|Publication number||US3788322 A|
|Publication date||Jan 29, 1974|
|Filing date||Dec 27, 1972|
|Priority date||Dec 27, 1972|
|Publication number||US 3788322 A, US 3788322A, US-A-3788322, US3788322 A, US3788322A|
|Original Assignee||Alza Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Referenced by (79), Classifications (10)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent Michaels Jan. 29, 1974  Inventor: Alan S. Michaels, Atherton, Calif.
 Assignee: Alza Corporation, Palo Alto, Calif.
 Filed: Dec. 27, 1972  App]. No.: 318,799
Related U.S. Application Data  Continuation of Ser. No. 300,674, Oct. 25, 1972,
 U.S. Cl 128/260, 128/2, 128/272  Int. Cl A6lm 31/00  Field of Search 128/1, 1.2, 260, 271, 272
 References Cited UNITED STATES PATENTS l,957,564 5/1934 West 128/272 3,485,235 12/1969 Felson 128/2 3,604,417 9/197! Stolzenberg 128/260 3,701,35! 10/1972 Harvey 128/260 Primary ExaminerAldrich F. Medbery Attorney, Agent, or FirmPaul L. Sabatine et a1.
 ABSTRACT A drug delivery device for the continuous administration of a drug at a controlled rate for a prolonged time is comprised of a drug delivery device attached to a support means for maintaining the device in the environment of use. The device is comprised of a housing with an internal space that acts as a reservoir for containing a drug and a discharge means communicating between the reservoir and the exterior of the device for releasing drug therefrom. The drug delivery device and the support are optionally contained in a container, and in the environment of use, the device is released from the container and the support inflated. Drug is discharged from the reservoir by the reservoir walls collapsing to exert an internal pressure against the drug to urge it through the discharge means. On completion of the drug discharge from the reservoir, the support collapses enabling the device to pass from the environment of use.
6 Claims, 8 Drawing Figures PATENTED JAN 2 91974 SHEET 1 0F 2 FiG.2
DRUG DELIVERY DEVICE WITH MEANS FOR MAINTAINING DEVICE IN ENVIRONMENT OF USE This invention is a continuation of application Ser. No. 300,674 filed on -25-72 now abandoned.
BACKGROUND OF THE INVENTION It relates to a novel and useful drug delivery device for releasing drug internally to a drug receptor such as a cavity in an animal, human or avian at a controlled rate for a prolonged period of time to produce a local or systemic physiological or pharmacological beneficial effect. The drug delivery device of the invention is comprised of a drug delivery device fixed to a hollow member, optionally housed in a container that is bioerodible in physiological environments. The hollow member is expandable from a collapsed state to an expanded state in the environment of use or on its release from the container and it is returnable to a collapsed state after an extended period of time. The device is comprised of a wall surrounding and forming an internal space to serve as a reservoir, that is a means for containing a drug. The wall of the reservoir is made of a flexible, or elastomeric material and it is substantially impermeable to drug and biological fluids. The device is provided with a drug discharge means for metering the release of drug from the reservoir to the environment of use or to any preselected drug receptor. Drug is released from the reservoir by its walls automatically collapsing thereby exerting a force into the reservoir to apply an internal pressure on the drug causing it to move through the discharge metering outlet while concurrently reducing its own volume for administering the drug at a controlled rate over a prolonged period of time.
Beneficial agents, such as medicaments, essential nutrients, vitamins, prophylatics and the like, normally are introduced into the body at repeated, spaced intervals, or in a sustained release form that attempts to release the agent over a prolonged period of time, especially if a particular dose level is to be maintained in vivo. In many instances, in the management of health and disease, for example, drug administration into body drug receptor sites such as the bladder, vagina, uterus or the gastrointestinal tract, it is especially desirable that the drug delivery have a preferred zero order time dependence, that is, the rate of drug release be independent of time.
Prior to the present invention various approaches have been tried to obtain a particular dose level over a prolonged period to these drug receptor sites, but these approaches have not led to generally acceptable results. One approach, which has received attention as used for administering a drug to the gastrointestinal tract, or for administering .a drug to the vagina, uterus or the like, is to mix a drug with a carrier material that is gradually broken down by the body fluids with the drug released as the carrier disintegrates. Numerous drug carriers have beerrxtsed for this purpose, including waxes, oils, fats, soluble-polymers, and the like, and while some of these have provided for a moderate delayed release of drug, gen'erally, the desired constant release rate for a prolonged period has not been achieved. One reason for this is that as the carrier disintegrates, the surface area of the dosage unit decreases, concomitantly exposing increasingly smaller quantities of the carrier and the drug to the surrounding body fluids. This inherently results in a decline in the release rate over time.
Another approach for administering a drug to drug receptor sites, such as the gastrointestinal tract, has been to enclose the drug within a single drug delivery capsule having a wall permeable to the drug through which it can pass, for example, by diffusion. An approach of this kind is set forth in US. Pat. No. 3,279,996; however, these too have inherent difficulties. For example, one difficulty associated with this prior art is that different delivery capsules having different drug release rates cannot readily be made because the only variable parameter is the thickness of the material used to make the capsule. Additionally, these drug delivery capsules have generally been based merely on the high permeability of a single material as the diffusion control wall for some important drug molecule without a consideration of release rate controlling properties over a large number of hours which can inherently defeat the primary object of the acceptable drug dose regimen.
Another method widely used to obtain a necessary and beneficial drug level in a drug recipient over a large number of hours comprises administering a pill or a number of pills at regular time intervals to achieve a dose frequency response relationship. However, this method, in addition to being troublesome and sub jected to forgetfulness, has certain inherent limitations that tend to defeat its purpose. For example, the pills often are rapidly cleared from the drug receptor site such as the gastrointestinal tract or the bladder before they are fully utilized, or an excessive quantity of fluid can be present in the environment of use that unfavorably effects the reaching of the desired drug level. Thus, a graphic illustration of the drugs concentration in the blood during a dosage schedule for this method has the appearance of a series of peaks and valleys; and, often these valleys may fall below the drug concentration needed to achieve the desired beneficial effects.
One other approach used by the art to obtain controlled release over a prolonged period is the sustained or coated slow release technique. In this technique, the dose of drug is divided into a group of pellets about one to two millimeters in diameter, and each group coated with a material resistant to mammalian fluids such as gastric, intestinal, vaginal fluids and the like. To time control the release, each group is coated with an increased number of coats, that is, the first group one coat, the second group two coats and so forth. However, this technique, as with the dose frequency response relationship technique described immediately above, has those certain inherent limitations, such as the high possibility of uneven coatings, an unequal bioerosion in the environment of use and like limitations that diminish the attainment of constant blood levels during a particular therapeutic program. Therefore, these types of coated slow release beads often are not suitable for releasing drug at a controlled rate for a prolonged period of time.
