CN1997421A - Oral devices and methods for controlled drug delivery - Google Patents

Abstract

Controlled drug delivery oral devices are implanted or embedded in the oral cavity, built on prosthetic crowns, artificial tooth plates, braces, dental implants, and the like. The device is refilled or replaced as needed. Controlled drug delivery can be passive based on dosage form, or electro-mechanically controlled for high precision smart drug delivery. Additionally, the controlled delivery may be any of the following: the administration of the drug is according to a preprogrammed schedule, the administration of the drug at a controlled rate, the administration of the drug in a delayed manner, the administration of the drug in a pulsed manner, the administration of the drug in a long-term treatment, the administration of the drug in a closed loop, the administration of the drug in response to input from a sensor, the administration of the drug according to instructions from a personal external system, the administration of the drug according to a schedule specifically defined by a personal external system, the administration of the drug through a personal external system according to instructions from a monitoring. Absorption of the drug in the oral cavity can be aided or induced by any one or combination of transport mechanisms such as iontophoresis, electroosmosis, electrophoresis, electroporation, sonoporation, and ablation. The oral device requires refilling or replacement at relatively long intervals of weeks or months, maintains a desired dosage level in the oral cavity for an extended period of time, thereby maintaining a desired dosage level in the gastrointestinal tract, for situations of narrow drug therapeutic index, and ensures compliance with a prescribed drug regimen in an automated manner. The oral devices and methods for controlled delivery of drugs are applicable to both humans and animals.

Description

Oral devices and methods for controlled drug delivery

technical field

The present invention relates to controlled drug delivery and monitoring, and more particularly, to oral devices and methods that provide multiple drug delivery protocols and clinical sampling methods.

Background technique

Oral administration is the most common route of drug delivery, and more than half of the drugs on the market are administered for this route. Drug delivery from the gastrointestinal tract at a controlled rate is desired to maintain controlled levels of the drug in the bloodstream and tissues through the patient, and to control diurnal variations resulting from oral intake at specific times of the day. However, the bioavailability of oral administration, the extent to which the drug reaches the target tissue, is affected by drug dissolution, drug degradation, and drug absorption in the gastrointestinal tract, and is generally not constant over time. Certain drugs have high bioavailability, which may dissolve and absorb so quickly that peak concentrations are reached shortly after ingestion. In this case, an attempt is made to slow down the dissolution process through a controlled release dosage form. Other drugs have very low bioavailability and may be eliminated through the gastrointestinal tract and first-pass before absorption. In this case, methods to increase absorption and methods to increase gastrointestinal retention may be employed.

The absorption of a drug (or drug precursor) into the systemic circulation is determined by the physicochemical properties of the drug, its formulation, and the route of administration, whether the route of administration is oral administration, rectal administration, vaginal administration, subcutaneous injection, Topical administration, inhalation administration, or intravenous administration. Oral administration includes swallowing, chewing, sucking, as well as buccal (ie, placing the drug between the gum and cheek), and sublingual (ie, placing the drug under the tongue). The advantage of chewing, pumping, and buccal and sublingual administration is that they also produce direct absorption through the mouth, avoiding the gastrointestinal tract and its attrition, and first pass in the liver before entering the system metabolic loss. A necessary condition for absorption is drug dissolution.

The extent of drug dissolution depends on whether the drug is in salt, crystalline, or hydrate form. To improve dissolution, disintegrants and other excipients such as diluents, lubricants, surfactants (substances that increase the rate of dissolution by increasing the wettability, solubility, and dispersibility of the drug) are often added during the manufacturing process , binder, or dispersant.

Drug degradation in the gastrointestinal tract is due to various gastrointestinal secretions, low pH, and degradative enzymes. Because the pH of the GI tract lumen changes along the GI tract, drugs must withstand different pH values. Interactions with blood, food, mucus, and bile may also affect the drug. Reactions that may affect the drug and reduce bioavailability are complex formation, such as between tetracycline and polyvalent metal ions; hydrolysis by gastric acid or digestive enzymes, such as penicillin and chloramphenicol palmitate hydrolysis; intestinal (gut ) conjugation in the wall, such as sulfoconjugation of isoproterenol; adsorption to other drugs, such as digoxin and cholestyramine; and metabolism by the microbial flora of the lumen of the gastrointestinal tract.

Table 1 below summarizes some parameters affecting the bioavailability of drugs by the oral route [Encyclopedia of Controlled Drug Delivery, Volume 2, edited by Edith Mathiowitz].

Table 1

parts Area M ² Fluid secretion, liter/day pH value passing time, hours Mouth ~0.05 0.5-2 5.2-6.8 short Stomach 0.1-0.2 2-4 1.2-3.5 1-2 duodenum ~0.04 1-2 4.6-6.0 1-2 small intestine 4500 (including fluff) 0.2 4.7-6.5 1-10 large intestine 0.5-1 ~0.2 7.5-8.0 4-20

In general, poor bioavailability is common among poorly water soluble, slowly absorbed drugs. Insufficient time in the gastrointestinal tract is another common cause of low bioavailability. Ingested drug is exposed to the entire gastrointestinal tract for up to 1 to 2 days and to the small intestine for only 2 to 4 hours. If the drug does not dissolve immediately or penetrate epithelial membranes rapidly, its bioavailability is reduced. Age, sex, behavior, genetic phenotype, stressful state, disease (eg, achlorhydria, malabsorption syndrome), or previous GI surgery can further affect drug bioavailability.

In addition to the physical barrier of epithelial cells, chemical and enzymatic barriers affect drug absorption.

Another important barrier to drug absorption is first-pass metabolism before entering the system, mainly hepatic metabolism. The dominant enzymes in this metabolism are the multigene family of cytochrome P450s that have a major role in metabolizing drugs. It appears that differences in P450 between individuals lead to differences in their ability to metabolize the same drug.

Additionally, multidrug resistance (MDR) may be a barrier to drug absorption. MDR, a major cause of cancer treatment failure, is a phenomenon whereby cancer cells develop broad-spectrum resistance to multiple chemotherapeutic drugs. MDR has been associated with overexpression of P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP), two A transmembrane transporter molecule that acts as a pump to remove toxic drugs from tumor cells. P-glycoprotein functions as a unidirectional efflux pump in the AML cell membrane and reduces the intracellular concentration of cytotoxic drugs by pumping them out of leukemia cells. In addition, it develops resistance to a variety of chemotherapeutic drugs including daunorubicin.

Ways to increase drug absorption:

In addition to the route of intravenous administration after dissolution, the drug must pass through several semipermeable biological barriers before entering the systemic circulation. Drugs can cross biological barriers by passive diffusion, or by other naturally occurring modes of transport, such as assisted passive diffusion (facilitated diffusion), active transport, or pinocytosis. Alternatively, it is possible to artificially assist the drug to cross the biological barrier.

In passive diffusion, transport depends on the concentration gradient of the solute across the biological barrier. Because drug molecules are rapidly removed through the systemic circulation, the drug concentration in the blood is low compared to the site of administration, resulting in a large concentration gradient. The diffusion rate of the drug is proportional to the gradient. However, the rate of drug diffusion also depends on other parameters, such as the lipid solubility and size of the molecule. Because cell membranes are lipid compounds, lipid-soluble drugs pass through the cell membrane more rapidly than relative lipid-insoluble drugs. Additionally, small drug molecules penetrate biological barriers more rapidly than larger drug molecules.

Another naturally occurring mode of transport is assisted passive diffusion, which occurs in certain molecules such as glucose. The carrier component is believed to reversibly bind to the substrate molecule outside the cell membrane. The carrier-substrate complex rapidly diffuses through the membrane, releasing the substrate on the inner surface. The method is characterized by selectivity and saturation: the support acts only on substrates with a relatively specific molecular configuration, and the method is limited by the availability of the support.

An option is nanotechnology, which derives its name from the size of the subjects involved. There are subjects that are typically smaller than 100 nanometers and on the molecular scale. For drugs, drug particles are reduced to "nanoscale" sizes for smoother delivery, better dissolution patterns, better control over absorption, and lower required doses.

Active transport, another naturally occurring mode of transport, appears to be restricted to drugs that are structurally similar to endogenous substances. Active transport is characterized by selectivity and saturation and requires energy expenditure by the cell. It has been confirmed for a variety of ions, vitamins, sugars, and amino acids.

Another naturally occurring mode of transport is pinocytosis, in which fluid or particles are engulfed by cells. The cell membrane wraps around the fluid or particle, then fuses again to form vesicles that then separate and move inside the cell. Like active transport, this mechanism requires energy expenditure. It is known to play a role in drug delivery of protein drugs.

The foregoing discussion refers to naturally occurring modes of transport. When these are not sufficient, eg in cases where large molecules and polar compounds cannot be efficiently passed through biological barriers, drug transport can be artificially induced.

Electron transport generally involves electrically induced passage of drugs (or prodrugs) across biological barriers. Several electron transport mechanisms are known, as follows:

Iontophoresis involves the electrically induced transport of charged ions by applying a low level of direct current (DC) current to a solution of a drug. Because like charge repulsion, applying a positive current pushes positively charged drug molecules away from the electrode and into the tissue; similarly, a negative current pushes negatively charged ions into the tissue. Iontophoresis is an efficient and rapid method of delivering water-soluble ionized drugs. When the drug molecule itself is not water soluble, it may also be coated with a coating that may form a water soluble entity such as sodium lauryl sulfate (SLS).

Electroosmosis involves the movement of solvents and drugs across membranes under the influence of an electric field.

Electrophoresis is based on the movement of charged species in an electromagnetic field. Ions, molecules, and charged particles in solution transmit an electric current when an electromagnetic field is applied. The movement of charged species tends towards the oppositely charged electrode. The voltage for continuous electrophoresis is quite high (hundreds of volts).

Electroporation is a method in which a biological barrier is subjected to a shock or pulse of high voltage alternating current (AC). AC pulses create temporary pores in biofilms, specifically, between cells. Pores allow macromolecules such as proteins, DNA, RNA, and plasmids to pass through biological barriers.

Iontophoresis, electroosmosis, and electrophoresis are diffusion processes in which diffusion is enhanced by electrical or electromagnetic driving forces. In contrast, electroporation breaks down biological barriers directly along cell boundaries, allowing macromolecules to pass.

Often, more than one of these approaches works in combination with passive diffusion and other naturally occurring modes of transport. Thus, electron transport refers to at least one of the above-mentioned transport mechanisms, and possibly a combination of the above-mentioned transport mechanisms, as a complement to the naturally occurring transport means.

Medical devices involving electrotransport drug delivery are described, for example, in U.S. Patent 5,674,196 to Donaldson et al; U.S. Patent 5,961,482 to Chien et al; U.S. Patent 5,983,131 to Weaver et al; U.S. Patent 5,983,134 to Ostrow; described, the disclosure of which is incorporated herein by reference in its entirety.

In addition to the electron transport methods described above, other electronically assisted drug delivery mechanisms are as follows:

Sonophoresis, or the application of ultrasonic waves to induce the growth and vibration of pores, is called cavitation. It breaks down lipid bilayers and thereby enhances transport. For effective drug delivery, low frequencies between 20 kHz and less than 1.5 MHz should be used rather than therapeutic frequencies. Ultrasonic poration devices are described, for example, in U.S. Patents 6,002,961, 6,018,678, and 6,002,961 to Mitragotri et al; U.S. Patents 6,190,315 and 6,041,253 to Kost et al; U.S. Patents 5,947,921 to Johnson et al; , the disclosure of which is incorporated herein by reference in its entirety.

Ablation, or the precise ablation of tissue by various means, is another way to push drugs across biological barriers. In addition to mechanical ablation using a hyperdemic needle, laser ablation, cryoablation, thermal ablation, microwave ablation, radiofrequency ablation, or electrical ablation may be used. In essence, electroablation is similar to electroporation, but tends to be more severe.

US Patent 6,471,696 to Berube et al. describes a microwave ablation catheter useful as a drug delivery device. US Patent 6,443,945 to Marchitto et al. describes a device for drug delivery using laser ablation. US Patent 4,869,248 to Narula describes a catheter for localized thermal ablation for drug delivery purposes. US Patents 6,148,232 and 5,983,135 to Avrahami describe drug delivery systems by electroablation. The disclosures of all of these are incorporated herein by reference.

Controlled release dosage form:

Oral controlled-release dosage forms are generally designed to maintain therapeutic drug concentrations for at least 12 hours. Several controlled release mechanisms are available, for example in the Encyclopedia of Controlled Drug Delivery edited by Edith Mathiowitz, Vol. 2, pp. 838-841. These are based on the use of specific substances (usually polymers) as substrates or coatings. These can be rapidly or slowly degrading substances, depending on the desired effect. For example, when the half-life of the drug in the body is too short, the drug can be coated with a slowly dissolving coating. Therefore, the drug must diffuse through the coating, slowing its half-life. Other coating materials form pores filled with gastrointestinal fluid, increase the contact area between the drug and gastrointestinal fluid, and shorten the diffusion path in the drug matrix, thereby increasing the half-life of the drug. In these and other ways, the modified drug release form prolongs, delays or sustains the release of the drug in a passive, controlled manner, where passive means a system that is not electronically controlled. An overview of modified drug release forms for passive, controlled release follows:

Osmotic systems rely on the uptake of water by the dosage form to increase the osmotic pressure within the system. The formation of osmotic pressure pushes the drug through the pores in the dosage form to release the drug in a controlled manner.

Film-coated tablets consist of water-soluble drug particles compressed to form a tablet core. Tablet cores are coated with a coating of a substantially insoluble polymer, such as polyvinyl chloride, wherein the coating is mixed with a water-soluble pore-forming compound. Additionally, the solubility of pore-forming compounds can be pH-dependent to target specific regions in the gastrointestinal tract. The drug release rate depends on the pH level and the porosity in the coating after the pores are formed.

Enteric coated dosage forms are dosage forms in which a drug core is coated with a mixture of polymers formed from soluble and insoluble particles. The soluble particles dissolve in the intestinal fluid, exposing the insoluble particles. As a result, a microporous layer forms around the drug core and the drug slowly permeates through the pores.

Multi-layer tablets consist of a drug core layered with several coatings with different solubility to provide release at specific time intervals and/or pH levels. As the individual layers dissolve, a pulsatile release is achieved. By varying the type and amount of polymer employed, the rate of release can be adjusted.

Tablets for pH-independent controlled release, produced by wet granulation of an acidic or basic drug mixed with buffers and suitable excipients. The granules are then coated with a coating which is permeable to gastrointestinal fluids, and the coated composite is compressed into tablets. Upon oral administration, gastrointestinal fluids permeate the membrane coating. Buffers adjust the pH of the tablet when in contact with gastrointestinal fluids; the drug dissolves and permeates at a constant rate regardless of the pH level in the gastrointestinal tract.

Hydrogel suppository forms consist of a capsule of water-insoluble solids sealed with a water-soluble cap, and further contain a hydrogel suppository. When the capsule is swallowed, the water soluble cap dissolves and exposes the hydrogel plug, which begins to swell. At a preset time after ingestion, the hydrogel plug is expelled and the drug is released into the gastrointestinal tract.

Multiparticulate dosage forms usually consist of sugar or nonpareil pellets that are sprayed with drug, dried, and then sprayed with a second coating composition that provides controlled release. The second coating composition is typically formed from polymers that are partially soluble or insoluble in gastric juices, where solubility depends on the desired drug release profile. The double-coated pellets are placed in capsules for swallowing. Capsules may contain pellets of various types and release patterns.

Gastro-retention Devices: Many orally administered drugs are efficiently absorbed in the upper GI tract, stomach, and near the small intestine but have little absorption in the colon [Singh et al., J, Controlled Release, 63(3) , 235 (2000); US Patent 5,443,843 to Curatolo et al.]. However, because the passage of the drug through the upper gastrointestinal tract, stomach, and adjacent to the small intestine is relatively fast, typically about 12 hours, drug bioavailability is limited, and thus the dosage form plays a major role during this time span. Most important for increasing bioavailability is prolonging the retention time of the drug at the upper site [Hwang et al., Crit. Rev. Ther. Drug Carrier Syst, 15(3), 243 (1998).

