AU2005203703A1 - Bioadhesive progressive hydration tablets - Google Patents

Description

S&F Ref: 545288D2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Columbia Laboratories (Bermuda) Limited, of Rosebank Center 14 Bermudiana Road, Pembroke, HM08, Bermuda William J Bologna Philippe Cartier Dominique De Ziegler Howard L Levine Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Bioadhesive progressive hydration tablets The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c BIOADHESIVE PROGRESSIVE HYDRATION TABLETS The present invention relates to bioadhesive, bioerodible compositions for the extended and controlled release of active ingredients treating agents). More particularly, the present invention relates to progressive hydration tablets for adhesion to the wall of a body cavity for the sustained release of active ingredients without premature degradation of the active ingredients caused by metabolism, or by moisture, enzymes or pH effects.

Medications and other pharmaceutical products have traditionally been administered in doses via oral ingestion, nasal sprays or injections. These delivery methods have proven ineffective for patients needing a prolonged and constant supply of an active ingredient delivered to the bloodstream. Particularly difficult are patients needing dosing during sleep time hours. For these patients, intravenous lines, slow-dissolving pills, and suppositories or transdermal patches have been prescribed.

However, the inconvenience and discomfort of IVs, the short life span of many ingested Is active ingredients from gastrointestinal degradation or first-pass liver metabolism, and the inability of many products to be comfortably delivered transdermally in suitable doses or in controlled concentrations have proven these methods unsatisfactory.

Previous artisans have attempted to meet the needs of the art by developing products for the transmucosal administration of active ingredients. For example, certain active ingredients can be administered quickly into the bloodstream via the walls of a body cavity, such as the buccal or vaginal cavities, without the risk of first pass hepatic degradation. Generally, delivery of active ingredients through mucosal surfaces may be enhanced by the use of bioadhesive formulations. However, one particular area where those in the art have attempted, but heretofore failed, to meet the needs of the art is in developing a bioadhesive tablet useful for sustained release applications without risking degradation of the active ingredient before it is actually released.

"Sustained release" generally refers to continuous or sporadic release of an active ingredient over an extended time after a single administration, whereby the level of active ingredient available to the host patient often is maintained at some constant level over a period of time. As used herein, it is also intended to cover the situation where the release of an active ingredient is controlled over a period of time wherein the level of active ingredient available to the host (bioavailability) may be at a variable but predetermined level at a particular instant in time of treatment.

r :Lr ln771cirooni The sustained release bioadhesive tablets known in the art can be generally broken down into two categories: tablets consisting of water soluble carbomers, and (2) tablets consisting of insoluble polymers. Both types of tablets have proven unsatisfactory for many applications. For example, numerous artisans haveattempted to formulate a suitable sustained release bioadhesive tablet from water soluble carbomers, such as carbomer 934P or CARBOPOL T M 974 resin (commercially available from B.F. Goodrich, Cleveland, Ohio). However, such tablets often are only able to adhere to the wall of a body cavity for short periods of time, six hours or less. Also, these tablets are easily dislodged from the wall of a body cavity and thus place patients using such tablets io buccally at risk of asphyxiation. Furthermore, these prior art tablets inherently become hydrated relatively quickly and thus may prematurely expose the reservoir of active ingredient to degradation by moisture or by enzymes from the host environment such as from bacteria in the septic oral or vaginal cavities.

Similarly, tablets comprised of insoluble polymers, such as Polycarbophil, have proven unsuitable for many applications. For example, although Polycarbophil tablets are capable of prolonged attachment to the wall of a body cavity, such tablets do not adhere immediately, making them impractical for certain treatments such a buccal delivery of active ingredients to patients during sleep time hours. Further, such tablets often do not soften sufficiently to provide comfort and imperceptibility, or provide safety from potential aspiration of the tablet.

Furthermore, for example, neither type of prior art tablet is particularly suitable for treating many conditions. As alluded to previously, there are numerous medical conditions in which a sustained and/or controlled release of active ingredient(s) is desired for any of numerous reasons including, for example, to alleviate the impact of first-pass hepatic metabolism of the active ingredient or the risk of premature degradation of the active ingredient by moisture, pH effects, or enzymes, or to attain the comfort and convenience offered by a suitable bioadhesive tablet. Such conditions include, but are not limited to, for example, those needing treatment with an active ingredient that may be, but is not limited to, a glycoprotein, protein, sex hormone, anti-hormone, nitrate, beta-agonist, beta-antagonist, opioid, opioid-antagonist, antidepressant, HMG CoA (3-hydroxy-3methylglutaryl Coenzyme A) reductase inhibitor, antihistamine, ACE (angiotensin converting enzyme) inhibitor, and/or prostaglandin. Heretofore the art has required such patients to undergo the more invasive and less suitable techniques and methods of delivery described above.

To illustrate the need in the art, consider hypogonadal men, for example.

Hypogonadism in man is characterized by a deficiency or absence of endogenous testosterone production. Abnormally low levels of testosterone may place men at risk of "Andropause", wherein men are at greater risk of cardiovascular disease, Alzheimer's s disease, and osteoporosis.

Testosterone has traditionally been used to treat hypogonadal men. However, to be most effective, the treatment must be capable of complete physiologic testosterone replacement. Moreover, the treatment must be capable of providing sustained levels of testosterone through the night, preferably sustaining a peak in the middle of the night.

Transdermal testosterone patches typically produce only sub-physiologic levels and thus incomplete relief Similarly, the prior art buccal tablets heretofore described would be ineffective or impractical for such sustained testosterone delivery.

The hormone testosterone, like many other drugs, including many other proteins and glycoproteins, undergoes high first pass metabolism. Accordingly, as will be is appreciated by one of ordinary skill in the art, buccal or vaginal tablets consisting of materials that are incapable of keeping the interior reservoir of the tablet in the dry state for prolonged periods are inherently incapable of preventing dissolution and swallowing or dissolution and rapid absorption of the active ingredient through the mucosa.

Furthermore, as will be appreciated by one of ordinary skill in the art, tablets which are unable to quickly adhere to the target area or are able to become dislodged are impractical for treatments which use night-time delivery, such as testosterone treatment.

