 An experiment was carried out with the transocular method in 5 male volunteers at the age of 20 to 30. The penetration of benzylpenicillin introduced transocularly is investigated in the cerebrospinal fluid (FCS) and in the blood. At the beginning an endolumbal puncture is carried out with each subject, taking 1 ml of FCS. The needle is left in the puncture site for the duration of the experiment (1.5 - 2 hours). Then, 1 ml of blood is taken fthe arm vein. They are investigated Subsequently both fluids for the presence of benzylpenicillin by means of a microbiological assay. This analysis is performed as follows. Three Petri dishes are taken with Streptococcus cultures. The first box only remains with the culture of streptococci. To the second one is added a drop of FCS. The third is added a drop of blood fthe vein. The three boxes of a thermostat are subsequently placed to analyze the capacity of the FCS and the blood to destroy the streptococcus. Then it is covered with cottons moistened in the solution of benzylpenicillin (0.2 g [200 000 units] per 5 ml of distilled water). A divided electrode covered by these cotton covers is placed over each of the eyes. Another division electrode covered by cotton moistened in water is attached to the mastoid processes. The intensity of the galvanic current for iontophoresis is 0.8-2 mA. The duration of the procedure is 30 minutes. 1.5 hours after iontophoresis with benzylpenicillin another 1 ml of FCS and 1 ml of blood are taken. Following the same procedure described above, they are investigated for the presence of benzylpenicillin. It is found that after 1.5 hours of iontophoresis the FCS shows significant presence of benzylpenicillin. However, benzylpenicillin can not be shown in the blood since streptococcal lysis does not occur. This is direct evidence that the iontophoresis allows benzylpenicillin to penetrate brain tissue without entering the blood. The electric current has no negative impact on the brain and is even used to treat a series of nervous system disorders. This treatment is called electro brain stimulation or sleep electrode. This method is performed by applying electrodes placed bilaterally on the eyes and the mastoid region for the neck [9]. One of the most comprehensive views of transocular iontophoresis has been given by Sarraf and Lee [21]. EXAMPLE 3 Methylprednisolone hemisuccinate according to the invention is administered to rabbits, using the following protocols. 5 Materials and Methods HPLC assay for methylprednisolone hemisuccinate and methylprednisolone: The mobile phase is a mixture of acetonitrile and phosphate buffer pH6 (30: 70 volume / volume). The flow rate is 1.2 ml minute-1. Effluent 10 is monitored at 242 nm. The injection volume is 2 μl. Retention time: methylprednisolone hemisuccinate (MPS) 6.5 minutes and methylprednisolone (MP) 14.6 minutes. Limits of quantification 10 ng / ml for both compounds. The intra and interday coefficients of variation are < 5%. CAS No .. MPS 2375-03- 15 3; MP 83-43-2. Molecular weight: 496.50 MPS; MP 374-50. Molecular formula: MPS C26H33Na08. 1000 mg of sodium methylprednisolone hemisuccinate (Solumedrol®, lot 12 / 2000A 95LI3 CLI0, Upjohn, the Neherlands) are dissolved in 5 ml of distilled water (200 mg / ml). Animals New Zealand white rabbits (2.5-3 kg body weight) are obtained fthe Central Animal Laboratory (University of Nijmegen, The Netherlands). The anesthetics are animals with Hypnorm 0.5 ml / kg (fentanyl citrate 0.315 mg / l and fluanisone 10 mg / ml, Janssen Pharmaceutica, Tilburg, the Netherlands). The animals are intubated and ventilated mechanically with N20, 02, 1: 2 (v / v), and 2.4% anther. The C02 entidal at 4% is maintained. A cannula is formed in the arterial femoralis with a Venflon 2 catheter, 18 G. Mechanical ventilation is maintained with an MK2 Amsterdam Infant Ventilator (Hoek, Loos, Amsterdam, Netherlands) and a Capnomac (Datex), Hoevelaken, the Netherlands). At the end of the experiment, the animals are sacrificed by the arterial injection of pentobarbital 2 ml 60 mg / ml (Narcovet® Apharmo, Arnhem, the Netherlands). Iontophoresis A stimulator is used. The applied current is 3 mA, at 8000 Hz, the pulse duration is 119 μ seconds, the pulse interval is 6 μ seconds. Observation: this type of current is used since it is less irritating at the nerve end and therefore less painful. The electrodes encapsulated in cotton wool and saturated with the drug solution are placed firmly