SUMMARY OF THE INVENTION means essentially overcomes the disadvantages associated with the prior art means of administration.
Still another important object of the invention is to provide a drug delivery device for releasing drug at a controlled and continuous rate for a prolonged period of time.
A further object of this invention is to provide a complete dosage regimen for administering a drug for a particular time period, the use of which requires intervention only for initiation of the regimen.
Still a further object of the invention is to provide a drug delivery device suitable for continuously administering drug to a preselected drug receptor site such as the stomach, the gastrointestinal tract, the uterus, vagina or bladder and remain there until the desired dosage regimen is essentially complete before the device is eliminated or removed from the drug receptor site.
Yet still a further object of the invention is to provide an administrable drug delivery device that is selfcontained and self-powered and will remain at the drug receptor site such as in the stomach for an extended time while administering drug from the device through a drug flow control element in response to forces produced in the drug delivery device.
In attaining the objects, features and advantages of the invention, a novel device is provided for the continuous dispensing of a drug which device is selfcontained, operates independently of its surroundings and has its own energy source for producing the desired pressure used as the driving force necessary for dispensing a drug from the drug delivery device. The device is optionally housed in an erodible container with the device consisting essentially of a shell suitably fixed to a hollow support with the shell having an internal space for a drug reservoir. The drug reservoir is comprised of a wall consisting of a flexible, elastomeric material which is substantially impermeable to vapor, drug and fluid, and it surrounds a space for containing a drug. The device has a discharge metering outlet for releasing the drug from the reservoir to the drug receptive environment. In operation, the wall of the reservoir automatically and continuously applies pressure on the drug in the reservoir and upon the opening of the reservoirs discharge outlet with the accompanying release of drug the wall automatically collapses and reduces the volume of the reservoir. These actions progressively exert an internal pressure on the drug to urge it through the discharge outlet. The hollow support is reversible from a collapsed to an inflated position in the environment of use or upon the devices freedom from the container. The support is also returnable to a collapsed position after the device has returned drug for an extended period of time to let the device pass from the environment of use.
Other objects, features and advantages of the invention will be apparent to those skilled in the art from the following detailed description of the invention, taken in conjunction with the drawings and the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, which are not drawn to scale, but rather are set forth to illustrate various embodiments of the invention, the drawings are as follows:
FIG. 1 is a plane, side view of a drug delivery device of the invention housed in a container.
FIG. 2 is an enlarged perspective side view illustrating a drug delivery device in a closed container with a section of the container removed for showing one of the devices of the invention therein.
FIG. 3 is a magnified, central elevational section illustrating the drug delivery device of the invention confined in a container with a section removed for showing details of the device.
FIG. 4 is an exploded side view of a drug delivery device with a memory for generating pressure affixed to a deformable member in the collapsed position.
FIG. 5a is a view diagrammatically illustrating a drug delivery device that has partially discharged some of its drug still fixed to an expanded hollow support.
FIG. 5b is a view of another embodiment of the invention illustrating a drug delivery device similar to the device of FIG. 5a, except that in FIG. 5b one wall acts as the housing and as the wall of the reservoir of the device.
FIG. 6 is a side view diagrammatically illustrating one embodiment of the invention comprising a container housing a drug delivery device descending in the esophagus.
FIG. 7 is a side view diagrammatically depicting a drug delivery device in one environment of use, that is, in the stomach.
In the drawings and specification, like parts in related figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawings, as well as embodiments thereof, are further described elsewhere in the disclosure.
DETAILED DESCRIPTION OF THE DRAWINGS Turning now to the drawings in detail, which drawings are examples of various drug delivery devices of the invention, and which examples are not to be construed as limiting, one generic example of a novel drug delivery device is generally indicated in FIG. 1 by numeral 10. Drug delivery device 10 is illustrated in side perspective view and it is comprised of a container 12 made of a material having bioerodible properties housing a drug delivery device 14 affixed to a hollow member 16 formed of a material that has expansible and deformable characteristics. In FIG. 1 a drug delivery device 14 is depicted in miniature in container 12 to exemplify one optional operative embodiment of the invention. An enlarged detailed illustration of FIG. 1 is set forth in FIG. 2.
Referring to FIG. 2, drug delivery device 10 is seen in a bioerodible container 12, with a section of container 12 removed to illustrate a device 14. Device 14 has a metering means 20 for administering a drug from device 14, not shown in FIG. 2, and it is housed in container 12 and mounted onto a deformable collapsed hollow member 16. Container 12 is advantageously formed of two parts with one part designed to telescope into the other for easily housing device 14 in container 12 to form a container that readily fits into body cavities or is of a swallowable size. The material forming container 12 is bioerodible at the temperature of use, preferably physiological temperatures, and in one embodiment it is made from gelatin or like materials. This feature generally lends itself to quick and easy movement through body passages such as the alimentary canal and also to quick disintegration when it reaches the stomach. On reaching the stomach, the container quickly bioerodes, and device 14 is freed for drug administration. Containers made of other bioerodible materials can also be used for releasing the device in the stomach. Device 14 is intimately joined to an expandable deformable hollow member 16 which member 16 is made of naturally occurring or synthetic flexible, polymeric materials essentially impermeable to gases and fluids that lend themselves to reversible changes in shape and size. Device 14 in one embodiment is suitably heat sealed or joined with adhesives such as with a-cyanoacrylate adhesives, acrylic and methacrylic adhesives, epoxy adhesives, plasticized polyvinyl adhesive, and the like, to member 16. Member 16 in FIG. 2 is optionally a completely sealed envelope, a tube, a flat bag, a balloon or the like, which member is represented as an elongated tube as shown in a collapsed state. Member 16 contains a fluid, a compound, or a mixture of chemicals that readily change at the temperature of use to a gas which inflates member 16 so it can act as a floating support or structure for device 14 in the environment of use, such as the stomach. Member 16 is optionally equipped with an erodible plug 18 that erodes after a predetermined time to release the gas from member 16, thereby deflating it to a collapsed state for eventual passage from the environment of use, such as through the lower gastrointestinal tract. Member 16 can also be made of a material that is bioerodible and does so after a period of time to deflate the member, or it can be made ofa material that is permeable to gas to let it diffuse therethrough to slowly deflate the support over a period of time.