Active ingredients such as testosterone may also undergo undesired metabolism. For example, 5a-reductase converts testosterone to 5cc-dihydrotesterone (DHT). DHT may cause adverse effects such as hair loss and prostate disorders. Similarly, may metabolize other active ingredients such as progesterone.

Various testosterone formulations have been developed to circumvent the problems inherent in rapid clearance of orally and parenterally administered agents. These include transdermal preparations (with or without emollient), pellets for subcutaneous implantation, biodegradable microcapsule formulations for injection, and inclusion complexes that enhance sublingual absorption of the hormone. Of these, the testosterone transdermal system for use on the scrotum and other skin patch products, are probably the most widely tested. Under optimal conditions, they are intended to approximate the physiological pattern of hormone levels throughout the day and provide an alternative to parenteral therapy.

rv-, _T 3 ly TnI7171CAC However, the scrotal preparation causes a disproportionate increase in plasma dihydrotestosterone (DHT) to a level that is 30 to 40% that of testosterone, presumably because of the high level of 5o-reductase in scrotal skin. Other skin patches likewise produce high levels of DHT. Such increases in serum DHT have also been reported after treatment with the extremely long-acting parenteral testosterone ester testosterone buciclate and with the oral ester testosterone undecanoate. Williams Textbook of Endocrinology, 9 th Ed., W.B. Saunders Company, p. 853. Thus, the present invention advantageously avoids the side effects that may be caused by 5a-reductase's metabolism of active ingredients.

to Furthermore, as will be appreciated by one of ordinary skill in the art, the advantages of a sustained release, bioadhesive tablet according to the present invention are not limited to the treatment of hypogonadism in men. For example, patients often require sustained release hormone treatment for various conditions. In addition, other medications, such as steroids for treating such conditions as asthma, involve treatments where desired peak levels are at night during sleep-time hours. Accordingly, one of ordinary skill in the art will appreciate that there exists a long-felt, yet unresolved, need to develop a bioadhesive, sustained release tablet to overcome the aforementioned needs of the art, including, but not limited to, the delivery of therapeutically effective amounts of an active ingredient which may be metabolized or otherwise degraded by moisture, enzymes, or pH effects, such as glycoproteins, proteins, sex hormones, anti-hormones, nitrates, beta-agonists, beta-antagonists, opioids, opioid-antagonists antidepressants, HMG CoA reductase inhibitors, antihistamines, ACE inhibitors, and/or prostaglandins.

For example, an advantage to administering treating agents such as terbutaline (especially for sleep time administration) through a sustained release bioadhesive tablet according to the instant invention is that such administration provides controlled, extended release to help prevent high peak blood serum levels of the terbutaline. This is particularly useful when the treating agent, such as terbutaline, is associated with adverse side effects at high blood serum levels.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a series of photographs depicting the progressive hydration of a bioadhesive tablet according to the invention.

Figure 2 is a flowchart depicting a presently preferred method of making bioadhesive tablets according to the invention.

in 3 SUMMARY OF THE INVENTION ;There is described herein 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. Also described herein is a bioadhesive tablet that can stay attached and deliver active ingredients in the buccal cavity for as much as eighteen C hours or more. There is also described herein a bioadhesive tablet that can stay attached Cc and deliver active ingredients vaginally for as much as 72 hours or more.

r Also described herein is a bioadhesive tablet that progressively hydrates, whereby the inner core of the tablet remains protected from moisture and the surrounding 1 0 environment. In accordance with this aspect 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.

In a related aspect there is described herein 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.

There is also described herein a bioadhesive tablet ao 1 16 ,nei-'tio that also gelifies and/or swells to help protect a patient using the tablet buccally from asphyxiation, particularly a sleeping patient undergoing treatment.

Also described are methods of making bioadhesive tablets described herein. There is described 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). There is described 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.

Also described are methods of using bioadhesive tablets as described herein. There is described herein a method of using a bioadhesive tablet to administer to a male patient a sustained release of testosterone. In accordance with a related aspect, there is described 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 the above may be achieved by making and using tablets comprising an active ingredient, one or more bioadhesive water soluble polymers carbomer 974P or 934P, or CARBOPOLTM 974P), and one or more bioadhesive, water insoluble water swellable cross-linked polycarboxylic polymers, preferably polycarbophil NOVEON®, available from B.F. Goodrich Specialty Polymers of Cleveland, OH), and preferably hydroxypropylmethyl cellulose (HPMC), lactose, corn starch and other standard tablets ingredients, such as magnesium stearate, talc, and silica.

Bioadhesive, progressive hydration tablets described herein may be used with any o0 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. The tablets may also be constructed in any suitable shape and any suitable size consistent with the intended therapeutic use of the tablet.

Tablets described herein may comprise any suitable amount of active ingredient.

Suitable amounts of active ingredient according to the invention may be from minuscule amounts to about 50%, or more. 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 described herein may comprise water soluble polymer(s) and water insoluble cross-linked polycarboxylic polymer(s). Also, exemplary tablets preferably have between about 1% and about 75% by weight water soluble polymer (preferably carbomer 974P) and between about 0.5% and about 10% by weight water insoluble, water-swellable cross-linked polycarboxylic polymer (preferably Polycarbophil). Such exemplary tablets also preferably include between about 5% and about 50% cellulose. Presently preferred tablets may have between about 0.5% and about by weight starch. These preferred tablets may also have between about 1% and about 50%, or as much as 95%, by weight lactose.