A possible solution to this problem is a long-term gastric retention device, which is orally administered and adapted for long-term drug release in the upper gastrointestinal tract. Long-term gastric retention devices are particularly useful in situations where medication is taken for a long period of time, such as in chronic disease and hormone therapy. It also simplifies treatment with different drugs.

Drugs considered for long-term gastric retention devices must meet the following criteria:

1. The therapeutic range is large such that deviations in drug release above or below predetermined levels do not cause significant symptoms; and

2. Overdose will not endanger the patient.

Possible options include: analgesics, anxiolytics, antimigraines, sedatives, antipsychotics, anticonvulsants, antiparkinsonian, antiallergic, antidepressants, antiemetics, Astma -profilactics, antacids, anti-constipation drugs, intestinal anti-inflammatory drugs, anthelmintics, anti-anginal drugs, diuretics, hypolipidemic agents, anti-inflammatory drugs, hormones, vitamins, antibiotics.

Additionally, potential drug candidates for long-term gastric retention devices include drugs for veterinary use, including drugs for large animals such as cattle, sheep, and pigs, and for poultry.

There are several methods used for long-term gastric retention devices, as follows:

1. Intragastric floating system: This system is designed to float in gastric juice. Three main techniques have been used to create buoyancy in gastric juice, as follows:

i. The mixture of bicarbonate and gastric juice produces _CO2 , which remains inside the matrix of the dosage form, allowing the dosage form to float in the stomach, allowing the dosage form to prolong its residence time in the stomach. Similarly, another gas may be produced.

ii. A low-density core system formed of a buoyant substance such as air, _CO2 or gel. It is coated with an outer dosage form suitable for controlled release.

iii. Gel-forming hydrophilic polymers that form a gel-like shell upon contact with gastric juices can be used to create hydrodynamic equilibrium systems whose buoyancy is ensured by their dry or hydrophobic cores. The gel-like shell is also responsible for controlled drug release.

However, these floating machines only have a stomach residence time of a few hours, and their effects depend on the amount of food and water in the stomach. Therefore, their performance is uneven and difficult to predict.

2. High Density System: This system is based on sinking the device to the bottom of the stomach. As a result, devices are often made of heavy materials. At first, this approach looked promising, but later studies showed no significant gastric retention.

3. Mucoadhesive system: This adhesive system is able to attach to the sticky wall of the stomach and is expected to remain in the stomach during the renewal of the mucosal layer. However, it also binds to almost any other material in the gastric fluid it comes into contact with: gelatin capsules, proteins, and free mucus. Another obstacle is that its viscosity is pH-dependent, with a pH higher than normal gastric pH levels significantly reducing viscosity. Therefore, the test results were disappointing and no significant increase in the retention time in the stomach was observed.

4. Magnetic system: A magnet is placed outside the stomach above the stomach to prevent the small magnetized particles in the dosage form from leaving the stomach. Even with some reported successes, the viability of these systems is doubtful because magnets need to be carried outside the body and placed with great precision in order to achieve the desired results. New and more convenient ways of applying magnetic fields must be found to improve on this concept.

5. Expandable system: This system is based on apparent changes in size in the stomach. Several methods have been proposed:

i. Hydrogels that swell upon contact with gastric fluid;

ii. Osmotic devices containing salt or sugar surrounded by a semipermeable membrane;

iii. A system comprising a low boiling point liquid that becomes a gas at body temperature and expands the device to its desired size, wherein the controlled release begins simultaneously with the expansion.

However, these systems have the disadvantage of slow expansion and therefore cannot be retained in the stomach. Furthermore, the ability to expand to the desired size and the subsequent degradation process remains a substantial challenge.

6. Superporous, biodegradable hydrogel system: This system is based on the expansion of a unique hydrogel system, superporous hydrogel, through a chemical reaction in acid and _NaHCO2 Synthesized by cross-linking polymerization of various vinylic monomers in the presence of bubbles formed. Compared to other deployable systems, it has a much higher level of swelling and expands at a faster rate than conventional hydrogels, reaching the desired deployed form within minutes as opposed to hours. However, this system is mechanically weak and thus its disruption, resulting in a short residence time in the stomach.

7. Mechanically Expandable System: This system is based on a mechanical device that expands or extends from an initial, compact size to an extended form that prevents passage through the gastric pylorus. Currently, mechanically deployable systems are the most promising in the field of gastric retention, however many technical issues related to their performance remain to be resolved.

Therefore, there is currently no reliable and effective long-term gastric retention device.

Patient Compliance Prescription Program: Low compliance with prescribed treatment is ubiquitous, however, it can undermine treatment success. Typical compliance rates for medications are about 50%, which is much lower than lifestyle prescriptions and other more behaviorally demanding regimens [Haynes RB, McDonald HP, Garg AX., JAMA 288(22):2880-3(2002 )]. In fact, a Hungarian study reported that, despite potentially life-threatening conditions, one-third of hypertensive patients take their medication irregularly. [Rapi J. Orv Hetil, 143(34):1979-83(2002)]. Another survey showed that 62.4% of patients with familial hypercholesterolemia were not taking their prescribed cholesterol-lowering medication [Umans-eckenhausen MA, Defesche JC, van Dam MJ, Kastelein JJ, Arch Intern Med, 163(1) : 65-8 (2003). ] In fact, non-dose occurs more often than overdose [De Klerk E, Van Der Heijde D, Landewe R, Van Der Tempel H, Urquhart J, Van Der Linden S, J Rheumatol, 30(1): 44-54( 2003). ]

Current approaches to improving medication compliance for chronic health problems are complex, labor intensive, and not very effective. Improving compliance with long-term regimens requires information about the regimen; counseling on the importance of compliance; advice on how to organize the drug regimen throughout life; reminders, rewards, and recognition for the patient's efforts to follow norms; and social support from family and friends. Comprehensive. The full benefits of a drug cannot be realized at low levels of compliance; therefore more research and innovative approaches to assisting patients in complying with prescriptions are needed [McDonald HP, Garg AX, Haynes RB, JAMA 288(22):2868-79 (2002). ]

Another problem with drug prescribing is the efficacy and safety of new and existing drugs. Efficacy and safety are relevant factors in the clinical profile of a drug. Drug doses were calculated for each drug based on its therapeutic window, which is the range of blood drug concentrations between the minimally effective therapeutic concentration and the minimally toxic concentration. The width of the therapeutic window can be adjusted by the therapeutic index, which is the ratio between the median lethal dose and the median effective dose. This is a safe range for specific medications. A drug with a broad therapeutic index is safer than a drug with a narrow therapeutic index.

The accepted rule in pharmacy is that a drug is considered to have a "narrow therapeutic index" when there is less than a two-fold difference between the toxic dose and the effective dose, and its use must be carefully monitored. However, several clinically important drugs have narrow therapeutic indices. These include anti-AIDS drugs such as AZT, antibiotics such as ciprofloxacin, CNS agents such as levodopa, and antidiabetic drugs.

Chronic Treatment : According to Stehlin [Stehlin I., "A Time to Heal: ChronotherapyTunes In to Body's Rhythms," U.S. Food and Drug Administration, http://www.fda.gov/fdac/features/1997/397 chrono.html] , our body's biological clock is influenced by the solar system to affect blood pressure, blood clotting, blood flow, and other functions. Several types of physiological cycles can be defined as follows:

i. A subcircadian rhythm, which is a cycle that is shorter than a day (eg, about a 90-minute sleep cycle);

ii. Circadian rhythm, which is the daily cycle (eg sleep-wake pattern);

iii. Transcircadian rhythms, which are cycles longer than 24 hours (eg, monthly menstruation); and

iv. Seasonal cycles (eg Seasonal Affective Disorder (SAD), which causes depression in susceptible individuals during the short days of winter).

For example, normal lung function undergoes circadian rhythmic changes and reaches a low point during the early morning hours. This decline was particularly pronounced in people with asthma.

Therefore, long-term treatment may be particularly useful in asthma. The aim is to achieve the maximum effect of the bronchodilator during the early morning hours. For example, the bronchodilator Uniphyl, manufactured by Purdue Frederick Co. of Norwalk and approved by the FDA in 1989, is a long-acting formulation of theophylline for long-term treatment. Taken once daily in the evening, Uniphyl produces peak theophylline blood levels and improves lung function during the early morning hours.

In addition, according to Stehlin, long-term treatment can be used to treat cancer, arthritis, high blood pressure, diabetes, heart attack, sexual dysfunction, and eating and sleeping disorders. For example, animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully chosen times. It appears that normal cells and tumor cells have different long-term biological cycles. Thus, cancer drugs are more effective against cancer and less toxic to normal tissues if administered timed according to the long-term biological cycle of tumor cells.

Furthermore, long-term biological patterns of arthritic pain have been observed. People with osteoarthritis, which is the most common form of the disease, tend to have pain at night. But for people with rheumatoid arthritis, the pain usually peaks in the morning. When used as long-term treatment for arthritis, NSAIDs and corticosteroids can be dosed at a timed interval to ensure that peak blood levels of the drug coincide with peak pain.

Drugs in Veterinary Medicine: There are several challenges with the application of drugs in veterinary medicine:

i. A variety of animals of different sizes and personalities, and different animals have unique anatomical and physiological characteristics;

ii. Some farm managements have only minimal contact with herds over weeks or months;

iii. The animal fails to actively cooperate during the administration of the drug or in compliance with a specific protocol; and

iv. When animals are marketed for consumption, they should have little drug residue.

Tooth Structures and Dental Implants: The following is a brief overview of tooth structures and dental restorations and reconstructions in relation to the present invention. Figure 1 is a cross-sectional view of a tooth 10 as taught, for example, at http://www.dentalreview.com/tooth anatomy.htm . As shown, the basic components of a tooth are: the crown 12 , the portion of the tooth on the gum 14 , and the root 16 which anchors the tooth in the palatine bone 15 . The pulp 18 is disposed within the pulp chamber 20 and the root canal 22 .

Crown 12 is formed from an inner structure of dentin 26 and an outer layer of enamel 24 , which defines a chewing surface 28 . There are one, two or more roots 16. Each has an outer layer of chalk 30 , an inner structure of dentin 26 and a root canal 22 . The pulp 18 is formed by the capillaries that carry nutrients to the tooth, and the nerves that provide sensation to the tooth. These enter the root canal 22 through the accessory canal 32 and the root opening 34 .

The tooth 10 may define a cylindrical coordinate system having a longitudinal axis x and a radius r. The coronal or incised end 36 may be defined as the end above the gum 14 and the pointed end 38 may be defined as the end below the gum 14 .

The various intraoral devices and methods of tooth reconstruction and restoration to which the present invention relates are reviewed below with reference to Figures 2A-7C.

Root canal: Root canal treatment is needed when the pulp of a tooth is diseased or damaged or dead. Common causes of pulp death are deep cavities, caulking, or chipped teeth. The bacteria then invade the tooth and infect the pulp. Inflammation and infection can spread down the root canal, often causing sensitivity to hot or cold foods and pain.

Root canal treatment involves removing diseased pulp and cleaning and sealing the pulp chamber and root canal before filling or restoring the crown. The steps of root canal treatment are described, for example, in http://your-doctor.com/patient_info/dental_info/dental_disorders/rootcanal.html#_1 " Root Canal (Endodontic) Therapy" and illustrated in Figures 2A-2G below.

2A-2C illustrate root canal treatment in which the crown 12 is not severely damaged. As shown in FIG. 2A , an opening 40 is generally formed through the crown 12 and dentin 26 into the pulp chamber 20 . The pulp 18 (FIG. 1) is then removed with a tiny file (not shown), and the pulp chamber 20 and root canal 22 are cleaned and shaped into a fillable form.

As shown in FIG. 2B, a drug 42 may be applied to the pulp chamber 20, and the root canal 22 for a period of about two weeks to sterilize them. A temporary filling 44 is placed in the crown opening 40 to protect the tooth between visits to the dentist.

As shown in FIG. 2C , after removal of the drug 42 and temporary filling 44 of FIG. 2B , the pulp chamber 20 and root canal 22 are cleaned and filled with a permanent filling 46 and the chewing surface 28 is restored.

2D-2G illustrate a situation in which the crown 12 (FIG. 1) is severely damaged. As shown in Figure 2D, the residual crown 12 is removed and the root canal 22 cleaned and shaped as above.

As shown in Fig. 2E, the drug 42 is applied to the root canals 22 for a period of about two weeks to sterilize them. A sealant layer 27 can then be applied over the exposed dentin to protect the dentin until the next visit to the dentist.

After removal of the drug 42 of FIG. 2E , the root canal 22 is cleaned and filled with a permanent obturator 46 as shown in FIG. 2F . A core 29 of permanent filling 46 is then constructed on the root to restore the crown, and a cast (not shown) of the remaining tooth structure and core 29 is taken. A temporary structure 50 is then placed over the remaining tooth structure and core 29 .

A permanent enamel-like structure 52 is prepared from the mold and placed on core 29, as shown in FIG. 2G.

On the other hand, when teeth are missing, alternatives include bridges, dental implants, and dentures.

Bridging: A bridge is used to fill a gap in up to four teeth where there are healthy natural teeth on both ends of the gap. 3A-3F illustrate the use of a three-unit bridge 60 between two healthy teeth 62 and 64 .

As shown in FIGS. 3A-3B , the dentist prepares teeth 62 and 64 on each side of the gap by removing portions of enamel and dentin, leaving stubs 66 and 68 . Imprints or molds are made for the stubs 66 and 68 and the gap between them for bridge construction. At the same time, temporary bridges are used to protect exposed stumps and temporarily restore missing teeth.

The dentist then installs the bridge 60 including the crown 70 over the stumps 66 and 68 as shown in FIGS. 3C-3D . If the fit is good, the dentist fixes the bridge 60 in place, restoring the function of the area.

3E-3F illustrate another technique: a bridge 72 can be formed from a prosthetic crown 70 and retainer 74, which is suitable for clipping to healthy teeth 62 and 64. Unlike the bridge 60 of FIGS. 3C-3D which is fixed in place, the bridge 72 is removable, eg, for cleaning.

Dental Implants: As an alternative to bridging, dental-implant-and-prosthetic-tooth-crowns80 are used. As shown in Figures 4A-4C, dental implants and crowns 80 include dental implants or fixtures 82 that are surgically implanted, for example, into the bone growing around them. After the dental implant 82 is secured to the bone, the stump 84 is installed thereon and is ready to receive the denture crown 70 .

Denture: When several teeth are missing, a denture 90 comprising multiple crowns 70 may be used as shown in Figures 5A-5C.

It is possible to have a total denture with all teeth as shown in Figure 5A or a partial denture with several teeth as shown in Figure 5B. Complete dentures conform to the shape of the ridges of the gums, and they are held in place with adhesive. Partial dentures can be fitted to fit around natural teeth to help them stay in place. Additionally, as shown in Figure 5C, dental implant posts 82 may be used to further secure the denture.

Crown: Sometimes, the root of the tooth is left intact. However, its upper part is severely corroded or damaged. As shown in Figures 6A-6C, an artificial crown may be placed on the tooth.

FIG. 6A illustrates a broken tooth 92 . It is prepared by removing portions of the enamel and dentin exposing stump 94 as shown in FIG. 6B . As shown in Fig. 6C, a crown 96 is then fixed on the stump 94, restoring the chewing surface.

Braces: Other known dental devices include braces for orthodontics. FIG. 7A illustrates an aligner 100 that includes a molar brace 102 , arcuate wires 104 , and brackets 106 .

Alternatively, FIG. 7B illustrates an aligner 110 comprising a metal or plastic sheet 112 and wires 114 and 116 adapted to fit against the palate. Alternatively FIG. 7C illustrates an invisible aligner 120 . In general, the aligners of Figures 7A-7C can be easily removed, eg, for cleaning.