In FIG. 3 a drug delivery device of the invention is set forth in detail to illustrate the mode and manner of the invention. In FIG. 3, a novel drug delivery device is generally indicated by numeral which is comprised of a container 12 preferably of swallowable size and it is made of non-toxic bioerodible material formed into two telescopically associated envelopes having an interior cavity 12a for housing the drug delivery device 14. Container 12 in one embodiment has a size and shape for swallowing and it is adapted for humans, farm animals such as cows, household pets such as dogs, and valuable sport animals for passage to their stomach by normal peristalsis. Device 14 is suitably joined to an expandable deformable hollow bladder 16 by adhesive sealing, integral fabrication, heat union and the like, and it is made of naturally occurring or synthetic flexible polymeric materials that can freely change their size and shape. Member 16 in FIG. 3 is illustrated as a completely sealed envelope which is shown in a collapsed state. The envelope is sealed at its margins and folded in a number of staggered folds 16a. Envelope 16 contains an agent, usually a fluid that readily changes at physiological temperatures to a gas to inflate member 16 to serve as a floating platform for device 14 in the animal environment of use, such as the stomach. Folded member 16 in the device illustrated is equipped with an erodible plug 18 that erodes after a predetermined time to release gas from member 16 causing it to deflate to essentially its original collapsed size.
Device 14 of FIG. 3 is comprised of a shell or wall with an internal space for containing a drug reservoir 17. Shell 15, in this embodiment, is made from a semirigid, or a thick flexible, material such as plastic, metal, alloy, plastic metal laminates and the like and it can optionally be made of materials impermeable to fluids and gases. Drug reservoir 17 is formed of a polymeric elastomeric material as discussed later in this application and it is equipped with a flow control means 19 that acts both as a passageway between reservoir 17 and the exterior of device 14 and as a means for metering drug from reservoir 17 to the exterior of the device 14. Flow control means 19 is suitably made of a porous inert material, a calibrated aperture, a needle valve, or the like to act as a meter for releasing a drug, for example according to the Hagen-Poiseuille equation, at a constant rate over a prolonged period of time. This controlled and constant rate of drug release substantially occurs throughout a decrease in volume of the reservoir as the flow control means meters drug therefrom. Flow control means 19 is originally sealed with an erodible plug that is made of commercially available materials such as cocoa butter, gelatin, mixtures thereof, or like bioerodible materials that readily erode at body temperatures to place flow control means 19 in operative condition.
Drug reservoir 17 serves as a reservoir for containing a drug 21 and it is optionally a thin walled bag, a thin walled tubing suitably sealed at one end, a foldable bag, a balloon, or the like. Reservoir 17 is made from naturally occurring or synthetic elastomeric materials generally possessing stress and strain properties similar to natural rubber, such as silicones, butyl rubber, chlorobutyl rubber, ethylene propylene terpolymers, and the like. Reservoir 17 is usually made from commercially available elastomers and it is filled with drug 21 that is released under a constant tension or pressure exerted on drug 21 by the walls of reservoir 17. This tension moves it through flow meter 20 at a constant rate until reservoir 17 is essentially evacuated. In one embodiment, constant tension is introduced into the reservoir for application on the drug contents for a long period of time by prestressing and annealing the reservoir. These processes are accomplished by preinflating the reservoir with a gas, for example nitrogen, or a fluid, for example water, to a size larger than required when filled with drug, and then soaking the reservoir in boiling water for a period of time, from 1 to 39 hours, usually to 3 hours, while inflated to produce desired degree of constant tension. Next, the reservoir is emptied and filled with the desired drug. Other processes that introduce reproducibility into the reservoir to give the same pressure over time while eliminating short and long term creep to give a normal and constant elastomeric tension can optionally be used for the purpose of this invention.
Device 14 of FIG. 3 is designed to release drug in the stomach, and in operation it is administered through the mouth for passage to the stomach. After it reaches the stomach, it is freed from container 12, deformable member 16 inflates to place the device in drug release position in the stomach. Drug 21 is discharged from device 14 by the constant pressure of reservoir 17 against drug 21 to move it through the discharge outlet 20 at a constant and controlled rate into the external environment of use. The flow control element 20 also could be preprogrammed to yield a wide variety of drug delivery rate patterns. In addition, to be self regulatory, it could also be controlled by external means using telemetry and an electronically activated element.
FIG. 4 graphically represents another embodiment of the invention for self administering a drug to the environment of use, such as the stomach with subsequent passage into the intestinal tract. In FIG. 4 a drug delivery device 10 is comprised of a container 12 having an internal space 12a for a drug delivery device 14. Device 14 consists essentially of a housing 15 having an internal space 15b and optionally vented at 15a. Housing 15 is suitably integrally formed or sealed to balloon 16 that contains a chemical for producing a gas or a gas in liquified form. Housing 15 has an erosion gas release plug 18 at one of its ends. A reservoir 17 is confined in housing 15 for containing a drug 21. Reservoir 17 has a drug metering outlet 20 extending through housing 15 for conveying drug from reservoir 17 to the exterior of the device, such as the stomach. Reservoir 17 has a memory 22 capable of automatically collapsing reservoir 17 to exert an internal pressure on the contents of reservoir 17 to easily advance the contents through the reservoir and out of the discharge meeting outlet 20.
Memory 22 of reservoir 17 is capable of rolling or coiling upon itself as the contents of reservoir 17 are metered therefrom. Memory 22 is conveniently imparted to reservoir 17 by winding reservoir 17 while emptying into a jelly roll or around a mandrel and treating it by standard thermal or irradiative methods to permanently impart the memory to the walls of reservoir 17. Generally, thermoplastic materials having a high tensile moduli, that is, a high ratio of stress to strain in the elastic range of the thermoplastic such as poly- (ethylene), poly(propylene), poly(styrene), poly(butylene), poly(vinylchlorides), poly(amides), poly(urethanes), poly(styrene-acrylonitriles), copolymers thereof and the like can be used for the purpose of the invention.
The standard thermal process can be performed by heating the rolled reservoir in a bath of water, oil, or the like to a temperature below the melting point of the material, for example 175 to 200 C, for about 5 minutes to 5 hours or longer. It will be obvious to those in the art that the specific temperature used is dependent on the particular material and these temperatures are known to the art in standard handbooks. the irradiative method consists of cross linking the material by irradiation with a Van De Graf generator, cobalt 60 radiation and the like. Next, the reservoir is unwound by filling it with drug and stoppering it with an erodible plug. In the stomach the plug erodes and drug is administered from the reservoir as its walls automatically collapse by progressively returning the reservoir to the preimparted jelly roll configuration.
