EP0869829A1 - Vorrichtung zur erhöhten verabreichung von biologisch wirksamen stoffen und verbindungen in einem organismu - Google Patents

Vorrichtung zur erhöhten verabreichung von biologisch wirksamen stoffen und verbindungen in einem organismu

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Publication number
EP0869829A1
EP0869829A1 EP96939840A EP96939840A EP0869829A1 EP 0869829 A1 EP0869829 A1 EP 0869829A1 EP 96939840 A EP96939840 A EP 96939840A EP 96939840 A EP96939840 A EP 96939840A EP 0869829 A1 EP0869829 A1 EP 0869829A1
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Prior art keywords
drug
compound
electrode
substance
interest
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French (fr)
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Eduard Naumovich Lerner
Leonid Lerner
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Individual
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Priority claimed from PCT/EP1996/005086 external-priority patent/WO1997018855A1/en
Publication of EP0869829A1 publication Critical patent/EP0869829A1/de
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  • Galvani provided a major stimulus for Volta to discover a source of constant current electricity, the voltaic pile or battery, and new research on the effects of direct current (DC) on animal tissues broadened the scientific basis for the entire subject of electrophysiology. It had long been known that medicines could be introduced into the human body by way of the skin. The skin has a selective permeability to lipophilic (lipid soluble) substances and acts as a barrier to hydrophilic (water soluble) substances. In 1747, Veratti suggested that hydrophilic drugs might be introduced to the subcutaneous tissue through human skin by the application of a direct current [5] . This mode has become known as iontophoresis (meaning ion transfer) .
  • iontophoresis meaning ion transfer
  • the skin is a multicomponent, multifunctional organ that is involved in the body's interactions with, and adaptation to, the environment. It is composed of the dermis and epidermis.
  • the thickness of the dermis varies from 1 mm on the scalp to 4 mm on the back. Blood vessels, lymphatic vessels, nerve endings, hair follicles, sebaceous glands, and sweat glands are all located in the dermis.
  • the epidermis ranges from 0.075 to 0.15 mm in thickness, except on the palm and the sole where it can be up to 0.6 mm thick.
  • lipophilic drugs such as scopolamine for motion sickness, clonidine for hypertension, and nitroglycerine for the treatment of angina pectoris
  • hydrophilic drugs [20] can be readily delivered through human skin.
  • these drugs the concentration gradient between the drug-loaded reservoir and the body is sufficient enough to deliver the drug through the skin at therapeutic dosage rates.
  • hydrophilic drugs [20] this is not the case for hydrophilic drugs [20] .
  • systemic administration may lead to massive inactivation of a drug as a result of the enzymatic action of the liver.
  • oral administration may give rise to incomplete or erratic absorption due to factors like food interaction, inactivation in the gastro-intestinal tract, disease status, and concomitant medication.
  • oral drug administration may give rise to fluctuations in the concentration of a drug in the systemic circulation. This may in turn result in toxic or subtherapeutic blood levels of the drug.
  • V IR
  • V voltage
  • I current
  • R resistance
  • permeability of skin may be altered as a result of the application of an electric potential across the skin [5, 6] .
  • Jung et al . in 1983 found that the only structural requirement for pore formation was the presence of alpha-helical polypeptides [12] .
  • an electric potential is applied across a physiological membrane, a voltage-dependent "flip-flop" of the helices occurs.
  • the skin permeability can be enhanced by the formation of "artificial shunts" by the use of direct current as applied during iontophoresis [5, 6] .
  • an organism receives only 10% of the substance on the electrode applied to the skin. In fact, an organism may receive from 1 to 10% of the substance.
  • a current density of less than 1 mA per square inch of electrode surface is recommended [7] .
  • An electrolyte can be defined as a substance that conducts electric current as a result of dissociation into positively and negatively charged particles called ions, which migrate toward and ordinarily are discharged at the negative and positive electrodes (cathode and anode respectively) , of an electric circuit.
  • the most familiar electrolytes are acids, bases, and salts, which ionize when dissolved in such polar solvents as water or alcohol.
  • An essential requirement for solvents to be used is that they conduct electric current and have to possess an electric dipole .
  • Polar solvents consist of strong dipolar molecules having hydrogen bonding. Water is a very unique polar solvent in that it also has a high dielectric constant, which indicates the effect that a substance has, when it acts as a medium, on the ease with which two oppositely charged ions may be separated. The higher the dielectric constant of a medium, the easier it is to separate two oppositely charged species in that medium, which is an essential requirement for the existence of ionized molecules that may be moved by an electric current, as with iontophoresis.
  • Table 2 shows some useful polar solvents with their dielectric constants. The values listed are relative to a vacuum which by definition has dielectric constant of unity.
  • Glycerin 46 Ethylene glycol 41 Methyl alcohol 33 Ethyl alcohol 25 n-propyl alcohol 22
  • the degree of dissolution and subsequent ionization can be improved and regulated by means of the addition of suitable electrolytes forming buffer systems in the selected polar solvent or mixtures thereof .
  • lidocaine is mainly in the ionized form at pH 3.4 and 5.2.
  • Drugs cross membranes by either passive processes or by mechanisms involving the participation of components of the membrane.
  • Both non-polar lipid-soluble compounds and polar water-soluble substances that retain sufficient lipid solubility can cross the lipid portion of the membrane by passive diffusion. Such transfer is directly proportional to the concentration gradient across the membrane. The greater the partition coefficient, the higher is the concentration of drug in the membrane and the faster is its diffusion.
  • the bulk flow of water carries with it any water-soluble molecule that is small enough to pass through the channels. Filtration is a common mechanism for transfer of many small, water-soluble, polar and nonpolar substances.
  • Capillary endothelial cells have large channels (40A ) , and molecules as large as albumin may pass to a limited extent from the plasma to the extracellular fluid.
  • the channels in the intestinal epithelium and most cell membranes are about 4A in diameter and permit passage only of water, urea, and other small, water-soluble molecules. Substances generally do not 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 channels in membranes, but their concentration gradient across the cell membrane is generally determined by the transmembrane potential.
  • the nonionized portion is usually lipid soluble and can readily diffuse across the cell membrane.
  • the ionized fraction is often unable to penetrate the lipoid membrane because of its low lipid solubility, or to pass the membrane channels because of its size. If the ionized portion of a weak electrolyte can pass through the channels, or through the membrane, it will distribute according to the transmembrane potential in the same manner as an inorganic ion.
  • Carrier-mediated active membrane transport Passive processes do not explain the passage of all drugs across cell membranes. Active transport is responsible for the rapid transfer of many organic acids and bases across the renal tubule, choroid plexus, and hepatic cells. The transported substance is transferred against an electrochemical gradient .
  • Transcellular fluxes are formed by the active transport of Na + across epithelial cells. Proteins and other macromolecules slowly cross epithelial cells by pinocytosis, a form of vesicular transport.
  • Absorption from all sites of administration is dependent upon drug solubility. Drugs given in aqueous solution are more rapidly absorbed than those given in oily solution, suspension, or solid form. For those given in solid form, the rate of dissolution may be the limiting factor in their absorption. Local conditions at the site of absorption alter solubility. Thus, at the low pH of the gastric juice, many acidic drugs are absorbed slowly because they precipitate in the fluid of the stomach, and dissolution occurs very slowly. Highly insoluble substances may not be absorbed from the alimentary tract at all. The concentration of a drug influences its rate of absorption.