Sustained release devices for attachment to or placement around teeth or implanted in the gums are disclosed, for example, in US Patent Nos. These devices deliver drugs into the oral cavity, but they lack a controlled rate of delivery for extended periods of time, which is extremely important for the prevention and treatment of the diseases and conditions mentioned above. For example US Patent 4,837,030 discloses an orally administrable pharmaceutical composition comprising beads coated with an ultrathin layer of a polymer that is erodible under gastric conditions. When suspended in water, more than 90% of the drug is released from the composition within 20 to 90 minutes; U.S. Patent 4,919,939 discloses a controlled release drug delivery system involving dissolution under the action of saliva and release within 10 to 18 hours A polymer matrix for the drug contained therein.

U.S. Patent 5,614,223 to Sipos, entitled "Intraoral medicament releasing device", describes a controlled release rate device for the release of a pharmaceutically active agent into the oral cavity by the solubilizing action of saliva, a method of making such a device and a method for delivering a pharmaceutically active substance to the oral cavity A method of preventing/treating a condition/disease in a mammal.

U.S. Patent 5,686,094 to Acharya, entitled "Controlled release formulations for the treatment of xerostomia," describes controlled or sustained release dosage forms, specifically disclosing certain polymer matrices or complexes suitable to achieve controlled or sustained delivery of the active composition. things. The composition is particularly suitable for the controlled release of active compositions such as medicaments in the form of particles, encapsulated capsules, tablets, chewing gums, absorbable and ingestible in the topical, parenteral, buccal, gingival, and oral cavity. Implanted pills, candies, lolipops, flowable liquids, gels, suppositories and other dosage forms.

US Patent 6,143,948 to Leitao et al. entitled "Device for incorporation and release of biologically active agents" describes a device coated with a layer of calcium phosphate and optionally one or more biologically active substances such as growth factors, lipids, (lipo)polymers Implantable devices of sugars, hormones, proteins, antibiotics, or cytostatics. The device can be obtained by a nanotechnology process comprising subjecting a substrate to a surface treatment until it has a surface roughness with an average peak distance (Ra value) of 10 to 1,000 nm, and subjecting the rough surface to a Precipitation of calcium phosphate from salt ions, optionally co-precipitating with biologically active substances. The implant can be used in biomedical applications, ie as bone substitutes, artificial joints, teeth for implantation (prosthetics), maxillofacial implants, etc.

Contents of the invention

One aspect of the invention provides a controlled drug delivery device comprising:

a reservoir containing the drug; and

Electronic drug delivery mechanisms for providing controlled delivery of drugs,

The device is adapted to be inserted into the oral cavity of a subject.

According to one aspect of the present invention, the medicament is provided as a pharmaceutical dosage form for electronically controlled delivery and passively controlled delivery.

According to one aspect of the invention, the medicament is provided in the form of a pharmaceutical dosage form suitable for release in controlled rate release, delayed release, and pulsed release.

According to a further aspect of the invention, the device is adapted to be removably inserted into the oral cavity of a subject.

According to an optional aspect of the invention, the device is adapted to be permanently embedded in the oral cavity of the subject.

According to a further aspect of the invention, the device is adapted to be permanently embedded in the oral cavity of the subject, and the device further comprises a removable assembly housing at least one of a drug reservoir and a power source.

According to another aspect of the present invention, the electronic drug delivery mechanism further includes:

a control unit for managing the controlled delivery;

an electro-mechanical delivery mechanism that opens in response to a command from the control unit to allow delivery of the drug to occur; and

A power supply to power the control unit and the electro-mechanical delivery mechanism.

According to one aspect of the invention, the electro-mechanical drug delivery mechanism includes a rotor.

According to a further aspect of the invention, the control unit is selected from dedicated dedicated electronics, processors, ASICs, and microcomputers.

According to a further aspect of the present invention, the controlled drug delivery device further comprises a timing device selected from the group consisting of timers, clocks, calendars, and combinations thereof.

According to a further aspect of the invention, the device further comprises at least one localized sensor integral with the device.

According to a further aspect of the invention, the device further comprises at least two local sensors integral with the device.

According to a further aspect of the invention, the at least one local sensor is a physiological sensor for administering the drug in response to a measurement by the sensor.

According to a further aspect of the invention, the local physiological sensor is selected from the group consisting of sensors for drug concentration in saliva, sensors for glucose concentration in saliva, sensors for metabolite concentration in saliva, sensors for electrolyte concentration in saliva, Sensors for pH levels in saliva, sensors for temperature in the mouth, heartbeat sensors, heart rate sensors, and snore sensors.

According to a further aspect of the invention, at least one of the local sensors is a condition sensor for ensuring that the device is in proper operating condition.

According to a further aspect of the invention, the local condition sensor is selected from the group consisting of a sensor for drug remaining in the drug reservoir, a sensor for drug flow rate, a sensor for power supply condition, and a sensor for short circuit detection.

According to a further aspect of the present invention, the device further comprises at least one communication component selected from a receiver, a transmitter, and a transceiver.

According to a further aspect of the invention, the communication module provides communication with a system outside the body of the individual.

According to a further aspect of the invention, the personal extracorporeal system is selected from the group consisting of remote control units, computer systems, telephones, mobile phones, palmtops, PDAs, laptops, and combinations thereof.

According to a further aspect of the invention, the personal extracorporeal system is adapted to provide communication between the device and the monitoring center.

According to a further aspect of the invention, the communication module provides communication with at least one remote sensor.

In a further aspect of the invention, the remote sensor is selected from the group consisting of sensors for drug concentration in blood, sensors for glucose concentration in blood, sensors for metabolite concentration in blood, sensors for electrolyte concentration in blood, sensors for Sensor for oxygen level in blood, sensor for pH level in blood, sensor for drug concentration in interstitial fluid, sensor for glucose concentration in interstitial fluid, sensor for metabolite concentration in interstitial fluid, sensor for electrolyte in interstitial fluid concentration sensor, sensor for oxygen content in interstitial fluid, sensor for pH level in interstitial fluid, sensor for drug concentration in sweat, temperature sensor, heartbeat sensor, heart rate sensor, blood pressure sensor, and for food in the mouth, Sensor for the presence of alcohol or smoke.

According to a further aspect of the invention, the device further comprises at least one drug transport component for increasing drug transport across biological barriers by a method selected from the group consisting of iontophoresis, electroosmosis, electrophoresis, electroporation, sonoporation, and ablation .

According to a further aspect of the invention, the drug delivery mechanism provides controlled delivery of the drug selected from the group consisting of: dosing according to a preprogrammed regimen, dosing at a controlled rate, delayed dosing, pulsed dosing, chronic therapeutic dosing, closed loop (closed-loop) dosing, dosing in response to sensor input, dosing on the order of a personal extracorporeal system, dosing according to a regimen specified by a personal extracorporeal system, dosing through a personal extracorporeal system on the order of a monitoring center, and in accordance with a monitoring The center-specific regimen is administered via the individual's extracorporeal system.

According to a further aspect of the invention, the device further comprises at least two drug reservoirs.

According to a further aspect of the invention, the drug is in the form of nanoparticles.

24. The device of claim 23, wherein each of the at least two drug reservoirs is controlled independently of the other.

According to a further aspect of the invention, the device is mounted on a dental appliance designed for use in the oral cavity of the subject.

According to a further aspect of the present invention, the dental appliance is selected from the group consisting of: dental crowns, dental bridges, dental three-unit bridges, dental implants, partial dentures, total dentures, braces, molar braces, night guards, and teethers ( mouth guard).

According to an optional aspect of the invention, the device is mounted on a fixture that can be fixed to the oral mucosa or the palatine bone.

According to an alternative aspect of the invention, the device does not contain anchors and it is implanted directly into the tissue.

According to a further aspect of the invention, the device is adapted for buccal administration.

According to a further aspect of the invention, the device is adapted for sublingual administration.

According to a further aspect of the invention, the device is adapted for labial mucosal administration.

According to a further aspect of the invention, the device is adapted for administration to the soft palate.

According to a further aspect of the invention, the device is adapted to be inserted into the mouth of a person.

According to an optional aspect of the invention, the device is adapted to be inserted into the mouth of an animal.

According to another aspect of the present invention, there is provided a method for controlled drug delivery comprising:

providing a drug controlled delivery device comprising a reservoir containing a drug and an electronic drug delivery mechanism for controllably releasing the drug; and

The device is inserted into the subject's mouth.

According to another aspect of the present invention, there is provided a controlled drug delivery device comprising:

a reservoir containing a drug in pharmaceutical dosage form; and

A dental appliance designed to be inserted into the oral cavity of a subject and adapted to support a drug reservoir.

According to another aspect of the present invention, there is provided a method for controlled drug delivery comprising:

providing a drug controlled delivery device comprising a reservoir having a drug in pharmaceutical dosage form; and

The devices described above are supported in the oral cavity of the subject on a dental appliance designed to be inserted into the oral cavity of the subject and used to support the device.

The present invention successfully addresses the shortcomings of currently known structures by providing an oral device for the controlled delivery of drugs, implanted or embedded in the oral cavity, built into denture crowns, denture plates, aligners, dental implants, etc. . The device is refilled or replaced as needed. Controlled drug delivery can be passive based on the dosage form, or electromechanical-controlled for high-precision smart drug delivery. Additionally, the controlled delivery of the drug can be any of the following: dosing according to a pre-programmed regimen, dosing at a controlled rate, delayed dosing, pulsed dosing, long-term therapeutic dosing, closed-loop dosing, sensor-based Infusion, administration on the order of the personal extracorporeal system, administration according to the regimen specified by the individual extracorporeal system, administration by the personal extracorporeal system on the order of the monitoring center, and administration by the personal extracorporeal system according to the regimen specified by the monitoring center. Absorption of the drug in the oral cavity can be facilitated or induced by a transport mechanism, such as any one or combination of the following: iontophoresis, electroosmosis, electrophoresis, electroporation, sonication, and ablation. Oral devices need to be refilled or replaced at relatively long intervals of weeks or months, maintain the desired dose level in the oral cavity and therefore in the gastrointestinal tract for a long time, and solve the problem of narrow therapeutic index of drugs Circumstances, and through automatic ones, ensure compliance with prescription drug regimens. Oral devices and methods for the controlled delivery of drugs have applications in humans and animals.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not restrictive.

Description of drawings

The invention is herein described, by way of example only, with reference to the accompanying drawings. Referring to the specific references in detail, it should be emphasized that the specific solutions expressed by the examples are only for the purpose of illustratively discussing the preferred embodiments of the present invention, and for providing the most useful and easiest way to explain the principles and concepts of the present invention. understand. In this regard, without attempting to go into further detail with respect to the details necessary for a basic understanding of the invention, the description together with the drawings makes apparent to those skilled in the art how to practice the invention in several forms.

In the picture:

Figure 1 is a cross-sectional view of a tooth, as known;

Figures 2A-2G schematically illustrate steps in root canal treatment, as known;

Figures 3A-3F schematically illustrate the application of dental bridges, as known;

Figures 4A-4C schematically illustrate the application of dental implants, as known;

Figures 5A-5C schematically illustrate dentures, as known;

Figures 6A-6C schematically illustrate the application of a dental crown, as known;

Figures 7A-7C schematically illustrate orthotics;

Figures 8A-8D schematically illustrate a dental bridge comprising a controlled drug delivery device according to a preferred embodiment of the present invention;

Figures 9A-9C schematically illustrate the electronic device for controlled drug delivery of a preferred embodiment of the present invention;

Figures 10A-10F schematically illustrate an electro-mechanical delivery mechanism of a preferred embodiment of the present invention operated with the electronic device for controlled drug delivery of Figures 9A-9C;

11A-11D schematically illustrate another preferred embodiment of the denture of the present invention, which includes at least one controlled drug delivery device;

Figures 12A-12H schematically illustrate another preferred embodiment of a dental appliance of the present invention comprising at least one drug controlled delivery device;

Figures 13A-13G schematically illustrate a computerized device in communication with a drug controlled delivery electronic device of a preferred embodiment of the present invention; and

14A-14D are electronic devices for the controlled delivery of drugs according to certain preferred embodiments of the present invention.

Detailed ways

The present invention relates to oral devices for the controlled delivery of drugs, which are implanted or embedded in the oral cavity, constructed on denture crowns, denture plates, aligners, dental implants and the like. The device is refilled or replaced as needed. Controlled drug delivery can be passive based on the dosage form, or electro-mechanically controlled for high-precision smart drug delivery. Additionally, the controlled delivery of the drug can be any of the following: dosing according to a preprogrammed regimen, dosing at a controlled rate, delayed dosing, pulsed dosing, chronic therapeutic dosing, closed loop dosing, based on sensor input , administration according to the instructions of the personal extracorporeal system, administration according to the regimen specified by the personal extracorporeal system, administration through the personal extracorporeal system according to the instructions of the monitoring center, and administration through the personal extracorporeal system according to the regimen specified by the monitoring center. Absorption of the drug in the oral cavity can be facilitated or induced by a transport mechanism, such as any one or combination of the following: iontophoresis, electroosmosis, electrophoresis, electroporation, sonication, and ablation. Oral devices need to be refilled or replaced at relatively long intervals of weeks or months, maintaining desired dose levels in the oral cavity and therefore in the gastrointestinal tract for long periods of time, addressing situations where the drug has a narrow therapeutic index, And through automatic, compliance with prescription drug regimens is guaranteed. Oral devices and methods for the controlled delivery of drugs have applications in humans and animals.

The principles and operation of the apparatus and methods of the present invention may be better understood with reference to the drawings and description.

Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application by virtue of the construction and arrangement of components set forth in the ensuing description or illustrated in the accompanying drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. At the same time, it should be understood that the phraseology and terminology used herein are for the purpose of description only and should not be regarded as limiting.

Referring now to the drawings, Figures 8A-8B schematically illustrate a controlled drug delivery device 140 mounted on a dental bridge 150 according to a preferred embodiment of the present invention. Preferably, the underlying dental bridge 150 is removable, constructed in the manner taught in Figures 3E-3F hereinafter.

The drug controlled delivery device 140 is designed as a prosthetic crown 160 and is mounted on the dental bridge 150 for insertion in the gap between the teeth 62 and 64 by the clamp 74 . Preferably, impressions of teeth 62 and 64 and the gap between them have been made and dental bridge 150 with prosthetic crown 160 tailored to the particular patient. Preferably the prosthetic crown 160 comprises a hard shell 154, such as metal or porcelain, having a coronal side 151 and a top surface 153, wherein the coronal surface is suitable for chewing.

The interior volume of the prosthetic crown 160 includes a drug reservoir 156 in a dosage form suitable for passive controlled delivery. As used herein, passive delivery of a drug refers to controlled delivery of a drug that is not controlled by an electronic device. Passive drug delivery includes, for example, dosage form preparation methods as described in items 1-14 below.

Preferably, the rigid shell 154 includes at least one, and preferably a plurality of perforations 157 for drug delivery. Additionally or alternatively, a semi-permeable membrane 159 may be used on top surface 153, for example. According to the present invention, one or several perforations 157 and/or semipermeable membrane 159 may be used in the controlled delivery of drugs. Padding 152 may be used around the drug reservoir if desired. When placed in the oral cavity, the drug is delivered to the oral cavity and/or oral tissues in a controlled manner by natural phenomena.

To maintain a steady supply of medication when refilling the device, the patient may be prepared with two or more dental bridges 150 . Alternatively, a single dental bridge 150 may be used, arranged for on-site, rapid refilling.

A major advantage of device 140 is that, unlike ingested dosage forms, which can maintain a predetermined therapeutic drug concentration in plasma for about 12 hours before being absorbed or eliminated through the gastrointestinal tract, orally implanted dosage forms can maintain a predetermined concentration for several months. therapeutic drug concentration. Thus, an orally implanted dosage form provides an alternative to gastric retention devices.