Furthermore, preferred tablets may comprise from about .01% up to about 2% silica; and/or up to about 5% to 8% by weight talc; and/or up to about 2.5% by weight magnesium stearate.

ffI\avl ih\.IIR77lS4SRRgneneci2.docd:mrr 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 that one way of increasing (decreasing) the time it takes a progressive hydration tablet to hydrate is by increasing (decreasing) the amount of lactose and/or starch and decreasing (increasing) 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 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: glycoproteins, such as follicle-stimulating hormone (FSH), luteinizing hormone human chorionic gonadotropin (HCG), thryoid-stimulating hormone (TSH), and the like; proteins, such as GnRH (agonist and antagonist), oxytocin analogs, somatostatin analogs, tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), corticotropin-releasing hormone analogs (CRH analogs), and the like; sex hormones, such as estradiol, testosterone, progesterone, and the like; anti-hormones, such as tamoxifen, mifepristone, and the like; nitrates, such as nitroglycerin, isosorbide, erythrityl tetranitrate, pentaerythritol tetranitrate, and the like; beta-agonists, such as terbutaline, albuterol, pirbuterol, bitolterol, ritodrine, and the like; beta-antagonists, such as propranolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, and the like; opioids, such as morphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone, leverophanol, levallorphan, buprenorphine, fentanyl, nalbuphine, butorphanol, pentazocine, and the like; 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.

Exemplary active ingredients suitable for use with the present invention include, but are by no means limited to: glycoproteins, such as follicle-stimulating hormone [R:\LIBXX1055 18speci.doc:NJC 7a (FSH), luteinizing hormone human chorionic gonadotropin (HCG), thyroidstimulating hormone (TSH), and the like; sex hormones, such as estradiol, testosterone, progesterone, other estrogenic and progestogenic compounds, and the like; anti-hormones and selective estrogen and progestin receptor modulators, such as s tamoxifen, mifepristone, raloxifene and the like; nitrates, such as nitroglycerin, isosorbide, erythrityl tetranitrate, pentaerythritol tetranitrate, and the like; betaagonists, such as terbutaline, albuterol, pirbuterol, bitolterol, ritodrine, and the like; (6) beta-antagonists, such as propranolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, and the like; opioids, such as morphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone, leverophanol, levallorphan, buprenorphine, fentanyl, nalbuphine, butorphanol, pentazocine, and the like; opioids-antagonists, such as naloxone, nalmefene, and the like; (11) prostaglandins, such as misoprostol and the like; (12) non-steroidal anti-inflammatory drugs (NSAIDS), such as diclofenac, etodolac, fenoprofen, lurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, fenamic acid, meloxicam, nabumetone, naproxin, oxaprozin, piroxicam, sulindac, tolmetin, and the like; (13) anti-infectives; (14) anesthetics, such as lidocaine, cocaine, chloroprocaine, tetracaine, prilocaine, mepivacaine, buipivacaine, levobupivacaine, articaine, ropivacaine, phenol, benzocaine, pramoxine, dyclonine, etidocaine, procaine, proparacaine, dibucaine, and pramoxine; immune system modifiers such as imiquimod and the like; (16) muscarinic agonists and antagonists such as bethanecol and oxybutinyn and the like; (17) anti-neoplastic agents including alkylating agents such as melphalan, antimetabolites such as fluorouracil, and natural products such as vinca alkaloids and bleomycin as well as agents such as cisplatin and the like; (18) antidepressants; (19) HMG CoA reductase inhibitors; antihistamines; (21) ACE inhibitors; (22) vitamin K; (23) ondansetron; (24) levocarnitine; anti-fungals; (26) carbamide peroxide; (27) dopamine antagonists (bromocriptine); (28) bisphosphonates; (29) nicotine; (30) anti-virals (acyclovir); (31) anti-diabetagenics (metformin); (32) peptides (octreatide, desmopressin, GNRH, other proteins); (33) insulin; (34) anti-Parkinson agents (levadopa); and (35) low molecular weight heparins.

Accordingly, one of ordinary skill in the [R:\LIBXX105518spci.doc:NJC art will appreciate that tablets according to the invention may be used with a wide variety of active ingredients to treat a wide variety of conditions.

There is also described herein a pharmaceutical composition comprising an effective amount of active ingredient, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver said active ingredient to the bloodstream of a mammal through a mucosal surface of the mammal.

Also described herein is a method of delivering to a mammal an active ingredient that is metabolized by 5c-reductase, comprising administering said active ingredient via a progressive hydration bioadhesive composition through a mucosal surface of the mammal.

In addition, there is also described herein a composition for delivering to the bloodstream of a mammal an active ingredient that is metabolized by comprising a water insoluble cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver said active ingredient through a mucosal surface of the mammal.

In addition, there is also described herein a bioadhesive progressive hydration pharmaceutical composition comprising: an effective amount of a treating agent, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver said treating agent to the bloodstream of a mammal through a mucosal surface of the mammal.

In addition, there is described herein a bioadhesive progressive hydration pharmaceutical composition comprising an effective amount of terbutaline, progesterone, testosterone, or desmopressin, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver said terbutaline, progesterone, testosterone, or desmopressin, to the bloodstream of a mammal through a mucosal surface of the mammal.

In addition, there is described herein a method of delivering to a mammal an effective amount of a treating agent, including without limitation, testosterone, terbutaline, progesterone, or desmopressin via a progressive hydration bioadhesive pharmaceutical composition through a mucosal surface of the mammal, comprising said treating agent, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer.

Preferably, the compositions described herein are formulated to deliver said active ingredient via the mammal's vaginal, buccal, nasal or rectal cavity.

According to a first embodiment of the invention there is provided a bioadhesive controlled, sustained release progressive hydration pharmaceutical composition comprising: an effective amount of an active ingredient, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver the active ingredient to the to bloodstream of a mammal through a mucosal surface of the mammal.

According to a second embodiment of the invention there is provided a method of delivering to a mammal an active ingredient, comprising administering the active ingredient via a progressive hydration bioadhesive composition through a mucosal surface of the mammal.

According to a third embodiment of the invention there is provided use of a water insoluble, water-swellable cross-linked polycarboxylic polymer, a water soluble polymer, and an active ingredient, in the manufacture of a medicament for transmucosal administration in a mammal.

According to a fourth embodiment of the invention there is provided a composition comprising a water insoluble, water-swellable, cross-linked, polycarboxylic polymer, a water soluble polymer, and an active ingredient, for use in a method of therapeutic treatment of the human or animal body comprising transmucosal administration of the active ingredient.