  • Drugs ingested or injected in solutions of high concentration are absorbed more rapidly than are drugs in solutions of low concentration.
  • the circulation to the site of absorption also affects drug absorption.
  • the area of the absorbing surface to which a drug is exposed is one of the more important determinants of the rate of drug absorption.
  • Absorption is usually more rapid and more predictable than when a drug is given by mouth.
  • parenteral administration is particularly serviceable. If a patient is unconscious, uncooperative, or unable to retain anything given by mouth, parenteral therapy may become a necessity.
  • the injection of drugs also has its disadvantages. Strict asepsis must be maintained to avoid infection, an intravascular injection may occur when it is not intended, pain may accompany the injection, and it is often difficult for a patient to perform the injection himself if self-medication is a necessary procedure. Parenteral therapy is also more expensive and less safe than oral medication. Oral Ingestion. The rate of absorption of drugs from the gastrointestinal tract is generally proportional to the lipid solubility of the compound in question.
  • the drug is a weak acid or base, its nonionized form is more lipid soluble, and the pH within the gastrointestinal tract becomes a 'major determinant.
  • Alcohol a lipid-soluble nonelectrolyte, is rapidly absorbed into the blood stream by diffusion across the gastric and intestinal mucosae .
  • Quaternary ammonium compounds and other completely ionized, lipid-insoluble drugs are very slowly absorbed.
  • Other drugs are poorly absorbed because even their nonionic forms are lipid insoluble.
  • 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 nonionized in the acid gastric contents, are more readily absorbed from the stomach.
  • gastric pH also influences solubility of the drug and dissolution of solid dosage forms.
  • the net effect of change in gastric pH may be relatively minor, since absorption of most drugs occurs primarily from the intestine because of its greater surface area. For the same reason, the absorption of most drugs is delayed or reduced if gastric emptying is retarded.
  • Absorption from the alimentary tract may be decreased if the ingested drug is unstable in gastrointestinal fluid or if it is bound to food or other gastrointestinal contents. Simultaneous ingestion of food also delays absorption by delaying gastric emptying. Drugs that are destroyed by gastric juice or that cause gastric irritation are sometimes administered in dosage forms 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 may be absorbed.
  • the dissolution rate of some preparations in gastrointestinal fucid may be quite irregular because of variations in gastrointestinal pH, gastric emptying, intestinal motility and other physiological factors that influence drug absorption. Moreover, slow absorption from the gastrointestinal tract is often incomplete and erratic. Drugs given for a brief therapeutic effect should not be in the timed-release form. Conversely, timed-release preparations are not needed for drugs with an inherent long duration of effect. Also, timed-release preparations of some drugs might not be safe.
  • Sublingual Administration Absorption from the oral mucosa is rapid, and higher concentration of the drug in the blood may be achieved by this route than by absorption lower in the alimentary tract. This can result because metabolism of drugs as a result of passage through the liver is minimized, and because the drug is not subjected to possible destruction by the gastrointestinal secretions or to formation of complexes with foods. However, substances that are distasteful or that are irritating should not be given by this route.
  • the sublingual route of administration permits rapid absorption of nitroglycerin and other drugs. It is a convenient method when the drug is suitable for such administration.
  • the rectal route is often useful when oral ingestion is precluded by vomiting or when the patient is unconscious.
  • the absorbed drug does not pass through the liver before entry into the systemic circulation.
  • rectal absorption is often irregular and incomplete, and many drugs cause irritation of the rectal mucosa.
  • the major routes of parenteral administration are intravenous, subcutaneous, and intramuscular. Absorption of lipid-soluble drugs from subcutaneous and intramuscular sites also occurs by simple diffusion through the capillary membranes into the blood.
  • Lipid-insoluble drugs are absorbed by penetration through the relatively large aqueous channels in the endothelial membrane; larger molecules, such as proteins, gain access to the circulation by way of lymphatic channels, Some large molecules and microcrystalline substances are absorbed from these sites by phagocytosis. Certain irritating and hypertonic solutions can be given only in this manner.
  • Drugs in an oily vehicle should not be given by this route. Injection at a subcutaneous site can be used only for drugs that are not irritating to tissue. Drugs in aqueous solution are rapidly absorbed after intramuscular injection. Irritating substances that cannot be injected subcutaneously may often be given intramuscularly. Occasionally a drug is injected directly in an artery to localize its effect in a particular tissue or organ. Antineoplastic agents are sometimes given in this manner for the treatment of localized tumours.
  • vaginal administration The vaginal route is sometimes useful when other routes are disadvantageous for some reason.
  • the blood-brain barrier and the blood-cerebrospinal fluid barrier often preclude or slow the entrance of drugs into the central nervous system (CNS) . Therefore, when local and rapid effects of drugs on the meninges or cerebrospinal axis are desired, as in spinal anaesthesia or acute CNS infections, drugs are sometimes injected directly into the spinal subarachnoid space. Intraperitoneal administration
  • peritoneal cavity offers a large absorbing surface from which drugs enter the circulation rapidly. Intraperitoneal injection is a common laboratory procedure, but it is seldom employed clinically. The danger of injection and adhesions are too great to warrant the routine use of this route. However, peritoneal dialysis is sometimes a valuable procedure in the treatment of drug poisoning.
  • Gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium and mucous membranes of the respiratory tract. Access to the circulation is rapid by this route.
  • solutions of drugs can be atomized and the fine droplets in air (aerosol) inhaled.
  • Topical Application Mucous membranes Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects.
  • systemic absorption is the goal.
  • CSF cerebrospinal fluid
  • the BBB separates the brain from the blood circulation and is involved in the homeostasis of the brain.
  • the BBB is situated in the brain microvessels and is composed of various cell types like endothelial cells, astrocytes, microglial cells, perivascular macrophages, and pericytes .
  • the cerebral and endothelial cells form the morphological and functional basis of the BBB.
  • the external nose is the tip or apex, the base (which includes the nares) , the root (where the nasal bones join the skull above) , the dorsum (between the root and the tip) , and the bridge (the upper part of the dorsum) .
  • Only the upper third of the external nose is bony. The lower two thirds are cartilaginous.
  • Internal Nose On each side of the nose are anterior and posterior openings called the nares.
  • the posterior nares are also called the choanae.
  • the vestibule is the anterior, skin-lined part of the nasal cavity.
  • the nasal septum divides the nose into the two nasal fossae.
  • the lateral wall of the nose is a complicated area anatomically.
  • nasal turbinates There are four nasal turbinates, or conchae . Named from below upward, they are the inferior, middle, superior, and supreme turbinates.
  • the mucous membrane of the inferior turbinate is very rich in blood vessels and is semierectile.
  • the several nasal meatuses are named according to the turbinates that overlie them.
  • the superior and supreme turbinates is the sphenosthmoid recess, into which the sphenois sinus opens.
  • the inferior meatus are large blood vessels (sphenopalatine branches) under the mucosa of the lateral wall of the inferior meatus.
  • Both the external and the internal carotid systems provide a blood supply to the nose.
  • the venous drainage is important because part of it, through the angular vein, leads to the inferior ophthalmic vein and eventually to the cavernous sinus. Most of the venous drainage, however, is downward through the anterior facial vein.
  • Lymphatic drainage of the nose is extensive and parallels the venous drainage.
