Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-04-30
2002-10-08
Williamson, Michael A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S277000, C514S408000, C514S529000, C514S532000, C514S534000
Reexamination Certificate
active
06461644
ABSTRACT:
According to one aspect of this invention, it has been discovered that anesthetics of amide or ester type, such aslidocaine base, tetracaine base, propafenone or other drugs of similar structure, are highly soluble, or otherwise can be incorporated in large, effective concentrations, in conventional polymers. Under suitable conditions, the drug is found to migrate gradually and steadily to the surface of the plastic. Because of the large concentration found possible, in many cases the percentage reduction of drug present relative to the initial amount of drug, decreases only gradually with time, and provides zero order time dependence in rate over prolonged periods of use. Unique ways have been realized for employing this phenomenon. The plastic is employed as a long-term protective reservoir for the drug. In many advantageous cases, the plastic forms the exterior portion of a functional wall or component of a device as well as serving as a drug reservoir. In other cases fine particles of the plastic are employed as the reservoir. In important cases the drug is of base form and/or is more soluble in the plastic than in water. In important cases, the plastic is a hydrophobic film-forming or structural resin.
In certain instances, the plastic reservoir material itself is directly exposed to body tissue as in the case of contact with the mucosal tissue or the skin. In certain instances, one or more intervening layers are included to determine release rate to the body or to facilitate transfer of the drug to the body or to isolate the reservoir plastic from contact with body tissue. In certain cases, as in certain dermal applications, the main limit on the dosage rate is the transmissivity of the skin itself and the reservoir serves to maintain a high or selected concentration of the drug in contact with the skin surface. In other instances, the migration rate of the drug in the resin controls the release of the drug into the patient.
The phenomenon that large concentrations of the drug can be incorporated in conventional plastic resin is found to be especially applicable to FDA-approved structural and film-forming thermoplastics such as fully polymerized polyvinyl chloride (PVC). By the techniques disclosed here and in the preceding patents and patent applications referenced above, PVC in which the drug is incorporated is employed as drug-carrying granules or to coat, print or to form the structure of tubes, films, sheets, bandages, coverings, rods, foams, molded devices, sutures, other medical devices, ingestible formulations, etc.
In a wide variety of important cases the drugs in base form, when used in significant quantities, are found to demonstrate a surprising plasticizing action upon compatible plastic polymers. This facilitates the making of safe, stable and convenient products. The polymer and the drug, alone, without additional plasticizers, forms useful articles in many instances. By selection of the relative proportions of the plasticizing drug and an added therapeutically and biologically inert second plasticizer, the concentration of the drug can be selected, e.g., for selection of dosage rate, while maintaining the desired physical properties of the plastic article, such as flexibility and conformability, as in a skin patch or covering.
An anesthetizing or drug delivering effect lasting days, weeks, perhaps even months and years can be achieved by controlling the thickness of the reservoir layer, the concentration of drug present in the layer, and other parameters that govern the particular application.
The products can increase the comfort and ease of drug administration with both prescription and over-the-counter products, and in the case of anesthetic drugs, can reduce the pain of adults and children in many circumstances, reduce hospital stay, increase the use of doctor's office and out-patient care, and increase the efficiency with which medical procedures may be accomplished.
According to one aspect of the invention, it has been discovered that effective concentrations of topical anesthetic compound at contacted tissue, suitable for maintaining topical anesthesia (concentrations that are, generally, extremely large compared to other classes of drugs) can be self-administered by a wall of a medical device by selection of particular materials and particular topical anesthetics that cooperatively meet certain selection criteria. The wall material and the topical anesthetic are selected such that (1) the necessary amount of topical anesthetic “dissolves”, i.e. forms a true solution in the wall material, while (2) the topical anesthetic is more soluble in the polymer than in water and (3) the concentration of the topical anesthetic compound in the wall material is such that when the wall is in contact with a body passage, the compound diffuses to a surface of the body at a rate effective in maintaining anesthesia.
The first and third criteria assure that the needed large amount of topical anesthetic can be incorporated and uniformly administered wherever tissue contacts occurs, while the first and second criteria help to enable criteria 3 to be met by assuring that the topical anesthetic, while effective, neither causes adverse systemic reaction of the patient by too rapid release, nor is wasted too soon from the surface of the device if in contact with aqueous body fluid. These three cooperating criteria enable a sufficient concentration of the topical anesthetic to be maintained at the tissue to maintain topical anesthesia for an extended time. Thus, the patient's long term discomfort is successfully eased.
The presently most preferred wall polymer for this aspect of the invention is polyvinyl chloride, while another preferred wall material is vinyl urethane copolymer. Presently preferred topical anesthetics for this aspect of the invention are lidocaine base,
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mixtures of lidocaine and prilocaine and tatracaine. Dibucaine base also meets the criteria.
Applicant's Example 1 in U.S. Pat. No. 5,279,594 dramatically demonstrates the principle. In this case polyvinyl chloride wall-forming polymer and lidocaine base anesthetic are employed. True solution of an effective quantity is achieved by exposing the wall polymer to an atmosphere containing the topical anesthetic sublimed in a vacuum chamber at elevated temperature. Note that lidocaine base is insoluble in water and thus is more soluble in the polymer than in water. This is to be distinguished from the commonly used hydrochloride or salt of this compound which is highly water soluble. The dissolved amount of 550 mg of Example 1 represents a concentration in the polymer wall of 6% (based on the weight, 8 gm, of a #16 urethral catheter); the wall was shown to maintain the anesthesia effect on the tissue. The specification expressly discloses concentrations in the polymer wall that work out to 5% (Example 3) and 10% (Example 4) that are successful in achieving the prolonged level at tissue within the body needed to maintain anesthesia on.
Unlike prior attempts, applicant's solution to the serious discomfort problem is highly practical. The preferred combinations of topical anesthetic and wall polymer that meet the criteria are all medically acceptable materials. Further, it is found that the common sterilization technique of ethylene oxide can be used with these combinations.
In short, the tubes of the invention have a predictable capability to deliver prolonged, effective concentrations of topical anesthetic to the tissue wherever required along the tube length to maintain anesthesia.
Among the aspects shown in the related U.S. Pat. No. 5,279,594 are tubes that have topical anesthetic incorporated in the material of which the wall of the tube is composed, the anesthetic being more soluble in the wall material than in water.
Among the preferred features shown are the following. The base form of the anesthetic is employed. The entire wall thickness of a tube is formed of the anesthetic-polymer material. Materials are employed that enable ethylene oxide sterilizability. PVC and viny
Jackson Richard R.
Williams John N.
Fish & Richardson P.C.
Jackson Richard R.
Williamson Michael A.
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