in the nasal passage, the opposite electrode is placed with a wet sponge pad on the back of the head (clear skin). The electrodes of the nose are used in the positive (+) and negative (-) electrode mode in separate experiments. Sampling Blood samples (2 ml) of each animal are collected in heparinized polypropylene tubes just before the start of the iontophoresis (t = 0) and at 15, 30, 45 and 60 minutes after the start of the stimulation. A sample of spinal fluid of 1 ml of the animal is collected after the sacrifice and just before the brain is dissected. After the sacrifice of the animal, the whole brain is dissected. The right temporal lobe, the frontal lobe, the brainstem and remains are collected. Preparation of the sample. During the whole experiment (6 hours), the blood samples are kept at room temperature (20 degrees C). After this the blood samples are centrifuged at 3000 g, and plasmas are stored in duplicate at -20 degrees C. The brain and liquor are stored at -20 degrees C until analysis. Drug analysis The HPLC system consists of a Marathon autosampler (separations, Hendrik Ido Ambacht, the Netherlands), a Spectra Systems P 4000 quaternary gradient pump, a Spectra Systems UV 1000 detector (Thermosepartions, Breda, the Netherlands) and an integrator Hitachi D2500 (Merck, Amsterdam, the Netherlands). The column is Spherisorb 50DS (250 x 4.6 mm) with a protection column (15 x 4.6 mm) packed with C18 reverse phase material 5 μm (Chrompack, Bergen op Zoom, the Netherlands). Sample preparation Vortex 150 g of plasma for 10 seconds with 150 μl of acetonitrile. The mixture is centrifuged at 3000 g for 5 minutes. 20 μl of the clear supernatant is injected into the column. Brain tissue. Two ml of distilled water are added to 1 gram of brain tissue. The mixture is homogenized in an ultratorax apparatus (Ystral, Dottingen, Germany) at 10,000 rpm for 30 seconds. The homogenate is centrifuged at 3000 g for 5 minutes and further treated as plasma. Rabbit I Two cotton wool are placed, saturated with MPS 200 mg / ml for one hour in the nostrils. Rabbit 2 Two cotton wool plus electrodes saturated with MPS 200 mg / ml are placed for one hour in the nostrils. Stimulation with + 3mA. Rabbit 3 Two cotton wool plus electrodes saturated with MPS 200 mg / ml are placed for one hour in the nostrils. The stimulation with -3mA. Conej o 4 5 mg / kg (12.5 mg) MPS are given intravenously in 5 minutes. Blood samples are taken at 0, 1, 3, 5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes. Brain samples are taken. Rabbit 5 1 mg / kg (2.5 mg) MPS is given intravenously in 5 minutes. Blood samples are taken at 0, 1, 3, 5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes. Brain samples are taken, rabbit 7 Cotton wool is placed saturated with MPS 0.5 ml 200 mg / ml (100 mg dose, the electrodes are immersed in 1 ml of solution) for one hour in the nostrils. Stimulation with -3mA. Fourth experiment. More solvent is used, and the electrodes are firmly placed deep in the nasal cavity. The following results are obtained. TABLE 1 Concentrations of plasma (μg / ml) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool saturated with MPS in the nostrils of each rabbit and without and with positive iontophoresis and negative. Time Rabbit number (minute) 1 2 (+ 3mA, 1 hour) 3 (-3mA, 1 hour) MPS MP MPS MP MPS MP 0 0 0 0 0 0 0 15 0.19 0.12 0.01 0.12 0.54 0.15 30 0.23 0.12 0. 0.11 0.22 0.11 45 0.16 0.16 0 0.17 0 0.02 60 0.21 0.20 0 0.13 0 0.01 (+) means: positive electrode in the nostril; (-) means: negative electrode in the blood orifice. The values obtained with rabbit No. 2 are compared with those obtained with rabbit No. 3 which shows that a positive electrode in the nostril is the polarity wrong, while the negative electrode in the nostril is the correct polarity for this type of substance. It is further observed that the plasma concentration of 0.15 μg / ml for rabbit No. 3 (-), obtained after 15 minutes is due to the fact that only after about 5 minutes is the effect of the electric current observed. In fact, the negative current is given 5 minutes after the installation of a cotton wool saturated with MPS in the nostrils. The concentrations of both substances in the brain 15 are also measured. The following results are obtained for the concentrations of the compounds in the brain. TABLE 2 Brain concentrations (μg / g) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool saturated with MPS in the nostrils of each rabbit and without and with positive and negative iontophoresis. Tissue Rabbit number 1 2 (+ 3mA, 1 h.) 3 (-3mA, lh) 25 MPS MP MPS MP MPS MP Frontal lobe 0 0 1.02 0 0 1.20 Right temporal lobe 0 0 0 0 0 0.52 Brainstem encephalon 0 0 0 0 0 3.73 5 Rest of the brain 0 0 0 0 0 0.70 Figure 2 shows the results obtained with rabbit No. 1, graphically. Figure 3 shows the result obtained with rabbit No. 3 graphically. 