  • the olfactory area is located high in the nasal vault above the superior turbinate. Sensory hairs extend from the surface of the olfactory area to the cells that lie deep in the mucosa.
  • Nerve fibres subserving the sense of smell have their cells of origin in the mucous membrane of the upper and posterior parts of the nasal cavity.
  • the entire olfactory mucosa covers an area of about 2.5 cm.
  • the central processes of olfactory fila are very fine unmyelinated fibres that converge to form small fascicles enwrapped by Schwann cells and pass through openings in the cribriform plate of the ethmoid bone into the olfactory bulb.
  • the axons of the mitral and tifted cells enter the olfactory tract, which courses along the olfactory groove of the cribriform plate to the cerebrum.
  • Some fibres project to the medial dorsal nucleus of the thalamus and the hypothalamus. That olfactory stimuli and emotional stimuli are strongly linked is not surprising, in view of their common roots in the limbic system [26] .
  • the olfactory system has direct neuroautonomical and neurophysiological input to the amygdala and eventually hypocampus. Therefore it is conceivable that chemical stimuli at low levels could trigger limbic dysfunction in patients who happen to meet descriptive criteria for somatization disorder It is also stated [29] that there is no blood-brain barrier in the nasal passages, limbic structure (e.g, the amygdala, olfactory bulb, and hypocampus) can become easily kindled. Therefore, olfactory nerves can transport toxins directly to the limbic system. This may result in symptoms including memory loss, irritable bowel, and migraine headaches.
  • limbic structure e.g, the amygdala, olfactory bulb, and hypocampus
  • the optic nerve mediating vision, is distributed to the eyeball. Most of its fibres are afferent and originate in the nerve cells of the ganglionic layer of the retina. Developmentally, the optic nerves and the retinae are parts of the brain, and their fibres are provided with glia.
  • the optic nerve about 4 cm long, is directed backwards and medially through the posterior part of the orbital cavity. It then runs through the optic canal into the cranial cavity and joins the optic chiasma.
  • the optic nerve is enclosed in three sheats, which are continuous with the membranes of the brain, and are prolonged as far as the back of the eyeball. Therefore, there is a direct connection between the optic nerve and the brain structures .
  • the oral cavity is bounded anteriorly by the lips, posteriorly by the anterior faucial arc, inferiorly by the floor 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 process and the teeth: first, the vestibule of the mouth lying between the lip and cheek on one side and the teeth and the alveolar process on the other and second, the oral cavity proper limited externally by 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 oral cavity ensures that the tongue adheres to the hard and soft palate, thus maintaining closure of the mouth.
  • the following parts of the tongue 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. Under its anterior tip a fold of mucous membrane forms the frenum, which attaches to the floor of the mouth. Between the floor of the mouth and the tongue is the sublingual space.
  • the sublingual space is bounded by the mandible anteriorly and laterally; the posterior wall is formed by the styloglossus muscles, the palatoglossus muscles, and the hyoid bone.
  • the roof is formed by the mylohyoid muscles.
  • the epithelial lining of the oral cavity consists of the nonkeratinized stratified squamous epithelium which is thickened in certain points such as the alveolar edges and hard palate where it is united with the underlying periosteum.
  • Subepithelial collection of minor salivary glands are found over the oral cavity, being more common at some parts than at others.
  • the normal palate at birth consists of three portions: hard palate, soft palate, and uvula. These are covered with nonciliated mucous membrane continuous with that of the alveolus and meet as a raphe (ridge) in the midline. The mucous membrane forms rugae 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 the mouth open it hangs free.
  • the hard palate offers support to the floor of the nose and is covered by the dense mucosa. Vascular supply.
  • 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 pharyngeal and descending palatine arteries.
  • the latter arises from the internal maxillary artery.
  • the venous drainage runs via the veins of the same names to the facial vein, the pterygoid venous plexus, and the internal ugular vein. There is also a connection to the cavernous sinuses via the pterygoid plexus.
  • the lymph drainage of the base of the tongue and the floor of the mouth is to the same side and to the opposite side.
  • the rectum commences where the taeniae coli fuse to form a continuous longitudinal muscle coat .
  • 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 peritoneum above, the obturator internus and the side walls of the pelvis laterally, by the rectum medially and by the levator ani bellow.
  • the rectum also follows the curve of the sacral hollow in its lower two-thirds but at the level of the levator ani, where it enters the anal canal, it turns abruptly backwards and downwards.
  • the posterior relations of the rectum are the sacrum, the coccyx, the puborectalis muscles and the middle sacral vessels.
  • the anterior relations differ according to sex.
  • the extraperitoneal rectum is related from below upwards to the prostate, seminal vesicles, vas and bladder.
  • the infraperitoneal rectum lies immediately behind the posterior vaginal wall.
  • the colon and rectum are supplied from the territory of the superior and inferior mesenteric arteries.
  • the superior mesentric artery arises from the front of the aorta just below the coeliac axis.
  • the inferior mesentric artery arises from the aorta at the under-surface of the third part of the duodenum.
  • the terminal portion of the inferior mesenteric artery continues down over the pelvic brim in the mesocolon as the superior haemorrhoidal artery and divides into right and left branches before subdividing into terminal anterior and posterior endarteries supplying the rectum.
  • the middle haemorrhoidal artery supplies the middle third of the rectum.
  • the inferior haemorrhoidal artery supplies the lower rectum.
  • the three haemorrhoidal vessels form a comprehensive anastomosis in the submucosa of the anal canal and lower rectum.
  • the veins of the rectum comprise the superior haemorrhoidal which drains into the inferior mesentric and portal system, and the middle and inferior haemorrhoidal which enter the systemic venous circulation via the internal iliac veins.
  • the superior haemorrhoidal venous plexus lies in the submucosa of the upper part of the anal canal and lower 2 cm or so of the rectum. Thence five or six collecting veins pass upwards in the wall of the rectum; at first they run in the submucosa but gradually they penetrate the muscle coat to be in the perirectal fat where they unite to form two main veins and eventually the single superior haemorrhoidal trunk.
  • the middle haemorrhoidal vein is relatively unimportant, but the inferior haemorrhoidal vein is connected with the vertebral plexus which surrounds the spinal cords. Therfore, some compounds can come from the venous inferior haemorrhoidalus through the plexus vertebrals into the spinal fluid, and from there into the spinal cord and into the brains.
  • the vagina is an elastic fibromuscular canal extending upwards from the vulva at an angle of 60-70 degrees to the horizontal, although it is not straight as is generally supposed but angulated backwards.
  • the vagina has a blind upper end except in so far that the cervix with its external os projects through its upper anterior wall.
  • the vault of the vagina is divided into four areas according to their relations to the cervix: the posterior fornix which is capacious, the anterior fornix which is shallow, and two lateral fornices .
  • the posterior vagina wall is approximately 10 cm, whereas the anterior wall is approximately 8 cm, in length.
  • the introitus is functionally closed by the labia which are in contact with each other.
  • the vagina of the nulliparous married woman has a diameter of approximately 4-5 cm at is lower end and is twice as wide at its upper end, but the width and length of the vagina show considerable individual variations.
  • the functional width is determined to a large extent by the tone and contractions of surrounding muscles.
  • the vagina is lined by stratified squamous epithelium which also extends on to and covers the vaginal cervix as far as the external os. Normally, the surface is devoid of keratin.
