An osmotic dosage form which utilizes a semipermeable wall containing at least one"exit means"which passes through the wall, surrounding a core containing an osmotic agent, a neutral and ionizable hydrogel and an active ingredient is taught in U. S. Patent No. 4, 971, 790. The coating of this device is permeable to water from the environment of use. Water moves into the core through the semipermeable membrane. Once inside the device, the water solubilizes the osmotic agent, and hydrates the hydrogels. Pressure builds up inside the device.

Ultimately, the solubilized hydrogel, containing the beneficial agent, and other core excipients are pumped out of the core, under pressure, through an exit means and into the environment of use.

The existing technology is limited since diffusion controlled systems are effective only when soluble agents are dispensed. For osmotically controlled devices, the technology relies upon a wall permeable to the passage of fluid present in the environment of use. Furthermore, these devices require a wall of carefully controlled permeability.

Devices which rely upon the establishment of an extra device super- structure can be altered during in vivo transit, for example, in the gastrointestinal tract. If portions of the superstructure break away, greater surface area is exposed to the environment and unpredictable release of the active agent may result.

A frequently encountered problem in the field of sustained release compositions is that many water-miscible drugs have a tendency to be dumped or surged into the body during the first hour or two after an oral dosage form is ingested.

This problem is particularly acute when the sustained release compositions are administered with food. Several U. S. Patents, 4, 789, 549, 4, 816, 264 and 4, 851, 233, have disclosed devices that have an improved sustained release activity. However, none are entirely satisfactory since they have a tendency to rapidly release water- miscible drugs when administered with food. Additionally, the devices disclosed are not insensitive to the pH of the environment of use.

Utilizing controlled or sustained release technologies, a single administration of the indicated daily dosage amount delivers the drug to the patient over an extended period of time (i. e. 6 to 24 hours) to yield an equivalent or improved therapeutic effect while lowering the peak drug plasma levels. Controlled delivery devices for the sustained release of therapeutically active agents are well known in the art. Generally, these devices may be characterized as either diffusion controlled systems, osmotic dispensing devices, dissolution controlled matrices, or erodible/ degradable matrices.

U. S. Patent No. 3, 538, 214 discloses a diffusion controlled device in which a tablet core containing an active ingredient is surrounded by a water insoluble coating which contains a film modifying agent soluble in the external fluids in the gastrointestinal tract.

An example of an osmotic device is described in U. S. Patent Nos.

3, 845, 770 and 3, 916, 899 which is a core composition of an active agent and an osmotically effective solute which is enclosed by an insoluble semipermeable wall having a release means. Numerous modifications to these types of delivery devices have been described in the art in an effort to improve their release characteristics.

U. S. Patent Nos. 4, 256, 108, 4, 160, 452, 4, 200, 098, 4, 285, 987, 4, 327, 725, 4, 612, 008 and 5, 376, 383 disclose such improved delivery devices.

U. S. Patent No. 4, 851, 228 and co-pending U. S. Patent Application Serial No. 073, 781, filed July 15, 1987 disclose systems which comprise an inner core compartment of osmotically active composition surrounded by an enclosed controlled porosity wall material that is substantially permeable to both solute and external fluid. These systems are osmotic dispensing devices for a broad range of therapeutically active agents. Co-pending U. S. Patent Application Serial No.

348, 099, filed May 1, 1989, discloses such a delivery system which is controlled through the influence of a controlled release solubility modulator contained within the drug delivery device. U. S. Patent No. 4, 795, 644 also discloses such a delivery system which is controlled through the influence of a water insoluble non-diffusible charged resin entity contained within the drug delivery device.

U. S. Patent No. 4, 755, 180 discloses a dosage form comprising a beneficial agent and a polymer coated osmotically effective solute for regulating the solubility of the beneficial agent.

Numerous examples of diffusion controlled and erodible/degradable devices are discussed in detail in Controlled Drug Deliverv : Fundamentals and Applications, 2nd Edition, J. R. Robinson and V. H. L. Lee, Eds., Marcel Dekker, Inc., New York and Basel, 1987, and in Controlled Drug Delivery : Basic Concepts, Vols. I and II, S. D. Brunk, Ed., CRC Press Inc., Boca Raton, Fla. (1983).

In addition, a review of osmotic drug delivery inventions is provided in detail by G. Santus and R. W. Baker in"Osmotic Drug Delivery : A Review of the Patent Literature,"J. of ControllerRelease, vol. 35, pp. 1-21 (1995).

It is well known that certain osmotic devices (referred to as "elementary osmotic pumps") can deliver water-soluble agents, which exhibit pH dependent solubility, largely independent of the pH of the surrounding environment.

However, these pumps comprise an osmotically active core that is surrounded by a semipermeable membrane. Semipermeable membranes are generally permeable to small solvent molecules, such as water, but comparatively impermeable to dissolved solutes. Even small ions are not readily exchanged across such membranes. Accord- ingly, semipermeable membranes, although able to prevent neutralizing ions from entering the core of an osmotically active dosage form, do not have the flexibility desired for modulating the rate of release of the beneficial agent from the device.

It would be useful to have a device where the mechanism of release is insensitive to the pH level of the environment of use. Such a device may be of particular importance for cancer patients since such patients may have metabolic or other gastrointestinal problems or abnormalities.

It is, therefore, an object of this invention to develop a controlled release drug delivery device, which has a mechanism of release that is insensitive to the pH level of the environment of use, for a drug with a pH-dependent solubility profile across a range of physiologically relevant pH values.

It is also an object of this invention to develop a controlled release drug delivery device that has an improved flexibility in modulating the rate of release.

SUMMARY OF THE INVENTION In a first embodiment, the present invention is related to a pH insensitive drug delivery device, specifically an osmotic pump, for the controlled release of a beneficial agent in an environment of use, which comprises a) a core prepared from an admixture comprising :

i) a therapeutically effective amount of at least one beneficial agent, or salts thereof, that has a solubility profile that is dependent on the pH level of the environment of use ; and ii) at least one pH modulating agent ; and b) a controlled porosity, microporous coating which surrounds the core.

In a second embodiment. the invention is also related to a pH insensitive. osmotic drug delivery device for the controlled release of a beneficial agent in an environment of use. which comprises a) a core containing a therapeutical) y effective amount of at ieast one beneficial agent. or salts thereof, that has a solubility profile that is dependent on the pH level of the environment of use ; and b) a controlled porosity, microporous coating which surrounds the core and has at least one aperture.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts a schematic of an operational osmotic drug delivery device showing permeability of the microporous, controlled porosity membrane to gastrointestinal fluids and the corresponding delivery of a solution of the beneficial agent from the device ; FIG. 2 illustrates the release profile of Compound A in the absence of a pH modulating agent and an aperture ; FIG. 3 depicts the release profile of Compound A from the drug delivery device of the instant invention where a pH modulating agent is present ; and FIG. 4 illustrates the release profile of Compound A from the drug delivery device of the instant invention where a pH modulating agent and at least one aperture are present.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention is related to a pH insensitive drug delivery device, specifically an osmotic pump, for the controlled release of a beneficial agent in an environment of use, which comprises a) a core prepared from an admixture comprising :

i) a therapeutically effective amount of at least one beneficial agent, or salts thereof, that has a solubility profile that is dependent on the pH level of the environment of use ; and ii) at least one pH modulating agent ; and b) a controlled porosity, microporous coating which surrounds the core.

In a further embodiment of the instant invention, the osmotic controlled release drug delivery device comprises : a) a core prepared from an admixture comprising : i) a therapeutically effective amount of at least one beneficial agent, or salts thereof, that has a solubility profile that is dependent on the pH level of the environment of use ; and ii) at least one pH modulating agent ; b) a controlled porosity, microporous coating which surrounds the core ; and c) at least one aperture in the controlled porosity, microporous coating.

In a second embodiment, the present invention is also related to a pH insensitive. osmotic drug delivery device for the controlled release of a beneficial agent in an environment of use. which comprises a) a core containing a therapeutically effective amount of at least one beneficial agent. or salts thereof, that has a solubility profile that is dependent on the pH level of the environment of use : and b) a controlled porosity, microporous coating which surrounds the core and has at least one aperture.

The instant invention provides a means for administering, in a controlled-release manner for up to about a 24-hour period, a therapeutic dose of a beneficial agent that has a water solubility profile that is highly dependent on the pH levels in the environment of use. In one embodiment of the instant invention, the osmotic pump is used for the controlled oral delivery of a water-soluble, beneficial agent or water-soluble salts of beneficial agents. Preferably, the beneficial agent or salt of the beneficial agent is weakly basic. These beneficial agents or salts of the beneficial agents will have a decrease in water solubility greater than about 100-fold across a range of physiologically relevant pH levels (about 2 to about 8). Preferably,

there will be a decrease in water solubility greater than about 500-fold. More preferably, there will be a decrease greater than about 1000-fold. Additionally, the beneficial agents, or salts of the beneficial agents, will have a dose : solubility ratio of less than about 7. 0 mL. The dose : solubility ratio is defined by the amount of beneficial agent per unit dosage form and the maximum water solubility of the beneficial agent within the physiologically relevant pH range.

The dose : solubility ratio is significant in that it represents the total volume of fluid that must penetrate the controlled porosity, microporous membrane during operation of the device in order to deliver the majority of the dose to the external environment of the device. For example, a device containing 100 mg of a drug that has a maximum solubility 50 mg/mL would result in a dose : solubility ratio of 2. 0 mL. Values greater than about 7. 0 mL would necessitate a controlled porosity, microporous membrane of such high permeability to GI fluids that the structural integrity of the membrane would likely be compromised during operation of the device. Therefore, preferably, the dose : solubility ratio of the beneficial agent (s) in the environment inside of the device is less than about 5. 0 mL. More preferably, the dose : solubility ratio is less than about 3. 0 mL. Most preferably, the dose : solubility ratio is less than about 1. 5 mL.

In an embodiment of the instant invention, the preferred beneficial agent is 1- (3-chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolyl methyl]- 2-piperazinone (Compound A), which has a solubility profile that is highly dependent on pH levels, in that it is very soluble (greater than about 700 mg/mL) at low pH levels (less than about 2) and practically insoluble (less than about 100, ug/mL) at near neutral pH levels (greater than about 5).

By"drug delivery device"is meant a dosage form that provides a convenient means of delivering a drug to a subject. The subject can be a human or any other animal. The device is designed to be useful for the delivery of a drug by any pharmaceutically accepted means such as by swallowing, retaining it within the mouth until the beneficial agent has been dispensed, placing it within the buccanal cavity, or the like.

By"controlled"production is meant that the rate of release of the beneficial agent, that is the amount of beneficial agent released from the device to the environment of use per unit time, follows a predetermined pattern. Thus, relatively

constant or predictably varying amounts of the beneficial agent can be dispensed over a specified period of time.