10 TABLE 3: Plasma concentrations (μg / ml) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool saturated with MPS in the nostrils of each rabbit and negative iontophoresis. Time Rabbit number 6 (minutes) MPS MP (-ImA, 1 hour) 0 0 0 15 0.0 0.0 20 30 0.0 0.0 45 0.0 0.0 60 0.0 0.0 Spinal fluid 0 0 TABLE 4: Brain concentrations (μg / g of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool with MPS in the nostrils of each rabbit and negative iontophoresis. Tissue rabbit number MPS MP (-ImA, lh) Right frontal lobe 0 0 Left frontal lobe 0 0.16 Right temporal lobe 0 0.09 Left temporal lobe 0 0 Cerebellum, 0 0 Brainstem encephalon 0 0 Rest of the brain 0 0 Cervical spinal cord 0 0 Spinal cord 0 0 Lumbar spinal cord 0 0 From the results in Tables 3 and 4 it seems that a current intensity of 1 mA is probably too small to effect an acceptable transport of the drug in all parts of the brain. The results are given graphically in Figure 4. TABLE 5: Plasma concentrations (μg / ml) of methylprednisolone hemisucsinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool saturated with MPS in the nostrils of each rabbit and negative iontophoresis. Time Rabbit number 7 (minutes) MPS MP (-3mA, 1 hour) 5 0 0 0 15 0.0 0.0 30 0.98 0.78 45 0.40 0.97 60 0.25 1.00 10 Spinal fluid 0.30 1.16 ** TABLE 6: Brain concentrations (μg / g) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after the installation of a cotton wool saturated with MPS in the nostrils and negative iontophoresis. Tissue No. of rabbit MPS MP (-ImA, lh) Right frontal lobe 0 0, .95 Left frontal lobe 0 1. .84 Right temporal lobe 0 2. .27 Left temporal lobe 0 0. .36 Cerebellum 0 0. .69 Brain stem 0 0. .41 Rest of the brain 0 1. .71 Cervical al cord al cord O 0.10 Lumbar al cord The results of tables 5 and 6 are given graphically in figure 5. COMPARATIVE EXAMPLE To show the superior results of the application of a biologically active substance from According to the invention, compared to the application by means of an intravenous injection, plasma concentrations and brain concentrations are measured in rabbits, which are treated in both forms. The following results are obtained. 10 TABLE 7: Concentrations in plasma (μg / ml) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after intravenous injection of MPS 1 mg / kg and 5 mg / kg respectively. Time Rabbit number (dose) 15 (minutes) 4 5 (5 mg / kg) (1 mg / kg) MPS MP MPS MP 0 0 0 0 0 1 72.91 12. .11 8.79 1.17 20 2.5 55.19 13. .18 1.77 0.32 5 14.12 7. .98 0.46 0.30 10 3.47 5. .75 0.22 0.28 15 1..48 3.97 0.14 0.25 20 1 .13 3.13 0.18 0.24 25 0, .87 2.95 0.11 0.23 30 0. .67 2.64 0.10 0.19 40 0 .42 2.00 <; 0.1 0.16 50 0. .28 1.62 0.17 60 0. .19 1.38 0.16 TABLE 8: Brain Concentrations (μg / mL) of Methylprednisolone Hemisuccinate (MPS) and Methylprednisolone (MP) in a rabbit after intravenous injection of MPS 1 mg / kg and 5 mg / kg, respectively. Tissue Rabbit number (dose) (5 mg / kg) (1 mg / kg) MPS MP MPS MP Right frontal lobe 0 0 0 0 Left frontal lobe 0 0 0 0 Right temporal lobe 0 0.069 0 0 Left temporal lobe 0 0.060 0 0 Cerebellum 0 0.055 0 0 Trunk of brain 0 0.038 0 0 Rest of brain 0 0.090 0 0 Cervical spinal cord 0 0.092 0 0 Spinal cord 0 0.076 0 0 Lumbar spinal cord 0 0.076 0 0 The results obtained with rabbit No. 4 are shown graphically in figure 6. 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[12] Jung G, Kutz E, Schmitt H, et al: Conformation requirements for the potential dependent formation of the peptide antibiotics alamethicin, suzukacilin and trichotoxin. In Spach G (ed): Physical Chemistry of Transmembrane Ion Motion. New York, New York, Elsevier, 1983. [13] Kuffler SW, Nicholls JG, Martin AR: From neuron to brain, A cellular approach to the function of the nervous, ^ system. 2nd ed. Sinauer Associates Inc. Publishers, pages T ^ 361-363. 