In FIG. 5a is seen a drug delivery device 14 consisting of a housing 15 having an internal space for a drug reservoir 17. Reservoir 17 has a drug metering outlet 20 at one of its ends. Housing 15 in this embodiment is attached to an inflated balloon 16 equipped with an eordible plug 18. Reservoir 17 is seen in drug discharge position with part of the drug discharged, that is, the reservoir has continuously metered some of its contents into the stomach. Member 16 initially contained a gas stored in solid or liquified form for producing a gas with a vapor pressure usually in excess of one atmosphere at the temperature of use, that is, the temperature of the stomach to cause it to inflate, as shown, to a predetermined size and shape. The dimensions of member 16 in the inflated state will, of course, be difierent for different environments of use or drug receptor sites, but it will be large enough to retain the device in the environment. For example, in the stomach it will be slightly larger than the diameter of the pyloric canal which is about 1 cm to 4 cm, usually 2 cm in humans, until completion of the prescribed therapeutic regimen. At the end of the therapeutic regimen, plug 18 erodes to vent balloon 16 causing it to collapse to a size smaller than the pyloric canal. Member 16 can alternatively be made of a material permeable to the gas to let the gas slowly diffuse therethrough causing it to collapse. Device 14 then passes through the lower gastrointestinal tract and out of the body.
FIG. 5b illustrates a drug delivery device 14 similar to the drug delivery device 14 illustrated in FIG. 5a. In FIG. 5b, device 14 is designed and manufactured without housing 15 and it is comprised of a wall 17 surrounding a reservoir for carrying drug. The reservoir is defined by the internal surface of wall 17. In this device of the invention, a single wall 17 simultaneously functions as the housing and the reservoir while achieving the desired programmed rate of drug release. Reservoir 17 is equipped with a drug metering outlet 20 that communicates with the interior of reservoir 17 and the exterior of device 14 for discharging drug therefrom. Reservoir 17 is either integrally formed or suitably heat sealed or adhesively bound to support 16. In FIG. 5b, support 16 is optionally equipped with a bioerodible plug, of the general type described above. The material forming 17 or the reservoir wall, in the present device, is a naturally occurring or synthetic material possessing elastomeric properties and it has a thickness that gives both dimension and support to the reservoir. For example, the wall can be about 5 to 25 mils thick, usually l5 to 20 mils, and the reservoir can have a capacity of about 5 to 25 milliliters. This device, while having a unitary wall is simultaneously capable of automatically collapsing to exert an internal pressure on the contents of the reservoir to easily urge the contents from the reservoir through the discharge metering outlet.
FIG. 6 and FIG. 7 diagrammatically illustrate the device of the invention in actual use. In FIG. 6 there is seen the outline ofa human 24 with a device 14 moving through the esophagus 27 and on into the stomach 25. In FIG. 7 the device 14 is seen in stomach 25 of human 24 administering a drug at controlled rate over a prolonged period of time.
DETAILS OF THE INVENTION Drug delivery device 14 of this invention can be made into assorted sizes and shapes with these dimensions adapted for administering a drug to a particular biological environment or animal and to the ease of manufacture. The shape of the device is usually tubular but other shapes such as cylindrical, oblong, oblate, prolate, spherical and the like can be made. The device is usually fabricated for administration into a body cavity or body opening, such as for oral administration into the stomach. In use, the size of the deformable hollow member 16 of the device in the inflated state will be slightly larger than the diameter of the cavity or opening, for example, the pyloric canal to let the device stay in the stomach during thee period of drug release. The dimensions of various cavities and openings are known to the art and recorded in medical literature, and for the purpose of the invention the following example will serve to illustrate the spirit of the invention. For example, the size needed to keep an inflated member in the stomach of a human, that is, to prevent premature passage through the pyloric canal will be for an inflated member about 2 to 6 cm in diameter to about 7 to 12 cm in length. Usually, for adults about 3 cm in diameter to about 10 cm in length. Of course, other sizes about 2 cm by 5 cm, 3.14 cm by 5 cm, 4 cm by 4 cm and the like are also within the mode and the manner of the invention.
Member 16 is generally made of naturally occurring or synthetic material that lends itself to reversible volume change in shape and size. In one embodiment, when an erodible plug is used to deflate an inflated member, the material is an elastomeric polymer that is essentially impermeable to gases and fluids. In another embodiment, the material can be permeable to gases to let a gas slowly diffuse through the material to deflate the member. The material is usually 0.2 to 100 mils thick and it can be natural rubber, silicone, poly(urethane), poly(acrylonitrile), poly(ethylene), copolymers of vinylidene chloride and vinyl chloride, or acrylonitrile, poly(ethylene terephthalite), acrylic elastomers, laminates such as poly(ethylene)-poly(vinylidene chloride), nylon-poly(vinylidene chloride) acrylic elastomers laminated with metal foils, and the like.
Shell or housing of the device, when optionally used herein, can be flexible or rigid or modifications thereof, and it can be made from a wide variety of materials such as aluminum, teflon, poly(ethylene), laminates of poly(propylene), poly(methylmethacrylate), poly( formaldehyde), nylon, laminates of poly(styrene), metal foils such as aluminum foil, tin foils, poly(vinylidene chloride), coated tin foil and the like. In an economical aspect, the devices of this invention are made of materials that lend themselves to single use devices and as such they are made from relatively inexpensive materials. The thickness of the shell can vary over a wide range, usually from 0.5 to mils or the like, generally in the range of 1.0 mils to 10.0 mils.
Materials suitable for forming reservoir 17 positioned in shell 15, or for forming reservoir 17 when it is both the housing and the reservoir, that can be used to contain drug 21 and also used to urge drug 21 from device 14 are elastomeric, flexible materials that are essentially impermeable to vapors, fluids and the like. The reservoir has a size and shape corresponding to the volume of the drug originally stored therein, and that can freely fit in a drug receptor site. Optionally it has a size that can be easily contained in housing 15. Reservoir 19 is manufactured to hold a maximum amount of drug for a prolonged drug delivery time and to permit the use of high drug delivery rates. This is preferably achieved by maximizingthe drug volume and minimizing all other design features. Reservoir 17 is typically made from a naturally occurring or a synthetic material, and it is about 0.2 mils to 100 mils thick, or more, usually 0.4 to 20 mils and the like. The reservoir can be made of a single material, a combination of materials in laminated forms, such as elastomeric materials bonded on foils and the like. Illustrative materials include silicones, poly(urethanes), poly(vinylidene chloride), poly(vinylidene fluoride), acrylic elastomers, ethylene propylene terpolymers, laminates such s poly(vinylidene)-poly(ethylene), poly(vinyl chloride)-butyl rubber, poly(vinylidene chloride-cispolyisoprene), and the like.
