CA2576556C - Drug delivery device - Google Patents

Abstract

A drug delivery device comprising a) one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers; and (d) humectant and/or trehalose.

Description

DRUG DELIVERY DEVICE
FIELD OF THE INVENTION
The present invention relates to a device for the delivery of active pharmaceutical ingredient(s). The present invention also relates to the use and method for making the same.
BACKGROUND OF THE INVENTION
Many techniques have been used to provide controlled and sustained-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance and the requirement of decreasing side effects of drugs by controlling their blood concentration.
For example, there are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. The semipermeable membrane acts to delimit a reservoir chamber. These tablets function by allowing a fluid, such as gastric or intestinal fluid, to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane by osmotic tension or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet devices can be found in U.S.
Patents Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337.
The problem with these devices is that they are tedious and difficult to fabricate. Their efficiency and precision is also in doubt as they have been known to break up prematurely or retain some of the drug content during transit in the gastrointestinal tract, which may lead to less drug being released and delivered by such devices. It is, therefore, not uncommon for such devices to contain an overage of drug of at least 10% to account for such inefficiencies in dose delivery. This practice is not economical and presents a =
danger, especially if potent drugs are used, as these devices have been known to rupture in transit thus releasing excess dose.
There have also been reports on sustained-release devices, such as tablets coated with a release-controlling coat, matrix tablets comprising water soluble polymeric compounds, matrix tablets comprising wax, matrix tablets comprising water insoluble polymeric compounds and the like. For example, U.S. Patent No. 3,629,393 (Nakamoto) utilizes a three-component system to provide slow release tablets in which granules of an active ingredient with a hydrophobic salt of a fatty acid and a polymer are combined with granules of a hydrocolloid and a carrier and granules of a carrier and an active or a buffering agent, which are then directly compressed into tablets.
U.S. Patent No. 3,728,445 (Bardani) discloses slow release tablets formed by mixing an active ingredient with a solid sugar excipient, granulating the same by moistening with a cellulose acetate phthalate solution, evaporating the solvent, recovering the granules and compressing under high pressure.
U.S. Patent No. 4,704,285 (Alderman) discloses solid slow release tablets containing 5-90% hydroxypropyl cellulose ether, 5-75% of an optional additional hydrophilic colloid, such as hydroxypropylmethyl cellulose, an effective amount of an active medicament, and optional binders, lubricants, glidants, fillers, etc.
U.S. Patent No. 6,605,300 is directed to the addition of disintegrants to premanufactured drug loaded beads which are to be combined with diluent to make a tablet in order to breakup the tablet and disperse the beads once the tablet is ingested. In this device, the disintegrants do not modulate the release of the active pharmaceutical ingredients. They only serve to break up the tablet in order to disperse the beads.
U.S. Patent No. 6,645,528 teaches porous drug matrices and methods of manufacture thereof.
These sustained-release devices have difficulty in controlling the release rate of water soluble or water insoluble active pharmaceutical ingredient(s) precisely. It is noted that when replacing a multiple times a day

- 2 -=
dosing with once a day dosing that the loading dose, which is represented by the first dose of an immediate release multiple times a day product, is captured to a certain extent by the once a day formulation via a loading dose effect which is built, ideally, into the formulation. Investigational studies over a long period of time were needed to obtain devices with a desired release rate.
The desired release rate being a rate of input and extent of release that simulate a loading dose effect and an extended release profile while using a single homogenous unit dose. The difficulty arises because conventional and current controlled release devices require higher amounts of polymers with high molecular weight and viscosity-imparting or gelling properties to achieve true extended release. Unfortunately, such high levels do not result in a loading dose effect. To obtain a loading dose effect in such devices, a lower amount of polymer concentration is required or a high amount of water soluble component must be added to moderate the effect of high concentration of polymer. However, at these levels, high variability is observed within and between lots. It is also difficult to obtain a product with a reproducible release rate and a loading dose effect. Such products also present problems in quality control as precise control and reproducibility of release profiles is difficult.
Conventional controlled release systems using only polymers with superdisintegrants do not meet the requirements for a stable controlled release device. Attempts have been made in the prior art to use water soluble components to modulate the effect of polymers on drug release.
These act by creating tortuous channels through which liquid and dissolved drug flows.
Devices containing superdisintegrants have been studied in order to obtain a desired controlled release rate. However, it has been found that such devices have stability issues and tend to fail the mandatory stability test set by ICH and the FDA. Superdisintegrants are very moisture sensitive and tend to swell in the presence of humidity resulting in the breakup of or, at the very least, the cracking of the surface of the device. This compromises the device and adversely alters the original release rate and drug release