10 [14] Lerner E. Electroautonomography: A diagnostic tool for CFS. First World Congress on Chronic Fatigue Syndrome and Related Disorders, Brussels, Nov 9-11 1995, page 63. [15] Nicholson C: Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in 15 striatum. Biophysical Journal 68: 1699-1715, 1995. J | fc [16] Nichell WT, Behbehani MM, Shipley MT: Evidence for GABAB-mediated inhibition of transmission from the olfactory nerve to mitral cells in the mouse olfactory bulb. Brain Research Bulletin, 35: 119-123, 1994. 20 [17] Pardridge WM: Knocking on the cerebral door. Odyssey, 1: 46-51, 1995. [18] Pardridge WM, Boado RJ, Kang WS: Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Nati Acad Sci USa 25 92 (12): 5592-5596, 1995. ^ [19] Philip P. Dmetes-Mainard J, Bourgeois M, Vincent JD: Efficency of transcranial electrostimulation on anxiety and insomnia sympotms during a washout period in depressed patients. A double-blind study. Biol Psychiatry 29: 451-456, 5 1991. [20] Phipps JB, Padmanabhan RV, Lattin GA: Transport of ionic species through skin. Solid State ionics 28-30: 1778-f783, 1988. [21] Sarraf D, Lee DA: A role of iontophoresis in the 10 ocular drug delivery. Journal of ocular Pharmacology 10: 69-81, 1994. [22] Siddiqui O, Roberts MS, Polack AE: The effect of iontophoresis and vehicle pH on the in-vitro permeation of lignocaine through human stratum corneum. H Pharm Pharmacol 37: 732-735, 1985. [23] Siddiqui O, Sun Y, Liu JC, Chien YW: Facilitated transdermal transport of insulin. J Pharm Sci 76: 341-345, 1987. [24] Swanson LW: Limbic system. From Encyclopedia of neurosience, v. I, ed. by Adelman G. Birkhauser, pages 589- 20 591. [25] Vries HE, Characteristics of blood-brain barrier endothelial cells in response to inflammatory stitauli. Proefschrift, RU Leiden, 1995. [26] Adams RD, Victor M: principies of neurology 4th .25 edition, McGraw-Hill Information Services Company, pages 183- [27] Bell IR: White paper: Neuropsychiatric aspects of sensitivity to low- level chemicals: A neural sensitization model - Toxicology and Industrial Health, 10: 277-312, 1994. 5 [28] Shipley MT: Transport of molecules from nose to brain: Transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin -horseradish ^ a ^ peroxidase applied to the nasal epithelium. Brain Research ^^ Bulletin, 15: 129-142, 1985. 10 [29] The CFIDS Chronicle. The CFIDS Association of America, May, 7-9, 1993. DEFINITIONS AND TERMINOLOGY: 1. Biologically active compounds: This invention is useful in the release of substances or compounds or drugs directly or indirectly within its broadest sense, or any other substance or compound of interest, in order to achieve a therapeutic, diagnostic or other desired effect, usually beneficial. The biologically active compounds, agents or substances can be related to compounds of chemical, biological or biotechnological origin; examples include organic or inorganic chemicals, and compounds belonging to animal, human, microbiological, plant or viral origin. 25 Throughout this text, the terms compound, drug and substance are used interchangeably. 2. Blood brain barrier: the barrier that separates the blood from the parenchyma of the central nervous system. Presumably this consists of the capillary walls of the central nervous system and the surrounding glial membranes (one extremity foot) Abbreviation used: BBB 3. Cerebrospinal fluid: abbreviation used: FCS 4. Container: any receptacle or reservoir that stores a liquid compound or a dissolved compound in a solvent or a combination of these. Alternatively, the container material can be part of the matrix that stores a biologically active compound.

Claims (41)

1. ? CLAIMS 1. A device for increasing the release of a drug or other substance or compound of interest in a target organ or tissue selected from an organism, characterized 5 because it comprises a special apparatus, special electrodes, one of the special electrodes that carries a special container with the drug or another substance or compound of selected interest, the electrodes that are capable of being located in preselected locations of the organ or tissue, where The electrodes are all connected to a selected energy source which generates and maintains an energy field before and during the increased release of the substance or compound, under the influence of which the release from the active electrode to the passive is carried out. and to the organ or 15 tissue. The device according to claim 1, characterized in that the device comprises an energy source which is provided with a means for electrically circuiting and internal the power supply in 20 the rest position of the device, which will automatically activate the electrodes in the release position after connection to the organism. 