Exemplary materials suitable for support or for inflating balloon 16 or the like are inorganic and organic compounds whose vapor is an equilibrium with its liquid phase to exert a constant pressure at physiologic temperature regardless of liquid volume. Representative of compounds are those that are liquids at ambient temperatures, usually 20 to C or less, and have a boiling point, BP, above this temperature to exert a vapor pressure greater than one atmosphere at physiological temperatures for inflating the balloon. Exemplary materials useful for inflating deformable hollow member 16 are halogenated hydrocarbons, fluorochlorinated lower saturated aliphatic hydrocarbons, halogenated unsaturated hydrocarbons, halogenated lower alkanes of 1 to 4 carbon atoms and the like, such as diethyl ether BP 34.6 C, methyl formate BP 31.5 C, tetramethyl silane BP 26.5 C, perfluoropentane isomers BP 31.0 C, n-pentane 36.0 C, iso-pentane 27.9 C, diethenyl ether 28 C, and the like. Usually, the amount of gas stored in the liquified phase in the deformable hollow member 16 will be about 0.2 cc to 5.0 cc or higher, and the volume of the vapor phase will be from to percent of the inflated member.
Support member 16 can also be inflated by having an effervescent couple contained therein that generates gas by the reaction of contained reagents in the presence of aqueous type fluids that diffuse through member 16 wall from the environment of use. The materials of the effervescent couple can be any of the known pharmaceutically acceptable materials used to generate carbon dioxide. For example, the effervescent couple can comprise either citric acid or a mixture of citric acid and tartaric acid and sodium bicarbonate or potassium bicarbonate to yield effervescence.
Materials suitable for use as bioerodible plug 18 are those materials that bioerode in the environment of use, such as the stomach, at a predetermined given time. The materials are those that erode by known processes, such as chemical degradation, acidic hydrolysis, enzymatic action, acidation, reduction, dissolution, slow solubilization, and the like. The bioerosion rate for suitable materials can be determined by standard assay procedures consisting of placing a section of material in natural or artificial gastric juices at normal body temperatures and observing the rate of erosion over a period of time. By prolonged period of time is meant, for the present purposes, 8 hours to 30 days, usually 1 day to 8 days.
Representative materials for use of plug 18 comprise hydrophilic polymers of uncross-linked hydroxylalkyl acrylates and methacrylates, hydrolytically biodegradable poly( anhydride)polymers as described in U.S. Pats. Nos. 2,073,700; 2,668,162; and 2,676,945; and in Introduction to Polymer Chemistry, Stille, J. K., Chapter 6, 1962, published by Wiley Publishing Co., bioerodible polyesters as described in Industrial and Engineering Chemistry, Vol. 36, No. 3, pages 223 to 228, 1964; Macrmol. Chem., Vol.75, pages 211 to 214, 1964; US. Pats. Nos. 2,703,316; 2,668,162; 3,297,033; and 2,676,945; cross-linked gelatin prepared with a cross-linking agent reactive with the hydroxyl carboxyl or amino functional groups of the gelatin molecule as described in J. Polymer Science, Part A-l, Vol. 5, No. 1, 1967; J. Polymer Science, Vol. 54, pages 321-335, 1961; Advances in Protein Chemistry, Vol. VI, Cross Linkage in Protein Chemistry, 1961, published by Academic Press, Inc.
Other materials include proteins and hydrocollides of animal and plant origins such as modified collagen, elastin, keratin, fibrin, karaya, algin, pectin, carrageenin, chitin, locust bean gum and the like. Also, synthetic polymers such as poly(ethylene oxide), poly(acrylic acid) copolymers of acrylamide and methacrylamide up to 40 percent by weight of N-methylene bisacrylamide or N,N-dimethy1ol urea, and the like.
The active drugs that can be administered with the delivery device of the invention, in accordance with their known use and dose, and combinations of these drugs, as described in The Pharmacological Basis of Therapeutics, 14th Edition, Goodman, L. S., and Gilman, A., 1970, The Macmillan Co.; Physicians Desk Reference, 25th Edition, 1971, Medical Economics, Inc; and Remingtons Pharmaceutical Sciences, 14th Edition, 1970, Mack Publishing Co, include without limitation: for example, drugs acting on the central nervous system-such as hypnotics and sedatives such as pentobarbital sodium, phenobarbital, secobarbital, thiopental, etc.; heterocyclic hypnotics such as dioxopiperidines, and glutarimides; hypnotics and sedatives such as amides and ureas exemplified by diethylisovaleramide and a-bromoisovaleryl urea and the like; hypnotics and sedative alcohols such as carbomal, naphthoxyethanol, methylparaphenol and the like; and hypnotic and sedative urethans, disulfanes and the like; psychic energizers such as isocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine, pargylene and the like; tranquilizers such as chloropromazine, promazine, fluphenazine reserpine, deserpidine, meprobamate, benzodiazepines such as chlordiazepoxide, and the like; anticonvulsants such as primidone, diphenyhydantoin, ethotoin, pehneturide, ethosuximide and the like; muscle relaxants and anti-parkinson agents such as mephenesin, methocarbomal, trihexylphenidyl, hiperiden, levo-dopa, also known as L-dopa and L133-4-dihydroxyphenylalanine, and the like; analgesics such as morphine, codeine, meperidine, nalorphine and the like; antipyretics and anti-inflammatory agents such as aspirin, salicylamide, sodium salicylamide and the like; local anesthetics such as procaine, lidocaine, naepaine, piperocaine, tetracaine, dibucaine and the like; antispasmodics and antiulcer agents such as atropine, scopolamine, methscopolamine, oxyphenonium, papaverine, prostaglandins such as PGE,, PGE PGE PGE PGA and the like; antimicrobials such as penicillin, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamides and the like; anti-malarials such as 4- aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal agents such as prednisolone, cortisone, cortisol and triaminolone; androgenic steroids, for example, methyltestosterone, fluoximesterone and the like; estrogenic steroids, for example, l7B-estradoil and ethinyl estradoil; progestational steroids, for example l7oz-hydroxyprogesterone acetate, l9-norprogesterone, norethindrone and the like; sympathomimetic drugs such as epinephrine, amphetamine, ephedrine, norepinephrine and the like; cardiovascular drugs, for example, procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate, mannitol nitrate and the like; diuretics, for example, chlorothiazide, flumethiazide and the like; antiparasitic agents such as bephenium hydroxynaphthoate and dichloropehn, dapsone and the like; neoplastic agents such as mechlorethamine, uracil mustard, S-fluorouracil, -thioquanine procarbazine and the like; hypoglycemic drugs such as sulfonylureas such as tolbutamide, acetohexamide, tolazamide, and chlorpropamide, the biguanides and the like; nutritional agents such as vitamins, essential amino acids, essential fats and the like; and other physiologically or pharmacologically active agents. Also, the
drugs can be present as the pharmacologically acceptable derivatives, such as ethers, esters, amides, acetals, etc. that lend themselves to passage into the circulatory system. These derivatives can be prepared by art known techniques and then used in the practice of the invention. Of course, the drug derivative should be such as to convert to the active drug within the body through the action of body enzymes assisted transformations, pH specific organ activities, and the like.