The term"core", or"core mixture", refers to an admixture of ingredients comprising at least one beneficial agent that has a pH dependent solubility profile, and may have at least one pH modulating agent and other ingredients that may affect (1) the stability of the components of the dosage form : or (2) the process characteristics of the admixture. These ingredients may be blended in such a way to produce a uniform material. This uniform material may then be compressed, within a die, to produce a desired form, normally in the shape of a tablet, capsule or bolus.

In the first embodiment of the instant invention, at least one pH moulating agent is contained in the core.

The term"beneficial agent"broadly includes any drug or mixture thereof, that can be delivered from the system to produce a beneficial result. In the specification and the accompanying claims, the term"beneficial agent","drug"or their equivalents include any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals. The term"animal" includes mammals, humans and primates such as domestic household, sport or farm animals such as sheep, goats, cattle, horses and pigs ; laboratory animals such as mice, rats and guinea pigs, fish, avians, reptiles and zoo animals.

The beneficial agent that can be delivered by the novel device of this invention, includes inorganic and organic compounds without limitation, including drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, skeletal systems, autocoid systems, alimentary and excretory systems, inhibitory and histamine systems, and those materials that act on the central nervous system such as hypnotics and sedatives. Examples of beneficial drugs are disclosed in Remington's Pharma- ceutical Sciences, 16 Ed., 1980, published by Mack Publishing Co., Eaton, Pa. ; and in The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 6'h Ed., 1980, published by the MacMillan Company, London ; and in The Merck Index, l 1th Edition, 1989, published by Merck & Co., Inc., Rahway, N. J.

Preferably, the beneficial agent is useful in the treatment of cancer.

More preferably, the beneficial agent is a prenyl-protein transferase inhibitor.

Specific examples of prenyl protein inhibitors, particularly farnesyl-protein transferase inhibitors, that may be useful in the instant invention are described in the following patents, pending applications and publications, which are herein incorporated by reference : U. S. Patent No. 5, 238, 922 issued on August 24, 1993 ; U. S. Patent No. 5, 340, 828, issued on August 23, 1994 ; U. S. Patent No. 5, 480, 893 issued on January 2, 1996 ; U. S. Patent No. 5, 352, 705 issued on October 4, 1994 ; U. S. Patent No. 5, 504, 115 issued on April 2, 1996 ; U. S. Patent No. 5, 326, 750 issued on July 16, 1994 ; U. S. Patent No. 5, 504, 212 issued on April 2, 1996 ; U. S. Patent No. 5, 686, 472 issued on November 11, 1997 ; U. S. Patent No. 5, 736, 539 issued on April 7, 1998 ; U. S. Patent No. 5, 439, 918 issued on August 8, 1995 ; U. S. Patent No. 5, 576, 313 issued on November 19, 1996 ; U. S. Patent No. 5, 571, 835 issued on November 5, 1996 ; U. S. Patent No. 5, 491, 164 issued on February 13, 1996 ; U. S. Patent No. 5, 631, 280 issued on May 20, 1997 ; U. S. Patent No. 5, 576, 293 issued on November 19, 1996 ; U. S. Patent No. 5, 468, 733 issued on November 21, 1995 ; U. S. Patent No. 5, 585, 359 issued on December 17, 1996 ; U. S. Patent No. 5, 523, 456 issued on June 4, 1996 ; U. S. Patent No. 5, 652, 257 issued on July 29, 1997 ; U. S. Patent No. 5, 661, 161 issued on August 26, 1997 ;

U. S. Patent No. 5, 578, 629 issued on November 26, 1996 ; U. S. Patent No. 5, 627, 202 issued on May 6, 1997 ; U. S. Patent No. 5, 624, 936 issued on April 29, 1997 ; U. S. Patent No. 5, 534, 537 issued on July 9, 1996 ; U. S. Patent No. 5, 710, 171 issued on January 20, 1998 ; U. S. Patent No. 5, 703, 241 issued on December 30, 1997 ; U. S. Patent No. 5, 856, 326 issued on January 5, 1999 ; U. S. Patent No. 5, 710, 171 issued on January 20, 1998 ; U. S. Patent No. 5, 756, 528 issued on May 26, 1998 ; U. S. Patent No. 5, 972, 984 issued on October 26, 1999 ; U. S. Patent No. 5, 817, 678 issued on October 6, 1998 ; U. S. Patent No. 5, 968, 965 issued on October 19, 1999 ; U. S. Patent No. 5, 914, 341 issued on June 22, 1999 ; U. S. Patent No. 6, 028, 201 issued on January 22, 2000 ; U. S. Patent No. 5, 981, 562 issued on November 9, 1999 ; U. S. Patent No. 5, 919, 785 issued on July 6, 1999 ; U. S. Patent No. 5, 859, 012, issued on January 12, 1999 ; USSN 08/834, 671, filed on April 1, 1997, and WO 97/36876 (October 9, 1997) ; U. S. Patent No. 5, 972, 942 issued on October 26, 1999 ; U. S. Patent No. 5, 852, 010 issued on December 22, 1998 ; U. S. Patent No. 5, 998, 407 issued on December 7, 1999 ; U. S. Patent No. 5, 780, 488 issued on July 14, 1998 ; U. S. Patent No. 5, 859, 015 issued on January 12, 1999 ; U. S. Patent No. 6, 028, 201 issued on January 22, 2000 ;

U. S. Patent No. 5, 922, 883 issued on July 13, 1999 ; U. S. Patent No. 5, 891, 889, issued on April 6, 1999 ; U. S. Patent No. 5, 885, 995 issued on March 23, 1999 ; U. S. Patent No. 5, 965, 578 issued on October 12, 1999 ; U. S. Patent No. 5, 925, 651 issued on July 20, 1999 ; U. S. Patent No. 6, 001, 835 issued on December 14, 1999 ; U. S. Patent No. 5, 869, 682 issued on February 9, 1999 ; U. S. Patent No. 5, 939, 557 issued on August 17, 1999 ; U. S. Patent No. 5, 859, 035 issued on January 12, 1999 ; U. S. Patent No. 5, 854, 264 issued on December 29, 1998 ; U. S. Patent No. 5, 833, 105 issued on March 16, 1999 ; U. S. Patent No. 5, 854, 265 issued on December 29, 1998 ; WO 97/36875 (October 9, 1997) ; U. S. Patent No. 5, 874, 452 issued on February 23, 1999 ; U. S. Patent No. 5, 880, 140 issued on March 9, 1999 ; U. S. Patent No. 5, 872, 136 issued on February 16, 1999 ; U. S. Patent No. 6, 015, 817 issued on January 18, 2000 ; U. S. Patent No. 5, 972, 966 issued on October 26, 1999 ; U. S. Patent No. 5, 932, 590 issued on August 3, 1999 ; U. S. Patent No. 5, 977, 134 issued on November 2, 1999 ; U. S. Patent No. 5, 939, 439 issued on August 17, 1999 ; U. S. Patent No. 6, 093, 737 issued on July 25, 2000 ; U. S. Patent No. 6, 103, 723 issued on August 15, 2000 ; USSN 09/167, 180, filed on October 6, 1998, and WO 99/17777 (April 15, 1999) ;

USSN 09/332, 769, filed on June 14, 1999and WO 99/65494 (December 23, 1999) ; U. S. Patent No. 6, 127, 390 issued on October 3, 2000, and WO 99/18096 (April 15, 1999) ; USSN 09/140, 919, filed on August 26, 1998 and WO 99/10329 (March 4, 1999) ; USSN 09/140, 584, filed on August 26, 1998 and WO 99/09985 (March 4, 1999) ; U. S. Patent No. 6, 054, 466 issued on April 25, 2000, and WO 99/27928 (June 10, 1999) ; U. S. Patent No. 5, 972, 984 issued on October 26, 1999, and WO 96/39137 (December 12, 1996) ; USSN 09/342, 701, filed on June 29, 1999, and WO 00/01702 (January 13, 2000) ; USSN 09/347, 673, filed on June 29, 1999, and WO 00/01701 (January 13, 2000) ; USSN 09/342, 577, filed on June 29, 1999, and WO 00/01382 (January 13, 2000) ; USSN 09/516, 756, filed on March 1, 2000, and WO 00/52134 (September 8, 2000) ; USSN 09/516, 945, filed on March 1, 2000, and WO 00/51547 (September 8, 2000) ; USSN 09/516, 750, filed on March 1, 2000, and WO 00/51611 (September 8, 2000 ; USSN 09/516, 757, filed on March 1, 2000, and WO 00/51612 (September 8, 2000) ; USSN 09/516, 944, filed on March 1, 2000, and WO 00/51614 (September 8, 2000) ; USSN 09/456, 153, filed on December 7, 1999, and WO 00/34437 (June 15, 2000) ; USSN 09/455, 627, filed on December 7, 1999, and WO 00/34239 (June 15, 2000) ; USSN 09/657, 451, filed on September 7, 2000 ; USSN 09/656, 653, filed on July 7, 2000.

The following compounds, which are inhibitors of farnesyl-protein transferase, may also be adapted for use in the instant invention described herein : (+)-6- [amino (4-chlorophenyl) (1-methyl-lH-imidazol-5-yl) methyl]-4- (3- chlorophenyl)-1-methyl-2 (lH)-quinolinone (Compound J)

(-)-6-[amino (4-chlorophenyl) (1-methyl-1 H-imidazol-5-yl) methyl]-4-(3- chlorophenyl)-1-methyl-2 (1H)-quinolinone (Compound J-A ; designated"comp.

74"in WO 97/21701) ; (+)-6- [amino (4-chlorophenyl) (1-methyl-lH-imidazol-5- yl) methyl]-4- (3-chlorophenyl)-1-methyl-2 (1H)-quinolinone (Compound J-B ; designated"comp. 75"in WO 97/21701) or a pharmaceutically acceptable salt thereof.

The syntheses of these compounds are specifically described in PCT Publication WO 97/21701, in particular on pages 19-28. The preferred compound among these compounds to use in the instant formulation is Compound J-B. Other compounds described in PCT Publication W097/21701 may also be beneficially administered using the instant formulation.

The following compound which is an inhibitor of farnesyl-protein transferase may also be adapted for use in the instant invention described herein :

or a pharmaceutically acceptable salt thereof.

The synthesis of this compound is specifically described in PCT Publication WO 97/23478, in particular on pages 18-56. In WO 97/23478, the above compound is designated compound"39. 0" and is specifically described in Example 10. Other compounds described in PCT Publication WO 97/23478 may also be beneficially administered using the instant formulation.

All patents, publications and pending patent applications identified are herein incorporated by reference. The above list of drugs is not meant to be exhaustive. Many other drugs will certainly work in the instant invention.

One particular beneficial agent that can be used in the instant invention is l- (3-chlorophenyl)-4- [l- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinone, or its pharmaceutically acceptable salt, as described in US Patent No. 5, 856, 326, which issued on January 5, 1999, or U. S. Serial Nos. 09/338, 643, 09/338, 064 or 09/338, 065, which were co-filed on June 23, 1999. This particular beneficial agent (also herein- after referred to as"Compound A") may be prepared using the techniques described in the above patent or pending patent applications, which are herein incorporated by reference.