3. The device according to claim 1 or 2, characterized in that the active electrode 25 is provided with a means for carrying the drug or another biologically active substance or compound. The device according to one or more of claims 1 to 3, characterized in that the active and / or passive electrode are divided into two or more parts. 5. The device according to claim 1 or 2, characterized in that the energy source is selected from the group comprising sources that provide an electric field, a magnetic field, ultrasonic waves, high energy waves such as laser beams or a combination from 10 the same. The device according to claim 1 or 2, characterized in that the energy source is a source of thermal energy or a combination of such source with another source of energy. The device according to claim 4, characterized in that the energy source that provides an electric field is adapted to provide a current of up to 25 mA, preferably of up to 10 mA. 8. An assembly comprising a device as defined in one or more of claims 1 to 7, characterized in that the active electrode is provided with at least one drug, or another biologically active substance or compound of interest. An electrode to be used in a device 25 according to claim 1, characterized in that * it comprises an electrical conductive base member, which may be connected to the selected energy source, wherein the upper area of a base member is capable of supporting the drug or other biologically active substance or compound, and the entire upper area of the base member is coated with an insulating material. The electrode according to claim 9, characterized in that the electrode is provided with a container for the drug or another substance or compound 10 biologically active to be released to the target organ or tissue, which has a close connection with the upper area of the electrode. 11. The electrode according to claim 9 or 10, characterized in that the base member 15 has a frusto conical cavity substantial or otherwise. The electrode according to one or more of claims 9 to 11, characterized in that at least one passage opening is present in the area covered with the insulating material in the base member. 13. The use of a drug or other biologically active substance or compound of interest for the manufacture of an iontophoretic assembly comprising an electrode as defined in one or more of claims 9 to 11, and the compound, wherein the compound is to release direct or to 25 through a carrier and is selected from the group of drugs and * other substances and compounds of interest that can be selected from the following listings and are given as examples and without limitation: amino acids, anabolics, analgesics and antagonists, 5 anesthetics, anthelmintics , anti-adrenergic, anti-asthmatic, anti-atherosclerotic, antibacterial, anticolesterolics, anti-coagulants, anti-depressants, antidotes, anti-emetics agents, anti-epileptic drugs, anti-fibrinolytic, anti-inflammatory, anti-hypertensive, 10 antimetabolites, anti-migraine agents, antifungal, anti-nausea, anti-neoplastic, anti-obesity agent, anti-Parkinson's agents, anti-protozoan, anti-psychotic, anti-rheumatic, antiseptic, anti-dizziness, anti-viral, appetite stimulants, bacterial vaccines, bioflavonoids, blockers 15 of calcium channels, hair stabilizing agents, coagulants, corticosteroids, detoxifying agents for cytostatic treatment, diagnostic agents (such as contrast media and radioisotopes), drugs for the treatment of chronic alcoholism, electrolytes, enzymes, inhibitors 20 enzymes, enzymes, enzyme inhibitors, gangliosides and derivatives of gangliosides, hemostats, hormones, hormone antagonists, hypotonic, immunomodulatory, immunostimulants, immunosuppressants, minerals, muscle relaxants, neuromodulars, inotropic neurotransmitters, 25 diuretics, osmotic, parasympatholytic, parasympathomimetic, peptides, proteins, psychostimulants, respiratory stimulants, sedatives, lipid-lowering agents in sera, smooth muscle relaxants, sympatholytics, sympathomimetics, vasodilators, protective vessels, vectors for people, viral vaccines, viruses, vitamins, and each type of neurotropic drugs and other substances. 14. The use of an electrode, provided with a drug or other substance or compound of interest in the manufacture of an iontophoretic device, for the release 10 increases the target substance or compound or target tissue of the organism without obtaining significant levels in the plasma of the drug, substance or compound by generating and maintaining an electric field on the target organ or tissue before and during the release of the drug or other substance or compound of interest. 