The above and other beneficial agents can be used per se or they are conveniently formulated into a pharmaceutical form by mixing with a non-toxic carrier. Carriers acceptable for the purpose of this invention are the art known carriers that do not adversely affect the active agent, the host, or the material comprising the delivery device. For example, suitable pharmaceutical carriers include sterile water; saline, dextrose, dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about to about moles of ethylene oxide per mole of caster oil; liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil; peanut oil; sesame oil and the like; with emulsifiers such as monoor di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrr0lidone); and the like, alone or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying, viscosity modifying agents, and the like.
The amount of active agent incorporated in the device varies depending on the particular agent, the desired effect, and the time span over which it is desired to have the agent released. Since devices of different sizes and shapes are intended to provide complete dosage regimen, there is no critical upper limit on the amount of drug incorporated in the device. The lower limit will depend on the activity of the drug and the time span of its release from the device. ln general, therefore,'the amount of the drug incorporated in the device is non-limited and it is an amount equal to, or larger than, the amount of drug that on release from the device is effective for bringing about the drugs physiological or pharmacological local or systemic effects. For example, the amount for larger farm animals will vary with the size of the device, while the amount of drug present in the delivery device when the device is used for adult humans for a period of time of 4 to 6 days to achieve local or systemic effect is for various drugs, such as propantheline 120 to 300 mg in the device; for glutamic acid hydrochloride an amount in the device of 100 to 500 mg; for pargyline hydrochloride to 100 mg; for erythrityl tetranitrate 50 to 100 mg; mannitol hexanitrate to mg; ephedrine sulfate 400 to 600 mg; nylidrin hydrochloride 12 to 48 mg; bethanechol chloride to 480 mg; phentolamine 100 to 400 mg; guanethidene 100 to 1,000 mg; methyl dopa 3 to 12 gms; atropine 100 mcg to 1,250 mcg; and the like.
The discharge outlet 20 suitable for the purpose of the invention includes flow resistive means for continuous administration of the drug in the body. The flow resistive elements are essentially self actuated, that is, no external intervention is needed to initiate the flow of drug. Numerous flow resistive means are commercially available, such as porous plugs, microporous membranes, capillaries, etched polymers, perforated polymers and the like. The flow resistive means can be made from a variety of materials such as poly(ethylene), nylon, teflon, epoxies, poly(methyl methacrylate), metals, alloys, ceramics, sintered ceramics, stainless steel capillaries of 0.1 to 1 cm in length with a diameter of 0.1 to microns, a stainless steel porous desk having a thickness of 0.1 cm, a diameter of 0.1 cm, a pore size of 0.1 micron, a porosity of 20 percent and a tortuosity of 0.5, and the like. The rate of flow through the resistive means is governed by the Hagen- Poisseuille equation wherein Q =17 D AP/128uL, where Q equals flow in ml/sec, D equals diameter in cm, ,u equals viscosity in poise, AP equals pressure in dyneslcm and L equals length of the means. The use of this equation allows the flow rate to be easily predicted and readily adjusted by changing the length and diameter parameters of the flow resistive means. Also, by altering the viscosity of the carrier the flow rate can easily be varried without altering the specifications of the flow resistive means. The viscosity of any carrier can easily be ascertained by employing standard viscometers, such as the Wells-Brookfield viscometer. The device of this invention can effectively meter from 0.001 ml/hour to 0.5 ml/hour, smaller or larger for various times such as 4 hours, 6 hours, a day, or longer. The viscosity of the carrier medium used to convey the drug can vary over a range of 1 to 10,000 centipoise at physiological temperature for administering a drug to a host.
A typical example of a drug delivery device prepared according to the spirit of the invention is comprised of a spherical collapsable balloon approximately 4 cm in diameter and it is fabricated from commercially available polyethylene terephthalate by a vacuum forming and heat sealing process. Before the final heat seal is made, 0.25 cm of isopentane is metered into the balloon. Passing through the final heat seal is a water soluble polyurethane erodible seal. A self powered delivery device consisting of a peroxide cured natural latex elastic member with an uninflated inner diameter of 0.8 mm and outer diameter of 1.6 mm and uninflated length of 3 mm is secured to the collapsed polyethylene terephthalate balloon by means of a cyanoacrylate adhesive. The elastic member is closed at one end and is equipped wth a flow control means consisting of a porous polyethylene plug 0.9 mm in diameter and 1.0 mm long which has a porosity of 20 percent, an average pore size of 1 micron, and a tortuosity factor of about 2; for example, the effective length is about twice the actual length. The elastomeric self powered delivery device is filled with 1 cm of drug formulation containing 16 mg of the diuretic, bendroflumethiazide in 95 percent ethanol to which carboxymethyl cellulose has been added to give a viscosity of 10,000 centipoise at 37 C. The inflated length of the elastomeric device is 12 mm. The porous flow control element is sealed with the water soluble polymer, sodium polystyrene sulfonate. The collapsed balloon is folded around the elastomeric delivery device and the whole assembly is placed in a gelatin capsule. On ingestion the capsule dissolves and the balloon inflates by virtue of vaporization of the isopentane. The sodium polystyrene sulfonate seal dissolves and the elastomeric device delivers 2 mg of hendroflumethiazide per day for seven days at which time dissolution of the water solube polyurethane seal is complete which allows for collapse of the polyethylene terephthalate balloon. The whole assembly is then eliminated from the gastrointestinal tract, that is, the environment of use.
Among the advantages of the device of the invention are the ease of construction by standard manufacturing techniques devices into units of different sizes, especially of a miniaturized size, also of shapes andforms that are suitable for delivering a drug internally to an animal or human. Another important advantage of the claimed delivery device is its ability to dispense at a controlled rate a beneficial agent having a wide variety of chemical and physical properties and over a wide range of release rates. Still another important advantage of the invention resides in the devices ability to effectively control the rate of release of the drug from the device throughout the major portion of drug administration in a substantial zero order release rate. A further advantage of the device resides in the use of low cost substantially vapor and fluid impermeable materials for the power communicating element resulting in a unit suitable for disposal, after comparatively short periods of use, for example, a day or week, without undue economic hardship on the user, yet providing a continuous and controlled administration of drug without any external energy source. And, although the invention has been described in detail, it will be understood that certain changes and modifications can be made without departing from the spirit and scope of the invention.