The dissolved beneficial agent can be in various forms, such as charged molecules, charged molecular complexes, ionizable salts or hydrates.

Pharmaceutically acceptable salts include, but are not limited to hydrochlorides, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate, malate, succinate, trimethamine, tartrate, oleate, salicylate, salts of metals, and amines or organic cations, for example quaternary ammonium.

Derivatives of the beneficial agents, such as esters, ethers and amides without regard to their ionization and solubility characteristics can be used alone or mixed with other drugs. Also, a beneficial agent can be used in a form that, upon

release from the device, is converted by enzymes, hydrolyzed by body pH or other metabolic processes to the original form, or to a biologically active form.

By"therapeutically effective amount"is meant that the quantity of beneficial agent contained in the core, which can be delivered to the environment of use, has been demonstrated to be sufficient to induce the desired effect during studies utilizing the beneficial agent.

The beneficial agent may comprise from about 0. 1% to about 95% by weight of the core, or"core mixture". Generally, the device can house from about 100 ig to about 1 gram of beneficial agent or more, with individual devices containing, for example about 25 ng, about 1 mg, about 5 mg, about 250 mg, about 500 mg, about 1 g, or the like. Preferably, the device comprises about 1 mg to about 1 gram of beneficial agent. Most preferably, the device comprises about 1 mg to about 100 mg of beneficial agent.

In the first embodiment of the present invention, at least one pH modulating agent is contained in the core. In this embodiment, the term"pH modulating agent"refers to an agent which is capable of offsetting the neutralizing capacity of various extraneous anions or cations that may be present and may affect the release of the beneficial agent during normal operation of the drug delivery device. Depending on the beneficial agent being used, the pH modulating agent may be selected from an acid or base. Preferably, the pH modulating agent is selected from a pharmaceutically acceptable organic acid. At least one organic acid, but in most cases preferably no more than 3, is present in the core of the instant invention.

Depending on the physical and chemical properties of the beneficial agent and the desired delivery profile, more than 3 organic acids may be included in the core of the instant invention. Types of organic acids that may be used include, but are not limited to, adipic acid, ascorbic acid, citric acid, fumaric acid, gallic acid, glutaric acid, lactic acid, malic acid, maleic acid, succinic acid, tartaric acid and other organic acids suitable for use in pharmaceutical preparations for oral administration. Prefer- ably, at least one of the organic acids is selected from succinic acid, citric acid and tartaric acid. Most preferably, in an embodiment where the beneficial agent is 1- (3- chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinone, at least one pharmaceutically acceptable organic acid is succinic acid.

In this first embodiment, the pH modulating agent, preferably a pharmaceutically acceptable organic acid, is used to control the pH of the core, due

to the solubility profile of the beneficial agent, and also controls the pH of the fluids exiting the core so that a precipitate of the beneficial agent is not formed within the controlled porosity, microporous membrane or on the external surface of the delivery device.

Other excipients such as lactose, magnesium stearate, microcrystalline cellulose, starch, stearic acid, BHA (butylated hydroxyanisole), calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients commonly utilized as stabilizing agents or to aid in the production of tablets may also be present in the core.

The core containing a beneficial agent, and any other necessary excipients, such as a pH modulating agent described in the first embodiment, as described herein, is typically in the form of a solid conventional tablet. Several techniques may be utilized to prepare the tablet formulation. For example, the core, or"core mixture", may be compressed into its final shape using a standard tablet compressing machine. The core may contain compressing aids and diluents such as microcrystalline cellulose and lactose, respectively, that assist in the production of compressed tablets. The core can be comprised of a mixture of agents combined to give the desired manufacturing and delivery characteristics. Other techniques to prepared a tablet formulation include, but are not limited to, extrusion, spheronization, coating of inert carriers (such as non-pareils), or other multi-particle, multi-unit technology, and the like. ("Pharmaceutical Pelletization Technology", Drugs and the Pharmaceutical Sciences, Vol. 37 (1998) ;"Multiparticulate Oral Drug Delivery", Drugs and the Pharmaceutical Sciences, Vol. 65 (1994)).

The number of agents that may be combined to make the core is substantially without an upper limit. Generally, the core will contain about 1% to about 95% by weight of the core mixture, of a beneficial agent admixed with other solute (s). Representative of compositions of matter that can be released from the device and can function as a solute are, without limitation, those compositions as described.

In the first embodiment, the number of agents that may be combined in the core has a lower limit equaling two components : (1) the beneficial agent (or drug) and (2) a pH modulating agent. In such an embodiment, the specifications for the core are summarized below and include :

1. Core Beneficial Agent Loading (size) : about 0. 1% to about 95% by weight of the total core mixture or about 100 micrograms to about 1 gram or more (includes dosage forms for humans and animals) ; and 2. pH Modulating Agent : about 0. 1% to about 95% by weight of the total core mixture.

More preferably, in this embodiment, the pH modulating agent will comprise about 5% to about 50% by weight of the total core mixture. Most prefer- ably, in this embodiment, the pH modulating agent will comprise about 10% to about 20% by weight of the total core mixture.

In the second embodiment, the core comprises at least one beneficial agent.

In cases where the beneficial agent and the pH modulating agent exhibit the desired release rate, stability, and manufacturing characteristics, there is no critical upper or lower limit as to the amount of beneficial agent that can be incorporated into a core mixture. The ratio of beneficial agent to excipient is dictated by the desired time span and profile of release, and the pharmacological activity of the beneficial agent. Generally, in either the first or second embodiments, the core will contain about 1% to about 95% by weight of the core mixture, of a beneficial agent admixed with other solute (s).

The coating, applied to the core, is a material that is microporous, can form films, and does not adversely affect the drug, animal body, or host. The micro- porous coating has a controlled porosity and allows for the rapid entry of the fluids of the environment of use into the core of the delivery device. The microporous coating enhances permeability, which in turn increases the release rate of the beneficial agent.

By"microporous"is meant that the coating comprises a rate controlling water insoluble wall, having a fluid permeability of about 6. 96 X 10-18 to about 6. 96 X 10-14 cm3sec/g and a reflection coefficient of less than about 0. 5, prepared from : (1) a polymer permeable to water but impermeable to solute and (2) about 0. 1 to about 60% by weight, based on the total weight of (1) and (2), of at least one pH insensitive pore forming additive dispersed throughout the wall. The wall is comprised of (a) polymeric material that is insoluble in the fluids of the environment of intended use (usually water) ; (b) other added excipients that will dissolve in the environmental fluids and leach out of the wall. The leached wall is a sponge-like structure composed of numerous open and closed cells that form a discontinuous

interwoven network of void spaces when viewed with a scanning electron microscope. This controlled porosity wall serves as both the water entry and core composition solution exit site. The wall is permeable to both water and solutes, and as constituted in the environment of use has a small solute reflection coefficient,, and displays poor semipermeable characteristics when placed in a standard osmosis cell.

The specifications for the wall are summarized below and include : 1. Fluid Permeability about 6. 96 X 10-18 to about 6. 96 X 10'4cm3sec/g (equivalent to 10-5 to 10-1 cm3/mil/cm2hr atm) 2. Reflection Coefficient Microporous coats to have a reflection coefficient,, defined as : Hydrostatic pressure difference a = X Osmotic volume flux Osmotic pressure difference X Hydrostatic volume flux where o is less than 1, preferably 0 to 0. 8 A specific embodiment of the present invention are those osmotic pumps wherein the reflection coefficient of the wall is less than about 0. 5.

Exemplifying this embodiment are those osmotic pumps wherein the reflection coefficient of the wall is less than about 0. 1.

Additional, preferred specifications for the wall include : 1. Plasticizer and Flux Regulating 0 to 50, preferably 0. 001 to 50, parts per 100 parts wall Additives material 2. Surfactant Additives 0 to 40, preferably. 001 to 40, parts per 100 parts wall material 3. Wall Thickness 1 to 1000, preferably 20 to 500, microns typically, although thinner and thicker fall within the invention 4. Microporous Nature 5% to 95% pores, between 10 angstroms and 100 microns diameter 5. Pore forming Additives 0. 1 to 60%, preferably 0. 1 to 50%, by weight, based on the total weight of pore forming additive, preferably : (a) 0. 1 to 50%, preferably 0. 1 to 40% by weight solid additive, (b) 0. 1 to 40% by weight liquid additive, but no more than 60% total pore formers

The water insoluble wall of the microporous coating must not be covered on its inner or outer surface by a layer of material that is impermeable to dissolved solutes within the core during the period of pumping operation.

Any polymer permeable to water but impermeable to solutes as previously defined may be used. Examples include cellulose acetate having a degree of substitution, D. S., meaning the average number of hydroxyl groups on the anhydroglucose unit of the polymer replaced by a substituting group, up to 1 and acetyl content up to 21% ; cellulose diacetate having a D. S. of 1 to 2 and an acetyl content of 21 to 35% ; cellulose triacetate having a D. S. of 2 to 3 and an acetyl content of 35 and 44. 8% ; cellulose propionate having an acetyl content of 1. 5 to 7% and a propionyl content of 39. 2 and 45% and hydroxyl content of 2. 8 to 5. 4% ; cellulose acetate butyrate having a D. S. of 1. 8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39% ; cellulose acetate having an acetyl content of 2 to 99. 5%, a butyryl content of 17 to 53%, and a hydroxyl content of 0. 5 to 4. 7% ; cellulose triacetylates having a D. S. of 2. 9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, cellulose triheptylate, cellulose tricaprylate, cellulose trioctanoate, and cellulose tripropionate ; cellulose diesters having a lower degree of substitution and prepared by the hydrolysis of the corresponding triester to yield cellulose diacylates having a D. S. of 2. 2 to 2. 6 such as cellulose dicapyrlate and cellulose dipentanate ; and esters prepared from acyl anhydrides or acyl acids in an esterification reaction to yield esters containing different acyl groups attached to the same cellulose polymer such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate palmitate and cellulose acetate heptanoate and the like.

Additional polymers that can be used for the purpose of the invention include cellulose acetate acetoacetate, cellulose acetate chloroacetate, cellulose acetate furoate, dimethoxyethyl cellulose acetate, cellulose acetate carboxymethoxy- propionate, cellulose acetate benzoate, cellulose butyrate napthylate, methylcellulose acetate methylcyanoethyl cellulose, cellulose acetate methoxyacetate, cellulose acetate ethoxyacetate, cellulose acetate dimethylsulfamate, ethylcellulose, ethyl-

cellulose dimethylsulfamate, cellulose acetate p-toluene sulfonate, cellulose acetate methylsulfonate, cellulose acetate dipropylsulfamate, cellulose acetate butylsulfonate, cellulose acetate laurate, cellulose stearate, cellulose acetate methylcarbamate, agar acetate, amylose triacetate beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate dimethyl aminoacetate, cellulose acetate ethyl carbonate, poly (vinyl methyl) ether copolymers, cellulose acetate with acetylated hydroxy-ethyl cellulose hydroxylated ethylenevinylacetate, poly (ortho ester) s, polyacetals, semipermeable polyglycolic or polyactic acid and derivatives thereof, selectively permeable associated polyelectrolytes, polymers of acrylic and methacrylic acid and esters thereof, film forming materials with a water sorption of one to fifty percent by weight at ambient temperatures with a presently preferred water sorption of less than thirty percent, acylated polysaccharides, acylated starches, aromatic nitrogen containing polymeric materials that exhibit permeability to aqueous fluids, membranes made from polymeric epoxides, copolymers of alkylene oxides and alkyl glycidyl ethers, polyurethanes, and the like. Admixtures of various polymers may also be used.