15. The use according to claim 14, characterized in that the electrode is an electrode as defined in accordance with one or more of claims 9 to 12. 16. The increased release of an amount 20 effective of a drug or other substance or biologically active compound in an organ or target internal tissue of an organism, such as a mammal, particularly in a human being, in need of such release with such a drug, or other substance or compound of interest , characterized because The compound increases in such organ or tissue from a carrier location in the body of the organism by means of energy-stimulated penetration, generated and maintained by a fixed field between at least two electrodes that are divided or not, after the connection to a selected energy source, of which one of the electrodes can function as an active electrode and one as a passive electrode of which at least one electrode is placed on the skin layer of the organism, and an electrode that has the opposite polarity is placed near the place where the drug or other substance or compound of interest is released. 17. The increased release according to claim 15, characterized in that the carrying location is separated from the target organ or tissue by a membrane having a low electrical resistance. 18. Increased release according to claim 15 or 16, characterized in that the drug or other substance or compound of interest is delivered transnasally into the central nervous system within the nasal cavity by passing the blood brain barrier, using a current of up to 10 mA or more, between an active electrode inserted internally in at least one nostril, and a fixed passive electrode in the head. 19. The increase according to claim 15 or 16, characterized in that the release of the drug or other substance or compound of interest increases transnasally to the central nervous system using an active electrode fixed externally on the organism's nose, a passive electrode in the head, while the passive electrode is applied intranasally after the 5 generation of the energy field. 20. The increased release according to one of claims 16 to 18, characterized in that the active electrode is divided into two parts, one of which is fixed externally to the nose, and the other that is provided with The active compound is introduced into a nasal orifice. 21. The increased release according to one or more of claims 16 to 18, characterized in that the release of the drug or other substance or compound of interest increases in some specific region of the brain 15 using a fixed active electrode intranasally or extranasally and a divided passive electrode, one of the parts that is externally fixed on the projection of the specific region on the head, while the compound has been applied in the nostril. 22. The increased release according to one of claims 16 to 18, characterized in that the release of the drug or other substance or compound of interest is increased in some specific region of the brain, for example a tumor, the direction of the release of the substance 25 active can be diverted by means of another group of active and passive electrodes r, connected to a different energy source. The pair of electrodes that are connected in the nasal cavity and in the posterior part of the head, while the second pair of electrodes is placed as follows: the passive on the projection of the tumor on the external part of the brain and the active , this time moistened with water on the opposite side in relation to the passive electrode mentioned last. 23. The increased release according to any of claims 16 and 17, characterized in that the passive electrode is divided into two parts, one of which is connected to the back of the head, and the other part is connected to the in front of the organism, while the active electrode carrying the drug or another substance or compound of interest connects with the palate of the mouth of the organism. 