According to a fifth embodiment of the invention there is provided a method of delivering to a mammal an effective amount of a treating agent via a controlled and sustained release, progressive hydration bioadhesive pharmaceutical composition through a mucosal surface of the mammal, comprising the treating agent, a water insoluble, water swellable, cross-linked polycarboxylic polymer, and a water soluble polymer.

The aforementioned and other aspects described herein will become more clear by reference to the Figures and descriptions of preferred embodiments.

A preferred embodiment of the invention is depicted in Figure 1. As shown in the first-frame of Figure 1, before the tablet is administered all of the active is in the dry state and thus, not subject to the deleterious action of moisture, pH effects, enzymes or other chemicals. It is also not available for absorption (bioavailable). As shown in frames 2-6 [I:\DayLib\L1BZZ]545288D speci2.doc:mrr of Figure 1, over time the residual portion of the active remains in the dry state which both protects it from water and the immediate environment as well as allowing it to serve as a reservoir for the sustained and controlled release of the active. Such a delivery system is well suited for the delivery of proteins, glycoproteins, and other drugs which must be protected from metabolism or during prolonged administration from enzymatic, pH, or moisture-induced degradation.

In a preferred embodiment, when used buccally, progressive hydration of the bioadhesive tablet protects the patient, should the tablet become dislodged, by gelifying and becoming heavier and thus less likely to float in the airway, risking aspiration. This makes this embodiment particularly well suited for agents that should reach their peak levels in the middle of the night, hormones like testosterone or steroids to treat asthma. According to the invention, the hydration of the tablet can preferably take hours 12 to 24 hours) when formulated for buccal tablets or even days when formulated for vaginal use. As will be appreciated by one of ordinary skill in the art, prior art bioadhesive tablets do not protect the active ingredient from moisture, pH, or from enzymes produced by bacteria in the septic oral and vaginal orifices.

Furthermore, as will be appreciated by one of ordinary skill in the art following the teaching of the present application, the tablet can be sized, shaped and dosed to meet the needs of the particular treatment being undertaken. For example, the buccal bioadhesive tablet depicted in Figure 1 was constructed to be only 9mm in diameter for the comfort of the patient, but made capable of delivering 7mg of testosterone per day, full physiologic level. By contrast, prior art transdermal patches were only capable of delivering 5mg per day, in other words a sub-physiologic level.

A presently preferred method of manufacturing bioadhesive tablets is diagramed in Figure 2. The presently preferred method involves three steps as described below: 1. First step: manufacture of the granulate.

Hydroxypropylmethyl cellulose 15000(=HPMC 15000) is mixed with corn starch and lactose and in case of an active ingredient not sensitive to moisture the active is added. The mixture is wet with an aqueous solution of hydroxypropylmethyl cellulose (=HPMC 5) and knead/granulated.

The granulate is dried in an oven under warm air (50'C) until moisture content is less than The dried granulate is broken with a stainless steel sieve oscillating granulator mesh size 1000 pm.

IIA\ravr ih\l TR771'4C42gnDJRnei7 dnr- 2. Second step: the tableting mixture.

Talc, silicon dioxide magnesium stearate, and in a case of an active ingredient sensitive to moisture, the active ingredient is added. All is sieved through a sieving machine having aperture size 500 jim and then transferred into a free-fall mixer.

Addition of the granulate of step 1, followed by polycarbophil, carbomer and lactose. The whole is mixed until homogenous.

3. Third step: tableting.

The tableting mixture is compressed into tablets by means of a rotative tableting machine equipped with punches 9mm flat on the upper side and curved (r=9mm) on the 1o lower side both with beveled edge. The tablets are dedusted and packed.

As depicted in Figure 2, an active ingredient that is not sensitive to moisture is preferably added during the manufacture of the granulate. However, alternatively, the active ingredient can be added during the second step after the granulate is dried and sieved. Also, as will be appreciated by one of ordinary skill in the art, this second method is particularly preferred when the active ingredient is sensitive to moisture.

In a presently preferred manufacturing process, the active ingredient is preferably protected from moisture. A wet granulation is made of lactose, corn starch and HPMC.

Testosterone, polycarbophil, carbomer 974P, talc and magnesium stearate are added dry for the final compression.

Furthermore, as will be appreciated by one of ordinary skill in the art following the teaching of the present application, the materials of construction can be varied to optimize the desired characteristics of the tablet. For example, the present inventors have discovered that by progressively increasing the amount of lactose and corn starch and progressively decreasing the amount of carbomer 974P, the amount of time it takes a tablet to hydrate is progressively increased. Accordingly, as will be appreciated by one of ordinary skill in the art, tablets suited for specific treatments specific active, specific dose, specific delivery time) can be manufactured.

These and other aspects of the invention may be more clearly shown by way of example.

12 EXAMPLE 1: TESTOSTERONE TABLET The following is an example of a formulation (Formulation 8, batch #00029906) designed for complete physiologic replacement of testosterone in men: INGREDIENT AMOUNT %w/w Testosterone 30.000 mg 24.0% HPMC 26.250 mg 21.0% Corn Starch 22.500 mg 18.0% Monohydrated Lactose 30.125 mg 24.1% 0o Silica 1.250 mg Polycarbophil (Noveon) 3.125 mg Carbomer 974P 9.375 mg Talc 1.500 mg 1.2% Magnesium stearate 0.875 mg 0.7% Formulations like the one above produced sustained release in in-vitro dissolution tests. When used in female subjects formulas like this one also produce a sustained and controlled release of testosterone for 12 hours or more.

Testosterone formulations have resulted in mean blood serum concentration ratios of testosterone to 5a-dihydrotestosterone (DHT) of 9.25 and 9.29 to 1, to as high as about 12 to 1, in the bloodstream of said mammal. It is contemplated that this mean serum concentration ratio preferably is about 9 to 1 to about 12 to 1.

The individual ingredients are well known and readily available from suppliers known in the industry.

HPMC, or hydroxypropylmethylcellulose, is a swelling, dispersing agent.

Alternates, which are well-known in the industry, include other water-swellable forms of cellulose and polymers.