The polymers described are known to the art or they can be prepared according to the procedures in Encyclopedia of Polvmer Science and Technology, Vol. 3, pages 325 to 354 and 459 and 549, published by Interscience Publishers, Inc., New York, in Handbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971, published by CRC Press, Cleveland, Ohio ; and in U. S. Patent Nos. 3, 133, 132 ; 3, 173, 876 : 3, 276586 ; 3, 541, 055 ; 3, 541, 006 ; and 3, 546, 142.

A controlled porosity wall can be generically described as having a sponge-like appearance. The pores can be continuous pores that have an opening on both faces of a microporous lamina, pores interconnected through tortuous paths of regular and irregular shapes including curved, curved-linear, randomly oriented continuous pores, hindered connected pores and other porous paths discernible by microscopic examination. Generally, microporous lamina are defined by the pore size, the number of pores, the tortuosity of the microporous path and the porosity which relates to the size and number of pores. The pore size of a microporous lamina is easily ascertained by measuring the observed pore diameter at the surface of the material under the electron microscope. Generally, materials possessing from about 5% to about 95% pores and having a pore size from about 10 angstroms to about 100 microns can be used.

Any pH insensitive pore forming additives may be used in the instant invention. The microporous wall may be formed in situ, by a pore-former being removed by dissolving or leaching it to form the microporous wall during the opera- tion of the system. The pores may also be formed in the wall prior to operation of the system by gas formation within curing polymer solutions which result in voids and pores in the final form of the wall. The pore-former can be a solid or a liquid.

The term liquid, for this invention, embraces semi-solids, and viscous fluids. The pore-formers can be inorganic or organic. The pore-formers suitable for the inven- tion include pore-formers that can be extracted without any chemical change in the polymer. Solid additives include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate and the like. The alka- line earth metal salts such as calcium chloride, calcium nitrate, and the like. The transition metal salts such as ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride, and the like. Water may be used as the pore-former. The pore-formers include organic compounds such as saccharides. The saccharides include the sugars sucrose, glucose, fructose, mannose, galactose, aldohexose, altrose, talose, lactose, monosaccharides, disaccharides, and water soluble polysaccharides. Also, sorbitol, manitol, organic aliphatic and aromatic ols, including diols and polyols, as exemp- lified by polyhydric alcohols, poly (alkylene glycols), polygylcols, alkylene glycols, poly (a-co) alkylenediols, esters or alkylene glycols poly vinylalcohol, poly vinyl pyrrolidone, and water soluble polymeric materials. Pores may also be formed in the wall by the volatilization of components in a polymer solution or by chemical reactions in a polymer solution which evolves gases prior to application or during application of the solution to the cores mass resulting in the creation of polymer foams serving as the porous wall of the invention. The pore-formers are nontoxic, and on their removals, channels form that fill with fluid. The channels become a transport path for fluid. In a preferred embodiment, the non-toxic pore-forming agents are selected from the group consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (a-co) alkylenediols, esters of alkylene glycols and glycols, that are used in a biological environment.

The microporous materials can be made by etched nuclear tracking, by cooling a solution of flowable polymer below the freezing point with subsequent evaporation of solvent to form pores, by gas formation in a polymer solution which

upon curing results in pore formation, by cold or hot stretching at low or high temperatures until pores are formed, by leaching from a polymer a soluble component by an appropriate solvent, by ion exchange reaction, and by polyelectrolyte processes.

Processes for preparing microporous materials are described in Synthetic Polymer Membranes, by R. E. Kesting, Chapters 4 and 5, 1971, published by McGraw Hill, Inc. ; Chemical Reviews, Ultrafiltration, Vol. 18, pages 373 to 455, 1934 ; Polymer Eng. And Sci., Vol. 11, No. 4, pages 284-288, 1971 ; J. Appl. Poly. Sci., Vol. 15, pages 811 to 829, 1971 ; and in U. S. Patent Nos. 3, 565, 259 ; 3, 615, 024 ; 3, 751, 536 ; 3, 801, 692 ; 3, 852, 224 ; and 3, 849, 528.

It is generally desirable from a preparation standpoint to mix the polymer in a solvent. Exemplary solvents suitable for manufacturing the wall of the osmotic device include inert inorganic and organic solvents that do not adversely harm the core, wall and the materials forming the final wall. The solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatics, heterocyclic solvents and mixtures thereof.

Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, ethyl lactate, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, metropropane, tetrachloroethene, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, dimethylbromamide, benzene, toluene, naphtha, 1, 4- dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol. Illustrative of mixed solvents are acetone-methanol (80 : 20), acetone-ethanol (90 : 10), methylene dichloridemethanol (80 : 20), nitroethane-ethanol (50 : 60), nitroethane-ethanol (80 : 20), ethyl acetate- ethanol (80 : 20), ethylene dichloride-methanol (80 : 20), methylenedichloride-methanol (78 : 22), acetone-water (90 : 10), chloroform-ethanol (80 : 20), methylenedichloride- ethanol (79 : 21), methylene chloridemethanol-water (75 : 22 : 3), carbontetrachloride- methanol (70 : 30), expressed as (weight : weight), and the like.

Exemplary plasticizers suitable for the present purpose include plasticizers that lower the temperature of the second-order phase transition of the

wall of the elastic modulus thereof ; and also increase the workability of the wall, its flexibility and its permeability to fluid. Plasticizers operable for the present purpose include both cyclic plasticizers and acyclic plasticizers. Typical plasticizers are those selected from the group consisting of phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, sulfonamides, and halogenated phenyls. Generally, from about 0. 001 to about 50 parts of a plasticizer or a mixture of plasticizers are incorporated into 100 parts of wall forming material.

Exemplary plasticizers include dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates and mixed alkylaryl as represented by dimethyl phthalate, dipropyl phthalate, di-(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate ; alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, tricresyl phosphate and triphenyl phosphate ; alkyl citrate and citrate esters such as tributyl citrate, triethyl citrate, and acetyl triethyl citrate ; alkyl adipates such as dioctyl adipate, diethyl adipate and di- (2-methyoxy- ethyl) adipate ; dialkyl tartrates such as diethyl tartrate and dibutyl succinate ; alkyl glycoates, alkyl glycerolates, glycol esters and glycerol esters such as glycerol diacetate, glycerol tyriacetate, glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate. Other plasticizers include camphor, N-ethyl- (o-and p-toluene) sulfonamide, chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide, and substituted epoxides.

Suitable plasticizers can be selected for blending with the wall forming materials by selecting plasticizers that have a high degree of solvent power for the materials, are compatible with the materials over both the processing and use temperature range, exhibit permanence as seen by their strong tendency to remain in the plasticized wall, impart flexibility to the material and are non-toxic to animals, humans, avians, fishes and reptiles. Procedures for selecting a plasticizer having the described characteristics are disclosed in the Encyclopedia of polymer Science and Technology, Vol. 10, pages 228 to 306, 1969, published by John Wiley & Sons, Inc.

Also, a detailed description pertaining to the measurement of plasticizer properties including solvent parameters and compatibility such as the Hildebrand solubility parameter 6, the Flory-Huggins interaction parameter X, and the cohesive-energy

density, CED, parameters are disclosed in Plasticization and Plasticizer Processes, Advances in Chemistry Series 48, Chapter 1, pages 1 to 26, 1965, published by the American Chemical Society. The amount of plasticizer added generally is an amount sufficient to produce the desired wall and it will vary according to the plasticizer and the materials. Usually about 0. 001 part up to about 50 parts of plasticizer can be used for 100 parts of wall material.

The expressions"flux regulator agent","flux enhancing agent"and "flux decreasing agent"as used herein mean a compound that when added to a wall forming material assists in regulating the fluid permeability of flux through the wall.

The agent can be preselected to increase or decrease the liquid flux. Agents that produce a marked increase in permeability to fluid such as water, are often essentially hydrophilic, while those that produce a marked decrease in permeability to fluids such as water, are essentially hydrophobic. The flux regulators in some embodiments also can increase the flexibility and porosity of the lumina. Examples of flux regulat- ors include polyhydric alcohols and derivatives thereof, such as polyalkylene glycols of the formula H-(O-alkylene) n-OH wherein the bivalent alkylene radical is straight or branched chain and has from 1 to 10 carbon atoms and n is 1 to 500 or higher.

Typical glycols include polyethylene glycols 300, 400, 600, 1500, 1540, 4000 and 6000 of the formula H-(OCH2CH2) n-OH wherein n is respectively 5 to 5. 7, 8. 2 to 9. 1, 12. 5 to 13. 9 29 to 36, 29. 8 to 37, 68 to 84, and 158 to 204. Other polyglycols include the low molecular weight glycols such as polypropylene, polybutylene and polyamylene.

Additional flux regulators include poly (a, o)) alkylendiols wherein the alkylene is straight or branched chain of from 2 to 10 carbon atoms such as poly (1, 3)-propanediol, poly (1, 4) butanediol, poly (1, 5) pentanediol and poly (1, 6) hexanediol. The diols also include aliphatic diols of the formula HOCnH2nOH wherein n is from 2 to 10 and diols are optionally bonded to a non-terminal carbon atom such as 1, 3-butylene glycol, 1, 4-pentamethylene glycol, 1, 5-hexamethylene glycol and 1, 8-decamethylene glycol ; and alkylenetriols having 2 to 6 carbon atoms such as glycerine, 1, 2, 3-butanetriol, 1, 2, 3-pentanetriol, 1, 2, 4-hexanetriol and 1, 3, 6- hexanetriol.

Other flux regulators include esters and polyesters of alkylene glycols of the formula HO- (alkylene-O) n-H wherein the divalent alkylene radical includes

the straight chain groups and the isomeric forms thereof having from 2 to 6 carbons and n is 1 to 14. The esters and polyesters are formed by reacting the glycol with either a monobasic or dibasic acid. Exemplary flux regulators are ethylene glycol dipropionate, ethylene glycol butyrate, ethylene glycol diacetate, triethylene glycol diacetate, butylene glycol dipropionate, polyester of ethylene glycol with succinic acid, polyester of diethylene glycol with maleic acid, and polyester of triethylene glycol with adipic acid.

The amount of flux regulator added to a material generally is an amount sufficient to product the desired permeability, and it will vary according to the lamina forming material and the flux regulator used to modulate the permeability.