  • the epithelium is multilayered, the basal cuboidal cells being the source of a continuous production of the squamous cells above.
  • the epithelium does not contain glands of any kind.
  • vaginal secretion consists of tissue fluids, epithelial debris, electrolytes, proteins, and lactic acid.
  • the amount of the last is governed by the glycogen content of the epithelium and the presence of Do derlein bacilli but, in the adult healthy vagina, is in a concentration of 0.75 per cent .
  • the pH varies with the level of the vagina, being highest in the upper part because of an admixture of alkaline cervical mucus. Estimates also vary according to the method used for its determination, but the generally accepted figures are from 4.0 to 5.5 with an average of 4.5.
  • the vagina not only "secretes"; it absorbs water, electrolytes and substances of low molecular weight . Absorption and re-absorption are believed to occur in the lateral recesses of the lower vagina.
  • the epithelium rests on a subepithelial connective layer which contains elastic tissue. Outside this are muscle coats in which the fibres are nearly all arranged in a crisscross spiral fashion. Outside the muscle layers is a strong sheath of connective tissue. The vaginal wall itself and the tissues around are extremely vascular so they usually bleed freely at the time of injury and operation.
  • the amount of glycogen is increased to a maximum and the acidity of the vagina is high (pH 3.5-4.5) .
  • the epithelium atrophies and loses its glycogen.
  • Do derlein' s bacilli are found in fewer numbers and the pH rises to a range of 6-8. Therefore, with vaginal iontophoresis the age and the vaginal pH of the patient must be taken into account .
  • the vaginal artery mainly; (2) branches of the uterine artery; (3) branches of the internal pudendal artery; (4) twigs from the middle and inferior rectal arteries.
  • the vagina artery is usually a separate branch (or branches) of the internal iliac artery but may come off the first part of the uterine artery. It passes forwards and inwards low in the broad ligament to reach the lateral vaginal fornix.
  • vaginal wall In the vaginal wall it anastomoses with the azygos branches of the circular artery of the cervix.
  • the lower vagina is supplied from the middle and inferior rectal (haemorrhoidal) vessels and by branches from the internal pudendal artery.
  • Venous A plexus of veins around the vagina connects with those around the bladder and rectum, and ultimately drains into the internal iliac veins by branches which mainly accompany corresponding arteries.
  • the veins of the pelvis normally accompany the arteries and have the same names. Sometimes there are two veins to one artery. There are plexuses of veins around the vagina, the urethrovesical junction and the anorectal junction and all ultimately drain into the internal iliac veins. The venous return from the rectum and pelvic colon enters the portal system by way of the inferior mesenteric veins. The pelvic plexuses and veins have communications with the presacral and lumbar channels of the vertebral plexus. This is probably the explanation for the occurrence of metastatic growths in the spine and brain when the primary tumor is in the uterus.
  • Each pelvic viscus drains into a venous plexus around its walls.
  • the vestical, uterovaginal and rectal venous plexuses drain into the internal iliac veins bilaterally.
  • the visceral venous plexuses communicate with the external vertebral venous plexus which surrounds the whole length of the vertebral column.
  • the external vertebral plexus communicate with the internal vertebral plexus which itself receives blood from the vertebrae. Since there are very few valves in this venous system it provides a possible pathway for the spread of neoplastic disease from the pelvic viscera to the vertebrae.
  • Hymen In virgins, the hymen is an impediment for vaginal iontophoresis.
  • the hymen is a delicate incomplete membrane guarding the entrance to the vagina prior to maturity and sexual experience. It has one or more apertures to allow the outflow of menstrual blood and, according to their number and shape, is described as being annular, crescentic, septate or cribriform. If no other way for the introduction of medication is possible and it has to be done more than once, then an incision has to be made in the hymen so that electrodes can be easily introduced into the vagina.
  • the autonomous nervous system innervates every organ in the body, creating, as Galen suggested, 'sympathy' between the various parts of the body. It has as complex a neural organization in the brain, spinal cord, and periphery as the somatic nervous system, but remains largely involuntary or automatic.
  • the hypothalamus can be considered the 'highest' level of integration of autonomic function [2] . It remains under the influence of the cortex and the group of structures known as the limbic system', which includes the olfactory areas, the hypocampus and amygdaloid complex, the cingulate cortex, and the septal area. The regions of the brain regulate the hypothalamus and are critical for emotional and affective expression. The hypothalamus is also concerned with maintaining 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 centres, many of which are situated in the hypothalamus.
  • the hypothalamus controls the autonomic nervous system in two ways, by means of the pituitary and hence other endocrine glands and by directed descending nervous pathways .
  • the limbic system includes the following cortical structures: the olfactory cortex, hypocampal formation, cingulate gyrus and subcallosal gyrus; as well as the following subcortical regions, which were known at that time to share direct cortical connections: the amygdala, septum, hypothalamus, epithalamus, anterior thalamic nuclei, and parts of the basal ganglia.
  • the limbic region of the telencephalon appears to constitute highly interconnected structures that lie between neocortical association areas on the one hand, and the hypothalamus on the other.
  • the limbic region may thus form the gateway for neocortical cognitive influence of hypothalamic mechanism associated with motivation and emotion, and vice versa.
  • the limbic system and the autonomous nervous system which is in fact a united limbico-autonomic system, regulate all tissues and organs of an organism including the cardiovascular system, the gastrointestinal system, the immune systems, the brain, and others.
  • Many substances such as metabolic products, drugs, and other substances cannot or only to a limited extent cross the BBB from the blood into the brain. From the nasal cavity these substances can penetrate into the brain because in the area of of 2.5 cm2 of the upper posterior part of the nasal cavity, the BBB does not exist. Therefore, substances introduced into the upper part of the nasal cavity can directly enter the brain. Access to the CNS is also possible through the optic nerve and through the inferior part of the rectum.
  • the olfactory nerve and the optic nerve we are thus able to deliver compounds into the CNS, bypassing the BBB; the compounds enter thus in all parts of the CNS and of course in the CSF.
  • the compounds enter thus in all parts of the CNS and of course in the CSF.
  • CSF spinal fluid
  • the above methods relate to the non-invasive delivery of biologically active compounds into the brain (CNS) or into the blood.
  • the present invention relates in a first embodiment to a device to enhance the delivery of an effective amount of a biologically active compound into a target organ or 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, said electrodes being capable of being positioned spaced apart from one another, at preselected locations of said organism, wherein the electrodes are all connected with a selected energy source, which generates and maintains an energy field before and during the enhancement of delivery of said compound under the influence of which said compound is propelled in a direction from the active to the passive electrode and into said 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 appeared to be possible to deliver the active compound in a direction from the active to the passive electrode.
  • the present device comprises an energy source which is provided with means for internal electrical circuiting, to hold the supply of energy in rest-position, which means that it can activate the electrodes in the compound-delivery position upon connection to said organism.
  • Any type of electrical current including but not limited to DC and AC of any wave form, can be used for all variants which will be described in this application. It is observed that said preselected locations are preferably with respect to the active electrode provided with the active substance: the nostril, or the bridge on the nose for the electrode without substance, with the substance applied in the nostril separately; and a supplementary pair of active and passive electrodes applied superficially.
  • the electrode acting as the active electrode is provided with means for carrying the active compound in a container of some sort .