Several controlled release mechanisms are available, such as in the Encyclopedia of Controlled Drug Release, edited by Edith Mathiowitz, Vol. 2, pp. 838-841. These are based on the use of specific substances, usually polymers, as a matrix or as a coating, which degrade quickly or slowly depending on the desired effect. However, the Encyclopedia of Controlled Drug Delivery generally considers gastrointestinal fluids as the ambient solvent, but according to the present invention, saliva with a pH of about 5.2-6.8 is the ambient solvent. According to the present invention, the reservoir 156 of drug may be a passive controlled release dosage form prepared by any of the following methods:

1. Drugs in the form of solids, liquids or suspensions in liquids can be encapsulated in polymeric materials such that drug release is controlled by diffusion through the capsule wall.

2. Drug particles may be coated with a wax or poorly soluble material mixed with a soluble pore-forming compound, or an insoluble material such as polyvinyl chloride, so that release of the drug from the reservoir 156 is controlled by disruption of the coating.

3. The drug may be embedded in a sustained release matrix, which may be biodegradable or non-biodegradable, such that release of the drug from the reservoir 156 is controlled by diffusion through the matrix, erosion of the matrix, or both.

4. Drugs can form complexes with ion exchange resins to slow down their release.

5. The drug can be laminated into a jelly roll with a membrane, such as a polymeric material, which can be biodegradable or non-biodegradable, allowing the drug to be released by diffusion, erosion, or both.

6. The drug can be dispersed in the hydrogel, or a substance that forms a hydrogel in the oral cavity, such that the release of the drug from the reservoir 156 is controlled by diffusion of the drug from the water-swellable hydrogel.

7. Osmotic pressure can be used to release the drug in a controlled manner - intake of water into the reservoir 156 can increase the osmotic pressure inside the reservoir 156 which will push the drug through one or more pores in a controlled manner way to release the drug.

8. The drug can be chemically bound to the polymer and released by hydrolysis.

9. The macromolecular structure of the drug can be formed by ionic or covalent bonds, which controls the release of the drug from the reservoir 156 by hydrolysis, thermodynamic dissociation or microbial degradation.

10. It can be a combination of drug-coating soluble and insoluble polymers, when the soluble particles dissolve, they will form a microporous layer around the drug core, so that the drug can slowly permeate through the micropores, and the release rate depends on Porosity and thickness of the coating layer.

11. Drugs can be designed for pH-independent controlled release, which is produced by wet granulation of a mixture of acidic or basic drug with a buffer and suitable excipients, wherein the particles are then compressed into tablets and produced as It is additionally coated with a saliva-permeable membrane. During oral administration, saliva permeates the membrane coating, at which point the buffer adjusts the pH of the tablet so that the drug can dissolve and permeate out of the dosage form at a constant rate independent of the pH level in the mouth.

12. The dosage preparation can be enclosed in insoluble capsules by way of water-soluble plugs and hydrogel plugs. When the capsule is placed in the mouth, the water-soluble cap dissolves and exposes the hydrogel plug, which begins to swell. At a predetermined time after placement, the hydrogel plug is expelled, releasing the sealed dosage formulation.

13. Multiparticulate dosage forms can be used. The drug can be spray coated with sugar or individual pellets, dried and then spray coated with a second coating composition providing controlled release. The second coating composition is typically formed from a polymer that is partially soluble or insoluble in saliva, where solubility depends on the desired drug release profile. The double-coated pellets are placed in capsules. Capsules can contain pellets of different types and release patterns.

14. A dosage form that may use nanoparticles for improved solubility.

Referring now to the drawings, FIGS. 8C-8D schematically illustrate another preferred embodiment of a device 142 for passive controlled drug delivery mounted on a three-unit bridge 155 of the present invention, similar to that shown in FIGS. 3A-3D below. The taught kind.

As shown in FIGS. 3A-3B , the dentist prepares the teeth 62 and 64 on either side of the gap by removing the enamel and dentin portions, leaving stubs 66 and 68 . An impression or mold is taken of the stubs 66 and 68 and the gap between them for the construction of the bridge 155 .

As shown in FIGS. 8C-8D , a three-unit bridge 155 includes a device for passive drug controlled delivery 142 designed as a prosthetic crown 165 . The prosthetic crown 165 has a hard shell 161, eg metal or porcelain, which is suitable as a chewing surface. The hard shell 161 includes detachable components such as a tow body 167 for refilling or for replacement. The drag body 167 includes a drug reservoir 156 in a dosage form suitable for passive drug controlled delivery, similar to, for example, that of Figures 8A-8B. Preferably, the hard shell 161 includes at least one, preferably several or more holes 163 for drug delivery, or another opening for drug delivery. Additionally or alternatively, a semi-permeable membrane 159 may be used. When placed in the mouth, the drug is released into the mouth and/or oral tissues in a controlled manner by natural phenomena.

Referring again to the drawings, FIGS. 9A-9C schematically illustrate another preferred embodiment of the electronic device 144 for controlled drug delivery of high-precision smart drug delivery.

Device 144 is mounted to dental bridge 170 as shown in FIGS. 9A and 9B . Preferably the dental bridge 170 is removable and constructed in the manner taught in Figures 3E-3F below.

Controlled drug delivery electronics 144 are designed to fit within the interior space of a prosthetic crown 180 that is inserted into the gap between teeth 62 and 64 by clamp 74 . Preferably, dental bridge 170 is tailored to a particular patient. Preferably, the prosthetic crown 180 includes a hard shell 174 adapted to act as a chewing surface. Two or more dental bridges 170 may be prepared for the patient to maintain a steady supply of medication while refilling the device. Alternatively, a single dental bridge 170 may be used, arranged for rapid refilling in the field.

The electronics of device 144 may be encased in a filler material 172, such as silicon. The prosthetic crown 180 includes a drug reservoir 176 with an orifice controlled by an electro-mechanical transport mechanism such as a solenoid 178 .

It should be appreciated that drug reservoir 176 may be a drug dosage form for controlled release, such as controlled rate release, delayed release, and/or pulsed release, which may be combined with electronically controlled release.

It should be understood that several drug reservoirs 176 may be incorporated in a single device 144 . Each drug reservoir can contain a different drug, each of which can be delivered independently according to a different protocol.

A power source 182 powers the prosthetic crown 180 . The control unit 184 controls the operation of the electro-mechanical delivery mechanism 178 for releasing the drug into the oral cavity and/or oral tissue in a controlled manner. The control unit 184 may be any of known dedicated control circuits 184, processors 184, application specific integrated circuits (ASICs) 184, or microcomputers 184, and may further include built-in intelligence. A memory unit 186 may be integrated therein. It should be understood that the control unit 184 can control both the delivery time and the delivery rate of the drug. It should be understood that the power source 182 can be any power source, such as a battery or a solid electrolyte fuel cell.

Preferably, the control unit 184 has built-in timing means, preferably including a timer, clock and calendar, and is operable for long-term therapy.

In addition, a receiver 188, which may additionally act as a transceiver, provides communication with a personal in vitro system 208, as described below in FIGS. 13A-13F. It should be understood that separate transmitters may be used. Transceiver 188 may operate via RF, IR, or ultrasound. It can additionally use any one of Bluetooth (Bluetooth), Wi-Fi, W-LAN, 802.11, CDMA, GSM protocols. It should be understood that other protocols may also be used.

According to the present invention, controlled drug delivery electronics 144 may further include at least one drug transport component for increasing drug transport across biological barriers to enhance direct buccal, sublingual, lip mucosal, and soft palate absorption. Drug delivery mechanisms may include iontophoresis, electroosmosis, electrophoresis, electroporation, sonication, ablation. The at least one drug transport component can be, for example, at least one or several electrodes for electron transport mechanisms, including known electroablation, ultrasonic transducers for ultrasonic perforation, microwave turns for microwave ablation, RF ablation RF turns, or laser diodes for laser ablation. Additionally, combinations of these may be used. These mechanisms can be controlled by the control unit 184 . Additionally or alternatively, they can be remotely controlled by a personal in vitro system 208 (FIGS. 13A-13F), such as a remote control unit 190, a computer system 200, a telephone 202, a mobile phone 206, a palmtop computer 207, a laptop computer 209 , or any other known remote control unit. Additionally or alternatively, they may be controlled by monitoring center 500 (FIG. 13G).

The device 144 may further comprise at least one, preferably several sensors 185, incorporated into the device, so called "local sensors" to distinguish them from remote sensors located elsewhere in the body. Local sensors 185 can be divided into two types:

i. Physiological sensors 185 for measuring, for example, drug concentration in saliva, glucose concentration in saliva, metabolite concentration in saliva, electrolyte concentration in saliva, pH level in saliva, concentration of food, alcohol or smoke in the oral cavity level, temperature in the oral cavity, and any other physiological parameters, preferably related to the drug delivery regimen; and

ii. Status sensor 185 for ensuring that the device is in the correct state by, for example, measuring the amount of drug remaining in the drug reservoir, drug flow rate, power condition, short circuit, or any other information related to the correct operation of the drug controlled delivery electronics 144 under proper operating conditions.

Physiological sensor 185 may be, for example, an electrochemical glucose sensor, such as an enzyme taught in http://www.cfdrc.com/applications/biotechnology/biosensor.html , reacted with electrodes that generate current or a potential difference for quantitative analysis Facilitative biosensors that exploit the biological specificity of enzymatic reactions. Enzymatic oxidation of glucose produces hydrogen peroxide, which in turn generates electrons through electrode reactions. Current density is used as a measure of glucose in a sample such as interstitial fluid.

Additionally or alternatively, glucose levels may be monitored as taught in U.S. Patent 6,201,980, entitled "Implantable medical sensor system," issued March 13, 2001 to Darrow et al., the disclosure of which is incorporated herein by reference. Darrow et al. disclose an implantable chemical sensor system for medical applications using a deployable biocompatible sensor such as a polymer that undergoes a size change in the presence of an analyte, enabling selective recognition of the analyte . Incorporating deployable polymers into electronic circuit assemblies allows the polymer to change its properties (such as frequency) when it changes dimensions. When the circuit changes its characteristics, an external interrogator transmits a signal transcutaneously to the transducer, and the analyte concentration is determined from the measured circuit change. An implantable chemical sensor system can be used for minimally invasive monitoring of blood glucose levels or interstitial fluid glucose levels in diabetic patients.

Additionally or alternatively, the physiological sensor 185 may be as taught, for example, in U.S. Patent 6,058,331, entitled "Apparatus and method for treating peripheral vascular disease and organ ischemia by electrical stimulation with closed loop feedback control," issued to King on May 2, 2000, The disclosure thereof is incorporated herein by reference. King discloses techniques for therapeutically treating peripheral vascular disease in which sensors are used to detect the degree of blood flow or ischemic pain in a patient's extremity and generate a response based on the sensor readings.

Alternatively, the physiological sensor 185 may be based on a method such as at http://www.ambri.com/Content/display.asp ? Ambri's Ion Channel Switch (ICS ^™ ) technology for self-assembling synthetic biofilm biosensors described in screen=174 . It is the world's first true bio-nano device. Ambri constructed biological switches: membranes that detect the presence of specific molecules and signal their presence by triggering an electrical current. The device - the Ambri Ion Channel Switch (ICS ^™ ) biosensor - is a bilayer self-assembled membrane based on the ion channel gramicidin.

As taught in PCT Publication WO 0174446 by Karachurov, multiple microsensors of the same type can be used to increase the accuracy of the measurements. Additionally or alternatively, different types of sensors may be used. Additionally, several sensor modules 185 may be used at different locations within the body.

Device 144 may further include at least one, and preferably several, remote physiological sensors 185 implanted or placed elsewhere in the body, each having its own power source and transmitter or transceiver. Additionally or alternatively, several remote sensor modules 185, possibly of different types of physiological sensors, may be used, where several sensors share a common power supply, transmitter or transceiver, and possibly a common control unit. The remote sensor module may further include a remote status sensor 185 for reporting the power status of the remote sensor.

Examples of remote physiological sensors 185 may include sensors for drug concentrations in blood, sensors for glucose concentrations in blood, sensors for metabolite concentrations in blood, sensors for electrolyte concentrations in blood, sensors for Sensor for oxygen level, sensor for pH level in blood, sensor for alcohol level in blood, sensor for drug concentration in interstitial fluid, sensor for glucose concentration in interstitial fluid, sensor for metabolite concentration in interstitial fluid , sensor for electrolyte concentration in interstitial fluid, sensor for oxygen content in interstitial fluid, sensor for pH level in interstitial fluid, sensor for alcohol level in interstitial fluid, sensor for drug concentration in sweat, temperature sensor, Heartbeat sensor, blood pressure sensor, heart rate sensor, and snore sensor.

Remote sensor 185 may be implanted subcutaneously in vivo under the chest or arm for measuring, for example, interstitial fluid drug concentration levels, interstitial fluid glucose levels, tissue temperature, blood pressure, and heart rate. Additionally or alternatively, remote sensor 185 may be implanted in vivo on a stent in a blood vessel for measuring, for example, blood drug concentration levels, blood glucose levels, or blood oxygen levels.

Additionally or alternatively, remote sensor 185 may be attached to the skin, eg, externally. In vitro sensors can include piezoelectric patches that can be adhesively bonded to the skin for measuring heart rate, patches for measuring body temperature, and/or measuring levels of drugs or other chemicals such as glucose in sweat sensor.

For example, in vitro remote sensors 185 may be similar to those of Lin, G. and Tang, W. in "WearableSensor Patches for Physiological Monitoring", NASA's Jet Propulsion Laboratory, Pasadena, California, available at http://www.nasatech . com/Briefs/FebOO/NP020651.html , or at NASA Tech Briefs available from Technology Reporting Office, JPL, Mail Stop, 122-116, 4800 Oak Grove Drive, Pasadena, CA 91109, (818) 354-2240: NPO -20651 found. Wearable sensor patches formed as miniature biotelemetry units can be used to measure temperature, heart rate, blood pressure, and possibly other physiological parameters. The sensor patches are designed to be small and cheaply mass-produced by state-of-the-art techniques for mass-producing integrated circuits and micro-electromechanical systems. The surface of each patch can be several centimeters, which is comparable to the size of ordinary adhesive bandages. Even the patch can be held on the wearer's skin by the same adhesive used for bandages. The patch may contain a non-intrusive micromechanical sensor integrated with the sensor output operable to process and send a radio signal conditioned by the sensor output.

For localized sensors, multiple miniature sensors of the same type can be used to increase the accuracy of the measurement. Additionally or alternatively, different types of sensors may be used. Additionally, several sensor modules 185 may be used at different locations within the body.

Communication between the remote sensor 185 and the denture crown 180 of the device 144 is preferably via ultrasound, but could also be via IR or RF, and possibly using communication protocols such as those in Bluetooth, Wi-Fi, W-LAN, 802.11, CDMA, GSM protocols any kind. It should be understood that other protocols may also be used. Additionally or alternatively, as shown below in FIGS. 13A-13F , the remote sensor 185 can communicate with one or more personal extracorporeal systems 208, preferably via IR or RF, and can employ communication protocols such as Bluetooth, Wi-Fi, W -Any one of LAN, 802.11, CDMA, GSM protocols. It should be understood that other protocols may also be used. Communication can be continuous, intermittent, question-and-answer, or when sudden changes in measured physiological parameters are observed.

According to certain embodiments, the remote sensors have no power source and respond to interrogations that further provide them with power to measure and respond, as for example in Doron et al. entitled "Acoustic biosensor for monitoring physiological conditions in a body implantation site US Patent Application 20010026111 for "; US Patent 6,140,740 entitled "Piezoelectric transducer" by Porat et al; US Patent 6,277,078 entitled "System and method for monitoring a parameter associated with the performance of a heart" by Porat et al; and Porat et al., entitled "System and method for monitoring pressure, flow and constriction parameters of plumbing and blood vessels," any one of U.S. Patent 6,237,398, the entire disclosure of which is incorporated herein by reference.

It should be understood that device 144 may also be an autonomous system, operating without an external system or any remote control.

It should be understood that a prosthetic crown 180 could also be designed on a three-unit bridge, in a sense similar to the prosthetic crown 165 of FIGS. In the towing body of the towing body 167.