Usually from about 0. 001 parts up to about 50 parts, or higher of flux regulator can be used to achieve the desired results.

Surfactants useful for the present purpose are those surfactants, when added to a wall forming material and other materials, aid in producing an integral composite that is useful for making the operative wall of a device. The surfactants act by regulating the surface energy of materials to improve their blending into the composite. This latter material is used for manufacturing devices that maintain their integrity in the environment of use during the agent release period. Generally, the surfactants are amphipathic molecules comprised of a hydrophobic part and a hydro- philic part. The surfactants can be anionic, cationic, nonionic or amphoteric and they include anionics such as sulfated esters, amides, alcohols, ethers, and carboxylic acids ; sulfonated aromatic hydrocarbons, aliphatic hydrocarbons, esters and ethers, acylated amino acids and peptides ; and metal alkyl phosphates ; cationic surfactants such as primary, secondary, tertiary and quaternary alkylammonium salts ; acylated polyamines ; and salts of heterocyclic amines arylammonium surfactants such as esters of polyhydric alcohols ; alkoxylated amines ; polyoxyalkylene ; esters and ethers of polyoxyalkylene glycols ; alkanolamine fatty acid condensates ; tertiary acetylamic glycols ; and dialkyl polyoxyalkylene phosphates ; and ampholytics such as betamines ; and amino acids.

Typical surfactants include polyoxyethylenated glycerol ricinoleate ; polyoxyethylenated castor oil having from about 9 to about 52 moles of ethylene oxide ; glycerol mannitan laurate, and glycerol (sorbitan oleates, stearates or laurates) ; polyoxyethylenated sorbitan laurate, palmitate, stearate, oleate, or hexalolate having from about 5 to about 20 moles of ethylene oxide ; mono-, di-, and poly-ethylene

glycol stearates, laurates, oleates, myristates, behenates or ricinoleates ; propylene glycol carboxylic acid esters ; sorbitan laurate, palmitate, oleate, and stearate ; polyoxyethylenated octyl nonyl, decyl and dodecylphenols having about 1 to about 100 moles of ethylene oxide ; polyoxyethylenated nonyl, lauryl, decyl, cetyl, oleyl and stearyl alcohols having from about 3 to about 50 moles of ethylene oxide ; polyoxypropylene glycols having from about 3 to about 300 moles of ethylene oxide ; sodium slat of sulfated propyl oleate ; sodium di- (heptyl) sulfosuccinate ; potassium xylenesulfonate, 1 : 1 myristic acid diethanolamide ; N-coco-P-aminopropionic acid ; bis- (2-hydroxyethyl)-tallowamine oxide ; (diisobutylphenoxy-ethoxyethyl) dimethyl- benzylammonium halide ; N, N'-polyoxypropylenated ethylenediamine having a molecular weight from about 500 to about 3000 ; tetra-alkylammonium salts with up to 26 carbon atoms in the cation ; sodium or potassium salt of polypeptide cocoanut, oleic or undecylenic acid condensate ; metal salts of N-acylated short chain aminosulfonic acids, soybean phosphatides ; and sulfobetaine.

Suitable surfactants can be selected from the above and from other surfactants for blending with wall forming materials by using the surfactant's hydrophile-lipophile balance number, HLB. This number represents the proportion between the weight percentages of hydrophilic and lipophilic groups in a disperant.

In use the number indicates the behavior of the surfactant, that is, the higher the number the more hydrophilic the surfactant and the lower the number the more lipophilic the surfactant. The required HLB number for blending wall forming materials is determined by selecting a surfactant with a known number, blending it with the materials and observing the results. A homogeneous composite is formed with the correct number, while a heterogeneous mixture indicates a different number is needed. This new number can be selected by using the prior number as a guide.

The HLB number is known to the art for many surfactants, and they can be experimentally determined according to the procedure in J. Soc. Cosmetic. Chem., Vol. 1, pages 311 to 326, 1949, or it can be calculated by using the procedure in J.

Soc. Cosmetic Chem., Vol. 5, pages 249 to 256, 1954, and in Am. Perfumer Essent.

Oil Review, Vol. 65, pages 26-29, 1955. Typical HLB numbers are set forth in Table 1. Generally a number of 10 or less indicates lipophilic behavior and 10 or more indicates hydrophilic behavior. Also, HLB number are algebraically additive. Thus, by using a low number with a high number, blends of surfactants can be prepared having numbers intermediate between the two numbers. The amount of surfactant needed is an amount that when blended with wall forming materials will form the desired wall composite, and it will vary according to the particular surfactant and materials that are blended to form the wall. Generally, the amount of surfactant will rang from about 0. 001 part up to about 40 parts for 100 parts of the wall.

TABLE 1 SURFACTANT HLB NUMBER Sorbitan trioleate 1. 8 Polyoxyethylene sorbitol beeswax 2. 0 Sorbitan tristearate 2. 1 Poloxyethylene sorbitol hexastearate 2. 6 Ethylene glycol fatt acid ester 2. 7 Propylene glycol fatty acid ester 3. 4 Propylene glycol monostearate 3. 4 Ethylene glycol fatty acid ester 3. 6 Glycerol monostearate 3. 8 Sorbitan monooleate 4. 3 Propylene glycol monolaurate 4.5 Diethylene glycol fatty acid ester 5. 0 Sorbitan monopalmitate 6. 7 Polyoxyethylene dioleate 7. 5 Polyoxypropylene mannitol dioleate 8. 0 Sorbitan monolaurate 8. 6 Polyoxyethylene lauryl ether 9. 5 Polyoxyethylene sorbitan monolaurate 10.0 Polyoxyethylene lanolin derivative 11.0 Polyoxyethylene glycol 400 monooleate 11. 4 Triethanolamine oleate 12. 0 Polyoxyethylene nonyl phenyl 13. 0 Polyoxyethylene sorbital monolaurate 13.3 Polyoxyethylene sorbital lanolin 14.0 Polyoxyethylene stearyl alcohol 15. 3 Polyoxyethylene 20 cetyl ether 15.7 Polyoxyethylene 40 stearate 16.9 Polyoxyethylene monostearate 17. 9 Sodium oleate 18. 0 Potassium oleate 20. 0

The microporous coating is applied to and adheres to the entire surface of the core. The coating is applied to a thickness of from about 1 to about 1000 microns. Preferably, the thickness of the coating is about 10 to about 500 microns, although thinner and thicker coatings fall within the scope of the invention.

Using a microporous coating eliminates the need for creating apertures in the drug delivery device. However, it may be preferable in certain instances to use laser or mechanical techniques to create one or more apertures in the drug delivery device.

The expression"aperture"as used herein, refers to ports through the coating which expose the surface of the core to the environment. The size and number of apertures is chosen to effect the desired release rate. Exposure of from about 0. 001% to about 5. 0% of the core surface is contemplated by this invention.

Preferably, the coating has a plurality of apertures exposing between about 0. 001% and about 5. 0% of the core surface, wherein the release rate of beneficial agent from the device is a function of the number and size of the apertures. More preferably, the coating has a plurality of apertures exposing between about 0. 01% and about 1. 0% of the core surface. Most preferably, the coating has a plurality of apertures exposing between about 0. 05% and about 0. 5% of the core surface. The apertures may be positioned in a regular or irregular pattern on one or both faces of the device although they can be positioned anywhere on the device, including the edges.

The apertures are generally circular, but may be of any design that results in the proper release rate. When the aperture is circular, its diameter ranges from about 0. 01 mm to about 1. 0 mm. Preferably, the diameters of the aperture are about 0. 05 mm to about 0. 5 mm. Most preferably, the diameter ranges are about 0. 1 mm to about 0. 5 mm. The number of apertures in each device may range from about 1 to about 10 or more. Typically, the number of apertures in each dosage form ranges from about 1 to about 5. Most preferably, there are about 1 to about 2 apertures.

While the microporous coating allows the release of the beneficial agent, it has been unexpectedly found that creating at least one aperture in the drug delivery device improves the release rate of the beneficial agent. In the instant invention, it is preferable to use laser or mechanical techniques to create one or more apertures in the drug delivery device. The aperture (s) acts to preferentially direct the flow of the beneficial agent, thus creating a concentrated volume stream.

This volume stream has a buffering capacity which allows the volume stream to buffer itself and, in the second embodiment of this invention, eliminates the need for an additional agent to control the pH of the device. In this second embodiment, the aperture (s) eliminate the necessity of an additional agent to modify the pH of the device even though the beneficial agent has a release profile which normally varies depending on the pH level of the environment of use. The number, size and configuration of the apertures would be manipulated in order to achieve a desired pharmacol<inetic profile.

The apertures may be made by permanently removing tablet coating material of the appropriate size using either a mechanical, coring, laser-based, or ultrasonic excitation process or other known techniques. Most preferably, a pulsed laser marking system is used to create the holes required. This system allows for an array of apertures to be created on both faces of a dosage form and at rates suitable for production of dosage forms.

This process utilizes a digitally controlled laser marking system (such as those manufactured by The Automation Partnership, Cambridge UK) to produce a programmable number of holes completely through the surface or coating of the dosage form, at rates practically suitable for production of dosage forms.

The steps involved in this laser drilling process are as follows : a pulsed laser marking system is focused at a tablet handling stage ; the dosage form is moved by the tablet handling stage into the area of focused radiation created by the laser ; the laser marking system is pulsed to provide sufficient power needed to remove areas of coating along a linear array on the dosage form ; the dosage form is moved forward on the tablet handling stage ; and the laser system is again pulsed as needed to produce additional linear arrays of apertures as necessary. The dosage form continues to be advanced by the tablet handling stage until it is eventually ejected from the system.

Coloring agents may be added to increase or decrease the absorption of the laser energy being utilized. Suspending agents may be added to the coating solution if the coloring agent being used is insoluble. Types of suspending agents include, but are not limited to, talc and titanium dioxide.

The polymers used in the coating which are herein described are known to the art or can be prepared according to the procedures in the Encyclopedia of Polymer Science and Technology, Vol. 3, published by Interscience Publishers,

Inc., New York, in Handbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971, published by CRC Press, Cleveland, Ohio.

In the instant invention, a film coating may be applied prior to the application of the water insoluble, water impermeable polymeric coating. This film coating protects the formulation, such as a tablet, from attrition during the application of the polymeric coating. Preferably, the film coating comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose.

The instant invention allows for the controlled release of a beneficial agent across a range of physiologically relevant pH levels. The ratio of pH modulat- ing agent to beneficial agent is a critical parameter in achieving the optimal release of the beneficial agent in a manner that is largely insensitive to the pH of the surround- ing environment. For example, where the beneficial agents is 1- (3-chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinone (Compound A) and no pH modulating agent is present, the release profile of the beneficial agent will vary greatly depending on the environment of use. In the stomach, which has an acidic pH level of about 1. 2, about 100% of Compound A is released over about an 8 hour period. However, in the intestine, which has a more alkaline pH of about 5 to 8, there would be a substantial decrease in both the rate and extent of release of Compound A from the device in the absence of the pH modulating agent. Surprisingly, the addition of a pH modulating agent to the drug delivery device provides an improved, controlled-release that is generally insensitive to the pH level of the environment of use.

