Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-08-10
2001-03-13
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S434000, C424SDIG001, C514S965000
Reexamination Certificate
active
06200590
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to suppository preparations and more specifically to a phased, systemic-delivery suppository preparation and its method of production.
As is well known, suppositories are medicated dosage forms inserted into body cavities such as the rectum, urethra, or vagina for the eventual delivery of one or more active agents to the systemic circulation and/or to local tissues. Suppositories are valuable, and often critical, additions to the symptom control armamentarium. This is especially true for those patients who, due to advanced disease, advanced age, nausea or other physiological or neurological problems, are unable to receive medications orally, intravenously or by injection. The problem is even more critical for the terminally ill patient who suffers from intense, intractable pain. Suppository dosage forms of medications presently being given to patients, particularly in the control of pain, are often times irregular in the delivery or bioavailability of the administered agents with the delivery of medications sometimes oscillating between levels which are far below the effective pain relieving dose to near toxic levels.
In recent years, prescribers have increasingly requested that pharmacists prepare extemporaneous suppository dosage forms for symptom control medications. However, because these dosage forms are not commonly compounded today, many prescribers who order drugs, the pharmacists who compound them, and the nurses who administer them, are unfamiliar with the criteria for properly formulated suppositories. Moreover, while suppository dosage forms have been formulated in the past for many agents, often the duration of the action of the drug is relatively short, requiring frequent administration thereby making usage inconvenient and/or ineffective. Attempts have been made, with limited success, to produce suppositories that are capable of delivering medications in a sustained or controlled release manner. Major obstacles include erratic absorption as herein described, and the timing of evacuations of the particular body cavity chosen for insertion. Many drugs can be delivered by the use of suppository dosage forms but the controlled release of such drugs has yet to be refined. Methods to prolong the action of drugs in a suppository sustained release form are therefore needed and desired.
Use of microparticles as a delivery system for drugs in clinical situations has been proven to be viable for many years. Since the advent of liposomes in the seventies, science has advanced to the point where many pharmaceutical materials are employed either singularly or in various percentages to produce optimum release rates for drugs or proposed drugs. However, prior art suppository preparations will typically release their active agents within the lower rectum thereby limiting the bioavailability of the agents. Substantial release of the active agent of the suppository into the lower rectum can and does limit the percentage of agent which can actually reach the systemic circulation system where it is needed.
It would be expedient, therefore, for the provision of a suppository formulation which will give more control over the release and bioavailability of medications. Furthermore, suppository preparations which are capable of releasing substantially all of their active agent(s) directly into the patient's systemic circulation instead of the lower rectum would greatly enhance the bioavailability and usefulness of such dosage forms and would substantially eliminate the problems associated with the untimely evacuation of the body cavity chosen for insertion.
The present inventor, through extensive experimentation and study, has developed a phased-release suppository delivery system incorporating a novel method of producing drug-ladened, polymeric “nanospheres” within a suppository base. The method of preparation of the “nanospheres” allows for the release of their active agent(s) only after a substantial number of the spheres have been transported across the capillary membranes of the rectum or other body cavity and have been taken up into the systemic circulation system. A small number of the spheres will inevitably become lodged within the mucus membrane of the chosen body cavity, however, even these spheres will, upon dissolution, release their active agent(s) from said area over an extended period of time.
SUMMARY OF THE INVENTION
In view of the foregoing, it is a primary object of this invention to provide a phased-release suppository preparation and delivery system which incorporates microscopic, drug-ladened, polymeric nanospheres within a homogenous suppository base.
According to an embodiment of the invention, a phased-release suppository delivery system comprises a novel method of producing polymeric nanospheres ladened with one or more active agents wherein the nanospheres are homogeneously incorporated into a pharmaceutically acceptable suppository base. The release of one or more active agents contained within the suppository nanospheres is controlled according to a four-phase delivery system. The first phase comprises the delivery of the suppository dosage form into the rectal cavity (or other body cavity); the second phase is the release, upon aqueous solubility of the suppository base, of the polymeric nanospheres into the mucosa of the chosen body cavity; the third phase is the uptake of nanospheres into fenestrated capillaries of the chosen cavity; and, the fourth phase comprises release of active ingredient(s) directly into the patient's systemic circulation upon dissolution of the polymeric nanosphere vehicles. The release of the active ingredient(s) of the nanospheres is controlled by the percentage composition of the polymer(s) used to produce the spheres.
An important advantage of the present invention is the provision of methodology for the production of a controlled, phased-release suppository preparation comprising substantially spherical microscopic particles consisting of a matrix of one or more active agents within a polymeric carrier. Said matrix forming a homogeneous, microscopic delivery system capable of being transported, substantially intact, across capillary membranes and into the systemic circulation system.
Another advantage of the present invention is the provision of methodology necessary to produce drug-ladened nanospheres no larger than 300 nanometers in diameter.
Another advantage of the present invention is the provision of a homogeneous suppository preparation containing drug-ladened nanospheres which will release their active agent(s) only after a substantial number of the spheres have been transported across fenestrated capillary membranes and have been taken up into the systemic circulation system.
A further advantage of the present invention is the provision of a homogeneous suppository preparation containing nanospheres wherein one or more active agents and polymers are caused to form a matrix whereby the agents are uniformly distributed throughout the nanosphere particle.
Another advantage of the present invention is the provision of a controlled release suppository preparation which can accommodate both water soluble and lipid soluble agents.
Another advantage of the present invention is the provision of a controlled release suppository preparation comprising a delivery system which provides for longer lasting action of its active agents.
A further advantage of the present invention resides in the bioavailability of the active agent(s) contained within the nanosphere matrix which is controlled by the percentage of polymers used to form the nanospheres.
Another advantage of the present invention is that any nanospheres which become lodged within the mucosa of the chosen body cavity will also release their active agent(s) from that area over an extended period of time.
A further advantage of the present invention is the provision of a phased release suppository preparation which is not an encapsulation and wherein one or more active agents are contained within a polym
Azpuru Carlos A.
May Wm. Randall
Naphcare, Inc.
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