Controlled drug delivery electronics 144 are designed as dental implants and crowns 210 as shown in FIG. 9C . The drug controlled delivery electronics 144 has a permanent portion 220 located in the post and a removable portion 230 located in the crown. A removable portion 230 in the crown of device 144 includes a drug reservoir 216 whose drug delivery is controlled by an electro-mechanical delivery mechanism 218 . Power supply 222 provides power. These are packed into a filler 212 such as silicon. Hard shell 214 provides a chewing surface. Preferably, an impression has been taken so that the detachable part 230 is suitable for a particular patient. Additionally, two or more removable sections 230 may be made such that one is in operation while the other is being refilled. Alternatively, a single removable portion 230 may be used, arranged for rapid on-site refilling of the drug reservoir 216 and/or power supply 222 .

The permanent portion 220 in the column may include a control unit 224 , such as a processor 224 for controlling the operation of the electro-mechanical delivery mechanism 218 , and preferably also includes a memory unit 226 and a transmitter-receiver 228 . At least one sensor 215 can be placed at the interface between the post and the crown and can be connected to either. Alternatively, at least one sensor 215 may be placed within the post or within the crown. Alternatively, one or more sensors may be placed elsewhere in the body. The electro-mechanical delivery mechanism 218 may be located in the post of the device 144 or in the crown.

The operation of this embodiment is similar to the operation of the embodiment of Figures 9A-9B, except with the advantage that only part of the electronics needs to be replaced, ie the drug reservoir and power supply are amenable to disassembly.

It should be understood that a similar configuration of permanent and removable portions may be used for connecting root canals (Figs. 2A-2G). The permanent part can be located in the tube and the removable part can be located in the crown.

It will be appreciated that the crown of device 144 could also be designed in a manner similar to the prosthetic crown 165 of FIGS. In the towing body of body 167.

Referring again to the drawings, Figures 10A-10F schematically illustrate an electro-mechanical delivery mechanism 178 operated with the controlled drug delivery electronics of Figures 9A-9C, in accordance with an embodiment of the present invention.

As shown in Figures 10A-10B, the electro-mechanical delivery mechanism 178 can be designed as a Vane motor 175A having a housing 171, a rotor 173, an inlet 177 and an outlet 179, wherein the inlet 177 communicates with a drug reservoir 176 and the outlet 179 opens into the oral cavity . As rotor 173 rotates in the direction of arrow 169 , inlet 177 opens allowing medication to enter cavity 141 of motor 175A from medication reservoir 176 and be expelled through outlet 179 .

It can be appreciated that the lumen 141 can be designed to avoid compressing the drug during the cycle.

According to the present invention, drug controlled delivery electronics 144 (FIGS. 9A-9C) may include one or several drug reservoirs 176, each communicating with an inlet 177 and a rotor arrangement. The control unit 184 (FIGS. 9A-9C) may translate the amount of drug to be released from the drug reservoir 176 into rotor rotations such that a predetermined amount of drug is expelled from the drug reservoir and dispensed into the oral cavity with each rotation.

As shown in FIGS. 10C-10D , the electro-mechanical delivery mechanism 178 can be designed as a Wankle motor 175B having a housing 171 , a rotor 173 , an inlet 177 and an outlet 179 . As the rotor 173 rotates in the direction of arrow 169 , the inlet 177 opens, allowing medication to pass from the medication reservoir 176 into the lumen 141 of the motor 175B and be expelled through the outlet 179 .

As shown in FIG. 10C , the electro-mechanical delivery mechanism 178 may be designed as a piston-cylinder arrangement 145 having a piston 143 , a cylinder 141 , and respective inlet 177 and outlet 179 . When the piston 143 is moved out in the direction of arrow 146A, the drug enters the lumen of the piston-cylinder arrangement 145 through the inlet 177 . Drug is expelled from the piston-cylinder arrangement 145 through outlet 179 when the piston is moved out in the direction of arrow 146A.

It will be appreciated that many other mechanical systems for withdrawing the drug from the reservoir 176 and delivering the drug to the oral cavity can be used.

Referring again to the drawings, Figures 11A-11D schematically illustrate another preferred embodiment of a total denture including at least one controlled drug delivery device of the present invention. It will be appreciated that partial dentures may similarly be used.

As shown in FIG. 11A below, the denture 240 includes a plurality of crowns 70 as taught in FIGS. 5A-5C . Additionally, the denture 240 includes a drug controlled delivery device 148 designed as a denture crown 242 . As taught in FIGS. 8A-8D , a prosthetic crown 242 may be adapted for passive controlled drug delivery. Alternatively, as taught in FIGS. 9A-9B , the prosthetic crown 242 may be adapted for electronically controlled drug delivery and is preferably operated using any one or combination of the following personal in vitro systems 208 described below in connection with FIGS. 13A-13F and using Operates in conjunction with the monitoring center 500 described below in FIG. 13G.

As shown in FIG. 11B , the denture 250 includes a plurality of crowns 70 as taught in FIGS. 5A-5C . In addition, denture 250 includes controlled drug delivery devices 147 and 149 designed as denture crowns 252 and 254 . These may be suitable for passive drug controlled delivery, as taught in Figures 8A-8D, or for electronically controlled drug delivery, as taught in Figures 9A-9B, and preferably using the following individuals of Figures 13A-13F Any one or combination of extracorporeal systems 208 operate and operate using the monitoring center 500 of FIG. 13G described below.

Alternatively more than two controlled drug delivery prosthetic crowns may be employed.

Alternatively, the prosthetic crowns 252 and 254 may form a single drug controlled delivery electronic device,

Where prosthetic crown 252 may form a removable part, which includes the drug reservoir and power supply, which must be replaced periodically, whereas prosthetic crown 254 may comprise permanent components, as taught in FIG. 10 .

11C and 11D illustrate the front and back sides of the total denture 260, which includes a plate 264 that can fit under the tongue for a lower denture, or against the palate for an upper denture. The dorsal side (FIG. 11D further includes a controlled drug delivery device 262. In this way, soft palate and/or sublingual, labial and buccal drug delivery can be enhanced. The advantage of this type of drug delivery is that they produce direct Absorption into the bloodstream avoids the GI pathway and the liver.

Drug controlled delivery device 262 may be passively controlled or electronically controlled.

Referring to the drawings, Figures 12A-12H schematically illustrate another preferred embodiment of a dental appliance comprising at least one controlled drug delivery device of the present invention.

Figure 12A schematically illustrates a conventional aligner 100, with a molar brace 102 as taught in Figure 7A; The device 272 is connected to the molar brace 102 by wires 276 .

Additionally, FIG. 12C illustrates an orthosis 280 comprising controlled drug delivery devices 282 and 284 in accordance with a preferred embodiment of the present invention. Devices 282 and 284 are connected to molar brace 102 by wire 286 . Additional means may similarly be employed.

Furthermore, FIG. 12D illustrates an arrangement 290 of a preferred embodiment of the present invention wherein a controlled drug delivery device 292 is connected to a molar brace 298 by wires 296 .

Figure 12E schematically illustrates a conventional orthotic 110, with plate 112 as taught in Figure 7B; Thus, device 302 is suitable for enhanced buccal and sublingual drug delivery.

Figure 12G schematically illustrates a conventional invisible aligner 120, incorporating the teachings in Figure 7C; In a similar manner, controlled drug delivery devices can be attached using teethers or night braces

It will be appreciated that because aligners are often used by children whose wisdom teeth have not yet come out, the space normally occupied by wisdom teeth can be used for extensions as shown in Figures 12B-12D and 12H.

Drug controlled delivery devices 272, 282, 284, 292, 302, and 312 may be passively controlled or electronically controlled.

Referring to the drawings, Figures 13A-13G schematically illustrate a computerized device in communication with a drug controlled delivery electronic device according to a preferred embodiment of the present invention. Figures 13A-13F depict various personal in vitro systems 208 that can communicate with electronics 144 (Figures 9A-9C), including with sensors or sensors 185, with each other, and with a monitoring center as described in Figure 13G.

Communication between the personal extracorporeal systems 208 can take place via the connector 196 and cable, such as via a UBS connector; or via RF or IR waves, such as using Bluetooth, Wi-Fi, W-LAN, 802.11, CDMA, GSM protocols of any kind. It will be appreciated that other protocols may also be used. Personal in vitro systems 208 are called "personal" because they are pre-patient to distinguish them from monitoring centers.

As shown in Figure 13A, the personal extracorporeal system 208 may be a remote control unit 190, which may include a display panel 192, control buttons 194, a connector 196 (preferably a UBS connector) for connection to a computer system, sensors 198 (which Also operable as a transceiver 198, preferably an antenna 191), a power source 193, and preferably also includes a plug 195 for recharging the power source. It will be appreciated that a separate receiver may be used. Transceiver 198 may operate via RF, IR, and may use any of Bluetooth, Wi-Fi, W-LAN, 802.11, CDMA, GSM protocols.

Additionally, as shown in Figures 13A-13F, personal in vitro system 208 may be a known computer system 200, telephone 202, mobile phone 206, palmtop or PDA 207, laptop 209, or another remote system. Typically, these in vitro systems 208 include a display panel 192 .

Communications with device 144 may include instructions to deliver the drug immediately, to stop delivery, to increase or decrease the delivery rate, or to specify a long-term or short-term delivery regimen and delivery rate for the drug.

Communications to device 144 may include delivery regimens and rates of operational medications and indications of operational sensors 185, such as drug concentration in saliva, glucose levels in saliva, amount of drug remaining in drug reservoir 176, drug flow rate, and low power indications. These measurements may be displayed on the display panel 192 of any of the personal in vitro systems 208 .

Either the personal extracorporeal system 208, or the prosthetic crown 180 of the device 144 may process the measurements notified by the sensors 185 with internal intelligence and algorithms to compensate for the measurements, correct their indicated conditions, and/or to improve potency and optimize drug delivery, resulting in optimal closed-loop operation. Additionally or alternatively, any of the extracorporeal system 208, or the prosthetic crown 180 of the device 144 may process the measurements informed by the sensor 185 to correct drug delivery by the measurement data to obtain an optimal drug delivery regimen for closed-loop operation.

As shown in FIG. 13G , the monitoring center 500 can monitor the drug delivery program of the device 144 . Monitoring center 500 may be a clinic, health center, drug rehab center, or another monitoring center as applicable. Preferably, the monitoring center 500 includes service personnel 506 , such as medical practitioners, nurses, social workers, and/or other service personnel as appropriate, a computer system 502 , and a telephone or cell phone 504 . The monitoring center 500 can also be, for example, a medical practitioner's center-on-the-go, his laptop computer, and his cell phone. Preferably, the communication between the device 144 and the monitoring center 500 is through any of the personal extracorporeal systems 208 .

It can be understood that any one or several of personal in vitro systems 208 such as telephone 202, mobile phone 206, palmtop computer 207 and PDA 207 can be designed to have specific codes for quick and easy communication with monitoring center 500 and with device 144 . For example, dialing ^* 10 can reach the health care provider 506 of the monitoring center 500, dialing ^* 11 can reach the computer system 502 of the monitoring center 500, dialing ^* 12 can communicate with the device 144 and initiate the delivery of the drug, and dialing ^* 13 can also Communicates with device 144 and increases the delivery rate of drug delivery. Generally, in vitro system 208 operates as an intermediary between device 144 and monitoring center 500 , relaying data from device 144 to monitoring center 500 and forwarding instructions from monitoring center 500 to device 144 .

Referring again to the drawings, FIGS. 14A-14D are schematic diagrams of an electronic device for controlled drug delivery according to a preferred embodiment of the present invention.

As shown in Figure 14A, the electronic device for controlled drug delivery 400 may include:

i. A first in vivo system 430 comprising a drug reservoir;

ii. A second in vivo system 435 of remote sensors;

iii. The first in vitro system 420 of the remote control unit; and

iv. A second in vitro system 437 of remote sensors.

In the figure, the in vivo system is lightly shaded and the in vitro system is darkly shaded.

The first in vivo system 430 comprises a drug reservoir 411, and a control unit 410 mainly for operating the electro-mechanical delivery mechanism 416 and for setting the delivery rate. The known control unit 410 can be any of the following known ones: a dedicated control circuit 410, a processor 410, an ASIC 410, or a microcomputer 410, and can further include a memory unit 414, preferably making the memory unit 414 integral with it. The power supply 408 powers the in-body system 430 and the transceiver 406, which operates via RF, IR or ultrasound, provides communication with the remote control unit for the personal in-body system 420, and may also provide communication with the remote sensor for the second in-body system 435 and the first Two in vitro system 437 communication.

The first in vivo system 430 may further include one or several local physiological sensors 412A, one or several status sensors 412B, and timing devices 422 for long-term therapy, preferably including timers, clocks, and calendars.

The control unit 410 activates the electro-mechanical delivery mechanism 416 for drug delivery from the drug reservoir 411, preferably via built-in intelligence and algorithms for drug delivery, the control unit responds to measurements notified by local sensors 412 and/or remote sensors 413 React to compensate for measurements, correct for conditions indicated by them, and/or improve efficacy and optimize dosing for optimal closed-loop operation, or use measured data to calibrate dosing for optimal delivery regimens . Additionally or alternatively, the control unit 410 may activate the electro-mechanical delivery mechanism 416 in response to an input from the timing device 422 , or in response to a command from the extracorporeal system 420 . Additionally or alternatively, the control unit 410 may be preprogrammed for a particular drug delivery regimen, which may take any of the following forms: dosing at a controlled rate, delayed dosing, pulsed dosing, long-term therapeutic dosing medicine.

In addition, the in vivo system 430 may further include at least one or several electrodes, turns or transducers 418 for one or several electron transport mechanisms, sonoporation, and/or ablation, which are controlled by the control unit 410 for enhancing Buccal and sublingual administration.

Second in vivo system 435 includes remote sensor 413 , power supply 417 , and transceiver 415 and can report its measurements directly to first in vivo system 430 or in vitro system 420 .

Similarly, a second in vitro system 437 preferably connected to the skin of the person receiving the drug includes remote sensor 413 , power supply 417 , and transceiver 415 and can report its measurements directly to first in vivo system 430 or in vitro system 420 .

The personal extracorporeal system 420 can be any of the following: a remote control unit 402 , a computer system 404 , a telephone or mobile phone 405 , and/or a palmtop or laptop computer 407 . These can communicate with each other, with the first in vivo system 430 of the drug reservoir, with the second in vivo system 435 of the remote sensor, and with the second in vitro system 437 of the human body, and act as an intermediary and monitoring center 500 between them ( Figure 13G) effect.

Figure 14B illustrates the drug controlled delivery electronics 440 without the remote control feature. Device 440 may be pre-programmed for a desired dosing regimen of drug reservoir 411 . Additionally, closed-loop operation may be used in which drug administration is activated by physiological sensor 412 or by timing device 422 . Device 440 may further include a remote sensor. A transceiver may be attached to provide communication between the remote sensor and the control unit 410 .

A much simpler drug controlled delivery electronics 450 is shown in Figure 14C, which has no remote control features and no sensors. The preferred device 450 includes a dedicated control circuit 452 , a timing device 422 , a power source 408 and an electro-mechanical delivery mechanism 416 in addition to a drug reservoir 411 containing the drug.

A device 460 that combines passive and electronic drug delivery is shown in Figure 14D. Device 460 includes two or more drug reservoirs, such as drug reservoirs 411A, 411B, and 411C, each having a passive controlled drug delivery dosage form, such as taught in FIGS. 8A-8B .

According to a first embodiment, the drug is delivered continuously. Thus, when inserted into the oral cavity, the electro-mechanical delivery mechanism 416 opens the first drug reservoir 411A and the drug is delivered to the oral cavity and tissues. When the first drug reservoir 411A is depleted, the electro-mechanical delivery mechanism 416 opens the second drug reservoir 411B, and when it is depleted, the electro-mechanical delivery mechanism 416 opens the third drug reservoir 411C. In this way, the interval between drug replacements can be extended significantly.