24. The increased release according to any of claims 16 and 17, characterized in that the drug or other substance or compound of interest is 20 delivers transocularly to the central nervous system from the eyelid using a current intensity of up to 10 mA between a fixed active electrode on the drug or another substance or compound of interest carried by the eyelid, and a fixed passive electrode at the back of the eyelid. head of 25 organism. # 25. Increased release according to any of claims 16 and 17, characterized in that the drug or other substance or compound of interest is delivered to the central nervous system using an electrode 5 active, put in contact with the compound, and both being introduced to the lower part of the rectum of the organism and a fixed electrode, on the spinal cord from another place, using a current intensity of up to 10 mA. * 26. The increased release according to claim 16, characterized in that the active electrode that is provided with the drug or another substance or compound of interest is placed in the sublingual space and the passive electrode is placed in the submandibular part or other place, to release the drug or other substance or compound of interest intravenously. 27. The increased release according to claim 16, characterized in that the active electrode that is provided with the drug or other substance or compound of interest is placed in the rectum or vagina, and the passive electrode 20 is fixed externally on the spinal cord or elsewhere on the skin of the organism to release the drug or other substance or compound of interest intravenously. 28. The increased release according to claim 16, characterized in that the active electrode that 25 is provided with the drug or other substance or compound of interest is introduced into a vein or artery and brought into contact with the pathological site, for example a thrombus, and the passive electrode is placed on the projection of the skin of the organ or pathological tissue to which the drug or substance or compound of interest is supplied. 29. The increased release according to claim 16, characterized in that the active electrode that is provided with the drug or another substance or compound of * Interest is introduced into the stomach or bladder or 10 intraperitoneally or another cavity or tissue, and the passive electrode is fixed externally in the skin of the organism to increase the release of the compound in the tumor or lesion. 30. The container that stores the drug or other substance or compound of interest to be connected to the electrode 15 active according to claim 14, characterized in that it can be made of any material or • combinations of materials, which meet the relevant criteria with respect to compatibility with the drug or other substance or compound of interest and with the environment 20 biological, but also with respect to ease of manufacture, sterilization, re-usability, low environmental impact, flexibility, connectivity, durability and availability. 31. The drug reservoir container to be connected to the electrode according to claim 14, characterized in that it must be constructed of any material in such a form that it is adapted to absorb and maintain a sufficient quantity of liquid in order to allow the transport of the drug through its wall by means of iontophoresis. 32. Optionally, the drug container or reservoir to be connected to the active electrode according to claim 14, characterized in that it must maintain an anti-sealing membrane or valve that allows the filling in. 10 with the drug solution, without the need for elimination and reinsertion of the present device. 33. The container or reservoir of the drug to be connected with the active electrode according to claim 14, characterized in that it may consist of 15 example of sponges, gauze or pads consisting of cotton or other absorbent fabric, either of natural or synthetic origin. More preferably, the containers or reservoirs are composed, at least in part, of one or more hydrophilic polymers. 34. The container or reservoir of the drug to be connected to the active electrode according to claim 14, characterized in that it can consist of multi-stratified solid polymer matrices, composed, at least in part, of hydrophilic polymer. The matrices of Hydrophilic insoluble polymers are preferred over the soluble hydrophilic polymers, since the probability of releasing the insoluble polymer by iontophoresis is very low. 35. The container or reservoir of the drug to be connected by the active electrode in accordance with Claim 14 can consist of a matrix that can be crosslinked with the drug components in a place such as the silastic matrix, or the polymers can be prefabricated or sipped with the components from the solutions, for example with sponges or pads fabricated 10 with cellulose or spun fiber. The container may also consist of a gel matrix structure, or be of a conventional deposit type that has no liquid. The polymers may be of the linear or crosslinked type. Examples of suitable hydrophilic polymers include polyethylene glycols, 15 polyacrylates, poly-oxyethylenealkyl ethers, polyvidone, iN poloxamers, polyethylene oxides, polyvinyl alcohols, polyacrylamide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copolyesters, cyclodextrins, crospovidone, crosslinked dextrans, croscarmellose sodium, 20 natural gums, and starch and its mixtures. 