- 3 -mechanism built into the device. Such a device fails to capture the loading dose effect which is represented by the first dose of an immediate release multiple times a day product which it is meant to replace.
Therefore, there is a need to develop stable drug delivery devices which exhibit a loading dose effect and an extended release profile, while using a single unit dose. There is also a need for a device that can be reproducibly manufactured and have the desired effect through less administration of the device per day.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is provided a drug delivery device comprising a) one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers; and (d) humectant and/or trehalose.
In accordance with another aspect of the present invention, there is provided a drug delivery device comprising one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; trehalose; and one or more swelling disintegrants and/or superdisintegrants to modulate the release of said one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients.
In accordance with a further aspect of the present invention, there is provided a method for providing a tableting granulated excipient for controlled release of water soluble active and/or water insoluble active pharmaceutical ingredients, the method comprising mixing an effective amount of said water soluble active and/or water insoluble active pharmaceutical ingredients to render a desired therapeutic effect with a premanufactured granulated excipient comprising from about 1 to about 90 percent by weight of trehalose from about 5 to about 95 percent by weight of a super-disintegrant and about

- 4 -to about 95 percent by weight water soluble polymer and/or water insoluble polymer material, and from about 5 to about 70 percent by weight of an inert pharmaceutical filler and silicone dioxide, and thereafter compressing the resulting blend to form a tablet.

5 In accordance with another aspect of the present invention, there is provided a tableting granulated excipient which is free-flowing and directly compressible for controlled release of water soluble active and/or water insoluble active pharmaceutical ingredients comprising an effective amount from about 1 to about 90 percent by weight of trehalose; from about 5 to about 95 percent by weight of a super-disintegrant; and about 5 to about 95 percent by weight water soluble polymer and/or water insoluble polymer material; from about 5 to about 75 percent by weight of an inert pharmaceutical filler; and from 0 to about 35 percent by weight of silicone dioxide.
In accordance with a further aspect of the present invention, there is provided a controlled release device, comprising a homogenous blend of:
(a) a disintegrant selected from a swelling disintegrant and a super-disintegrant, (b) a water soluble polymer, in an amount of from about 20% to about 60% by weight based on the total amount of material in the device, (c) an active pharmaceutical ingredient selected from a water soluble active pharmaceutical ingredient and a water insoluble active pharmaceutical ingredient, and (d) trehalose, in an amount of from about 5% to about 50% by weight based on the total amount of material in the device.
In accordance with another aspect of the present invention, there is provided a method of making a universal tableting granulated excipient, which is free-flowing and directly compressible, for controlled release of a therapeutically active medicament selected from a water soluble or an insoluble therapeutically active medicament comprising:
homogenously blending said therapeutically active medicament with a premanufactured granulated controlled release excipient comprising from about 5 to about 50 percent by weight of trehalose, from about 5 to about 95 percent by weight of a super-disintegrant, about 20 to about 60 percent by weight of a water soluble polymer material, from about 5 to about 75 percent by weight of an inert pharmaceutical filler and silicone dioxide, and;
thereafter directly compressing the resulting blend to form a tablet.
In accordance with a further aspect of the present invention, there is provided a universal tableting granulated excipient, which is free-flowing and directly compressible, for controlled release of a therapeutically active medicament selected from a water soluble therapeutically active medicament or an insoluble therapeutically active medicament, comprising a homogenous blend of:
from about 5 to about 50 percent by weight of treha lose, from about 5 to about 95 percent by weight of a super-disintegrant, from about 20 to about 60 percent by weight of a water soluble polymer material, from about 5 to about 75 percent by weight of an inert pharmaceutical filler, and from 0 to about 35 percent by weight of silicon dioxide.
The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising: (a) one or more water soluble active pharmaceutical ingredients -5a-and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers;
and (d) humectant and/or trehalose. The composition may be used for delivering one or more active pharmaceutical ingredients. Optional components may be added to the composition, for example, and without - 5b -=
being limited thereto, silicone dioxide, one or more inert pharmaceutical fillers, and/or one or more oil components.
More specifically, the pharmaceutical composition can be used in any drug delivery device such as, and without being limited thereto, a sustained release, pulsed release, delayed release and/or controlled release device that controls the release of one or more active pharmaceutical ingredients. The device can be a solid unit dosage form. The device can be selected from one or more granules, one or more compressed tablets, one or more pellets and/or one or more capsules. In a specific embodiment, the device is a stable single homogeneous unit controlled release device which controls the release rate, without significant variability, and with a reproducible controlled release rate and a loading dose effect of water soluble and/or insoluble active pharmaceutical ingredients.
The pharmaceutical composition may be administered in any suitable manner. For example and without being limited thereto, the composition can be in the form of a suitable device for oral, vaginal, anal, ocular, subcutaneous, intramuscular administration or for implantation.
The term "sustained release", "pulsed release", "delayed release" and "controlled release" are used interchangeably in this application and are defined for purposes of the present invention as the release of the drug from the dosage form at such a rate that when a dose of the drug is administered in the sustained release, pulsed release, delayed release or controlled-release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a selected period of time.
The term "swelling disintegrant" and "expanding disintegrant" are also used interchangeably in this application.
The use of humectant(s) and/or trehalose may be used to stabilize the combination of superdisintegrant(s) and water soluble and/or water insoluble polymer(s) and optionally an oil component for the controlled or sustained release of water soluble and/or water insoluble active pharmaceutical ingredient(s).