1. A drug delivery device for the controlled and continuous administration of a drug to an environment of use to produce a therapeutic effect comprising: a hollow expandable closed member having therein selfcontained means for expanding the member and self contained means for contracting the member after a given period of time of expansion, the member being affixed to drug delivering means for delivering a drug at a controlled rate over the given period of time, the delivering means comprising a drug, elastomeric container means defining a single compartment for enclosing the drug and applying an elastomeric pressure to the drug and discharge means communicating with the drug for discharging the drug at a controlled rate from the container by the elastomeric pressure, the delivering means thereby causing a therapeutically effective amount of drug to be released through the discharge means for the given period of time while the member is in an expanded state, thereafter the means for contracting causing the member to contract.
2. A drug delivery device for the controlled and continuous administration of drug according to claim 1 wherein the self-contained means for expanding the member comprises a liquid that vaporizes at physiological temperature to produce a gas which expands the hollow expandable closed member from a collapsed position to an expanded position.
3. A drug delivery device for the controlled and continuous administration of a drug according to claim 2 wherein the self-contained means for contracting the member comprises means for venting the interior of the member to the environment of use.
4. A drug delivery device for the controlled and continuous administration of drug according to claim 3 wherein the means for venting the interior of the mem- 16 her to the environment of use comprises a bioerodible a material that lets the gas slowly diffuse through the plug. material to the environment of use.
5. A drug delivery device for the controlled and con- 6. A drug delivery device for the controlled and continuous administration of drug according to claim 3 tinuous administration of drug according to claim 1 adwherein the means for venting comprises the hollow ex- 5 ditionally comprising'an outer bioerodible container. pandable closed member, the member being formed of
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US1957564 *||Nov 23, 1932||May 8, 1934||West Aubra T||Expanding capsule body|
|US3485235 *||Dec 4, 1967||Dec 23, 1969||Felson Ronald||Capsule for the study and treatment of the digestive tract|
|US3604417 *||Mar 31, 1970||Sep 14, 1971||American Cyanamid Co||Osmotic fluid reservoir for osmotically activated long-term continuous injector device|
|US3701351 *||Jun 28, 1971||Oct 31, 1972||Harvey Douglas G||Inflatable intravaginal applicator for animals|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3901232 *||Oct 26, 1973||Aug 26, 1975||Alza Corp||Integrated device for administering beneficial drug at programmed rate|
|US4055178 *||Mar 10, 1976||Oct 25, 1977||Harrigan Roy Major||Drug delivery device for preventing contact of undissolved drug with the stomach lining|
|US4311050 *||Oct 8, 1980||Jan 19, 1982||Bessman Samuel P||Reservoir for medicaments|
|US4312347 *||Feb 25, 1980||Jan 26, 1982||Iowa State University Research Foundation, Inc.||Positive pressure drug releasing device|
|US4564363 *||Jul 13, 1983||Jan 14, 1986||Smithkline Beckman Corporation||Delayed action assembly|
|US4718430 *||Sep 20, 1985||Jan 12, 1988||Walter Holzer||Procedure and device for the administering of insulin or similar long-term medicaments|
|US4861268 *||Jun 13, 1988||Aug 29, 1989||Transpharm Group||Tooth-anchored beneficial agent delivery device|
|US5187011 *||Jan 9, 1992||Feb 16, 1993||Exxon Research And Engineering Company||Composition comprising encapsulated substrate with thermoplastic polymer overcoating|
|US5192615 *||Jan 3, 1992||Mar 9, 1993||Exxon Research & Engineering Company||Composition comprising encapsulated substrate and thermoplastic polymer overcoating|
|US5194003 *||Jan 3, 1992||Mar 16, 1993||Transpharm Group, Inc.||Removable device for delivering beneficial agents orally|
|US5198229 *||Jun 5, 1991||Mar 30, 1993||Alza Corporation||Self-retaining gastrointestinal delivery device|
|US5204183 *||Jan 3, 1992||Apr 20, 1993||Exxon Research And Engineering Company||Composition comprising polymer encapsulant for sealing layer encapsulated substrate|
|US6171298||Mar 11, 1998||Jan 9, 2001||Situs Corporation||Intravesical infuser|
|US6179118 *||Apr 12, 1999||Jan 30, 2001||Glaxo Wellcome Inc.||Method and package for storing a pressurized container containing a drug|
|US6183461||Sep 14, 1999||Feb 6, 2001||Situs Corporation||Method for delivering a medication|
|US6283943 *||Feb 19, 1999||Sep 4, 2001||Minimed Inc.||Negative pressure pump|
|US6315112||Jun 22, 2000||Nov 13, 2001||Smithkline Beecham Corporation||Method and package for storing a pressurized container containing a drug|
|US6352152||Jun 20, 2000||Mar 5, 2002||Smithkline Beecham Corporation||Method and package for storing a pressurized container containing a drug|
|US6375978||Dec 17, 1998||Apr 23, 2002||Alza Corporation||Rate controlling membranes for controlled drug delivery devices|
|US6390291||May 15, 2000||May 21, 2002||Smithkline Beecham Corporation||Method and package for storing a pressurized container containing a drug|
|US6679374||Feb 7, 2002||Jan 20, 2004||Smith Kline Beecham Corporation||Package for storing a pressurized container containing a drug|
|US7396574 *||May 28, 2003||Jul 8, 2008||Robert C. Bogert||Self-inflating cushion and footwear including same|
|US7828150||Jun 5, 2001||Nov 9, 2010||Glaxosmithkline Llc||Container for medicament powder|
|US7879417||Feb 1, 2011||Robert C. Bogert||Self-inflating cushion and footwear including same|
|US8124166||Feb 23, 2010||Feb 28, 2012||Medtronic Vascular, Inc.||Method for loading nanoporous layers with therapeutic agent|
|US8162969||Oct 15, 2009||Apr 24, 2012||Obalon Therapeutics, Inc.||Intragastric device|
|US8292911||Oct 23, 2012||Obalon Therapeutics, Inc.||Intragastric device|
|US8449602 *||May 28, 2013||Medtronic Vascular, Inc.||Methods for using a stent having nanoporous layers|
|US8562589||Dec 23, 2010||Oct 22, 2013||Rani Therapeutics, Llc||Swallowable drug delivery device and method of delivery|
|US8647358||Jan 21, 2011||Feb 11, 2014||Obalon Therapeutics Inc.||Intragastric device|