  • Such an arrangement has the advantage that the amount of active compound to be delivered to a target organ or tissue from a preselected place at some distance of said organ or tissue can be supplied as accurate as possible. If, for example, said active electrode, provided with the active substance of choice is placed in the nostril of an animal, or human being, and the passive electrode fixed on the back of the head, a generated electric field having a current intensity of up to 10 mA, will result in the almost complete penetration of the active substance into the brain.
  • the duration of iontophoresis is generally up to 60 minutes (sometimes up to several days) .
  • the passive electrode may be split into two or more parts. It will then be possible to enhance the delivery of active substance more accurately to the desired organ or tissue, for example by said split electrode, fixed at different places of the organism, sequentially. It is in this respect observed that at least one passive electrode must preferably be fixed at the projection at the skin of said living organism, of the target organ or tissue to which the biologically active compound will be delivered.
  • the active compound will be diffused and dispersed randomly into said organism from the location onto which said compound was applied. Only by connecting both active and passive electrodes into the circuit, the active compound will be delivered directly into the target organ or tissue.
  • the power source preferably an electric power source
  • Electrodes are comprised of electrically conductive material such as a metal like aluminum, stainless steel, gold, silver, titanium, and zinc.
  • electrically conductive materials include carbon, graphite, and metal salts like silver chloride.
  • Electrodes may be formed of metal foil, metal screen, metal deposited or painted on a suitable carrier backing by means of calendaring, film evaporation, or by mixing the electrically conductive material in a polymer binder matrix.
  • electrodes may be formed of a polymer matrix containing a conductive filler such as a metal powder, powdered graphite, carbon fibers, or other known electrically conductive filler material.
  • Polymer based electrodes may be manufactured by mixing the conductive filler in a polymer matrix, preferably a mixture of hydrophilic and hydrophobic polymers.
  • the hydrophobic polymers provide structural integrity, while the hydrophilic polymers may enhance ion transport.
  • metal powder, carbon powdered, carbon fibers and mixtures thereof can be mixed in a hydrophobic polymer matrix.
  • the energy source connected with the electrodes of the present device is preferably a source providing an electric field, a magnetic field, high energy waves like laser beams or ultrasonic waves, etcetera., in a special embodiment.
  • the energy source may be a combination of these sources.
  • the' energy source is a source of thermal energy.
  • Such a source can, of course also be combined with a source as mentioned above.
  • a combination of a source of electric energy and a source of thermal energy has the advantage that a compound with a relatively high molecular weight can be delivered in the organism, because the supply of thermal energy will allow a better penetration into tissues due to dilatation effects.
  • the energy source is provided with means for changing the polarity of the electrodes connected to said energy source, in order to prevent an irritation or burning sensation in tissues at the site of electrodes.
  • the mechanism of irritation is related to the intensity and duration of the unidirectional current of ions into tissues, as introduced by means of iontophoresis.
  • Electrochemical burns may originate from hydrogen and hydroxide ions generated by the DC current, where 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 to electrochemical burns. This can be avoided by the periodical reversal of current polarity in order to neutralize these ions.
  • the drug or other biologically active substance or compound can be selected from the following listed, and that are given as examples and without limitation: amino acids, anabolics, analgesics and antagonists, anesthetics, anthelmintics, anti-adrenergic agents, anti-asthmatics, anti-atherosclerotics, antibacterials, anticholesterolics, anti-coagulants, antidepressants, antidotes, anti-emetics, anti-epileptic drugs, ant-fibrinolytics, anti-inflammatory agents, antihypertensives, antimetabolites, antimigraine agents, antimycotics, antinauseants, antineoplastics, anti-obesity agents, anti-Parkinson agents, antiprotozoals, antipsychotics, antirheumatics, antiseptics, antivertigo agents, antivirals, appetite stimulants, bacterial vaccines, bioflavonoids, calcium channel blockers, capillary stabilizing agents, coagulants, cor
  • the invention further relates to electrodes to be used in a device according to the invention, comprising an electric conductive base member which can be connected to said selected energy source, wherein the top area of said base member is capable of supporting the biologically active compound, and all but the top area of said base member is coated with an insulating material.
  • the electrode should be inserted as deep as possible into the nose because of two reasons. As was mentioned before, in the upper part of the nasal cavity the BBB does not exist and can be bypassed, and secondly, the lower parts of the nasal cavity contain many capillaries and veins that provide easy access for the drugs to the bloodstream.
  • Such an electrode can be placed into a nostril, but can also be adapted for use in the arteries or veins or in another body cavity or organ.
  • the active electrode is then inserted, for example intra-arterially or intravenously to be positioned next to a thrombus by checking with X-rays, while the passive electrode is connected outside on the body.
  • the electric energy field then enhances the delivery of the active compound (such as an anticoagulant) completely into the thrombus, to remove the thrombus or the arteriosclerotic plaque, which may be located in the brain, in the heart or in the other organs, and thus avoid surgical interventions.
  • iontophoresis to deliver drugs directly into tumours or other morphological disorders in the stomach, in the urinary tract, in the bladder, intraperitoneally, intrathoracally, etc.
  • the base member of the present electrode has a substantial frusto-conical hollow shape.
  • a shape allows the easy insertion into a nostril; nevertheless, any other shape might do as well, such as a tube-like shape.
  • such an electrode according to the invention contains at least one hole or opening in the area coated with the insulating material present in the base member. Such an opening will prevent a complete blocking of the organ flow in which said electrode has been inserted, for example a nostril. In this way, it will be possible to continue normal breathing through the nose during the procedure.
  • the electrode according to the invention is provided with a container for the active compound to be delivered, having a security-stop connection with the top area of the electrode.
  • the container can be made of any suitable material or combination of materials, that fulfills relevant criteria with respect relevant criteria with respect to compatibility with the drug or other substance or compound of interest and with the biological environment, but also with respect to ease of manufacturing, sterilizability, re-usability, low environmental impact, flexibility, connectibility, disposability and durability.
  • the drug container or reservoir should be constructed of any material in such way that it is adapted to absorb and hold a sufficient quantity of liquid in order to permit transport of drug through its wall by means of iontophoresis.
  • the container should hold a self-sealing membrane or valve that allows the in-situ refilling with drug solution, without the necessity of removal and re-insertion of the present device.
  • containers or reservoirs are composed, at least in part, of one or more hydrophylic polymers.
  • hydrophylic polymers Typical preference is for hydrophylic polymers because water is the preferred ion transport medium and hydrophylic polymers have a relatively high equilibrium water content.
  • Multilayered solid polymer container matrices are composed, at least in part of hydrophylic polymer. Insoluble hydrophylic polymer matrices are preferred over soluble hydrophylic polymers since the probability of delivering insoluble polymer by iontophoresis is very low.
  • the container matrix can be cross-linked with the drug components in place such as a silastic matrix, or the polymers can be prefabricated and sorbed with the components from solutions, for example with sponges or pads made of cellulose or woven fibre.
  • the container may also consist of a gel matrix structure, or be of a classical reservoir type holding a liquid.
  • the polymers can be either of linear or cross-linked type.
  • hydrophylic polymers examples include polyethylene glycols, polyacrylates, polyoxyethylene alkylethers, polyvidone, poloxamers, polyethylene oxides, polyvinyl alcohols, polyacrylamide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, co-polyesters, cyclodextrins, crospovidone, crosslinked dextrans, crosscarmellose sodium, natural gums, and starch, and mixtures thereof.