FIG. 1 depicts the instant invention of the first embodiment where the pH modulating agent is preferably a pharmaceutically acceptable organic acid.

FIG. 1 illustrates the movement of the gastrointestinal (GI) fluids into the osmotic, controlled-release drug delivery device. In operation, the drug delivery device of the instant invention is ingested by a mammal and is contacted by the fluids in the environment of use (i. e. gastrointestinal tract). The GI fluids pass through the controlled porosity microporous membrane to the core of the device and dissolve the components of the core. Because small amounts of beneficial agent are released into a large volume of fluids (e. g. gastrointestinal system) over a period of time, the beneficial agent is easily dissolved, regardless of the pH of the environment of use.

Thus, this device allows the delivery of a beneficial agent without relying on the pH of the environment of use to dissolve the beneficial agent or the other components of

the core. Once dissolved, the pH modulating agent, preferably a pharmaceutically acceptable organic acid, maintains an acidic pH level inside the core. This allows the beneficial agent to remain soluble and enhances the release of the beneficial agent into the environment of use. The organic acid also acidifies the fluids, or volume stream, exiting the delivery device so that when it enters the environment of use, the beneficial agent does not precipitate within the controlled porosity, microporous membrane or onto the external surface of the device.

Additionally, in a further embodiment of the first embodiment, the use of at least one aperture in the instant invention has also provided an unexpected benefit. For example, in situations where the viscosity of a solution of the beneficial agent inside the device increases markedly, due to the concentration level of the beneficial agent, the hydrostatic pressure within the device would be expected to increase significantly, ultimately resulting in membrane failure. Thus. at high concentrations, an aperture would act as a pressure-release value, simultaneously enabling the majority of the beneficial agent to enter into the environment of use in the form of a concentrated volume stream via the aperture rather than through the microporous membrane. In such an instance, the aperture (s) could potentially allow one to decrease the amount of pH modulating agent needed within the core of the delivery device. The number, size and configuration of the apertures would be manipulated in order to achieve a desired pharmacokinetic profile.

Furthermore, the use of the aperture (s) alone, without a pH modulating agent, has also provided the controlled release of a beneficial agent that has a pH- dependent solubility profile. In the operation of the second embodiment, where no pH modulating agent is present, the drug delivery device of the instant invention is ingested by a mammal and is contacted by the fluids in the environment of use (i. e. gastrointestinal tract). The G1 fluids pass through the controlled porosity microporous membrane or the aperture (s) to the core of the device and dissolve the components of the core. Because small amounts of beneficial agent are released into a large volume of fluids (e. g. gastrointestinal system) over a period of time, the beneficial agent is easily dissolved, regardless of the pH of the environment of use.

Thus, this device allows the delivery of a beneficial agent without relying on the pH of the environment of use to dissolve the beneficial agent or the other components of the core.

Once dissolved, the beneficial agent is released into the environment of use. While the beneficial agent would normally exit through the microporous coating, the aperture (s) in the microporous coating enhances the release rate by enabling the majority of the beneficial agent to enter into the environment of use in the form of a concentrated volume stream via the aperture rather than through the microporous membrane. This volume stream has a buffering capacity which eliminates the need for an additional agent to control the pH of the device, even though the beneficial agent has a release profile which normally varies depending on the pH level of the environment of use.

For example, in the stomach, which has an acidic pH level of about 1. 2, about 100% of l- (3-ch) orophenyl)-4- [l- (4-cyanobenzyl)-5-imidaxoly) methyl]-2- piperazinone. Compound A. is released over about an 8 hour period. However, in the intestine, which has a more alkaline pH of about 5 to S. there would be a substantial decrease in both the rate and extent of release of Compound A from the device in the absence of some modulating ugent. In such instances, an additional agent would usually be needed to control the release rate. However, by creating an aperture in the drug delivery device, the beneficial agent is released in a concentrated stream, regardless of the ptl of the environment of use. Thus. the release rate of'the beneficial agent is more controlled over a range of'physiologically relevant pH levels due to the presence of at least one aperture.

In the second embodiment of the instant invention, the preferred beneficial agent is I- (3-chlo)'ophenyl)-4- [l- (4-cyanobenzyl)-5-imidazolyl methyl]- 2-piperazinone. Compound A. which has solubility profile that is highly dependent on pH levels, in that it is very soluble (greater than about 700 mg/mL) at low pH levels (less than about 2) and practically insoluble (less than about 100 ug/mL) at near neutral pH levels (greater than 5). Preferably. an excipient, such as sodium chloride, magnesium chloride, calcium chloride, potassium chloride and the like. is added to the core. More preferably, sodium chloride is added to the core in addition to Compound A.

The drug delivery device of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condi-

tion that is being treated. Included in such combinations of therapeutic agents are combinations of a prenyl-protein transferase inhibitors and an antineoplastic agent.

It is also understood that such a combination of antineoplastic agent and inhibitor of prenyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.

Examples of an antineoplastic agent include, in general, microtubule- stabilizing agents (such as paclitaxel (also known as Taxons)), docetaxel (also known as Taxotere (E)), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives) ; microtubule-disruptor agents ; alkylating agents, anti- metabolites ; epidophyllotoxin ; an antineoplastic enzyme ; a topoisomerase inhibitor ; procarbazine ; mitoxantrone ; platinum coordination complexes ; biological response modifiers and growth inhibitors ; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.

Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, trastuzumab (HerceptinTM), 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.

Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant invention to treat cancer.

Additionally, the instant invention may also be useful for administering inhibitors of prenyl-protein transferase, which may be used as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein incorporated by reference.

The following examples illustrate the preparation of the drug delivery device of this invention and their controlled release of one or more therapeutically beneficial agents into an environment of use and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to further illustrate the invention and not limit the reasonable scope thereof.

In the following example the farnesyl transferase inhibitor, 1- (3- chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinone (as described in U. S. Patent No. 5, 856, 326 and incorporated herein by reference), hereafter"Compound A", is used as the model drug. The preparation of 1- (3- Chlorophenyl)-4- [l- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinone is also described in the following examples.

EXAMPLE 1 Preparation of p-Cvanobenzvlamine H3PO4 salt A slurry of HMTA in 2. 5 L EtOH was added gradually over about 30 min to about 60 min to a stirred slurry of cyanobenzyl-bromide in 3. 5 L EtOH and maintained at about 48-53°C with heating and cooling in a 22L neck flask (small exotherm). Then the transfer of HMTA to the reaction mixture was completed with the use of 1. 0 L EtOH. The reaction mixture was heated to about 68-73°C and aged at about 68-73°C for about 90 min. The reaction mixture was a slurry containing a granular precipitate which quickly settled when stirring stopped.

The mixture was cooled to a temperature of about 50°C to about 55°C.

Propionic acid was added to the mixture and the mixture was heated and maintained at a temperature of about 50°C to about 55°C. Phosphoric acid was gradually added over about 5 min to about 10 min, maintaining the reaction mixture below about 65°C

to form a precipitate-containing mixture. Then the mixture was gradually warmed to about 65°C to about 70°C over about 30 min and aged at about 65°C to about 70°C for about 30 min. The mixture was then gradually cooled to about 20-25°C over about 1 hour and aged at about 20-25°C for about 1 hour.

The reaction slurry was then filtered. The filter cake was washed four times with EtOH, using the following sequence, 2. 5 L each time. The filter cake was then washed with water five times, using 300 mL each time. Finally, the filter cake was washed twice with MeCN (1. 0 L each time) and the above identified compound was obtained.

EXAMPLE 2 Preparation of 4-Cyanobenzylamine Hydrochloride via Hexamethylene- tetrammonium salt A 72 liter vessel was charged with 190 proof ethanol (14. 4 L) followed by the addition of 4-cyanobenzylbromide (2. 98 kg) and HMTA (2. 18 kg) at ambient temperature. The mixture was heated to about 72-75°C over about 60 min. On warming, the solution thickens and additional ethanol (1. 0 liter) was added to facilitate stirring. The batch was aged at about 72-75°C for about 30 min.

The mixture was allowed to cool to about 20°C over about 60 min, and HCI gas (2. 20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65°C. The mixture was heated to about 70-72°C and aged for about 1 hour. The slurry was cooled to about 30°C and ethyl acetate (22. 3 L) added over about 30 min. The slurry was cooled to about-5°C over about 40 min and aged at about-3 to about-5°C for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3 x 3 L). The solid was dried under an N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5. 5 L). The pH was adjusted to about 10-10. 5 with 50% NaOH (4. 0 kg) maintaining the internal temperature below about 30°C. At about 25°C, methylene chloride (2. 8 L) was added and stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2 x 2. 2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25°C to give a free base as a yellow oil.

The oil was transferred to a 50 liter vessel with the aid of ethanol (1. 8 L). Ethyl acetate (4. 1 L) was added at about 25°C. The solution was cooled to about 15°C and HCI gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40°C. At about 20-25°C, ethyl acetate (5. 8 L) was added to the slurry, followed by cooling to about-5°C over about 1 hour. The slurry was aged at about-5°C for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9 : 1 v/v) (1 x 3. 8 L), then the cake was washed with chilled EtOAc (2 x 3. 8 L). The solids were dried in vacuo at about 25°C to provide the above-titled compound.

IH NMR (250 MHz, CDC13) b 7. 83-7. 79 (d, 2H), 7. 60-7. 57 (d, 2H), 4. 79 (s, 2H), 4. 25 (s, 2H) ; 13C NMR (62. 9 MHz, CDCl3) 8149. 9, 139. 8, 134. 2, 131. 2, 119. 7, 113. 4, 49. 9, 49. 5, 49. 2, 48. 8, 48. 5, 48. 2, 43. 8.

EXAMPLE 3 Preparation of 1- (4-Cyanobenzvl)-2-Mercapto-5-Hvdroxymethylimidazole 7% water in acetonitrile (50 mL) was added to a 250 mL roundbottom flask. Next, an amine phosphate salt (12. 49 g), as described in Example 2, was added to the flask. Next potassium thiocyanate (6. 04 g) and dihydroxyacetone (5. 61 g) was added. Lastly, propionic acid (10. 0 mL) was added. Acetonitrile/water 93 : 7 (25 mL) was used to rinse down the sides of the flask. This mixture was then heated to 60°C, aged for about 30 minutes and seeded with 1% thioimidazole. The mixture was then aged for about 1. 5 to about 2 hours at 60°C. Next, the mixture was heated to 70°C, and aged for 2 hours. The temperature of the mixture was then cooled to room temperature and was aged overnight. The thioimidazole product was obtained by vacuum filtration. The filter cake was washed four times acetonitrile (25 mL each time) until the filtrates became nearly colorless. Then the filter cake was washed three times with water (approximately 25-50 mL each time) and dried iii vacuo to obtain 1-(4-Cyanobenzyl)-2-Mel-capto-5-Hydroxymetllyl imidazole.