Corn (maize) starch is a filler and binder. Alternates are well-known in the industry.

Lactose is a filler. Alternatives are well-known in the industry.

Silica, or silicon dioxide (silicium dioxyde), acts as a suspending and thickening agent. Alternatives are well-known in the industry.

Talc and magnesium stearate are lubricant powders commonly used in the manufacture of compressed tablets. Alternatives are well-known in the industry.

HA-\av1 ih\f T1t77154;)Rncrri1 -0mr Carbomer 934P or 974P (or CARBOPOLTM 974P) is the water soluble polymer.

This polymer provides the initial bioadhesion. Alternatives are well-known in the industry, and include, for example, other water-soluble polymers.

Polycarbophil is the water insoluble polymer, and provides the extended bioadhesion. Alternatives would include, for example, other water-insoluble, waterswellable bioadhesive polymers.

Table 1 depicts nine different formulations of bioadhesive tablets according to the invention. The active ingredient, testosterone, was held constant at 30.0 mg (24% by weight) so the effect of varying the proportions of the inactive ingredients could be io studied.

The testosterone dissolution rates of selected formulations were then studied. Table 2 depicts the testosterone dissolution rate of six tablets selected from Formula 1, batch #0069904. Table 3 depicts the testosterone dissolution rate of six tablets selected from Formula 3, batch #0049904. Table 4 depicts the testosterone dissolution rate of six tablets selected from Formula 5, batch #0029904. Table 5 depicts the testosterone dissolution rate of Formula 6, batch #0019904.

The dissolution rate data was then graphed to illustrate the percent of testosterone released per hourl Chart 1 depicts the testosterone release rate for Formula 1 (see Table Chart 2 depicts the testosterone release rate for Formula 3 (see Table Chart 3 depicts the testosterone release rate for Formula 5 (see Table Chart 4 depicts the testosterone release rate for Formula 6 (see Table 2005203703 12 Aug 2005 Testosterone KT I T1 T T Form I IForm 2 IFoff. Form 4 Famr 5 Fnrml.

Fa,.3Fr.2Iom3Fr.4Form 5 6 F '7 1 II 8Form 9 Batch 0 0069904 0059904 0049904 0039904 0029904 0619904 nmlaonr nrrn~rmnr 09 004 090 0090 001M000 1990 002 mF I %b t I %b L I J.ZZZ.I-" Weiight y g by~:7 1115 7%by by g %by Im %by Weight Weih Wih _eigt g Ieight eiti Wi gh t Testosteroe 1 30.0001 24.00 t OOD 0 A nii I 1 30gh Wih tJW 4W 3tt .00 .000~ 2 30.OOWO 30.0.00 O.D0 30.000 24.00 30.000 24.00 000: mg 30.

26.

22.

31.250( 25.002 30.000 1 2i17tf I )'vNt I I i I 15000 I I 0 21.00 26150~(LaU 26-250 211.00 26.250 Comstarh 1 2-52.01 22.0 5 00oI 22.5012 I 21.00 18-00 .00 7."

-IM~L

10-00 17.500V 14.00 22-500) is .09 22.50 22500 I UO.00 22.500 Moohdrud 11.375 9.10 13.875 11.10 16-375 13.10 15.875 15.10 21.375 17.10 24500 19.60 27.625 22.10 30.125 24.10 33 lactose 41 Silica 1.250 1.00 1.25 1.00 1.250. 1.00 1.250 1.00 1.250 1.00 M 1.00 1.250 1.00 1.50 1.00 1.

Polycarbophil 3.12.5 2.50 3125 2.50 3.125 2.50 3.125 2.50 3.125 2.50 3.125 2.5 3.125 2.50 3.125 2.50 3.

acid (Novcon 3

AA-

CArboer 43.750 35.00 37.500 30.00 31.250 25.00 25.000 20.00 18.750 15.00 15.625 12.50 12.500 10.00 9.375 7.50 6.

974 P .0 0 .7 6 Talc 0.875 0.70 0.875 0.70 0.87 0.70 0.875 0.70 00.. 1.20 1.

Magnesium 0.875 0.70 0.875 0.70 085 07(1 0a75 0-_ 39906 by Weights .000 24.00 .250 21.00 .500 18.00 .250 26.60 .250 1.00 125 2.50 250 5.00 500 1.20 875 0.70 000 100.00 sterte

I

.70 0.

.70 .5 0.I' 0.875 0.975 0.70 0.875 0.70 TotalWelght r24. nnoIMl ,1non 1 I 12s.

.00 12DO 0000 12500 UVV.IU I 312.WU0 1uu.uu ,.Ou 12 .001105.000 100.00 1.000 1210000 12&000 100.00 *HydraxypropylmeIhyl cellulose TABLE 1 2005203703 12 Aug 2005 TESTOSTERONE DISSOLUTION RATE PERCENT DISSOLUTION BATCH: 0069904 (Formula 1) DISSOLUTION APPARATUS: ROTATING PADDLE 60 RPM PLATINUM WIRE SPIRAL SAMPLE WiTHDRAW WITHDRAW WITHRAW WITHRAW WnAfDRAW WIHDRAW WITHDRAW (HOUR) (HOUR) (HOUR) (HOUR) (HOUR) (HOUR) (HOUR) 0 1 2 4 6 8 24 1 0.0 -0.7 1.9 7.6 10.6 16.0 83.6 2 0.0 0.6 1.7 6.7 11.7 18.0 88.5 3 0.0 0.7 2.0 6.9 11.7 17.9 84.9 4 0.0 0.6 1.7 7.0 11.2 17.1 88.3 0.0 0.7 1.9 6.8 10.9 17.0 87.4 6 0.0 0.7 2.1 6.6 .12.4 18.3 86.6 AVERAGE 0.0 0.7 1.9 6.9 11.4 17.4 86.6 VALUE TAB3LE 2 2005203703 TESTOSTERONE DISSOLUTION RATE PERCENT DISSOLUTION BATCH: 0049904 (Formula 3) DISSOLUTION APPARATUS: ROTATING PADDLE 60 RPM PLATINUM WIRE SPIRAL 12 Aug 2005 CA WAT P I Uf 7 IUfD Aw I wrru mD An. I i 'irwirm I I u~uru u~

(HOUR)

0

(HOUR)

T ii L1ZAr W

(HOUR)

W1MI U)KAW

(HOUR)

A

WKI-11RAW

(HOUR)

WrrHDRAW

(HOUR)

U

-1 I 0.0 019 5.6 1 10.6 16.5 U nT~ZHDRAW

(HOUR)

24 83.6 1.1 in q IL A A3 1.2 6.3 1 11.8 1 18.0 1 83.