  • the container matrix may contain a hydrophobic polymer, to improve structural integrity.
  • the hydrophobic polymer is heat fusible in order to enhance the lamination of container layers.
  • hydrophobic polymers include but are not limited to polyethylene, polypropylene, ethylene-vinylacetate copolymers, polyvinylacetate, polyisobuty1enes , polyamides, polyurethanes, polyvinylchloride, and acrylic or methacrylic resins.
  • the container may be a polymeric matrix structure formed by mixing the selected drug, solvent, electrolyte, or other component (s) with an inert polymer by means of melt blending, solvent casting, compression or extrusion.
  • the form of the container may be such as to enable its combination and attachment or coupling with the active electrode.
  • the form, size and shape of the active electrode and its drug container are determined by the physiological environment related to its application and introduction into the body, for instance in the nostril, in the blood vessels, in the stomach, in the rectum, and in the vagina.
  • the connection of the container onto the active electrode may be of permanent or semi-permanent type, or of cartridge type for easy exchange of containers.
  • suitable adhesives for permanent connection of container and active electrode is foreseen, while physical locking and connecting means like slide lock, luer-lock, screw lock are more suitable for semi-permanent connections to enable exchange or cartridge type containers.
  • the energy source providing an electric field is preferably adapted to provide a current of up to 25 mA. Such a current appeared to be sufficient in practical tests. Nevertheless, it will be obvious for the expert that some deviation of this value might be used as well, and will also fall within the scope of the present invention.
  • the invention is also directed to an enhanced delivery of an effective amount of a drug into an internal target organ or tissue of an organism, such as a mammal, particularly a human being, being in need of such a delivery with such a drug, wherein the delivery of said compound is enhanced as such into said organ or tissue from a carrying location in the body of said organism by means of energy-stimulated penetration generated and maintained by a field between at least two electrodes that may be split, upon connection with a selected energy source, of which electrodes one can function as an active electrode and one as passive electrode, of which at least one electrode is placed on the outer layer of said organism, and one electrode, having the opposite polarity, is placed near place where said active compound is applied.
  • the passive electrode must be fixed at 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 the active compound is administered directly 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.
  • the passive electrode is wetted with water or hydrogel or an electricity conducting adhesive before its fixation to the skin, whereas the active electrode is provided with the active compound before its fixation.
  • a hydrogel or conductive adhesive onto the container of the active compound, for example in order to temporarily allow fixation onto the outside of a tumor. For example a patient with a tumour in the right temporal lobe.
  • the active electrode with the drug is inserted in the nasal cavity and of the split passive electrode 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 tumour. Then the drug is delivered into the brain and the concentration will be much higher in the region of the tumo r.
  • the location of the active electrode holding the drug container is spaced apart from the target tissue by a membrane or tissue having low resistance. A direct penetration, for example from the nasal cavity into the brain, is thus possible due to the absence of the blood-brain barrier.
  • the delivery of said active compound is enhanced transnasally to the CNS from the nostril by passing the BBB by using a current intensity of up to 10 mA between an active electrode introduced into at least one nostril, and a passive electrode fixed on the back of the head or another place of the head.
  • the delivery of said compound is enhanced transnasally to the CNS by using an active electrode fixed externally on the nose of the organism, a passive electrode fixed on the back of the head or another place, while the active compound is applied intranasally after the generation of the energy field.
  • the active electrode is split into two parts, one of which is fixed externally to the nose, and the other one, being provided with the said active compound is introduced into a nostril.
  • the delivery of said compound is enhanced into some specific region of the brains by using an active electrode fixed intranasally or extranasally and a split passive electrode, whereof one part is fixed externally on the projection of said specific region on the head, and another part is fixed on the back of the head or another place of the head, while said compound has been applied into a nostril.
  • a variant thereof comprises that the passive electrode is split into two parts, of which one is connected with the back of the head, and the other part is connected with the forehead or another region of the head of said organism, while the active electrode carrying the active compound is connected with the palate in the mouth of said organism.
  • an embodiment comprises a kit consisting of two different sets of active and passive electrodes, wherein one set consisting of an active electrode to be placed into a nostril and being provided with a biologically active substance, and a passive electrode to be fixed on the back of the head; and another set consisting of an active electrode, wetted in water, to be fixed at the part of the head opposite to the place of treatment, and a passive electrode wetted in water to be fixed on the projection of the place of treatment, wherein both sets of electrodes can be connected to two different sources, if desired, or to one source, will also fall within the claimed scope of protection of the present invention.
  • iontophoresis i.e. according to the invention
  • other methods which are suited for the delivery of biologically active compounds.
  • Exemplary for such methods are diathermy, use of magnetic field, use of ultrasonic energy, high energy like laser etc., or use of compounds providing a dilatation effect.
  • These dilatating compounds can either be administered separately via oral or parenteral routes or be combined with the drug delivered via iontophoresis.
  • Diathermy and dilatators are preferred when the delivery of biologically active compounds having a high molecular weight must be enhanced through some tissue of the body, for example by passing the BBB.
  • the compound is enhanced transocular to the CNS from the eyelid by using a current intensity of up to 10 mA between an active electrode fixed over the active compound carried by said eyelid, and a passive electrode fixed on the back of the head or on the mastoides of the organism.
  • the compound is delivered to the CNS by using an active electrode, brought into contact with said compound, and both being introduced into the lower part rectum of the organism, and a passive electrode, fixed on the spine or another place, by using a current intensity of up to 10 mA.
  • the active electrode being provided with the biologically active compound is placed in the sublingualis space, and the passive electrode is fixed sub-mandibularly to enhance the delivery of said compound intravenously.
  • the active electrode being provided with the biologically active compound is placed in the rectum or vagina, and the passive electrode is fixed externally on the spine or another place on the skin of the organism to enhance the delivery of said compound intravenously.
  • the active electrode being provided with the biologically active compound is introduced into a vein or artery, and the passive electrode is fixed on the projection on the skin of the pathological organ or tissue, for instance a thrombus, to which a antocoagulant or fibrinolytic agent is delivered in a high concentration.
  • a thrombus to which a antocoagulant or fibrinolytic agent is delivered in a high concentration.
  • the active electrode being provided with the biologically active compound is placed in the stomach or bladder or intraperitoneally, and the passive electrode is fixed externally on the skin of the organism to enhance the delivery of said compound into the tumour or lesion.
  • Electrodes metal, conductive rubber or another conductive material, such as mentioned before
  • the electrodes have to be covered by the cotton or other material wetted in the solution of the necessary drug or compound and to touch the nose mucous membrane. Electrodes must be introduced as deep as possible, but without causing unpleasant feelings. Electrodes themselves must touch neither skin nor the nose mucous membrane, only through the container with active substance.
  • Another electrode or split electrode covered by cotton or other material and wetted in the water has to be fixed on the mastoid processes or to be fixed on the back of the head in the area of cervical vertebrae or another place.
  • current intensity can increase up to 10 mA. Subsequently the current intensity can be decreased until any unpleasant feeling disappears.
  • iontophoresis according to a second embodiment through the oral cavity.
  • intracerebral transoral The nasal cavity and the pharynx are connected with each other and all together are called nasopharynx.
  • the oral cavity is connected to the nasal cavity by the upper part of the pharynx.
  • the upper part of the oral cavity that is the hard and soft palates, is a bottom of the nasal cavity.
