Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-19
2001-10-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000
Reexamination Certificate
active
06306420
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the delivery or administration of solid compositions that include an active ingredient such as a drug.
The effective use of drug compositions, either for an immediate bolus delivery or for a continuous, controlled delivery, often requires parenteral administration in order to achieve the desired effect. Traditionally, parenteral administration is achieved by a liquid injection using a syringe, a perfusion, or a pump. However, these methods cause both inconvenience and discomfort for patients, especially those requiring daily treatments for months or even a lifetime, e.g., diabetics who require one or two injections of insulin daily for the rest of their lives.
Furthermore, the parenteral route usually requires an extemporaneous preparation of a liquid drug formulation, which can lead to instability of the drug and waste of the drug in the formulation. In addition, liquid drug formulations must sometimes be stored at 4° C., which makes it difficult for patients to transport such liquid drug formulations without specialized carrying devices.
For bolus injections of liquid drug formulations, pen injectors are utilized to control the dosage and to avoid certain problems of single-dose syringes. See, for example, Harris et al., U.S. Pat. No. 5,226,895. In such devices, patients are able to store several days worth of a liquid drug formulation within replaceable cartridges, and the quantity of injection is generally modulated by a screw plunger. However, these devices often require cold storage between uses, and the solutions or suspensions in the cartridges typically lack long term stability.
Various microcapsules, microparticles, and larger sustained-release implants have been used to deliver pharmaceuticals to patients over an extended period of time. For example, polyesters such as poly-DL-lactic acid, polyglycolic acid, polylactide, and other copolymers, have been used to release biologically active molecules such as progesterone and luteinizing hormone-releasing hormone (LH-RH) analogs, e.g., as described in Kent et al., U.S. Pat. No. 4,675,189, and Hutchinson et al., U.S. Pat. No. 4,767,628.
However, microcapsules and larger implants have certain drawbacks. First, the drug release or delivery profile of such implants cannot be precisely controlled over time, because the delivery rate is modulated only by polymer degradation characteristics. Second, even if these implants are designed to maintain a constant drug delivery rate, this rate is not precise and can change over time, resulting in an undesirable decrease or increase in the proper effective dosage. Third, there are few existing excipients or carriers that can be used effectively to provide the desired long-term, sustained-release, constant drug release profile. Moreover, as the amount of such carriers in a microcapsule or implant increases, their toxic effect on the body also increases.
The rate of delivery of drugs from microcapsules and implants is not very high, because any increase in the quantity of the active ingredient, e.g., the drug, typically causes a corresponding increase in the quantity of the carrier. The carrier plays two contradictory roles. First, it must protect and isolate the drug from body fluids. Second, the carrier must release the drug and control its delivery over an extended period of time into the very same body fluids. In addition, the total dosage that can be delivered is limited by the size of the implant.
Mechanical pumps are also used to provide long-term parenteral delivery of liquid drug compositions. In such pumps, a power source, such as an electric motor, inflated balloon, the vapor pressure of volatile liquids, a mechanical spring, or osmotic force, is used to expel the liquid drug formulation from the pump. However, these pumps require a large reservoir to provide infusion over a prolonged time period. Thus, their size is restricted by the volume of drug formulation to be delivered, i.e., they are either large in size to provide a sufficient drug volume, or small in size with a small drug volume. Furthermore, a large liquid volume requires a strong motor and energy source which further increases the size of these delivery systems.
Some pumps for liquid drug formulations are implantable, but because of their limited reservoirs, they are restricted to use with only certain drugs, and can deliver the drug formulation for only a limited time. Furthermore, some of the larger implantable pumps result in great discomfort to the patient. All of these factors make implantable pumps for liquid drug solutions inefficient, and single use, disposable pumps impractical.
SUMMARY OF THE INVENTION
The invention applies a new approach to solving problems of existing injection pens, pumps, microcapsules and implants by using new solid compositions including active ingredients that reduce the volume, compared to the same active ingredients in solution, by hundreds to thousands of times. The invention also covers devices specifically designed for use with these new solid compositions.
The invention features anhydrous, solid drug compositions for parenteral administration, e.g., as a long-term administration with a pump or other micro-mechanical system that dispenses the solid drug composition according to an adjustable delivery profile or as a pulsatile bolus delivery. The drug delivery profile is controlled by introducing predetermined portions of the entire composition, drug and carrier, if any, into the body. Accordingly, the carrier has no primary delivery role as in a sustained-release matrix, but is rather a texture and/or support agent. Once a portion of the drug composition contacts body fluids, the drug is quickly released from that portion of the carrier in the composition. This also allows the carrier to play secondary roles to improve drug activity, e.g., by coating, or targeting the drug.
In general, the invention features a device for the automatic delivery of an active ingredient, e.g., to an aqueous or air environment, according to an adjustable delivery profile, the device including a housing; a reservoir operatively connected to the housing and arranged to store a solid composition including the active ingredient; an actuator arranged within the housing to move the solid composition from the reservoir to a transit area, wherein the solid composition exits the housing at the transit area; a controller that acts on the actuator to adjust movement of the solid composition out of the housing according to the adjustable delivery profile; and a power source arranged to provide energy to the actuator and the controller. The device can be used to administer the active ingredient to an animal or human patient, e.g., by implanting the device into the patient.
The solid composition includes up to 90 percent, or preferably between 10 and 70 percent, by weight, of a carrier, e.g., a water-soluble carrier such as a cellulose derivative, hyaluronic acid, sugar, or gelatin, or a water-insoluble carrier such as a plastic, cotton, or silk.
The active ingredient in the solid composition is preferably a drug such as a polypeptide, protein, or peptide. Particular drugs include insulin, adrenalin, xylocaine, morphine, a corticoid compound, atropine, a cytostatic compound, estrogen, androgen, interleukin, digitoxin, biotin, testosterone, heparin, cyclosporin, penicillin, a vitamin, an anti-platelet activating factor agent, somatostatin, SOMATRIPTAN™, triptorelin, or diazepam.
When the device is designed for use in an aqueous environment, the housing is preferably filled with an oil, and includes an opening sealed with a flexible membrane arranged to flex into or out of the housing in response to ambient pressure around the device. A preferred device is designed to store and deliver the solid composition in the form of a filament, and the actuator preferably includes two rotating wheels arranged to contact and move the solid composition from the reservoir to the transit area.
The invention also features a method of automatically administering a drug to
Feeney Alan F.
Fish & Richardson
Morrill Brian R.
Page Thurman K.
Societe de Conseils de Recherches et d'Applications Scienti
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