EXAMPLE 4 Preparation of 1- (4-Cyanobenzyl)-5-Hydroxymethylimidazole

A 1L flask with cooling/heating jacket and glass stirrer (Lab-Max) was charged with water (200 mL) at 25°C. The thioimidazole (90. 27 g), as described in Example 3, was added, followed by acetic acid (120 mL) and water (50 mL) to form a pale pink slurry. The reaction was warmed to 40°C over 10 minutes. Hydrogen peroxide (90. 0 g) was added slowly over 2 hours by automatic pump maintaining a temperature of 35-45°C. The temperature was lowered to 25°C and the solution aged for 1 hour.

The solution was cooled to 20°C and quenched by slowly adding 20% aqueous Na, ? S03 (25 mL) maintaining the temperature at less than 25°C. The solution was filtered through a bed of DARCO G-60 (9. 0 g) over a bed of SolkaFlok (1. 9 g) in a sintered glass funnel. The bed was washed with 25 mL of 10% acetic acid in water.

The combined filtrates were cooled to 15°C and a 25% aqueous ammonia was added over a 30 minute period, maintaining the temperature below 25°C, to a pH of 9. 3. The yellowish slurry was aged overnight at 23°C (room temperature). The solids were isolated via vacuum filtration. The cake (100 mL wet volume) was washed with 2 x 250 mL 5% ammonia (25%) in water, followed by 100 mL of ethyl acetate. The wet cake was dried with vacuum flow and the above-titled compound was obtained.

1H NMR (250 MHz, CDC13) : b 7. 84-7. 72 (d, 2H), 7. 31-7. 28 (d, 2H), 6. 85 (s, 1H), 5. 34 (s, 2H), 5. 14-5. 11 (t, 1H), 4. 30-4. 28 (d, 2H), 3. 35 (s, 1H).

EXAMPLE 5 Preparation of 1- (4-cyanobenzyl)-5-chloromethyl imidazole HC1 salt 1- (4-Cyanobenzyl)-5-hydroxymethylimidazole (1. 0 kg), as described above in Example 4, was slurried with DMF (4. 8 L) at 22°C and then cooled to-5°C.

Thionyl chloride (390 mL) was added dropwise over 60 min during which time the reaction temperature rose to a maximum of 9°C. The solution became nearly homo- geneous before the product began to precipitate from solution. The slurry was warmed to 26°C and aged for 1 h.

The slurry was then cooled to 5°C and 2-propanol (120 mL) was added dropwise, followed by the addition of ethyl acetate (4. 8 L). The slurry was aged at 5°C for 1 h before the solids were isolated and washed with chilled ethyl

acetate (3 x 1 L). The product was dried in vacuo at 40°C overnight to provide the above-titled compound.

1H NMR (250 MHz DMSO-d6) : 59. 44 (s, 1H), 7. 89 (d, 2H, 8. 3 Hz), 7. 89 (s, 1H), 7. 55 (d, 2H, 8. 3 Hz), 5. 70 (s, 2H), 4. 93 (s, 2H). 13C NMR (75. 5 MHz DMSO-d6) : ãc 139. 7, 137. 7, 132. 7, 130. 1, 128. 8, 120. 7, 118. 4, 111. 2, 48. 9, 33. 1.

EXAMPLE 6 Preparation of 1- (4-Cyanobenzyl)-5-Chloromethyl Imidazole HCl salt via addition of Hydroxvmethylimidazole to Vilsmeier Reagent To an ice cold solution of dry acetonitrile (3. 2 L, 15 LJKg hydroxy- methylimidazole) was added 99% oxalyl chloride (101 mL, 1. 15 mol, 1. 15 equiv.), followed by dry DMF (178 mL, 2. 30 mol, 2. 30 equiv.), at which time vigorous evolution of gas was observed. After stirring for about 5 to 10 min following the addition of DMF, solid hydroxymethyl-imidazole (213 g, 1. 00 mol), as described above in Example 4, was added gradually. After the addition, the internal temper- ature was allowed to warm to a temperature of about 23°C to about 25°C and stirred for about 1 to 3 hours. The mixture was filtered, then washed with dry acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash).

The solid was maintained under an N2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H20. This yielded the crystalline form of the chloromethylimidazole hydrochloride.

1H NMR (250 MHz DMSO-d6) : 59. 44 (s, 1H), 7. 89 (d, 2H, 8. 3 Hz), 7. 89 (s, 1H), 7. 55 (d, 2H, 8. 3 Hz), 5. 70 (s, 2H), 4. 93 (s, 2H). 13C NMR (75. 5 MHz DMSO-d6) : 5cl39. 7, 137. 7, 132. 7, 130. 1, 128. 8, 120. 7, 118. 4, 111. 2, 48. 9, 33. 1.

EXAMPLE 7 Preparation of 1- (4-Cyanobenzyl)-5-Chloromethyl Imidazole HCl salt via addition of Vilsmeier Reagent to Hydroxymethylimidazole To an ice cold solution of dry DMF (178 mL, 2. 30 mol, 2. 30 equiv.) in dry acetonitrile (2. 56 L, 12 L/Kg Hydroxymethylimidazole) was added oxalyl chloride (101 mL, 1. 15 mol, 1. 15 equiv). The heterogeneous mixture in the reagent

vessel was then transferred to a mixture of hydroxymethylimidazole (213 g, 1. 00 mol), as described above in Example 4, in dry acetonitrile (1. 7 L, 8 L/Kg hydroxy- methylimidazole). Additional dry acetonitrile (1. 1-2. 3 L, 5-11 L/Kg hydroxy- methylimidazole) was added to the remaining solid Vilsmeier reagent in the reagent vessel. This, now nearly homogenous, solution was transferred to the reaction vessel at Tj 2 +6°C. The reaction vessel temperature was warmed to a temperature of about 23°C to about 25°C and stirred for about 1 to 3 hours. The mixture was then cooled to 0°C and aged 1 h. The solid was filtered and washed with dry, ice cold acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash).

The solid was maintained under an N2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H2O. This yielded the crystalline form of the chloromethylimidazole hydrochloride.

EXAMPLE 8 Preparation of the amide alcohol At 22°C, 3-chloroaniline (50. 0 g) was combined with 460 ml isopropyl acetate and 20% aqueous potassium bicarbonate (72. 5 g dissolved in 290 ml water).

The biphasic mixture was cooled to 5°C and chloroacetyl chloride (42 ml) was added dropwise over 30 minutes, keeping the internal temperature below 10°C. The reaction mixture was warmed to 22°C over 30 min. The aqueous layer was removed at 22°C and ethanolamine (92 ml) was added rapidly. The reaction mixture was warmed to 55°C over 30 minutes and aged for 1 hour. At 55°C, 140 ml water was added with 30 ml isopropyl acetate to the reaction mixture. The biphasic reaction mixture was agitated for 15 minutes at 55°C. The layers were allowed to settle and the aqueous layer was removed. The organic layer was cooled to 45°C and seed was added. The mixture was cooled to 0°C over 1 hour and aged for 1 hour. The solids were filtered and washed with chilled isopropyl acetate (2 x 75 ml). The solids were dried in vacuo at 40°C for 18 hours to provide the above-identified amide alcohol.

1H NMR (300 MHz ; DMSO-d6) 8 7. 85 (t, 1H 2. 0 Hz), 7. 52 (m, 1H), 7. 32 (t, 1H, 8. 0 Hz), 4. 5-4. 8 (br s, 1H), 3. 47 (t, 1H, 5. 5 Hz), 3. 30 (s, 1H), 2. 60 (t, 1H 5. 0 Hz).

13C NMR (75. 4 MHz ; DMSO-d6) bc 170. 9, 140. 1, 133. 0, 130. 3, 122. 8 118. 5, 117. 5, 60. 3, 52. 7, 51. 5.

EXAMPLE 9 Synthesis of 1- (3-Chlorophenyl)-2-Piperazinone Hydrochloride with DPAD An amide alcohol, as described above in Example 8, was slurried with THF (37 ml) at 22°C, followed by the addition of tributyl phosphine (8. 7 ml).

The mixture was cooled to 0°C and the DPAD was added in portions over 15 min.

The slurry was aged at 0-5°C for 30 minutes, warmed to 25°C and aged for 18 hours.

The reaction mixture was filtered and the cake was washed with THF (2 x 25 ml).

The filtrate was concentrated in vacuo at < 35°C and combined with 50 ml of 2- propanol. The solution was cooled to 5°C, seeded with authentic material and treated with ethanol HC1 (2. 6 mi ; 8. 4M solution) dropwise over 20 min. The resulting slurry was re-cooled to 10°C and aged for 1 hour. The solids were isolated and the cake and flask rinsed with chilled 2-propanol (2 x 10 ml). The product was dried in vacuo at 40°C for 18 hours to provide the above-titled compound. lH NMR (300 MHz ; DMSO-d,) 5 10. 24 (br s, 2H), 7. 50-7. 30 (m, 4H), 3. 92 (t, 2H, 5. 5 Hz), 3. 84 (s, 2H), 3. 51 (t, 5. 5 Hz) ; 13C NMR (75. 4 MHz ; DMSO-d6) bc 162. 1, 142. 6, 132. 9, 130. 7, 127. 0, 126. 1, 124. 54, 46. 1, 44. 9, 39. 8.

EXAMPLE 10 Synthesis of 1-(3-Chlorophenvl)-2-Piperazinone Hvdrochloride with DIAD 58 mL of EtOAc was charged to an N2-purged flask. Tributyl- phosphine (28. 3 mL, 113. 8 mmol) was added, via syringe, and the solution was cooled to about-10°C. DIAD (22. 4 mL, 113. 8 mmol) was added dropwise over 30 minutes, maintaining the temperature at < 0°C. The above mixture was cannulated into a slurry of an amide alcohol (20. 0 g, 87. 5 mmol), as described above in Example 8, in 117 mL EtOAc over 20 minutes, maintaining the temperature at < 0°C. The reaction was warmed to room temperature over 25 minutes. 99% conversion was

observed by LC assay. Water (0. 55 mL) was then added, and the reaction was warmed to 40°C. The solution was seeded with 200 mg of authentic material, and 1. 0 eq. HCl (4. 0 N in abs. EtOH) was added dropwise over 2 hours. The slurry was cooled to 0°C over 2 hours and aged at 0°C for 1 hour. The mixture was filtered, and the cake was washed with chilled EtOAc (3x16 mL). The cake was dried in vacuo overnight at 40°C to afford the above-titled compound.

EXAMPLE 11 Preparation of 1- (3-chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone H_O A 50 L four-neck flask, equipped with a mechanical stirrer, cooling bath, teflon-coated thermocouple, and nitrogen inlet was charged with 4. 0 L of acetonitrile. Then 4-cyanobenzyl-5-chloromethylimidazole hydrochloride, as described in Examples 8, 9 or 10, (958 g, 3. 36 mol), 1- (3-chlorophenyl)-2-piper- azinone hydrochloride, as described in Examples 2 or 3, (883 g, 3. 54 mol), and the remaining 1. 25 L of acetonitrile were added to the flask at room temperature.