According to a second embodiment, the dose is delivered on command. Instructions may come, for example, from a remote control unit, such as a palmtop computer 407, in response to, for example, a sudden onset of pain. Alternatively, the commands may react to sensor readings such as glucose levels or heart rate. Alternatively, the instructions may respond to timer device 422 . Each time the instruction is executed, the electro-mechanical delivery mechanism 416 opens the drug reservoirs 411A, 411B, and 411C and depletes the reservoirs. When all drug reservoirs are depleted, they must be replaced.

The device 460 of FIG. 14D may further include a personal extracorporeal system 420, and possibly an extracorporeal and in vivo remote sensor system, such as systems 435 and 437 of FIG. 14A.

According to the present invention, a dentist may examine a person's mouth for optimal placement and/or fixation of a drug controlled delivery device in the person's mouth. If the patient has dental appliances, such as crowns, dentures, bridges, dentures, braces, night braces, or teethers, any of these can be replaced with the device of the present invention. Alternatively or additionally, a patient may require a dental appliance, such as a crown, denture crown, bridge, denture, braces, night braces, or teether, the required appliance can be prepared to include the device of the present invention. Alternatively or additionally, a wisdom tooth may be missing or not yet erupted, or because it has been extracted, its space available for eg a device of the present invention attached to a molar brace, as taught in Figure 12D. Alternatively or additionally, as taught in Fig. 12F, the device may be mounted on an aligner plate, even when not required for dental reasons. Alternatively or additionally, the device may be mounted on night braces or teethers, even when not required for dental reasons. It will be appreciated that combinations of the above may be used.

It will be appreciated that the controlled drug delivery dosage form or electronic device may be mounted on any anchor that can be secured to the oral mucosa or palatine bone. Alternatively, dosage forms or electronic devices for controlled drug delivery can be implanted directly into tissue without specific fixation components.

It will be appreciated that other known immobilization devices such as those described in US Pat. Nos. 4,175,326, 4,020,558, and 4,681,544 may be used as immobilization devices for the controlled delivery of drugs of the present invention.

Candidate drugs for use in the present invention include antiarthritics, antibiotics, anticoagulant antagonists, antihypertensives, antineoplastics, and antirheumatics.

In addition, blood modulating agents such as anticoagulants, antiplatelet agents, and thrombolytic agents may be used.

In addition, cardiovascular agents such as adrenergic blocking agents (central, peripheral, and combined), alpha/beta adrenergic blocking agents (such as propranolol), angiotensin transferase inhibitors, angiotensin Angiotensin transferase inhibitors and calcium channel blockers, angiotensin transferase inhibitors and diuretics, angiotensin II receptor antagonists, angiotensin II receptor antagonists and diuretics, antiarrhythmic drugs (section Classes I, II, III, Miscellaneous), Antilipidemics, HMG-CoA Reductase Inhibitors, Niacin, β-Adrenergic Blockers, β-Adrenergic Blockers and Diuretics, Calcium Channel Blockers , miscellaneous cardiovascular agents, vasodilators (coronary, peripheral, pulmonary, and combination), and vasopressors.

In addition, respiratory drugs such as bronchodilators, sympathomimetic drugs and combinations thereof, xanthine derivatives and combinations thereof, miscellaneous respiratory drugs, and respiratory stimulants may be used.

In addition, cutaneous and mucosal agents such as antihistamines and combinations thereof, salicylic acid, and antineoplastic agents may be used.

In addition, Viagra and other sexual dysfunction drugs can be used.

Additionally, antidepressants, and medications for psychiatric disorders may be used.

In addition, insulin and similar drugs may be used.

In addition, topical treatments such as:

1. Glucocorticoids such as betamethasone, triamcinolone, fluocinolone and similar drugs,

2. Antifungal agents such as meclomidazole, miconazole, clotrimazole, bifonazole, ketoconazole, and itraconazole;

3. Antiviral drugs such as acyclovir; and

4. Antibiotics such as cefazolin, amoxicillin, vancomycin, gentamicin, and chloramphenicol.

In addition, systemic and long-term therapeutic drugs are used, such as:

1. Antineoplastic drugs such as 5-fluorouracil, tegafur, octreotide, interferon and hydroxyurea;

2. Antiepileptic drugs such as carbamazepine, valproate, perphenazine, phenytoin, and primidone;

3. Antiarrhythmic drugs such as atenolol and timolol;

4. Antihypertensive drugs such as enalapril;

5. Anti-HIV drugs, such as AZT;

6. Immunosuppressants such as rapamycin and tacrolimus;

7. CNS drugs such as galantamine;

8. Alzheimer's disease drugs such as risperidone and galantamine;

9. Drug addiction treatment agents such as buprenorphine, naloxone or naltrexone;

10. Long-term pain/palliative tumor treatment, such as opiates or opioid drugs;

11. Rheumatic pain such as NSAIDs; and

12. Hormones, such as luteinizing hormone releasing hormone (LHRH).

In addition, medications for eating disorders such as:

Medications used for anorexia nervosa:

1. Citalopram (selective serotonin reuptake inhibitor, 20mg);

2. Fluoxetine hydrochloride (antidepressant, for relapse prevention in maintenance therapy); and

3. Olanzapine (atypical antipsychotic).

Medications for Bulimia Nervosa:

Fluoxetine (60mg/day).

Medications used for obesity:

1. L-tryptophan (essential amino acid, 1-3g, administered 1 hour before eating every day);

2. Sibutramine (serotonin-norepinephrine reuptake inhibitor, 10-20 mg per day); and

3. Bitter elements such as nicotine.

Medications for Binge Eating Disorder:

1. Antidepressants; and

2. Sony Sema (antiepileptic drug, 100-600mg/day).

Other medicines for eating disorders:

1. Ondansetron (serotonin receptor antagonist, 16 mg/kg twice daily), also effective for alcoholism; and

2. Topiramate (anticonvulsant, 100 mg/day, 25-400 mg/day).

Appetite suppressants that alter food intake by altering taste sensitivity and/or palatability:

1. Quinine hydrochloride (0.1mM): bitter taste for taste aversion;

2. Capsaicin (4.9-109mM), which reduces the sensory intensity of xylitol for certain taste qualities;

3. Bitter element that suppresses appetite.

In addition, medications to aid in smoking cessation are available, such as

1. Nicotine.

In addition, medications for bad breath may be used, such as:

1. CHX-Alc;

2. CHX-CPC-Zn;

3. Zinc gluconate;

4. OXYD-8; and

5. Mint spice.

According to the present invention, the drug controlled delivery device can be implanted or embedded in animals, such as pets such as dogs and cats; livestock animals such as sheep, goats, cattle, horses, pigs, etc.; or poultry such as chickens, ducks, geese, fire Chicken and other poultry.

Examples of veterinary drugs that may be used with the device of the present invention include:

1. Methiacil tartrate;

2. Oxytetracycline;

3. Albendazole;

4. Monensin;

5. Monensin sodium;

6. Zinc oxide;

7. Selenium;

8. Cobalt;

9. Copper;

10. Ivermectin;

11. Ionphore;

12. Oxfendazole

13. S-methoprene;

14. Potent antiparasitacides;

15. Minerals;

16. Vitamins;

17. Antibacterial drugs;

18. Antibiotics;

19. Hormone;

20. Steroids;

21. Norandrostrienolone acetate;

22. Estradoil;

23. Ebralenone;

24. Progesterone;

25. Fluprogesterone acetate;

26. Methyl acetoxy;

27. Estradiol (Estradoil);

28. Prostaglandins;

29. Norgemate;

30. Desherelin;

31. N-terminated bovine

32. Bovine growth hormone;

33. Porcine growth hormone; and

34. Luteinizing hormone.

In addition, drugs for diseases with a circadian rhythm pattern can be used.

Additionally, other medications may be used.

Drugs contained in the devices of the present invention may be macromolecules, peptides, or other, which can be absorbed directly from the mouth or oral tissues into the general circulation, rather than passing through the gastrointestinal tract, which has numerous restrictions. Thus, the present invention provides an alternative to gastric retention systems, as well as conventional buccal and sublingual administration, and conventional buccal controlled release dosage forms.

Additionally, the drug included in the device may be of any type having any physicochemical properties. In the case of poorly soluble drugs, solubility improving methods such as complexation or sub-micronization (nanosystems) can be used, stabilized in any manner suitable for improving solubility.

A particular advantage of the controlled drug delivery of the present invention relates to the economics of the drug. Many medicines are now very expensive. When administered orally, however, only a portion of the dosage form is utilized, while the remainder reaches the colon and is excreted from the body. When implanted in the mouth and delivered in a controlled manner, drug waste is greatly reduced.

In addition, when using a device 400 (FIG. 14A) or 460 (FIG. 14D) with a state sensor for determining and controlling the state via, for example, a remote control unit 402 or a palmtop computer 407, or another remote control unit (FIGS. 13A-13G) When the display reports the amount of drug remaining in the drug reservoir, the drug is only replaced when needed, and the unused drug is not discarded.

Example

Reference is now made to the following examples, which, together with the foregoing description, illustrate the invention in a non-limiting manner.

Example 1: Passive Controlled Delivery of Drugs

Device 140 designed as a prosthetic crown 160 ( FIGS. 8A-8B ) for passive drug-controlled delivery, or another device for passive drug-controlled delivery, may include a drug reservoir 156 that is coated with osmotic A semipermeable membrane cyclosporine dosage form for sexually controlled drug delivery. Semipermeability is formed by hydrophobic polymers mixed with water soluble additives, such as cellulose acetate, or ethyl cellulose, such as sugar, PEG, etc. Upon administration, the soluble additive dissolves and creates a semipermeable membrane. Cyclosporine is delivered continuously at a rate of 0.5-2 mg per day. Tablets can be replaced about once a month. In comparison, when absorbed, gastric retention in the upper gastrointestinal tract typically does not exceed about 12 hours.

Levodopa can be used in place of cyclosporine in a similar manner. Alternatively, somatotropin in combination with a stabilizer can be used instead of cyclosporine.

Example 2: Delayed Passive Controlled Delivery of Drugs

A device 140 designed as a prosthetic crown 160 ( FIGS. 8A-8B ) for passive drug controlled delivery or another device for passive drug controlled delivery may include several drug reservoirs 156 where a first reservoir includes Dosage forms suitable for passively controlled delivery, e.g. by diffusion and erosion; the second drug reservoir comprises a dosage form coated with a specific functional coating designed to delay the delivery of the second reservoir until the dosage form of the first reservoir is depleted do. In this way, the replacement interval can be extended.

Example 3: Pulsed Passive Drug Controlled Delivery

A device 140 designed as a prosthetic crown 160 ( FIGS. 8A-8B ) for passive drug controlled delivery or another device for passive drug controlled delivery may include a drug reservoir 156 comprising a dosage form having a multilayer coating , and designed for passively controlled delivery in pulses that can be synchronized with, for example, the circadian rhythm cycle for desired long-term therapy.

Example 4: Passive Controlled Delivery of Drugs

A prosthetic crown 160 for passive drug controlled delivery ( FIGS. 8A-8B ) or another device for passive drug controlled delivery may include a drug reservoir 156 for the anti-HIV drug AZT incorporated in a small in balls or flakes. The drug delivery mechanism is diffusion or erosion. The dosage form is replaced once a week.

Example 5: Electronic and Passive Controlled Delivery of Drugs

Drug controlled delivery electronics 460 (FIG. 14D) may include two or more drug reservoirs of the anti-HIV drug AZT, such as 411A, 411B, and 411C, which are passively controlled delivery devices incorporated into pellets or tablets. Release dosage form, which lasts about a week. Upon insertion, the electro-mechanical delivery mechanism 416 opens the first drug reservoir 411A and controlled release occurs by diffusion. When the first reservoir 411A is depleted, the status sensor 412B notifies the control unit 410, which instructs the electro-mechanical delivery mechanism 416 to open the second drug reservoir 411B. After about a week, the second reservoir is depleted and the third drug reservoir 411C is opened. In this way, the replacement interval is extended from one week in Example 2 to several weeks, depending on the number of drug reservoirs.

Example 6: Electromechanical controlled drug delivery

According to the present invention, drug controlled delivery electronics 144 (FIGS. 9A-9C) may include one or several drug reservoirs 176, each communicating with an inlet 177 and a rotor arrangement. The control unit 184 (FIGS. 9A-9C) can translate the amount of drug to be released from the drug reservoir 176 into the number of rotor rotations such that with each rotation a predetermined amount of drug is expelled from the drug reservoir and dispensed in the oral cavity.

Example 7: Controlled drug delivery with transport mechanism for buccal, sublingual, labial mucosal and soft palate absorption

The present invention is suitable for drug absorption through any of the buccal, sublingual, mucous membranes of the lips, and/or the soft palate, which may additionally be assisted by mechanisms for increasing drug transport across biological barriers, e.g. Mechanisms for osmosis, electroosmosis, electrophoresis, electroporation, sonication, and ablation. Accordingly, controlled drug delivery electronics 144 (FIGS. 9A-9C) may include at least one drug transport component for increasing drug transport across biological barriers.

Specifically, the location of the controlled drug delivery device can determine the primary route of absorption. For example:

Sublingual and labial mucosal drug absorption can be achieved by placing a controlled drug delivery device on the lower denture plate (Figure 11C-11D), or the lower aligner position (Figure 12F), or on the base plate of an overnight brace or teether ;

Similarly, soft palate drug absorption is achieved by placing the drug controlled delivery device on the upper denture plate (Figures 11C-11D), or on the upper aligner position (Figure 12F), or on the top plate of night braces or teethers; and

Oral drug absorption was achieved by placing a drug controlled delivery device on the denture crown (Figures 8A-8D).

Transport mechanisms such as iontophoresis can be incorporated.

For example, two biocompatible electrodes can be placed adjacent to the oral tissue for applying a maximum current of 0.5 mA to the buccal surface. The current can be applied in pulses, which can vary over time; or with modulated frequency; or as a direct current (M.B. Delgado-Charro, R.H.Guy: "Transdermal iontophoresis for controlled drug delivery and non-invasive monitoring" October 2001). In a similar manner, the transport tissue can be any of sublingual, labial mucosa, and/or soft palate tissue. Drugs that can be delivered by this method can include, for example, anti-migraine drugs such as alnitidan, methotrexate, anesthetics such as lidocaine, antiparkinsonian drugs, antiemetics, peptides such as insulin, and pain relievers such as morphine, hydromorphone, fen Tenyl, sufentanil, etc.

Alternatively or additionally, another transport mechanism such as sonoporation may be used. Piezoelectric transducers can be placed against any of the buccal, sublingual, labial mucosa, and/or soft palate tissues and are adapted to resonate at frequencies from 20 KHz to 1.5 Mhz. Additionally, resonances can vary in power, frequency, amplitude modulation, duration, and pulse width.

Drugs that can be delivered by this method include, for example, antimigraine drugs such as alnitidan, methotrexate, anesthetics such as lidocaine, antiparkinsonian drugs, and antiemetics, and peptides such as insulin.

Example 8: Controlled Delivery of Drugs for Veterinary Use

According to the present invention, the delivery of hormones can be controlled by a device implanted in the oral cavity of a cow so that many cows can ovulate at about the same time for reproductive management. It will be appreciated that many other veterinary uses are also possible.

Example 9: Long-term administration of cancer

According to Stehlin [Stehlin I., "A Time to Heal: Chronotherapy Tunes In to Body's Rhythms", FDA, http://www.fda.gov/fdac/features/1997/397 chrono.html] , long-term treatment can be used in the treatment of cancer. Animal studies have shown that chemotherapy can be more effective and less toxic if cancer drugs are given at carefully chosen times, seemingly because normal and tumor cells have different long-term biological cycles. Thus, cancer drugs are more effective in cancer and less toxic to normal tissues if their administration is synchronized with the long-term biological cycle of tumor cells. Accordingly, any of drug controlled delivery electronics 400, 440, 450, or 460 (FIGS. 14A-14D) may be preprogrammed for timed administration of chemotherapy, eg, for long-term treatment.