36. The container or reservoir of the drug to be connected to the active electrode according to claim 14, characterized in that it may optionally consist of a matrix also containing a polymer 25 hydrophobic, to improve structural integrity. Preferably the hydrophobic polymer is heat fusible in order to improve the lamination of the container layers. Examples of suitable hydrophobic polymers include, but are not limited to polyethylene, polypropylene, ethylene-vinylacetate copolymers, polyvinylacetate, polyisobutylenes, polyamides, polyurethanes, polyvinyl chloride, and acrylic or methacrylic resins. 37. The container or reservoir of the drug to be connected with the active electrode in accordance with Claim 14 may be a polymer matrix structure formed by mixing the drug, solvent, electrolyte or other selected compound with an inert polymer by means of melt mixing, solvent melting, compression or extrusion. 38. The container or reservoir of the drug to be connected with the active electrode according to claim 14, characterized in that it can have a shape to allow its combination and union or coupling with the active electrode. The shape, size and shape of the electrode The active substance and its drug container is determined by the physiological environment related to its application and introduction into the body, for example, in the nasal orifice, in the blood vessels, in the stomach, in the rectum and in the vagina. 39. The container or reservoir of the drug to be 25 connected to the active electrode according to claim 14, it may have a permanent semi-permanent type connection, or of the cartridge type for easy exchange of containers, the use of suitable adhesives for permanent connection of the container and the active electrode is subsequently observed , while the fixed closure and the connection means such as the sliding lock, luer lock, screw lock, are more suitable for permanent connections, to allow reciprocating type containers or cartridge. 40. The drug or other biologically active substance or compound of interest according to claim 13, proposed to increase the release by means of an iontophoretic assembly characterized in that it comprises an electrode as defined in one or more of claims 9 to 11. Y 15 contained in a container or reservoir as defined in claims 28 to 35, must in part be ionized, which can be brought into contact approximately in solution in a medium or solvent that is capable of conducting the electric current and possessing a dipole electrical, preferably a The polar solvent, which has a high dielectric constant, preferably a polar solvent having a dielectric constant, allows the separation of oppositely charged ions. Examples of some useful polar solvents include, but are not 1 imitated to water, glycerin, Ethylene glycol, methyl alcohol, ethyl alcohol, n-propyl alcohol, and mixtures thereof. The degree of dissolution and subsequent ionization can be improved and regulated by the addition of suitable electrolytes which form buffer systems in the selected polar solvent or mixtures thereof. 41. With respect to the electrodes which can be used in the present invention according to claims 1 to 4, and 8 to 15, they are characterized in that they are comprised of electrically conductive material such as 10 metal, aluminum, stainless steel, gold, silver, titanium and zinc. Examples of other suitable electrically conductive materials include carbon, graphite, and metal salts such as silver chloride. The electrodes can be formed of metal sheets, metal sieves, metal deposited or painted on 15 a suitable carrier by means of rolling, evaporating film, or mixing the electrically conductive material in a polymer binder matrix. Alternatively, the electrodes of an electrode matrix containing a conductive filler such as powder may be formed. 20 metallic, powdery graphite, carbon fibers, or other known electrically conductive filler material.