Diisopropylethylamine (1. 99 L, 11. 4 mol) was added to the mixture. The bulk of the solid dissolved immediately upon addition of diisopropylethylamine, leaving a slightly turbid solution.

After stirring 30 min, the solution was cooled to 0°C over 60 min. The solution was stirred 26 h at 0°C, then warmed to 20°C over 20 min. Water (2 L) was added to the slightly turbid solution over 20 min. Authentic seed was added to 8 L of water, which was subsequently added to the solution over 70 min. Additional water (17 L) was added over 90 min, and the mixture was aged 60 min thereafter. The temperature throughout the addition and aging was from about 20°C to about 22°C.

The mixture was filtered through a polypropylene filter pot. The crystals were washed with 1 : 5 acetonitrile/water. The crystalline solid was dried by passage of nitrogen through the filter cake (36 h) to provide the above-titled compound.

13C NMR (62. 9 MHz, CDC13) : d 165. 2, 142. 7, 142. 1, 139. 4, 134. 8, 133. 0, 131. 0, 130. 2, 127. 3, 127. 1, 126. 3, 126. 0, 123. 9, 118. 1, 112. 0, 57. 7, 50. 6, 49. 9, 148. 8, 148. 3.

EXAMPLE 12 Preparation of 1- (3-chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinoneHCl An IPA/toluene mixture (7 L) is made up as a 69 : 31 wt% ratio by mixing IPA (3. 90 Kg, 4. 97 L) and toluene (1. 76 Kg, 2. 03 L).

A pre-weighed 1 L graduated cylinder was charged with IPA (500 mL, 392 g). The cylinder was cooled to 0 °C. Gaseous HCl was bubbled into the IPA until a volume change of roughly +80 mL was observed. The new weight of the cylinder and its contents indicated that 140 g HCl (3. 84 moles) had been charged, making up a 6. 62 M solution (or 7. 22 molal solution). An aliquot (500 mL, 458 g) was transferred to a 5 L flask. To this solution was added toluene (192 mL, 166 g) and the 69 : 31 IPA/toluene mixture (2. 07 Liters, 1. 7 Kg).

A 22 L flask was charged with the free base form of 1- (3- chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, as described above in Example 11. The 69 : 31 IPA/toluene mixture (11. 0 L) was added to this flask, which resulted in dissolution of the solid. The solution was heated to 40°C. The hot solution was filtered through an in-line filter into a pre- heated (40°C) 22 L flask. The dissolution flask was further washed with the 69 : 31 IPA/toluene solution (0. 5 L), which was transferred to the crystallization flask through the in-line filter. The in-line filter was replaced with a 4 L addition funnel.

The 1. 21 M HCl solution (1. 93 L, 1. 63 Kg, 2. 34 moles, 0. 99 equiv.) was charged to the addition funnel. A fraction of the HCl solution (0. 19 Liters, 0. 23 moles, 0. 10 equiv.) was added to the solution of free base over 10 min, whereupon the solution was seeded. After aging the thin slurry for 10-15 min, the remaining HCl solution was added over 2 h. The thick mixture was cooled to-10°C over 2 h, aged for 30 min, then filtered. The crystals were washed with ice-cold 69 : 31 IPA/toluene and was then washed three times with ice-cold IPA. The crystals were dried under vacuum with a nitrogen stream and the above-titled compound was obtained.

EXAMPLE 13 Preparation of 1- (3-Chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone-HCl A solution of HCl in ethanol was prepared by passing HCI gas (118 g, 3. 24 mol) via a Teflon tube into ethanol (385 mL) contained in a 500 mL graduated cylinder cooled in an ice bath. The volume of the solution increased to 447 mL after addition of the correct weight of HCI, making a 7. 25 M solution. A one-neck, 22 L flask, fitted with a heating mantle and nitrogen inlet, was charged with 1- (3- Chlorophenyl)-4- [1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone H2O, as described in Example 11, (1. 14 kg, 2. 69 mol) and ethanol (1. 36 L). The mixture was heated to 60°C, whereupon EtOAc (1. 7 L) was added. The mixture was stirred at 60°C until dissolution was complete. A separate one-neck, 5 L flask, fitted with a heating mantle and nitrogen inlet, was charged with EtOAc (2. 4 L) and heated to 70°C.

A solkafloc pad (100 g) in a 2 L sintered-glass funnel equipped with an electrically heated jacket was washed with hot EtOH (1 L), followed by hot 1 : 1 EtOH/EtOAc (1 L). The funnel containing the washed solkafloc fitted to a 50 L four- neck flask, which was equipped with a water bath, mechanical stirrer, Teflon-coated thermocouple, and three-way stopcock. The three-way stopcock was connected to a nitrogen inlet and to a house vacuum. The hot solution of 1- (3-Chlorophenyl)- 4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone H2O in EtOAc/EtOH was filtered into the 50 L flask through the heated (70°C) solkafloc pad under static vacuum. The hot EtOAc (2. 4 L) was then used to wash the solkafloc pad. The solution of 1- (3-Chlorophenyl)-4- [1- (4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone H2O was maintained at 55-60°C while the 7. 25 M solution of HCI in EtOH (386 mL, 2. 80 mol) was added over 30 min.

The solution was seeded with authentic material (1 g total) at about 5 min, and then at about 10 min, after the addition of the HCl had begun. Crystalliza- tion ensued after the second seeding when 120 mL of HCl in EtOH had been added.

The slurry was aged at 55-60°C for 20 min, whereupon EtOAc (9. 65 L) was added at a constant rate over 3 h. The slurry was cooled from 55°C to 0°C over 95 min and aged at 0°C for 20 min. The slurry were filtered on a polypropylene filter pot. The crystals were washed four times with approximately 5 to about 7L of 9 : 1 EtOAc/

EtOH solution. The filter cake was partly dried under a stream of nitrogen through the filter pot for 2 h. The crystals were transferred to Pyrex trays and dried in a vacuum oven (27"vacuum, 20-25°C, 18 h) yielding the above-titled compound.

13C NMR (62. 9 MHz, D20) : dc 169. 4, 142. 3, 141. 8, 138. 0, 135. 0, 133. 7, 131. 7, 130. 6, 128. 9, 128. 0, 126. 9, 125. 3, 121. 0, 119. 8, 111. 5, 55. 9, 51. 0, 50. 3, 49. 1, 48. 6 EXAMPLE 14 The formulation of the instant invention was prepared using 1- (3- chlorophenyl)-4- [l- (4-cyanobenzyl)-5-imidazolyl methyl]-2-piperazinoneHCl (Compound A) as the beneficial agent. The solubility of Compound A decreases from greater than about lg/mL at pH 2 to about 70 Ag/mL at pH 7, with the solubility cliff occurring at about pH 3. 5.

In the first embodiment of the instant invention, tablets for the pH- insensitive controlled release of Compound A were prepared with the following composition : Amount Per Ingredient Tablet (mg) CORE TABLET Compound A 109. 0 Succinic Acid 81. 00 Magnesium Stearate, NF (Non-Bovine) 2. 000 Polyvinylpyrrolidone (K-29/32) 10. 00 2-propanol (50. 00) Total Tablet Weight 202. 0 Compound A, succinic acid and polyvinylpyrrolidone were dry mixed in a 1-L high shear mixer and wet granulated using 100% isopropanol. The resulting granules were dried and milled, and subsequently lubricated with magnesium stearate.

The lubricated granules were compressed to a target weight of 202 mg and were com- pressed on a small rotary tablet press using 10/32"RSC tooling. In certain cases, the tablet cores were film-coated using an aqueous solution of Hydroxypropyl cellulose (HPC) and Hydroxypropyl Methylcellulose (HPMC) in a side-vented pan coater.

This film coating was applied in order to minimize tablet attrition during the next coating step.

The tablets were then charged to a fluid bed column coater fitted with a Wurster insert and coated using a solution of cellulose acetate, sucrose and poly-

ethylene glycol 400, in a trisolvent vehicle comprising acetone, methanol and water.

The thickness of the resulting controlled porosity, microporous coating ranged from approximately 150 to 200 m.

The in vitro release of Compound A from the tablets prepared as above was determined using USP Apparatus II, paddle speed 50 rpm, at 37°C in 900 ml of dissolution media with pH values 1. 2 and 6. 8. The pH 1. 2 media consisted of O. 1N HCl solution adjusted to the appropriate pH by the addition of sodium hydroxide.

The pH 6. 8 medium consisted phosphate buffered media of various molar concen- trations. The pH 7. 5 medium comprised simulated intestinal fluid, which contains monobasic potassium phosphate, sodium hydroxide, and water.

EXAMPLE 15 Tablets for the pH-insensitive controlled release of Compound A were prepared with the following composition : Amount Per Ingredient Tablet (mg) CORE TABLETCompound A327. 0 Sodium Chloride 163. 5 Magnesium Stearate. NF (Non-Bovine) 2. 60 f'olyvinylpyrrolidone 1 K-29/32) 25. 80 2-propanol (l 3 (). ()) Total Tablet Weight 518.9 Compound A, sodium chloride. and polyvinylpyrrolidone were dry mixed in a 1-L high shear mixer and wet granulated using 100% isopropanol.

The resulting granules were dried and milled. and subsequently lubricated with magnesium stearate. The lubricated granules were compressed to a target weight of about 519 mg and were compressed on a small rotary tablet press using 9/23" x 21/32"capsule tooling. In certain cases, the tablet cores were tilm-coated using an aqueous solution of Hydroxypropyl cellulose (HPC) and Hydroxypropyl Methyl- cellulose (HPMC) in a side-vented pan coater. This film coating was applied in order to minimize tablet attrition during the next coating step.

The tablets were then charged to a fluid bed column coater fitted

with a Wurster insert and coated using a solution of cellulose acetate, sucrose and poiyethytene gtyco) 400, in a trisolvent vehicle comprising acetone. methanol and water. The thickness of the resutting controlled porosity, microporous coating ranged from approximately 150 to about 300 um. Each face of the tablet had one aperture, approximately 150 u. m in size. These apertures were created using methods previously discussed.

Experiments were conducted using various ratios (w/w) of sodium chloride : drug (l : l to 0. 125 : 1 were studied). The preferred ratio of about 0. 5 : 1 was used in the formulation described in this example.

The in-vitro release of Compound A from the tablets prepared as above was determined llilll, USP Apparatus 11, paddle speed 50 rpm, at 37°C in 900 ml of dissolution media with pH values 1. 2 and 5. 0. The pH 1. 2 media consisted of 0. IN HO sotution adjusted to the appropriate pH by the addition of sodium hydroxide. The pH 5. 0 medium consisted of phosphate buffered media of various molar concentrations. For a pH 6. 8 medium, a phosphate buffered media of various molar concentrations is used. For a pH 7. 5 medium, simulated intestinal fluid is used, which contains monobasic potassium phosphate, sodium hydroxide, and water.