Z

4 in q IL 5 0.0 1 1.1 I 11 1 I j f A~~mD~j~ t t 4 1.U 1.

I

82.7 83.0 85.6 83.4 r% v LAftxjl3

VALUE

10.9 16.9 J. J I I.

I

TABLE 3 2005203703 TESTOSTERONE DISSOLUTION RATE PERCENT DISSOLUTION BATCH: 0029904 (Formula DISSOLUTION APPARATUS: ROTATING PADDLE 60 RPM PLATINUM WIRE SPIRAL 12 Aug 2005 'CADRA WITDRA WIHDA W1HD g' YJ.17 SL EL'~JLr..t%

(HOUR)

0 wI l.JZ'vJ't W

(HOUR)

I

W IIIDKAW

(HOUR)

WITHDRAW

(HOUR)

WIH-DRAW

(HOUR)

2 4 .2.

0.0 1 0.9 2.2 591.

A.0 11 0 110 I t I J U.9 11)12 4 0.0 0.9 2.3 6.8 12.4 0.0 0.9 2.5 6.9 12.9 6 0.0 0.9 2.2 6.6 12.2 AVERAGE 0.0 0.9 2.4 6.6 12.1

VALUE

WITHDRAW

(HOUR)

8 16.3 17.8 17.7 18.6 19.5 18.8 18.1

WITHDRAW

(HOUR)

24 80.3 87.5 75.2 82.4 83.2 86.6 82.5 TABLE 4 2005203703 TESTOSTERONE DISSOLUTION RATE PERCENT DISSOLUTION BATCH: 0019904 (Formula 6) DISSOLUTION APPARATUS: ROTATING PADDLE 60 RPM PLATINUM WIRE SPIRAL 12 Aug 2005 SAMPLE WITHDRAW WITHDRAW WITHDRAW WITHRAW WiTHDRAW 1WITHDRAW WM (HOUR) (HOUR (HOUR) (HOUR) (HOUR) I (HOUR) I (HI I_ _1 0 1 4 -6 8

DRAW

OUR)

I I I 2 0.0 0.8 2.0 1 5.09. 1 3 0.9 4 2.3 f 6.4 1.

14.1 15.8 A.0 I A 0. 0. 1-4.6 71.7 70.1 74.6 68.6 76.6 70.3 72.'0 I I A A II'~ I Afl I I 4 t.7 L 13.1 11 V r-fur

VALUE

0.9 5.4 10.3 14.8 I TABLE 2005203703 12 Aug 2005 CHART 1 FORMULA I OF TESTOSTERONE RELEASE (DISSOLUITION/ROTATING PADDLE 60 RPM PLATINUM SPIRAL) SINGLE VALUE BATCH 0069904 100.0- 90.0 80.0 70.0 60.0 TESTOSTERONE 50.0

RELEASED

0. 2 4 6 8 10 12 14 16 18 20 22 24 26 TIME (HOUR) -3 6 2005203703 12 Aug 2005 CHART 2 OF TESTOSTERONE RELEASE (DISSOLUTION/ROTATING PADDLE 60 RPM PLATINUM SPIRAL) SINGLE VALUE BATCH 0049904 100.0 90.0 80.0- 70.0- 60.0

OF

TESTOSTERONE 50.0 RELEASED 40.0-- 0 2 4 6 8 10 12 14 16 18 20 22 24 26 TIME (HOUR) 2 2005203703 12 Aug 2005 CHART 3 OF TESTOSTERONE RELEASE (DISSOLUTION/ROTATING PADDLE60 RPM PLATINUM SPIRAL) SINGLE VALUE BATCH 0029904 100.0

OF

TESTOSTERONE

RELEASED

90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 8 10 12 14 16 18 2 TIME (HOUR) -1 0-2 3 -444- 2005203703 12 Aug 2005 CHART 4 OF TESTOSTERONE RELEASE (DISSOLUTIONJROTATING PADDLE 60 RPM PLATINUM SPIRAL) SINGLE VALUE BATCH 0019904 100.0 90.0 80.0 70.0 60.0 50.0

OF

TESTOSTERONE

RELEASED

40.0 30.0 20.0 10.0 0.0 z 4 6 8 10 12 14 16 TIME (HOUR) 18 20 22 24 26 -e-1-u-2 3 4m-5 e-6- As shown in the charts and tables, by decreasing the amount of lactose and corn starch and increasing the amount of water-soluble polymer, the time it takes for the tablet to hydrate is progressively decreased. Formulation 1 (0069904) and others like it with high levels of carbomer 974P and low levels of lactose and corn starch are probably best suited to buccal administration where 12 hours of delivery is usually sufficient. In the first example given above Formulation 8 (0029906), where the levels of lactose and corn starch are high and carbomer 974P is low, the formula is probably better suited for vaginal administration where release is often required over a period of days.

