Title:  Bioadhesive progressive hydration tablets and methods of making and using the same

United States Patent:  6,248,358

Assignee:  Columbia Laboratories, Inc. (Rockville Centre, NY)

Filed:  August 23, 1999

A bioadhesive tablet wherein the active ingredient may be protected from water or the surrounding environment, thereby protecting it from metabolism or from other degradation caused by moisture, enzymes, or pH effects, and making it bioavailable only at a controlled rate. The active ingredient may be protected from moisture during the manufacturing process and more importantly may be protected from moisture and the immediate septic environment until after the patient has applied the tablet, and then only at a slow and controlled rate. It is by this process of progressive hydration that the active ingredient remains protected for many hours after administration. It is also by the process of progressive hydration that controlled and sustained release is achieved because only that part of the active ingredient that is the hydrated (aqueous) fraction of the tablet is available for absorption (bioavailable).

SUMMARY OF THE INVENTION

The present invention meets the aforementioned needs in the art. Accordingly, it is an object of the invention to provide a bioadhesive tablet that adheres immediately or almost immediately to the target tissue area of a body cavity and generally stays attached substantially throughout treatment. In accordance, with this aspect of the invention, there is provided a bioadhesive tablet that can stay attached and deliver active ingredients in the buccal cavity for as much as eighteen hours or more. In accordance with a related aspect of the invention, there is provided a bioadhesive tablet that can stay attached and deliver active ingredients vaginally for as much as 72 hours or more.

It is another object of the invention to provide a bioadhesive tablet that progressively hydrates, whereby the inner core of the tablet remains protected from moisture and the surrounding environment. In accordance with this aspect of the invention there is provided a bioadhesive tablet suitable for sustained release use in mucosal and other body cavities even with active ingredients comprising proteins or glycoproteins or other treating agents that are particularly susceptible to metabolism, or to enzymatic, pH, or moisture-induced degradation.

It is a related object of the invention to provide a bioadhesive tablet having both controlled and sustained release properties due to a tablet formulation wherein the active ingredient is only progressively made bioavailable over an extended time period by the progressive hydration of the tablet's dry reservoir of active ingredient.

It is another object of the invention to provide a bioadhesive tablet according to the invention that also gelifies and/or swells to help protect a patient using the tablet buccally from asphyxiation, particularly a sleeping patient undergoing treatment.

It is yet another object of the invention to provide methods of making bioadhesive tablets in accordance with the aforementioned objects of the invention. In accordance with one aspect of the invention, there is provided a method of making bioadhesive tablets wherein an active ingredient resistant to premature metabolism and/or degradation is added in the first and/or second step (manufacture of granulate). In accordance with a related aspect of the invention there is provided a method of making bioadhesive tablets wherein an active ingredient prone to premature metabolism and/or degradation is added in the second step (manufacture of the tableting mixture) after the granulate is dried and sieved. Of course, other concerns or factors may affect the choice of which step or steps are appropriate for adding a particular active ingredient.

It is yet another object of the invention to provide methods of using bioadhesive tablets as described herein. In accordance with one aspect of the invention, there is provided a method of using a bioadhesive tablet to administer to a male patient a sustained release of testosterone. In accordance with a related aspect of the invention, there is provided a method of using a bioadhesive tablet to administer to a female patient a sustained release of a hormone, such as testosterone.

The inventors of the present invention have discovered, quite unexpectedly, that these and other objects for the invention may be achieved by making and using tablets comprising an active ingredient, water soluble polymers (e.g., CARBOPOL.TM. 974P), and insoluble polycarbophil (e.g., NOVEON.RTM., available from B.F. Goodrich Specialty Polymers of Cleveland, Ohio), and preferably hydroxypropylmethyl cellulose (HPMC), lactose, corn starch and other standard tablets ingredients, such as magnesium stearate and talc.

Bioadhesive, progressive hydration tablets according to the invention may be used with any suitable active ingredient and may be used to deliver a therapeutic amount of the active ingredient to a patient at controlled rates for sustained periods of time. Tablets according to the invention may also be constructed in any suitable shape and any suitable size consistent with the intended therapeutic use of the tablet.

Tablets according to the invention may comprise any suitable amount of active ingredient. Suitable amounts of active ingredient according to the invention are may be from minuscule amounts of active ingredient to about 50%, or more, by weight active ingredient. As will be appreciated by one of ordinary skill in the art, "minuscule amounts" is intended to cover those amounts of active ingredient that are disproportionately small relative to the tablet, for example, when only a few micrograms of active ingredient are to be delivered via a tablet weighing over a hundred milligrams. Accordingly, one of ordinary skill in the art will appreciate that any amount of active ingredient, in any ratio, is within the scope of the present invention.

The balance of the tablet according to the invention may comprise water soluble polymer(s) and water insoluble cross-linked polycarboxylic polymer(s). Also, according to the invention, exemplary tablets preferably have between about 1% and about 75% by weight water soluble polymer and between about 0.5% and about 10% by weight water insoluble cross-inked polycarboxylic polymer. In accordance with the invention, such exemplary tablets also preferably include between about 5% and about 50% cellulose. Also in accordance with the invention, presently preferred tablets may have between about 0.5% and about 25% by weight starch. These preferred tablets may also have between about 1% and about 50% by weight lactose.

