Title:  Intravesical drug delivery

United States Patent:  6,207,180

Appl. No.:  525609

Bioerodible, sustained release preparations are provided for placement into the bladder through the urethra which provide sustained release of drugs. Configurations are provided which are insertable through a catheter, such as a coiled filament, patch or a flowable gel. The device is bioeroded during or after the sustained release of the drug such that there is no blockage of the urinary tract while the device is in place within the bladder.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

A bioerodible carrier according to the present invention means a carrier which is readily dissolved, eroded, or is subject to degradation in the bladder. In one embodiment, the carrier material according to the present invention does not substantially decompose, disperse, disintegrate or dissolve in the bladder until most of the drug has been released.

In another embodiment, portions of the device will decompose, disperse, disintegrate or dissolve in a controlled manner so as to provide a controlled release of the drug contained in the decomposing portions.

Many carrier materials which are suitable for these embodiments are natural products, such as keratin, salol, triglycerides, fatty acids, lipids, latexes, as well as derivatives of natural products such as modified collagens, modified gelatins, regenerated proteins, celluloses, cellulose derivatives, salts of cellulose derivatives, alkaline or alkaline earth salts of cellulose acetate phthalate, ammonium salts of hydroxypropyl methyl cellulose phthalate, polysaccharides, synthetic polymers, such as, polyglycolic acid and derivatives of polyethylene glycol, polycaprolactone, polylactic acid, and copolymers thereof; materials such as starch, fatty alcohols, alginate polymers, albumin, calcium caseinate, calcium polypectate or gellan gum.

The carrier for the active ingredient may made by any number of methods known in the art for forming materials which contain medicaments. For example, a filament can be made with a centrifugal extrusion device or by coextrusion. The filament texture is preferably a porous, open cell foam. Filaments may also be made by interfacial polymerization processes, known in the art, for example, for the manufacture of nylon. The filament may be formed into random or regular coils, hoops, spheres, and the like.

Production by extrusion also enables the changing of the amount of the drug contained in the filament along the length of the filament, thereby allowing control of the dosage delivered in the bladder. Extrusion also enables the containment of the drug in one portion of the filament and the use of one or more additional drugs or an alternate formulation of the same drug, in other portions of the filament for the same purpose. The filament may contain two or more incompatible drugs in spatially distinct portions of the filament. The drugs may also be encapsulated in the carrier.

As discussed above, the time release of the drug may be controlled by diffusion from the carrier and/or erosion of the carrier, which simultaneously releases the drug. The bioerosion mechanism may be controlled by serially degrading segments of a filament. This may be accomplished, for example, by providing an outer layer of slowly bioerodible material with a core of rapidly bioerodible material containing the drug. Thus the exposed ends of the core will preferentially bioerode. At various points along the filament, weakened portions may be provided by which an outer layer may be detached once the core has been bioeroded, thereby causing the filament to be eroded in segments starting from the exposed ends.

In the case of carriers in the shape of sheets or spheres, the carrier materials may be formed in the desired shape or formed into sheets and cut into the appropriate form.

The carrier material will be typically one of two types. One type bioerodes rather uniformly over time, so that the bioerosion of the carrier is also the primary mechanism for releasing the drug into the bladder. The second type is a material which essentially remains intact during a substantial portion of the release period of the drug. The mechanism of release of the drug is by diffusion or other mechanism which does not require the carrier to be concurrently bioeroded. However, in such cases, shortly after the drug has been depleted from the carrier, erosion should proceed in order to avoid the necessity of removing the device from the bladder.

In either of these mechanisms of drug release, the sustained delivery of the drug into the bladder will be for an extended period, longer than about three days and preferably, at least about one week. For incontinence, cancer, or other chronic conditions, it is preferred that the drug be delivered over a period up to about one month. The carrier materials, containing or impregnated with the drug, may have a specific gravity less than or equal to that of urine, which is normally about 1.005 gm/ml to 1.033 gm/ml at 25^oC. This allows the device to be neutrally buoyant or float in the urine of the bladder to minimize the occurrence of blockage of the urethra.

A preferred embodiment of the delivery system is a flowable gel or set-in-place system that can be introduced into the bladder via a cannula. By set-in-place, it is meant that the gel sets when introduced into the bladder. In this system the drug is dispersed or placed in a carrier (microsphere, liposome, emulsion, etc.) which in turn is dispersed in a gel-forming system, such as gellan gum, a polysaccharide derived fermentation of Pseudomonas elodea, available as Gelrite.RTM. from Kelco. Solutions of this material gel when contacted with an ionic environment, which, in this case, is the urine in the bladder. The preferred gel is an ionic gel-in-place type, such as gellan gum. In this case, the retention mechanism is the buoyancy of the device, so its specific gravity must be less than or equal to that of human urine. The ionic strength of the urine causes, for example, a solution of gellan gum to gel. Since oils have a density less than 1 gm/ml, a lipid emulsion component of the gel has a density less than 1.0 gm/ml. Thus, the combination of the gel, having a density approximately equal to the surrounding medium, and a lipid, having a density less than 1.0 gm/ml, affords a device with a net density less than the surrounding medium. The gellan gum will slowly solubilize into the urine and be excreted, as will the lipid droplets.

The gelling system will preferably contain, in addition to the phase changing component (gellan, gum, alginate, CMC, polyacrylic acid, carboxymethyl chitosan, and the like), a rheology modifier. This modifier will be a water-soluble high molecular weight polymer such as polyethylene oxide, PVP, dextran, dextrose, PEO/PVP copolymers, hyaluronic acid, hydroxyethyl cellulose, polyacrylamide, PVA, chitosan, gelatin or other high molecular weight water-soluble polymers. The molecular weight of the rheology modifier is preferably in the range of about 10⁵ -10⁷ daltons.