By using any of the drug controlled delivery electronics 400, 440, 450, or 460 (FIGS. 14A-14D), drug delivery can be synchronized to a predetermined pattern or to a physiological parameter measured in real time. Thus, cancer patients receive cancer drugs in an efficient manner with minimal side effects and waste.

Example 10: Long-term treatment of arthritis and remote drug delivery

Long- term Treatment is available for the treatment of arthritis. People with osteoarthritis tend to have less pain in the morning and worse pain at night, while people with rheumatoid arthritis often have pain peaks in the morning and gradually decrease throughout the day. Long-term treatment of various arthritis with NSAIDs such as ibuprofen can be timed to ensure that the highest blood level of the drug coincides with the peak pain. Drug controlled delivery electronics 400 or 460 (FIGS. 14A and 14D) can be preprogrammed for time-operated dosing that is synchronized with the circadian rhythm of the disease based on the patient's medical history for long-term therapy.

Long-term therapy can be supplemented by remote operation from the personal extracorporeal system 420, preferably by the patient when in pain, such as from the remote control unit 402, palmtop computer 407, or another remote control unit.

Example 11: Long-term treatment of diabetes, remote control and sensor-activated drug delivery

Glucose levels change to some extent throughout the day. Additionally, there is an increase in glucose levels shortly after eating. Drug controlled delivery electronics 400 or 460 (FIGS. 14A and 14D) can be preprogrammed for time-operated dosing that is synchronized with the circadian rhythm of glucose for long-term therapy. Preferably, the synchronization is based on the patient's history of periodic changes in glucose levels.

Long-term therapy can be supplemented by remote operation from the personal extracorporeal system 420, when the patient is about to eat, by the patient, such as from the remote control unit 402, palmtop computer 407, or another remote control unit, knowing that the glucose level will subsequently rise .

Additionally, remote operation may be performed in response to a report from one or several sensors 413 when glucose levels in the blood or interstitial fluid have increased. Remote operation of the personal extracorporeal system 420 may be operated by the patient from the remote control unit 402 or the palm computer unit 407 while the patient sees the glucose level measurement on the display. Additionally or alternatively, the patient may send the measured values according to the dosing regimen to the monitoring center 500 ( FIG. 13G ) via, for example, the remote control unit 402 or the palmtop computer unit 407, or another remote control unit, to obtain information from the monitoring center such as a computer. 502 decision.

Alternatively, closed loop operation can be performed without patient intervention, and when the glucose sensor 413 reports a measurement, the device's built-in intelligence and algorithms determine that the value is too high. The order to deliver the drug can be made directly by eg the control unit 410 of the in vivo system 430 of the device 400 for reacting to the notified measurements based on its built-in intelligence and algorithms. Alternatively, the decision and instructions to deliver the drug may come from the computer system 502 (FIG. 13G) of the monitoring center 500, where the sensor measurements are sent to the monitoring center by, for example, the remote control unit 402 or palmtop computer unit 407, or another remote control unit. 500, and they simultaneously accept instructions from the monitoring center 500 and transmit them to the control unit 410 of the in-vivo system 430. In this way, drug delivery can be administered remotely, without the patient's knowledge, and drug delivery can be precisely tailored to the patient's needs.

Example 12: Long-term treatment of asthma, remote control and sensor-activated drug delivery

Long- term Treatment can be used in the treatment of asthma, because patients with asthma tend to attack in the morning hours, such as 3 o'clock to 5 o'clock in the morning. Drug controlled delivery electronics 400 or 460 (FIGS. 14A and 14D) can be pre-programmed for timed operation to deliver drugs that are synchronized with the circadian rhythm of the disease for long-term treatment, which can be further supplemented by remote operation. The drug delivered can be eg a bronchodilator, Uniphyl. Dosage forms may be tablets, minitablets, etc., but may include certain formulation modifiers. As with other dosage forms, replace about once a week.

The case can be synchronized by pre-programming the device based on the patient's medical history.

Additionally or alternatively, the rate of delivery of the drug can be increased a little before the expected time of onset.

Long-term therapy can be supplemented by remote operation from the personal extracorporeal system 420, preferably by the patient, for example, from the remote control unit 402 or palmtop computer unit 407 or another remote control unit when the patient feels sick.

Additionally or alternatively, long-term therapy may be supplemented by closed-loop operation without patient intervention when any of the physiological sensors 413, such as the heart rate sensor 413, report measurements that cause the device's built-in intelligence and algorithms to determine a morbidity. Decisions and instructions for drug delivery may be made directly by eg the control unit 410 of the in vivo system 430 of the device 400 for dosing in response to the notified measurements. Alternatively, decisions and instructions for drug delivery may come from a system 420 outside the individual's body, such as from computer system 404 . Alternatively, the decisions and instructions for drug delivery may come from the monitoring center 500 (FIG. 13G), where sensor measurements are sent to the monitoring center via, for example, the remote control unit 402 or palmtop computer unit 407, or another remote control unit, and these are also The instructions from the monitoring center 500 are accepted and transmitted to the control unit 410 of the in-vivo system 430 . In this way, drug delivery can be performed remotely, even while the patient is sleeping.

Example 13: Sensor Activated Drug Delivery for Snoring and Other Sleep Disorders

For sleep disorders, closed loop operation may be most suitable, and device 440 of FIG. 14B may be used. Sensor 412 may be a piezoelectric transducer that detects sounds such as snoring, or a heartbeat. Decisions and instructions for drug delivery can be made directly through the control unit 410 for reacting to the notified measurements for drug delivery according to its built-in intelligence and algorithms. For snoring, the notified measurement may be the sound of snoring. For insomnia, the notification measurement might be the heart rate indicating when the patient fell asleep or woke up.

Example 14: Remote drug delivery for psychiatric disorders

The drug controlled delivery electronic device 400 or 460 (FIGS. 14A and 14D) may be used by patients suffering from psychiatric disorders such as depression or anxiety. When the situation worsens, drug delivery can be initiated by the patient, or an attendant, such as a parent, via, for example, remote control unit 202, palmtop computer 407, or another remote control unit.

For elderly patients suffering from aging or Alzheimer's disease, the sensors 412 or 413 may further include global positioning devices, and these may be mounted on the remote control unit 202 and/or palmtop computer 407, or another remote control unit on, for reporting the location of the patient and the location of the remote control unit to the monitoring center.

Example 15: Sexual dysfunction

The drug controlled delivery electronics 400 or 460 can be used for sexual dysfunction where when one wishes to be aroused the person uses the remote control unit 402 or palmtop 407, or another remote control unit, for the delivery of agonistic drugs such as Viagra.

Example 16: Drug rehabilitation

When using the device 400 or 460 with the status sensor to determine and report the amount of drug remaining in the drug reservoir on the display of the remote control unit 402 or palmtop 407, or another remote control unit, the user can observe and Actively participate in the rate of drug use. Thus, users can establish goals for themselves, reducing the rate of drug delivery in small increments until recovery.

Example 17: Drugs with Narrow Therapeutic Index

Drug controlled delivery electronics 400 or 460 including a remote sensor 413 for drug concentration levels in blood or interstitial fluid may be used for drugs with a narrow therapeutic index, where the drug concentration in blood or interstitial fluid is monitored, preferably continuously, and determined according to The response to drug delivery is monitored.

Example 18: Controlled Delivery of Drugs in the Treatment of Eating Disorders

Eating disorders are characterized by persistent patterns of abnormal eating behavior. As defined by the Academy Of Eating Disorder, these patterns of eating behavior are associated with significant emotional, physical, and related distress. Some common eating disorders are described below:

1. Anorexia nervosa is defined as a severe, potentially life-threatening eating disorder characterized by self-starvation and excessive weight loss. Typically, oral administration therapy may include citalopram (selective serotonin reuptake inhibitor, 20 mg), fluoxetine hydrochloride (antidepressant, for relapse prevention in maintenance therapy), and olanzapine ( atypical antipsychotics).

In accordance with the present invention, oral devices for controlled drug delivery and methods for controlled drug delivery may be used in conjunction with any of the teachings of FIGS. 8A-14D in place of conventional orally administered drug therapy.

An oral device for controlled drug delivery has the advantage over conventional methods that the user can observe and actively participate in the rate of drug use. Users can establish goals for themselves, reducing the dosing rate in small increments until a normal eating pattern is achieved.

2. Binge eating disorder is defined as a severe, potentially life-threatening eating disorder characterized by binge-eating behavior and binge-compensatory behavior cycles such as self-induced vomiting to counteract or compensate for the effects of binge eating. Typically, oral drug therapy may include fluoxetine (60 mg/day).

An oral device for controlled delivery of a drug and a method for controlled delivery of a drug as taught in any of FIGS. 8A-14D may be used in accordance with the present invention.

A first advantage of oral devices for controlled drug delivery over conventional methods is that the user can observe and actively participate in the rate of drug use. Users can establish goals for themselves, reducing the dosing rate in small increments until a normal eating pattern is achieved.

Another advantage resides in the fact that a controlled rate of administration aimed at maintaining a substantially constant concentration of the drug in the blood may be more effective in preventing binge eating and diarrhea than oral administration.

In addition, the long-term delivery controlled drug delivery oral device can be programmed to schedule higher rates of drug delivery during known binge or emptying times.

3. Obesity, or overweight is usually treated by L-tryptophan (essential amino acid, 1-3g, administered 1h before eating), sibutramine (serotonin-norepinephrine reuptake inhibitor, 10-20mg daily), and (or) bitter elements such as nicotine treatment.

According to the present invention, the oral device for controlled delivery of drugs and the method for controlled delivery of drugs taught in any one of Figs. 8A-14D can be used with advantages similar to those described in item (2).

4. Repetitive binge eating disorder and/or compulsive overeating involving any of the following:

i. Conducted in an uncontrolled manner;

ii. Eating unusually large amounts of food;

iii. proceed very quickly;

iv. Eat until you feel very uncomfortable;

v. Eating large amounts of food even when not hungry;

vi. Eating alone due to embarrassment with eating habits and quantities; and

vii. Feeling disgusted, depressed, and guilty after overeating.

Binge eating disorder is usually treated with antidepressants, and sonisema (antiepileptic drug, 100-600 mg/day).

According to the present invention, the oral device for controlled delivery of drugs and the method for controlled delivery of drugs taught in any one of Figs. 8A-14D can be used with advantages similar to those described in item (2).

5. Eating Disorders Not Otherwise Specified (EDNOS) defined as changes between anorexia nervosa or bulimia nervosa because they do not meet the diagnostic criteria for anorexia nervosa or bulimia nervosa, despite the need for treat. Examples include those who are consistent with anorexia nervosa in addition to continuing until menstruation, regularly emptied but not binge-eating, and individuals who nearly meet criteria for binge eating disorder but binge eating less than twice a week women with symptoms. It is usually given orally ondansetron (serotonin receptor antagonist, 16 mg/kg twice daily), which is also effective for alcoholism, and/or topiramate (anticonvulsant, 100 mg/day , 25-400 mg/day).

According to the present invention, the oral device for controlled delivery of drugs and the method for controlled delivery of drugs taught in any one of Figs. 8A-14D can be used with advantages similar to those described in item (2).

A variety of overeating disorders are commonly administered orally for the treatment of appetite suppressants that alter food intake by altering taste sensitivity and/or palatability. Taste receptors are epithelial cells modified with receptor proteins that protrude from the extracellular matrix and aggregate in taste buds. Most taste buds are located on the surface of the tongue or on the raised papillae. Thus, taste sensations are caused by taste receptors on the tongue binding ions and molecules such as small organic molecules, carbohydrates, proteins, fatty acids, etc. (Dulac, Catherine, "The Physiology of Taste.", Cell. 100., pp. 607-610, 2000). There are four taste sensations: sweet, salty, sour, and bitter, with receptors for each concentrated in different areas of the tongue. Each taste sensation is associated with a different chemical structure or ion charge: glucose rings for sweetness, sodium ions for salty sensations, etc. The brain translates multiple sensory inputs and generates complex taste sensations (Chandrasheker, Jayaram et al. (2000), "T2Rs Function as Bitter Taste Receptors.", Cell. 100., pp. 703-711).

The bitter taste sense is used to identify toxic substances such as heavy metals, and most animals generally display an aversion to bitters. This suggests that transmission of bitter taste develops as an important defense against ingestion of noxious substances (Chandrasheker, Jayaram et al. (2000), "T2Rs Function as Bitter Taste Receptors" Cell. 100., pp. 703-711; Garcia, J., and Hankins, W.G. (1975), "The Evolution of Bitter and the Acquisition of Toxipodia in Olfaction and Taste.", Procedings of the 5th International Symposium in Melbourne, Australia, edited by D.A. Denton and J.P. Coghlan, New York: Academic Press, pp. 39-45; Glendinning J.I. (1995), "Is the Bitter RejectionResponse Always Adaptive?", Physioloical Behavior., 56, pp. 217-1227; Glendinning, J.I. et al. (1999), "Contributions of Different Bitter-Sensitive Taste Cells to Feeding in arhibition (Manduca sexta)", Behavioral Neuroscience., 113, pp. 840-854).

T2Rs are a family of taste receptor proteins that have been shown to function as bitter taste receptors (Alder, Elliot et al. (2000), "A Novel Family of Mammalian TasteReceptors", Cell, 100, pp. 693-702m; and Chandrasheker, Jayaram et al. (2000), "T2Rs Function as Bitter Taste Receptors", Cell, 100, pp. 703-711). T2Rs can include as many as 80 different members that together help detect various bitter tastes.

Examples of appetite suppressants that can be administered orally and that alter food intake by altering taste sensitivity and/or palatability include quinine hydrochloride (0.1 mM): bitter for taste aversion; capsaicin (4.9-109 mM) , which reduces the perceived intensity of certain gustatory qualities xylitol, and other bitters that suppress appetite.

According to the present invention, the oral device for controlled delivery of drugs and the method for controlled delivery of drugs taught in any one of Figs. 8A-14D can be used with advantages similar to those described in item (2).

Example 19: Smoking Cessation Treatment

According to the present invention, the oral device for the controlled delivery of drugs and the method for the controlled delivery of drugs taught in any one of FIGS. People trying to quit smoking. By intraoral delivery, desired levels of bupropion hydrochloride in the bloodstream can be achieved and the noradrenergic and dopaminergic pathways in the brain stimulated. Thus, the boredom and latent feelings that make one smoke a cigarette are satisfied by bupropion hydrochloride.

Example 20: Treatment of Alcoholism

Conventional treatment of alcoholism uses, for example, oral administration of ondansetron (serotonin receptor antagonist, 4 to 16 mg/kg twice daily). Certain serotonin receptors in the brain can have an effect on how alcohol affects the brain. Ondansetron affects those receptors and has been shown to reduce alcohol consumption.

According to the present invention, the oral device for controlled delivery of drugs and the method for controlled delivery of drugs taught in any one of Figs. 8A-14D can be used with advantages similar to those described in item (2).

Example 21: Halitosis Treatment

Anaerobic bacteria on the tongue and throat surface cause bad breath by destroying proteins at a very high rate. The sulfur-rich amino acids, cysteine and methionine, are by-products of the above process and are delivered to the tongue and Bad breath in the throat. Usual treatment is oral administration of any of the following: 0.2% chlorhexidine solution, chlorhexidine 0.05% plus etylpyridinium chloride 0.05% plus zinc lactate 0.14%, zinc gluconate, OXYD-8, or mint flavor.

An oral device for controlled delivery of a drug and a method for controlled delivery of a drug as taught in any of FIGS. 8A-14D may be used in accordance with the present invention. Control regimens may include controlled delivery of either chlorhexidine solution 0.2%, chlorhexidine 0.05% plus etylpyridinium chloride 0.05% plus zinc lactate 0.14%, zinc gluconate, OXYD-8, or mint flavor .

Example 22: Personalized drug delivery based on DNA analysis

Dosing regimens can be based on DNA recombination and analysis to match individual patient DNA. DNA parameters can be manipulated prior to or during dosing to determine the optimal dosing strategy for a particular patient. DNA-driven delivery regimens can be formulated, for example, after determining a patient's DNA, including genes that make the patient more susceptible to certain diseases, such as breast cancer, or heart attack.