  • the hard palate is a thin bone structure and as well as the soft palate is covered from both sides by the epithelium, which is known to have low resistance and to conduct easily the current.
  • An electrode metal, conductive rubber or another conductive material
  • the electrode has to be covered by the cotton or other material wetted in the solution of the necessary drug or substance and to cling close to the hard palate.
  • the electrode must be introduced as deep as possible, but without causing unpleasant feelings.
  • the electrode itself must touch neither skin nor the mucous membrane of the oral cavity, only through the container (here the cotton wool or other kind of pad) with active substance.
  • Another split electrode covered by cotton or other material and wetted in water has to be fixed on the mastoid processes or a single passive electrode has to be fixed on the back of the head in the area of cervical vertebrae or at any other place on the head.
  • current intensity can increase up to 10 mA or more. Subsequently the current intensity can be decreased until unpleasant feelings disappear.
  • the duration of the iontophoresis is up to 60 minutes or more, sometimes several days, dependent on the dosage of a necessary substance, its concentration, the resistance of the epithelium on the hard palate, and other factors. Influenced by the current, a drug or other substance penetrates into the nasal cavity and from there through the olfactory structures into the CNS, without having to pass the BBB.
  • a drug or other substance penetrates into the nasal cavity and from there through the olfactory structures into the CNS, without having to pass the BBB.
  • the skin of the eyelid has a resistance lower than that on the rest of the skin surface and a resistance of the cornea and of the sclera is negligible.
  • a split active electrode metal, conductive rubber, or another conductive material
  • the active electrodes have to be covered by the cotton or other material wetted in the solution of the necessary active substance and to touch the skin. Electrodes themselves must not touch the skin, but only through the container (here the cotton) holding the active substance.
  • Another split electrode covered by cotton or other material and wetted in the water has to be fixed on the mastoid processors or on another place or a single passive electrode has to be fixed on the back of the head in the area of cervical vertebrae or on another place.
  • current intensity can increase up to 10 mA. Subsequently the current intensity can be decreased until unpleasant feelings disappear. This method is called transocular.
  • transcorneal and transscleral are realized by applying two special electrodes directly to the cornea and the sclera, respectively.
  • the electrodes brought in the contact with the cornea or the sclera must deliver the necessary drug or active substance.
  • Another split electrode covered by cotton or other material and wetted in water has to be fixed on the mastoid processes or one part of the passive electrode has to be fixed on the back of the head in the area of cervical vertebrae on another place, and another part has to be fixed on the forehead.
  • current intensity can increase up to 2 mA or more.
  • We called this method “Non-invasive intravenous delivery of drugs and other substances" .
  • Our method 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 to conduct easily the current .
  • An electrode metal, conductive rubber, or another conductive material
  • An electrode has to be covered by the cotton or other material wetted in the solution of necessary active compound and must be introduced into the mouth and brought into the contact with the mucosa of the sublingual space. During the procedure the mouth must be tightly shut in order to keep the electrode on its 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 the cotton or other material wetted in the solution of the necessary drug or substance.
  • the electrode itself must touch neither skin nor the mucous membrane of the oral cavity, only through the container with active substance.
  • the rectum and the vagina are covered with the epithelium, which is known to have low resistance and to conduct easily the electric current. According to Ohms law the current intensity by the same voltage has to be much more higher than the iontophoresis done through the skin. It is known that the quantity of substance introduced by the current is directly proportional to the current intensity. Hereby, the proportion of the substance introduced into the organism will be higher than if it were done through the skin. In the blood, the concentration of the substance introduced by our method will be the same as by intravenous administration. We suggest the following method for this embodiment .
  • An electrode metal, conductive rubber, or another conductive material
  • An electrode has to be covered by the cotton or other material wetted in the solution of necessary active compound and must be introduced into the rectum or the vagina and brought into contact with the mucosa of the space. During the procedure the rectum must be free from the excrements
  • 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 wetted in water has to be fixed on the skin of the sacralis or superpubitalis or on another place.
  • current intensity can increase up to 5 mA or more.
  • the duration of this kind of iontophoresis is up to 60 minutes or more, dependent on the dosage of a necessary drug, its concentration, etc.
  • - figures 2 to 6 show graphically the results obtained by using a device and method according to the invention, while - figures 7a and 7b show the conveyance route of an active substance from a nostril into the brains.
  • the electrode comprising the conductive base member is represented by 1; this base member has preferably a hollow form, and is expediently coated with an insulating material for example a plastic, except the top areas, which carries the biologically active substance 2.
  • the base member 1 is further connected to a source of current by means of line 3 , connected to the conductive base material .
  • the base member is further provided with one or more perforations 4.
  • the electrode as represented in the f igure has a tube-like form, a substantial frusto-conical form or another form can be used. Further, the perforations 5 can have any form.
  • FIG 7a and 7b the delivery of an active compound into the brains is schematically shown.
  • the compound is according to fig. 7a applied into a nostril by means of the active electrode a.
  • the passive electrode b is fixed on the back of the head. Both electrodes are connected with an energy source I.
  • the active compound Upon activation of the electrodes a and b the active compound will be forced in a direction from a to b, as indicated by dotted lines f .
  • the direction of delivery of the active substance can be bended by means of another pair of electrodes, i.e. the active electrode c and the passive electrode d.
  • These electrodes c and d are connected to a different energy source II.
  • Iontophoresis sessions were conducted daily for 15-30 minutes, with a total of 20-25 sessions. As a rule, the improvement came after 3-5 sessions.
  • To healthy volunteers we administered a solution of piracetam. 16 of them have shown significant improvement of memorizing abilities and increase of activity.
  • Another experiment was conducted in 5 male volunteers in the age from 20 to 30.
  • CSF cerebrospinal fluid
  • the first dish remained only with the streptococcus culture.
  • To the second one was added one drop of the CSF.
  • To the third one was added one drop of blood from the vein. All three dishes were subsequently placed into a thermostat to analyze the ability of the CSF and the blood to destroy the streptococcus .
  • we wetted cotton covers in the benzylpenicillm solution (0,2 g [200 000 units] per 5 ml of distilled water) .
  • a split electrode covered by these cotton covers was placed over each of the the eyes.
  • Another split electrode covered by cotton wetted in water was fixed on the mastoid processes.
  • the intensity of galvanic current by iontophoresis was 0. 8 - 2 mA. The duration of the procedure was 30 minutes.
  • Electric current does not have a negative impact on the brain and is even used for treatment of a series of the nervous system disorders.
  • This treatment is called cerebral electrostimulation or electrosleep.
  • This method is realized by application of electrodes bilaterally placed over the eyes and the mastoid or neck region [9] .
  • Methylprednisolone hemisuccinate was according to the invention administered to rabbits, using the following protocols.
  • HPLC assay for Methylprednisolone hemisuccinate and methylprednisolone The mobile phase was a mixture of acetonitrile and phosphate buffer pH6 (30:70% v/v) . The flow rate was 1.2 ml min 1 . The effluent was monitored at 242 nm. Injection volume 2 ⁇ 1. Retention times: Methylprednisolone hemisuccinate (MPS) 6.5 min and Methylprednisolone (MP) 14.6 min. Limits of quantitation 10 ng/ml for both compounds. Intra and interday coefficients of variation were ⁇ 5%. CASno. MPS 2375-03-3; MP 83-43-2. Molecular weight: MPS 496.50; MP 374.50. Gross formula: MPS C26H33Na08.