Furthermore, according to the invention, preferred tablets may comprise from about 0.01% up to about 2% by weight, including about 1% by weight silica; and/or up to about 2% by weight, including about 0.5% to about 2% by weight and up to about 0.5% by weight talc; and/or up to about 2.5% by weight, including about 0.5% to about 2% by weight magnesium stearate.

In one embodiment, said starch is present in about 2% to about 10% by weight, said lactose is present in about 8% to about 16% by weight, said water soluble polymer is present in about 25% to about 35% by weight, and said tablet is adapted for delivering said active ingredient to the bloodstream of a patient via the patient's vaginal cavity.

In another embodiment, said starch is present in about 14% to 24% by weight, said lactose is present in about 17% to about 27% by weight, said water soluble polymer is present in about 5% to about 20% by weight, and said tablet is adapted for delivering said active ingredient to the bloodstream of a patient via the patient's buccal cavity.

In yet another embodiment, the tablet comprises:

an effective amount of an active ingredient,

about 2% to about 30% by weight binder,

about 5% to about 40% by weight lactose,

about 1% to about 3% by weight water insoluble cross-linked polycarboxylic polymer, and

about 5% to about 50% by weight water soluble polymer.

The tablet may further comprise from about 0.2% to about 2% by weight silica; and/or about 0.5% to about 2% by weight talc; and/or about 0.5% to about 2% by weight magnesium stearate.

Accordingly, one of ordinary skill in the art will appreciate that the components of the tablets can be varied to suit a particular purpose. For example, the inventors of the present invention have discovered, quite unexpectedly, that one way of increasing (decreasing) the time it takes a progressive hydration tablet to hydrate is by decreasing (increasing) the amount of lactose and/or starch and increasing (decreasing) the amount of water soluble polymer. Alternatively, the density of the tablet may be altered to affect the hydration period.

Active ingredients suitable for use in the present invention include any active ingredient or ingredients requiring sustained or controlled release, any active ingredient or ingredients requiring extended protection from premature degradation of the active by moisture, pH effects, or enzymes, or any active ingredient requiring administration to a patient with protection from first-pass hepatic metabolism. Exemplary active ingredients suitable for use with the present invention include, but are by no means limited to: (1) glycoproteins, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (HCG), thryoid-stimulating hormone (TSH) and the like; (2) proteins, such as GnRH (agonist and antagonist), oxytocin analogs, somatostatin analogs, tissue plaminogen activator (TPA), growth hormone releasing hormone (GHRH), corticotropin-releasing hormone analogs (CRH analogs), and the like; (3) sex hormones, such as estradiol, testosterone, progesterone, and the like; (4) anti-hormones, such as tamoxifen, mifepristone, and the like; (5) nitrates, such as nitroglycerin, isosorbide, erythrityl tetranitrate, pentaerythritol tetranitrate, and the like; (6) beta-agonists, such as terbutaline, albuterol, pirbuterol, bitolterol, ritodrine, and the like; (7) beta-antagonists, such as propranolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, and the like; (8) opioids, such as morphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone, leverophanol, levallorphan, buprenorphine, fentanyl, nalbuphine, butorphanol, pentazocine, and the like; (9) opioids-antagonists, such as naloxone, nalmefene, and the like; (10) antidepressants, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, maprotilen, nortriptyline, protripyline, trimipramine, fluoxetine, trazodone, and the like; (11) HMG CoA reductase inhibitors, such as lovastatin, mevastatin, simvastatin, pravastatin, atorvastatin, and the like; (12) antihistamines, such as loratadine, chlorpheniramine maleate, brompheniramine maleate, diphenhydramine, dimenhydrinate, carbinoxamine, promethazine, tripelannamine, and the like; (13) ACE inhibitors, such as captopril, enalapril, lisinopril, and the like; and, (14) prostaglandins, such as misoprostol and the like. A preferred active ingredient is about 1% to about 30% by weight testosterone. Accordingly, one of ordinary skill in the art will appreciate that tablets according to the invention maybe used with a wide variety of active ingredients to treat a wide variety of conditions.

Claim 1 of 25 Claims

What is claimed is:

1. A sustained release, progressive hydration bioadhesive tablet comprising:

an effective amount of active ingredient selected from the group consisting of glycoproteins, proteins, sex hormones, anti-hormones, nitrates, beta-agonists, beta-antagonists, opioids, opioid-antagonists, antidepressants, HMG CoA reductase inhibitors, antihistamines, ACE inhibitors, prostagladins, and any other active ingredient which is metabolized or degraded by moisture, enzymes or pH,

about 5% to about 50% by weight cellulose,

about 0.5% to about 25% by weight starch,

about 1% to about 50% by weight lactose,

about 0.5% to about 10% by weight water insoluble cross-inked polycarboxylic polymer, and

about 1% to about 75% by weight water soluble polymer.

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