EXAMPLE 2: TESTOSTERONE TABLET (30 mg) The following is an example of a formulation designed therapy: for testosterone replacement

INGREDIENT

Testosterone

HPMC

Corn Starch Lactose Silica Polycarbophil (Noveon) Carbomer 974P Talc Magnesium stearate AMOI NT/tahlet %w/w

T

30.000 mg 26.250 mg 22.500 mg 45.125 mg 1.250 mg 3.125 mg 9.375 mg 1.500 mg 0.875 mg 21.4% 18.8% 16.1% 32.2% 0.9% 2.2% 6.7% 1.1% 0.6% EXAMPLE 3: TESTOSTERONE TABLET (6 mg) The following is an example of a formulation designed for testosterone replacement therapy: INGREDIENT AMOT INT/thle.t ow/w Testosterone

HPMC

Corn Starch Lactose Silica AMOUNT/tablet 6.000 mg 5.250 mg 4.500 mg 78.970 mg 0.700 mg 5.3% 79.0% 0.7% FI-M -1 ;6klI 1Q771';Ar1Qloprn1,-; m ;Z 1 Polycarbophil (Noveon) Carbomer 974P Talc Magnesium stearate 2.230 mg 1.000 mg 0.850 mg 0.500 mg 2.2% 0.9% EXAMPLE 4: TESTOSTERONE TABLET (3 mg) The following is an example of a formulation designed therapy: for testosterone replacement 0o INGREDIENT Testosterone

HPMC

Corn Starch Lactose Silica Polycarbophil (Noveon) Carbomer 974P Talc Magnesium stearate AMOUNT/tablet %w/w 3.000 mg 2.625 mg 2.250 mg 86.845 mg 0.700 mg 2.230 mg 1.000 mg 0.850 mg 0.500 mg 2.6% 2.3% 86.8% 0.7% 2.2% 0.9% Testosterone dosage levels as low as 3 mg have been tested on female patients. The 3 mg dosage produced serum levels of about 1-1.5 ng/ml. This is about 3-6 times greater than would typically be desired to supplement women with testosterone. Thus, as the serum levels achieved from testosterone dosing are linear with respect to the dosage in the formulation, doses of around 0.5-1 mg should be sufficient to replace testosterone in women.

In men, it would be desirable to replace testosterone using a formulation that lasts about 16-18 hours. Dosage levels of 30 mg supply physiologic concentrations of testosterone when administered twice daily, once every 12 hours. Thus, a 16-18 hour formulation would require about 45 mg to supply physiologic testosterone replacement.

EXAMPLE 5: TERBUTALINE TABLET (4 MG) The following is an example of a terbutaline formulation designed to provide certain therapeutic benefits ofterbutaline administration: I:\DayLib\LIBZZ]545288D I speci2.doc:mrr

INGREDIENT

Terbutaline sulfate

HPMC

Corn Starch Lactose Silica Polycarbophil (Noveon) Carbomer 974P Talc Magnesium stearate AMOJUNT/tahblet %w/w AM UNTV abet %w/ 4.000 mg 18.760 mg 16.070 mg 39.640 mg 0.900 mg 2.235 mg 6.700 mg 1.070 mg 0.625 mg 4.4% 20.8% 17.9% 44.0% 7.4% 1.2% 0.7% EXAMPLE 6: TERBUTALINE TABLET [2 MG] The following is an example of a terbutaline formulation designed to provide Is certain therapeutic benefits of terbutaline administration:

INGREDIENT

Terbutaline Sulfate

HPMC

Corn Starch Lactose Silica Polycarbophil (Noveon) Carbomer 974P Talc Magnesium stearate AMOI NT/tahlet o/Xwl AMOUNT/tabletr 2.000 mg 18.760 mg 16.070 mg 41.640 mg 0.900 mg 2.235 mg 6.700 mg 1.070 mg 0.625 mg 2.2% 20.8% 17.9% 46.3% 7.4% 1.2% 0.7% EXAMPLE 7 TERBUTALINE TABLET [1MG] The following is an example of a terbutaline formulation designed to provide certain therapeutic benefits of terbutaline administration:

INGREDIENT

Terbutaline Sulfate

HPMC

AMOTINT/tnhlet O/,/u/w AM UNT/ablet 0-Ixl/xx 1.000 mg 18.760 mg 1.1% 20.8% 1 Corn Starch 16.070 mg 17.9% Lactose 42640 mg 47.4% Silica 0.900 mg Polycarbophil (Noveon) 2.235 mg Carbomer 974P 6.700 mg 7.4% Talc 1.070 mg 1.2% Magnesium stearate 0.625 mg 0.7% EXAMPLE 8 DESMOPRESSIN TABLET [0.1MG] The following is an example of a desmopressin formulation designed to provide certain therapeutic benefits ofdesmopressin administration: INGREDIENT AMOUNT/tablet Desmopressin Acetate 0.105 mg Magnesium Stearate 1.000 mg Silicon Dioxide 1.000 mg Talc 1.000 mg Hydroxypropylmethylcellulose 5cps 1.500 mg Polycarbophil (Noveon) 2.235 mg Carbopol 971P 6.700 mg Hydroxypropylmethylcellulose 100,000cps 20.000 mg Lactose, anhydrous 32.460 mg Lactose, monohydrate 34.000 mg EXAMPLE 9 DESMOPRESSIN TABLET [0.2MG] The following is an example of a desmopressin formulation designed to provide certain therapeutic benefits of desmopressin administration: INGREDIENT AMOUNT/tablet Desmopressin Acetate 0.210 mg Magnesium Stearate 1.000 mg Silicon Dioxide 1.000 mg Talc 1.000 mg Hydroxypropylmethylcellulose 5cps 1.500 mg ry., I .1 Polycarbophil (Noveon) 2.235 mg Carbopol 971P 6.700 mg Hydroxypropylmethylcellulose 100,000cps 20.000 mg Lactose, anhydrous 32.460 mg Lactose, monohydrate 33.895 mg Data on desmopressin suggests that the 0.1 mg and 0.2 mg dosages provide serum concentrations that are linear with respect to dosages administered in a formulation.

Some formulations have shown mean serum concentrations of about 60 pg/ml, ranging up to about 100 pg/ml. This concentration is extremely high and needs to be decreased about 4-fold. In addition, the use of this product in children will necessitate the dosage being reduced even further to about 0.025 mg.

As will be appreciated by one of ordinary skill in the art, the examples and preferred embodiments are not intended to be limiting, and the invention applies to tablets Is comprised of any active ingredient and any combination of tablet materials. Furthermore, as will be appreciated by one of ordinary skill in the art, the invention is intended to cover the methods of manufacturing and therapeutic uses of the aforementioned tablets.