|US8682440||Aug 3, 2010||Mar 25, 2014||Incube Labs, Llc||Swallowable capsule and method for stimulating incretin production within the intestinal tract|
|US8721620||Dec 23, 2010||May 13, 2014||Rani Therapeutics, Llc||Swallowable drug delivery device and methods of drug delivery|
|US8734429||Mar 15, 2013||May 27, 2014||Rani Therapeutics, Llc||Device, system and methods for the oral delivery of therapeutic compounds|
|US8740927||Jan 21, 2011||Jun 3, 2014||Obalon Therapeutics Inc.||Intragastric device|
|US8759284||Dec 23, 2010||Jun 24, 2014||Rani Therapeutics, Llc||Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8764733||Jun 29, 2012||Jul 1, 2014||Rani Therapeutics, Llc||Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8781591||Feb 12, 2014||Jul 15, 2014||Incube Labs, Llc||Swallowable capsule and method for stimulating incretin production within the intestinal tract|
|US8809269||Jun 29, 2012||Aug 19, 2014||Rani Therapeutics, Llc||Therapeutic agent preparations comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8809271||Jun 29, 2012||Aug 19, 2014||Rani Therapeutics, Llc||Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8845674||Apr 23, 2012||Sep 30, 2014||Obalon Therapeutics, Inc.||Intragastric device|
|US8846040||Jun 29, 2012||Sep 30, 2014||Rani Therapeutics, Llc||Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8852151||Aug 19, 2013||Oct 7, 2014||Rani Therapeutics, Llc||Swallowable drug delivery device and method of delivery|
|US8958879||May 9, 2014||Feb 17, 2015||Incube Labs, Llc||Swallowable capsule and method for stimulating incretin production within the intestinal tract|
|US8969293||Jun 29, 2012||Mar 3, 2015||Rani Therapeutics, Llc||Therapeutic agent preparations comprising exenatide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8980822||Jun 29, 2012||Mar 17, 2015||Rani Therapeutics, Llc||Therapeutic agent preparations comprising pramlintide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US8992561||May 25, 2012||Mar 31, 2015||Obalon Therapeutics, Inc.||Intragastric device|
|US9011477||May 5, 2014||Apr 21, 2015||Obalon Therapeutics, Inc.||Intragastric device|
|US9072583||Oct 15, 2009||Jul 7, 2015||Obalon Therapeutics, Inc.||Intragastric volume-occupying device and method for fabricating same|
|US9149617||Jun 25, 2012||Oct 6, 2015||Rani Therapeutics, Llc||Device, system and methods for the oral delivery of therapeutic compounds|
|US9205127||May 20, 2014||Dec 8, 2015||Rani Therapeutics, Llc||Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US9259386||Jun 29, 2012||Feb 16, 2016||Rani Therapeutics, Llc||Therapeutic preparation comprising somatostatin or somatostatin analogoue for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US9283179||Jun 29, 2012||Mar 15, 2016||Rani Therapeutics, Llc||GnRH preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device|
|US9284367||Jun 29, 2012||Mar 15, 2016||Rani Therapeutics, Llc|
|US20030140923 *||Jun 5, 2001||Jul 31, 2003||Taylor Anthony James||Container for medicament powder|
|US20030209453 *||Jun 22, 2001||Nov 13, 2003||Herman Craig Steven||Method and package for storing a pressurized container containing a drug|
|US20040089561 *||Jun 22, 2001||May 13, 2004||Herman Craig Steven||Method and package for storing a pressurized container containing a drug|
|US20040230183 *||Feb 18, 2004||Nov 18, 2004||Wisam Breegi||Drug delivery device and syringe for filling the same|
|US20040237346 *||May 28, 2003||Dec 2, 2004||Rudy Marion Franklin||Self-inflating cushion and footwear including same|
|US20060032763 *||Oct 13, 2005||Feb 16, 2006||Herman Craig S||Method and package for storing a pressurized container containing a drug|
|US20060058829 *||Aug 15, 2005||Mar 16, 2006||Sampson Douglas C||Intragastric volume-occupying device|
|US20060121080 *||Aug 10, 2005||Jun 8, 2006||Lye Whye K||Medical devices having nanoporous layers and methods for making the same|
|US20060193888 *||Feb 10, 2006||Aug 31, 2006||Whye-Kei Lye||Methods for using medical devices having nanoporous layers|
|US20060249419 *||Jun 29, 2006||Nov 9, 2006||Taylor Anthony J||Container for Medicament Powder|
|US20090013557 *||Dec 19, 2007||Jan 15, 2009||Marion Franklin Rudy||Self-inflating cushion and footwear including same|
|US20090234331 *||Nov 22, 2005||Sep 17, 2009||Koninklijke Philips Electronics, N.V.||Electronically controlled pill and system having at least one sensor for delivering at least one medicament|
|US20100100117 *||Oct 15, 2009||Apr 22, 2010||Obalon Therapeutics, Inc.||Intragastric device|
|US20100260922 *||Oct 14, 2010||Medtronic Vascular, Inc.||Method for loading nanoporous layers with therapeutic agent|
|US20110160129 *||Jun 30, 2011||Incube Labs, Llc||Therapeutic Agent Preparations for Delivery Into a Lumen of the Intestinal Tract Using a Swallowable Drug Delivery Device|
|US20110160699 *||Jun 30, 2011||Incube Labs, Llc||Swallowable Drug Delivery Device and Methods of Drug Delivery|
|US20110208270 *||Aug 3, 2010||Aug 25, 2011||Incube Labs, Llc||Swallowable Capsule and Method for Stimulating Incretin Production Within the Intestinal Tract|
|US20120089121 *||Apr 12, 2012||Taris Biomedical, Inc.||Implantable Drug Delivery Device with Bladder Retention Feature|
|CN100388916C||Dec 3, 1998||May 21, 2008||阿尔扎有限公司||Rate controlling membranes for controlled drug delivery device|
|CN101524199B||May 27, 2004||Jun 15, 2011||马里恩·富兰克林·鲁迪||Self-inflating cushion and footwear including same|
|EP0075062A1 *||Sep 18, 1981||Mar 30, 1983||Anton Dr. Sadjak||Implantable device for the constant delivery of a substance|
|EP0334516A2 *||Mar 10, 1989||Sep 27, 1989||Pfizer Inc.||Method for enhancing the unrolling of a rolled matrix device|
|WO1999032095A1 *||Dec 3, 1998||Jul 1, 1999||Alza Corporation||Rate controlling membranes for controlled drug delivery devices|
|WO2010022716A1 *||Aug 28, 2009||Mar 4, 2010||Hochschule Offenburg||Electronic pill for dispensing a substance, in particular a drug, in a human or animal body in a controllable manner|
|WO2011101833A2 *||Feb 22, 2011||Aug 25, 2011||Microsert Ltd.||Slow release liquid drug delivery device|
|WO2011101833A3 *||Feb 22, 2011||Nov 24, 2011||Microsert Ltd.||Slow release liquid drug delivery device|
|U.S. Classification||604/890.1, 424/453, 206/522, 123/222|
|International Classification||A61K9/00, A61M31/00|
|Cooperative Classification||A61M31/002, A61K9/0004|
|European Classification||A61K9/00L4, A61M31/00D|