Example 23: Personalized Dosing Based on Physical Parameters and Personal History

Dosage regimens can be tailored to a particular patient based on physical parameters and personal history analysis. Physical parameters and personal history analysis may include the patient's weight, height, age, sex, physiological history, medical status, other concomitant medications, blood pressure, blood analysis, and the like. These parameters can be manipulated prior to or during drug administration to determine the dosing strategy to achieve the best effect for a particular patient.

Example 24: Penetration enhancers

The epithelium of the oral cavity is structurally similar to other stratified epithelium of the body, and enhancers used to improve drug penetration in other absorbing mucosa have been shown to be effective for buccal drug penetration as well (Shojaei, A.H., "Buccal Mucosa As A Route For Systemic Drug Delivery", Review, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8). Some examples of penetration enhancers are: 23-Lauryl Ether, Aprotinin, Azone, Benzalkonium Chloride, Cetylpyridinium Chloride, Cetrimide, Cyclodextrin, Dextran Sulfate, Lauryl Acid, Lauric Acid/Propylene Glycol, Lysolecithin, Menthol, Methoxysalicylate, Methyl Oleate, Oleic Acid, Lecithin, Polyoxyethylene, Polysorbate 80, Sodium EDTA , sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, cysteamine deoxycholate, dimethyl sulfoxide, and various alkyl glycosides.

It is anticipated that many related oral devices and methods for the controlled delivery of drugs will be developed during the life of this patent, and the scope of these terms includes all such new technologies derived therefrom.

As used herein, the term "about" means ±30%.

Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following non-limiting examples. In addition, each of the various embodiments and aspects of the present invention described above and claimed in the following section is empirically supported by the following examples.

It is to be understood that features of the invention which are, for clarity, described in separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in a single embodiment may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the present invention embraces all such substitutions, modifications, and changes that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference herein. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims (102)

1. A controlled drug delivery device comprising: a reservoir containing the drug; and an electronic drug delivery mechanism for providing controlled delivery of said drug, The device is adapted to be inserted into the oral cavity of a subject. 2. The device of claim 1, wherein the drug is provided in the form of a drug dosage form for a combination of electronically controlled release and passively controlled release. 3. The device of claim 1, wherein the drug is provided in a pharmaceutical dosage form suitable for: delivery at a controlled rate, delayed delivery, and pulsed release. 4. The device of claim 1, wherein said electronic drug delivery mechanism further comprises: a control unit for controlling said controlled delivery; an electro-mechanical delivery mechanism that opens in response to an instruction from the control unit to allow delivery of the drug to occur; and a power source to power the control unit and the electro-mechanical delivery mechanism. 5. The device of claim 4, wherein the electro-mechanical delivery mechanism comprises a rotor. 6. The device of claim 4, wherein said control unit is selected from the group consisting of dedicated electronics, processors, ASICs, and microcomputers. 7. The device of claim 1, wherein said controlled drug delivery device further comprises a timing device selected from the group consisting of timers, clocks, calendars, and combinations thereof. 8. The device of claim 1, further comprising at least one localized sensor integral with said device. 9. The device of claim 8, further comprising at least two local sensors integral with said device. 10. The device of claim 8, wherein said at least one local sensor is a physiological sensor for administering drugs in response to measurements of said sensor. 11. The device of claim 10, wherein said local physiological sensor is selected from a sensor for drug concentration in saliva, a sensor for glucose concentration in saliva, a sensor for metabolite concentration in saliva, a sensor for electrolyte concentration in saliva sensor for pH level in saliva, sensor for oral temperature, heartbeat sensor, heart rate sensor, and snore sensor. 12. The device of claim 8, wherein said at least one local sensor is a status sensor for ensuring that the device is in proper operating condition. 13. The device of claim 12, wherein the local state sensor is selected from a sensor for drug remaining in the drug reservoir, a sensor for drug flow rate, a sensor for power supply condition, and a sensor for short circuit detection. 14. The device of claim 1, further comprising at least one communication component selected from the group consisting of: a receiver, a transmitter, and a transceiver. 15. The device of claim 14, wherein the communication component provides communication with a system outside the body of the individual. 16. The apparatus of claim 15, wherein the personal extracorporeal system is selected from the group consisting of remote control units, computer systems, telephones, mobile phones, palmtops, PDAs, laptops, and combinations thereof. 17. The device of claim 16, wherein the personal extracorporeal system is adapted to provide communication between the device and a monitoring center. 18. The apparatus of claim 14, wherein said communication component provides communication with at least one remote sensor. 19. The device of claim 18, wherein said remote sensor is selected from a sensor for drug concentration in blood, a sensor for glucose concentration in blood, a sensor for metabolite concentration in blood, a sensor for electrolyte concentration in blood sensor, sensor for oxygen level in blood, sensor for pH level in blood, sensor for drug concentration in interstitial fluid, sensor for glucose concentration in interstitial fluid, sensor for metabolite concentration in interstitial fluid, sensor for Sensors for electrolyte concentration in interstitial fluid, sensors for oxygen content in interstitial fluid, sensors for pH level in interstitial fluid, sensors for drug concentration in sweat, temperature sensors, heartbeat sensors, heart rate sensors, blood pressure sensors, and Sensors for the presence of food, alcohol or smoke in the mouth. 20. The device of claim 1, wherein said device further comprises at least one sensor for increasing drug transport across biological barriers by means selected from the group consisting of iontophoresis, electrophoresis, electrophoresis, electroporation, sonication, ablation, and combinations thereof. Drug delivery components. 21. The device of claim 1, wherein said device further comprises components for applying iontophoresis, electroosmosis, electroporation, sonoporation, ablation, and combinations thereof for increasing drug transport across biological barriers. 22. The device of claim 1, wherein said drug delivery mechanism provides controlled delivery of said drug in the following manner: dosing according to a preprogrammed regimen, dosing at a controlled rate, delayed dosing, pulsed dosing, long-term therapy Dosing, closed-loop dosing, dosing in response to sensor input, dosing on the order of a personal extracorporeal system, dosing according to a dosing regimen specified by a personal extracorporeal system, dosing through a personal extracorporeal system on the order of a monitoring center, and The dosing regimen specified by the monitoring center is administered through the individual's extracorporeal system. 23. The device of claim 1, further comprising at least two drug reservoirs. 24. The device of claim 23, wherein each of the at least two drug reservoirs is controlled independently of the other. 25. The device of claim 1, wherein the drug is in the form of nanoparticles. 26. The device of claim 1, wherein the device is mounted to a dental appliance designed for use in the oral cavity of a subject. 27. The device of claim 26, wherein said dental appliance is selected from the group consisting of a denture crown, a dental bridge, a dental three-unit bridge, a dental implant, a partial denture, a total denture, aligners, molar braces, night braces, and teethers. 28. The device of claim 1, wherein said device is mounted on a fixture fixable to the oral mucosa or palatine bone. 29. The device of claim 1, wherein said device is anchor-free and is implanted directly into tissue. 30. The device of claim 1, wherein the device is adapted to be removably inserted into the oral cavity of a subject. 31. The device of claim 1, wherein the device is adapted to be permanently embedded in the oral cavity of a subject. 32. The device of claim 1, wherein said device is adapted to be permanently embedded in the oral cavity of a subject, and said device further comprises a removable assembly housing at least one of said drug reservoir and said power source one. 33. The device of claim 1, which is adapted for buccal administration. 34. The device of claim 1, which is suitable for sublingual administration. 35. The device of claim 1, which is adapted for labial mucosal administration. 36. The device of claim 1 adapted for administration to the soft palate. 37. The device of claim 1 adapted to be inserted into the mouth of a human. 38. The device of claim 1, adapted to be inserted into the mouth of an animal. 39. A method of controlled drug delivery comprising: providing a controlled drug delivery device comprising a drug-containing reservoir and an electronic drug delivery mechanism for controllably releasing said drug; and The device is inserted into the oral cavity of the subject. 40. The method of claim 39, wherein said drug is provided in the form of a pharmaceutical dosage form. 41. The method of claim 39, wherein the drug is provided in a pharmaceutical dosage form suitable for release in controlled rate release, delayed release, and pulsed release. 42. The method of claim 39, wherein said electronic drug delivery mechanism further comprises: a control unit for controlling said controlled delivery; an electro-mechanical delivery mechanism that opens in response to an instruction from the control unit to allow delivery of the drug to occur; and a power source to power the control unit and the electro-mechanical delivery mechanism. 43. The method of claim 42, wherein the electro-mechanical delivery mechanism comprises a rotor. 44. The method of claim 42, wherein said control unit is selected from the group consisting of dedicated electronics, processors, ASICs, and microcomputers. 45. The method of claim 39, wherein said controlled drug delivery device further comprises a timing device selected from the group consisting of timers, clocks, calendars, and combinations thereof. 46. The method of claim 39, further comprising at least one local sensor integral with said device. 47. The method of claim 46, further comprising at least two localized sensors integral to said device. 48. The method of claim 46, wherein said at least one local sensor is a physiological sensor for drug delivery in response to measurements of said sensor. 49. The method of claim 48, wherein the local physiological sensor is selected from a sensor for drug concentration in saliva, a sensor for glucose concentration in saliva, a sensor for metabolite concentration in saliva, a sensor for electrolyte concentration in saliva sensor for pH level in saliva, sensor for oral temperature, heartbeat sensor, heart rate sensor, and snore sensor. 50. The method of claim 46, wherein said at least one local sensor is a status sensor for ensuring that the device is in proper operating condition. 51. The method of claim 50, wherein the local state sensor is selected from a sensor for drug remaining in a drug reservoir, a sensor for drug flow rate, a sensor for power supply condition, and a sensor for short circuit detection. 52. The method of claim 39, further comprising at least one communication component selected from the group consisting of: a receiver, a transmitter, and a transceiver. 53. The method of claim 52, wherein said communication component provides communication with a system outside the body of the individual. 54. The method of claim 53, wherein the personal extracorporeal system is selected from the group consisting of remote control units, computer systems, telephones, mobile phones, palmtops, PDAs, laptops, and combinations thereof. 55. The method of claim 54, wherein the personal extracorporeal system is adapted to provide communication between the device and a monitoring center. 56. The method of claim 52, wherein said communication component provides communication with at least one remote sensor. 57. The method of claim 56, wherein said remote sensor is selected from a sensor for drug concentration in blood, a sensor for glucose concentration in blood, a sensor for metabolite concentration in blood, a sensor for electrolyte concentration in blood sensor, sensor for oxygen level in blood, sensor for pH level in blood, sensor for drug concentration in interstitial fluid, sensor for glucose concentration in interstitial fluid, sensor for metabolite concentration in interstitial fluid, sensor for Sensors for electrolyte concentration in interstitial fluid, sensors for oxygen content in interstitial fluid, sensors for pH level in interstitial fluid, sensors for drug concentration in sweat, temperature sensors, heartbeat sensors, heart rate sensors, blood pressure sensors, and Sensors for the presence of food, alcohol or smoke in the mouth. 58. The method of claim 39, wherein said device further comprises at least one sensor for increasing drug transport across biological barriers by means selected from iontophoresis, electrophoresis, electrophoresis, electroporation, sonication, ablation, and combinations thereof. Drug delivery components. 59. The method of claim 39, wherein said device further comprises applying components of iontophoresis, electroosmosis, electroporation, sonication, ablation, and combinations thereof for increasing drug transport across biological barriers. 60. The method of claim 39, wherein said drug delivery mechanism provides controlled delivery of said drug in the following manner: dosing according to a preprogrammed regimen, dosing at a controlled rate, delayed dosing, pulsed dosing, long-term treatment Dosing, closed-loop dosing, dosing in response to sensor input, dosing on the order of a personal extracorporeal system, dosing according to a dosing regimen specified by a personal extracorporeal system, dosing through a personal extracorporeal system on the order of a monitoring center, and The dosing regimen specified by the monitoring center is administered through the individual's extracorporeal system. 61. The method of claim 39, further comprising at least two drug reservoirs. 62. The method of claim 61, wherein each of the at least two drug reservoirs is controlled independently of the other. 63. The method of claim 39, wherein the drug is in the form of nanoparticles. 64. The method of claim 39, wherein the device is mounted to a dental appliance designed for use in the oral cavity of the subject. 65. The method of claim 64, wherein the dental appliance is selected from the group consisting of denture crowns, dental bridges, dental three-unit bridges, dental implants, partial dentures, total dentures, aligners, molar braces, night braces, and teethers. 66. The method of claim 39, wherein said device is mounted on a fixture fixable to the oral mucosa or palatine bone. 67. The method of claim 39, wherein the device is anchor free and implanted directly into the tissue. 68. The method of claim 39, wherein the device is adapted to be removably inserted into the oral cavity of the subject. 69. The method of claim 39, wherein the device is adapted to be permanently embedded in the oral cavity of the subject. 70. The method of claim 39, wherein said device is adapted to be permanently embedded in an oral cavity of a subject, and said device further comprises a removable assembly housing at least one of said drug reservoir and said power source one. 71. The method of claim 39, which is suitable for buccal administration. 72. The method of claim 39, which is suitable for sublingual administration. 73. The method of claim 39, which is suitable for labial mucosal administration. 74. The method of claim 39, which is suitable for administration to the soft palate. 75. The method of claim 39, wherein said subject is a human. 76. The method of claim 39, wherein said subject is an animal. 77. A controlled drug delivery device comprising: a reservoir containing the drug in pharmaceutical dosage form; and A dental appliance designed to be inserted into the oral cavity of a subject and adapted to support the drug reservoir. 78. The device of claim 77, wherein said dental appliance is selected from the group consisting of a denture crown, a dental bridge, a dental three-unit bridge, a dental implant, a partial denture, a total denture, aligners, molar braces, night braces, and teethers. 79. The apparatus of claim 77, wherein the dental appliance is designed to be removably inserted into the oral cavity of the subject. 80. The apparatus of claim 77, wherein the dental appliance is designed to be permanently embedded in the oral cavity of the subject. 81. The device of claim 77, further comprising at least two drug reservoirs. 82. The device of claim 77, wherein said pharmaceutical dosage form provides drug delivery selected from the group consisting of delivery at a controlled rate, delayed delivery, and pulsatile delivery. 83. The device of claim 77, wherein the drug is in the form of nanoparticles. 84. The device of claim 77, which is adapted for buccal administration. 85. The device of claim 77, which is suitable for sublingual administration. 86. The device of claim 77, which is adapted for labial mucosal administration. 87. The device of claim 77 adapted for administration to the soft palate. 88. The device of claim 77 adapted to be inserted into the mouth of a person. 89. The device of claim 77, which is adapted to be inserted into the mouth of an animal. 90. A method of controlled drug delivery comprising: providing a drug controlled delivery device comprising a reservoir containing a drug in the form of a pharmaceutical dosage form; and In the oral cavity of the subject, the device is supported on a dental appliance designed to be inserted into the oral cavity of the subject and used to support the device. 91. The method of claim 90, wherein said dental appliance is selected from the group consisting of denture crowns, dental bridges, dental three-unit bridges, dental implants, partial dentures, total dentures, aligners, molar braces, night braces, and teethers. 92. The method of claim 90, wherein the dental appliance is designed to be removably inserted into the oral cavity of the subject. 93. The method of claim 90, wherein the device is designed to be permanently embedded in the oral cavity of the subject. 94. The method of claim 90, further comprising at least two drug reservoirs. 95. The method of claim 90, wherein the pharmaceutical dosage form provides drug delivery selected from the group consisting of delivery at a controlled rate, delayed delivery, and pulsatile delivery. 96. The method of claim 90, wherein the drug is in the form of nanoparticles. 97. The method of claim 90, which is suitable for buccal administration. 98. The method of claim 90, which is suitable for sublingual administration. 99. The method of claim 90, which is suitable for labial mucosal administration. 100. The method of claim 90, which is suitable for administration to the soft palate. 101. The method of claim 90, wherein said subject is a human. 102. The method of claim 90, wherein said subject is an animal.

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