The invention being thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. Such variations are included within the scope of the appended claims.

All publications and patents or applications mentioned in this specification are herein incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference.

ri-m-t\ ;6%vI71 nC9n.~;?rr~r

Claims (31)

1. A bioadhesive controlled, sustained release progressive hydration pharmaceutical composition comprising: an effective amount of an active ingredient, a water insoluble, water-swellable cross-linked polycarboxylic polymer, and a water soluble polymer, wherein said composition is formulated to deliver the active ingredient to the bloodstream of a mammal through a mucosal surface of the mammal.

2. The composition of claim 1, wherein the active ingredient comprises one or 0o more of testosterone, progesterone, terbutaline, or desmopressin.

3. The composition of claim 1, wherein the active ingredient comprises testosterone and is present in an amount of about 0.5 mg. to 45 mg. per unit dosage of the composition.

4. The composition of claim 3, wherein the composition is formulated to provide a blood serum concentration ratioh of testosterone to 5 -dihydrotestosterone (DHT) of about 9 to 1 to about 12 to 1 in the bloodstream of the mammal.

The composition of any one of claims 1-4, formulated to deliver the active ingredient via the buccal, vaginal, nasal, or rectal cavity.

6. The composition of any one of claims 1-5, wherein the water insoluble, water- swellable cross-linked polycarboxylic polymer is polycarbophil.

7. A method of delivering to a mammal an active ingredient, comprising administering the active ingredient via a progressive hydration bioadhesive composition through a mucosal surface of the mammal.

8. The method of claim 7, wherein the composition comprises: a water insoluble, water-swellable cross-linked polycarboxylic polymer, a water soluble polymer, and the active ingredient.

9. The method of claim 8, wherein the active ingredient comprises one or more of testosterone, terbutaline, desmopressin, or progesterone.

10. The method of claim 9, wherein the active ingredient comprises testosterone, and the method provides a blood serum concentration ratio of testosterone to 5 dihydrotestosterone (DHT) of about 9 to 1 to about 12 to 1 in the bloodstream of the mammal. [I:\DayLib\LIBZZ]545288D 1 speci2.docmrr

11. The method of claim 9, wherein the active ingredient comprises testosterone and is present in an amount of about 0.5 mg. to 45 mg. per unit dosage of the composition.

12. The method of any one of claims 7-11, wherein the composition is formulated to deliver the active ingredient via the buccal, vaginal, nasal, or rectal cavity.

13. The method of any one of claims 8-12, wherein the water insoluble, water- swellable cross-linked polycarboxylic polymer is polycarbophil.

14. Use of a water insoluble, water-swellable cross-linked polycarboxylic polymer, a water soluble polymer, and an active ingredient, in the manufacture of amedicament for transmucosal administration in a mammal.

The use of claim 14, wherein the active ingredient comprises one or more of testosterone, terbutaline, desmopressin, or progesterone.

16. The use of claim 15, wherein the active ingredient comprises testosterone, and the medicament provides a blood serum concentration ratio of testosterone to 5 dihydrotestosterone (DHT) of about 9 to 1 to about 12 to 1.

17. A composition comprising a water insoluble, water-swellable, cross-linked, polycarboxylic polymer, a water soluble polymer, and an active ingredient, for use in a method of therapeutic treatment of the human or animal body comprising transmucosal administration of the active ingredient.

18. The composition of claim 1, wherein the treating agent comprises one or more of glycoproteins, proteins, sex hormones, anti-hormones, nitrates, beta-agonists, beta- antagonists, opioids, opioids-antagonists, antidepressants, HMG CoA reductase inhibitors, antihistamines, ACE inhibitors, or prostaglandins.

19. The composition of claim 18, wherein the composition is formulated as a tablet for delivery of the treating agent via the buccal or vaginal cavity.

The composition of claim 18, wherein the treating agent comprises terbutaline which is present in an amount of about 1 mg. to 4 mg. per unit dosage of the composition.

21. The composition of claim 18, wherein the treating agent comprises desmopressin which is present in an amount of about 0.025 mg; to 0.2 mg. per unit dosage of the composition.

22. The composition of any one of claims 18-21, wherein the water insoluble, water-swellable cross-linked polycarboxylic polymer is polycarbophil.

23. A method of delivering to a mammal an effective amount of a treating agent via a controlled and sustained release, progressive hydration bioadhesive pharmaceutical [I:\DayLib\LIBZZ]545288D1speci2.doc:mrr composition through a mucosal surface of the mammal, comprising the treating agent, a water insoluble, water swellable, cross-linked polycarboxylic polymer, and a water soluble polymer.

24. The method of claim 23, wherein the water insoluble, water-swellable cross- linked polycarboxylic polymer is polycarbophil.

The method of claim 23, wherein the treating agent comprises one or more of progesterone, terbutaline, desmopressin, or testosterone.

26. The method of claim 23, wherein the treating agent comprises one or more of glycoproteins, proteins, sex hormones, anti-hormones, nitrates, beta-agonists, beta- antagonists, opioids, opioids-antagonists, antidepressants, HMG CoA reductase inhibitors, antihistamines, ACE inhibitors, or prostaglandins.

27. The method of claim 25, wherein the treating agent comprises testosterone and is present in an amount of about 0.5 mg. to 45 mg. per unit dosage of the composition.

28. The method of claim 25, wherein the treating agent comprises desmopressin and is present in an amount of about 0.025 mg. to 0.2 mg. per unit dosage of the composition.

29. The method of claim 25, wherein the treating agent comprises terbutaline and is present in an amount of about 1 mg. to 4 mg. per unit dosage of the composition.

30. A bioadhesive controlled, sustained release progessive hydration pharmaceutical composition according to claim 1, substantially as hereinbefore described with reference to any one of the examples.

31. The method according to claim 7 or 23, wherein said composition is a composition according to claim Dated 12 August, 2005 Columbia Laboratories (Bermuda) Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [I:\DayLib\LIBZZ]545288D speci2.doc:mrr