When using a lipid carrier or release rate modifier, described below, the drug formulation is typically introduced into the lipid phase by mixing a salt form of the drug in water in the oil phase and increasing the pH. Deprotonation of the drug causes selective partition into the lipid phase, then the remainder of the components (the gelling component) are added.

Alternatively, an un-ionized form of the drug is dissolved in the lipid phase, the release modifier is added, then the mixture is emulsified. The remaining components are then added.

The second preferred embodiment of a delivery system is a device physically capable of being retained in the bladder without blocking the urinary tract. These devices are retained in the bladder by their shape such as a filament. These systems must be formed from a bioerodible polymer that will reliably release drug over the predefined period of time and completely erode during that period. It is not necessary that this type of device have a density less than human urine.

In one modified embodiment of a delivery system, at least one surface of the device may be coated with a mucoadhesive in order that the device adhere to the wall of the bladder. Mucoadhesive coated microspheres are preferred. Such mucoadhesives may be selected from a number of known synthetic, naturally-occurring or modified naturally-occurring substances which exhibit of tackiness. The adhesive must be biocompatible, that is, nontoxic and/or inert, within the bladder. The adhesive will also be compatible with the material forming the carrier, as well as the drug. Substances appropriate for use as mucoadhesives include, but are not limited to, carboxymethyl and hydroxypropyl methyl cellulose, and other cellulose derivatives; tragacanth, caraya, locust bean and other synthetic and naturally gums such as algin, chitosan, starches, pectins, and naturally-occurring resins, polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid.



It is a feature of the present invention that the devices containing the drug are insertable into the bladder through the urethra by a catheter. Thus, the devices are preferably made of flexible or gel-like material so that they may be coiled or compressed to fit through a catheter of sufficient size. Upon being released from the catheter, the devices will have a sufficient shape memory to uncoil or expand into the shapes shown, for example, in the accompanying figures. By retaining such shapes, the devices per se will not be drawn into the urethra to cause blockage, but will be retained within the bladder for an extended period of time. For devices having a mucoadhesive coating, by virtue of the random motion within the bladder, the mucoadhesive surface will eventually contact the bladder wall, thus achieving the desired implantation.

The drugs which may be utilized include, but are not limited to the following. Drugs for urge incontinence include dicyclomine, desmopressin, oxybutynin, estrogen, terodiline, propantheline, doxepin, imipramine and flavoxate. Other drugs include phenylpropanolamine, terazosin, praxosin, pseudoephedrine and bethanechol. Oxybutynin and impranine are the two most widely used for urge incontinence and are preferred. For treatment of bladder cancer, doxorubicin is preferred. In addition, Bacillus Calmette-Guerin, a mycobacterium, may be utilized for treatment of carcinoma in situ of the bladder. For treatment of interstitial cystitis, DMSO or an anesthetic agent may be utilized. Thus, it is contemplated that any drug may be utilized for the treatment of any condition related to the bladder or urethral tract, including urge incontinence, cancer, infections, inflammation, and the like.

The dosages utilized will depend upon the protocol required for the treatment of the particular condition and the patient. Particularly by use of filaments, variation in dosages is readily available since it is merely a case of using a longer or shorter length.

In a preferred embodiment, the drug will be combined with a carrier and, optionally, a release modifier which alters the release of the drug into bladder. Typical carriers include corn oil, soybean oil, canola oil, safflower oil, polypropylene glycol and other natural oils. Typical release rate modifiers include oleic, stearic, palmitic and other saturated or unsaturated fatty acids; cholic acid, diacylphosphoric acid and other hydrophobic anionic compounds; phospholipids, diesters of citric acid, benzoic acid, substituted benzoic acids, substituted phenols, ion exchange polymers, Eudragit.TM., methacrylate-methacrylic acid copolymers, Tweens.TM., Spans.TM., lecithin, alkyl nitrates, ethyl or methyl cellulose.

Therefore, preferably a gel-in-place drug delivery system will include two components: the gelling components containing the phase change material and, optionally, a rheology modifier; and the drug release component containing the drug, carrier and, optionally, a release rate modifier.

The drug release rate may also be regulated by the carrier per se when there is a chemical affinity of the drug to the carrier. Alternatively, a release rate modifier may be incorporated into the carrier, forming complexes or conjugates of carrier and modifier, and the like.

The drug release component may also comprise a drug unmodified by release modifiers. Such a component, for example, may comprise the drug dispersed in a solid lipophilic system such as anionic wax, self-emulsifying wax, cholesterol, fatty acid esters, beeswax or tallow.

A reservoir device may be utilized where the reservoir can contain a much larger dose of drug compared to, for example, the filament configuration. If a gel is used to provide sustained delivery of the drug it can be readily sterilized during preparation, then aseptically loaded into a sterile delivery device. Gels may be formulated as low viscosity dispersions with the drug or drug carrier which, when in contact with urine in the bladder, then gel or precipitate to form a solid filament or mass, thereby forming a delivery vehicle which can be retained in the bladder.

The device must have a configuration, not limited to those disclosed, such that it does not block the flow of urine from the bladder or cause excessive mechanical irritation to the bladder wall.

Claim 1 of 19 Claims

What is claimed is:

1. A bioerodible, sustained-release preparation for placement into the bladder through the urethra,

comprising a pharmaceutically active ingredient and a bioerodible pharmaceutically acceptable carrier;

said carrier being capable of sustained delivery within the bladder of said active ingredient and said carrier being excretable through the urinary tract after bioerosion.

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