  • New Zealand White rabbits (2.5-3 kg body weight) were obtained from the Central Animal Laboratory (University of Nijmegen, The Netherlands) .
  • the animals were anesthetized with 0.5 ml/kg Hypnorm (fentanylcitrate 0.315 mg/L and fluanisone 10 mg/ml; Janssen Pharmaceutica, Tilburg, the Netherlands) .
  • the animals were intubated and mechanically ventilated with N20, 02, 1:2 (v/v) , and ethrane 2.4%. Endtidal C02 was maintained at 4%.
  • the artery femoralis was cannulated with a Venflon 2, 18 G catheter.
  • Electrodes encapsulated in cotton wool and saturated with drug solution were firmly placed in the nasal passage, the opposite electrode was placed with a wet sponge pad at the shaven back of the head (clear skin) .
  • the nose electrodes were used in the positive (+) and negative (-) mode in separate experiments.
  • a spinal fluid sample of 1 ml was collected from the animal after killing and just before the brain was dissected. After killing of the animal the whole brain was dissected. The right Temporal lobe, the Frontal lobe, Brain stem and remaining were collected.
  • Sample preparation During the whole experiment (6 h) blood samples were kept at room temperature (20 degrees C) . Thereafter the blood samples were centrifuged at 3000 g, and plasma was stored in duplo at -20 degrees C until analysis. Brain and liquor were stored at -20 degrees C until analysis. Drug analysis
  • the HLPC system consisted of a Marathon autosampler
  • the column was a Spherisorb 50DS
  • 150 gl plasma was vortexed for 10 sec with 150 ⁇ 1 acetonitrile. The mixture was centrifuged at 3000 g for 5 min. 20 ⁇ 1 of the clear supernatant was injected onto the column.
  • Braintissue Two ml of distilled water was added to 1 gram of brain tissue. The mixture was homogenized in an ultratorax apparatus (Ystral, Dottingen, Germany) at 10,000 rpm during 30 seconds. The homogenate was centrifuged at 3000 g during 5 min and further treated like plasma.
  • Plasma concentrations ( ⁇ g/ml) of methylprednisolone hemisuccinate (MPS) and methylprednisolone (MP) in a rabbit after installation of a MPS saturated cotton wool in the nostrils of each rabbit and without and with positive and negative iontophoresis.
  • (+) means : positive electrode into the nostril;
  • (-) means : negative electrode into the nostril.
  • the concentrations of both substances in the brains were also measured. The following results were obtained for the concentrations of the compounds in the brains.
  • Fig. 2 shows the results obtained with rabbit Nr. 1 graphically.
  • Fig. 3 shows the result obtained with rabbit Nr. 3 graphically.
  • the concentration of methylprednisolone in the brain is between 10 and 100 times higher.
  • Andrianov W Neurochemical mechanisms of the participation of individual neurons in the processes of anticipation and evaluation of the results of behavorial activity. Neuroscience and Behavorial Physilogy, 24: 489-494, 1994.
  • Burnette RR, Marrero D Comparison between the iontophoretic and passive transport of thyrotropin releasing hormone across excised nude mouse skin. J Pharm Sci 75:738-743, 1986.
  • Currier DP (eds) Clinical Electrotherapy, 2nd ed. Norwalk, Connecticut, Appleton and Lange, 1991.
  • Gerfin CR O'Leary DDM
  • Cowan VM A note on the transneural transport of wheat germ agglutinin - conjugated to horseradish peroxidase in the avian and rodent visual systems. Exp Brain Res 48: 443-448, 1982.
  • Glass Jm, Stephen RL, Jacobson SC The quality and distribution of radiolabeled dexamethasone delivered to tissue by iontophoresis. Int J Derm 19:519-525, 1980.
  • Nicholson C Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum. Biophysical Journal 68:1699-1715, 1995.
  • Nickell WT, Behbehani MM, Shipley MT Evidence for GABAB-mediated inhibition of transmission from the olfactory nerve to mitral cells in the rat olfactory bulb. Brain Research Bulletin, 35:119-123, 1994.
  • Pardridge WM Knocking on the cerebral door. Odyssey, 1:46-51, 1995.
  • Vries HE de Characteristics of blood-brain barrier endothelial cells in response to inflammatory stitauli. Proefschrift, RU Leiden, 1995.
  • Bell IR White paper: Neuropsychiatric aspects of sensitivity to low-level chemicals: A neural sensitization model - Toxicology and Industrial Health, 10: 277-312, 1994.
  • Bioly active compounds This invention is useful in the delivery of directly or indirectly active substances or compounds or drugs within their broadest sense, or any other substance or compound of interest, in order to achieve a therapeutic, diagnostic or other desired, usually beneficial, effect.
  • Biologically active compounds, agents or substances may relate to compounds of chemical, biological or biotechnological origin; examples include organic and inorganic chemical substances, and compounds pertaining to animal, human, microbiological, plant, or viral origin.
  • compound (s) drug(s) and substance (s) are used interchangeably.
  • Blood brain barrier The barrier separating the blood from the parenchyma of the central nervous system. Presumably it consists of the walls of the cappilaries of the central nervous system and the surrounding glial membranes (glial end-feet) . Abbreviation used: BBB
  • Container any receptacle or reservoir that holds a liquid compound or a compound dissolved in a solvent or combination of these.
  • the container material may form part of the matrix hat holds the biologically active compound.

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  • Electrotherapy Devices (AREA)
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EP96939840A 1995-11-21 1996-11-19 Vorrichtung zur erhöhten verabreichung von biologisch wirksamen stoffen und verbindungen in einem organismu Withdrawn EP0869829A1 (de)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
EP95203173 1995-11-21
EP95203173 1995-11-21
EP95203601 1995-12-22
EP95203601 1995-12-22
EP96200082 1996-01-22
EP96200081 1996-01-22
EP96200081 1996-01-22
EP96200082 1996-01-22
PCT/EP1996/005086 WO1997018855A1 (en) 1995-11-21 1996-11-19 Device for enhanced delivery of biologically active substances and compounds in an organism

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EP0869829A1 true EP0869829A1 (de) 1998-10-14

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EP96939840A Withdrawn EP0869829A1 (de) 1995-11-21 1996-11-19 Vorrichtung zur erhöhten verabreichung von biologisch wirksamen stoffen und verbindungen in einem organismu

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EP (1) EP0869829A1 (de)
JP (1) JP2000500999A (de)
AU (1) AU7693296A (de)
CA (1) CA2238055A1 (de)

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US20120310140A1 (en) * 2010-12-01 2012-12-06 Spinal Modulation, Inc. Directed delivery of agents to neural anatomy
CA2823486A1 (en) * 2011-01-04 2012-07-12 Sanofi-Aventis Deutschland Gmbh Adaptor means for use in combination with a pre-filled syringe and a safety device, safety device and injection device
WO2013157937A1 (en) * 2012-04-16 2013-10-24 Lerner Eduard N Device for enhanced intercerebral multi-delivery of biologially active substances
MX2020013519A (es) * 2018-08-23 2021-05-12 Novocure Gmbh Uso de campos electricos alternativos para aumentar la permeabilidad de la barrera hematoencefalica.

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Title
See references of WO9718855A1 *

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CA2238055A1 (en) 1997-05-29
JP2000500999A (ja) 2000-02-02

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