- 6 -= =
Trehalose is a disaccharide composed of two glucose molecules bound by an a,a-1,1 linkage. Since the reducing end of a glucosyl residue is connected with the other, trehalose has no reducing power. Trehalose is widely distributed in nature. It is known to be one of the sources of energy in most living organisms and can be found in many organisms, including bacteria, fungi, insects, plants, and invertebrates. Furthermore, trehalose protects organisms against various stresses, such as dryness, freezing, and osmopressure. In the case of resurrection plants, which can live in a dry state, when the water dries up, the plants dry up too. However, they can successfully revive when placed in water. The anhydrobitic organisms are able to tolerate the lack of water owing to their ability to synthesize large quantities of trehalose, and the trehalose plays a key role in stabilizing membranes and other macromolecular assemblies under extreme environmental conditions. Trehalose has high thermostability and a wide pH-stability range. Therefore, it is one of the most stable saccharides.
Trehalose has a very high glass transition temperature compared to other disaccharides. This allows trehalose to remain stable under a greater range of temperature extremes. Trehalose dihydrate is stable up to 94%
relative humidity. The low hygroscopic nature of trehalose dihydrate results in a free-flowing stable dry product.
In an embodiment, the drug delivery device comprises (a) one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers; and (d) trehalose. The device may further comprise other excipients such as one or more oil components and/or silicone dioxide.
Superdisintegrant(s) and/or swelling disintegrant(s) are used in combination with water soluble and/or water insoluble polymers, instead of water soluble components or low amounts of polymers, to obtain the desired release rate of input and extent of release that simulate a loading dose effect such that an extended release profile could be achieved using a single

- 7 -homogenous unit dose. Superdisintegrants and/or swelling disintegrant(s) are able to moderate the negative effect of high concentration of polymer and allow better control of drug release albeit with the disadvantage that the presence of superdisintegrants and/or swelling disintegrant(s) introduces stability issues and truncated shelf life. Typically, superdisintegrants and/or swelling disintegrant(s) present in the device make it reactive to levels of relative humidity that it would otherwise not react to. Such devices may disintegrate or breakup during storage.
Without being limited thereto, it is believed that the combination of swelling/expanding disintegrant(s) and/or superdisintegrant(s) and water soluble and/or water insoluble polymers improve and modulate the release of the active pharmaceutical ingredient(s) while trehalose and/or one or more humectants are used to stabilize the device and the disintegrants from adverse relative humidity effects, which are common with systems containing superdisintegrants. The addition of a humectant and/or trehalose can decrease moisture sensitivity and enhance product stability.
In another embodiment, the present invention also relates to a drug delivery device comprising one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; trehalose; and one or more swelling disintegrants and/or superdisintegrants to modulate the release of said one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients. The swelling disintegrants and/or superdisintegrants can modulate the release of the water soluble active pharmaceutical ingredients and/or water insoluble active pharmaceutical ingredients in order to produce multiple peaks. Multiple peaks can encompass first releasing the active pharmaceutical ingredients from the device and reaching a peak, and then another starts, releasing the active pharmaceutical ingredients, which peaks as the previous one is declining.
The present invention also relates to a tableting granulated excipient for use as a controlled release excipient, the tableting granulated excipient comprises one or more superdisintegrants and/or one or more swelling

- 8 -disintegrants; one or more water soluble polymers and/or one or more water insoluble polymers; and humectant and/or trehalose. In a more specific embodiment, the tableting granulated excipient comprises trehalose, one or more superdisintegrants, and one or more water soluble polymers and/or one or more water insoluble polymers. Optionally, an inert pharmaceutical filler and/or silicone dioxide may also be included in the excipient.
The tableting granulated excipient is typically free-flowing and directly compressible for use as a controlled release excipient.
There are no specific restrictions as to the methods of manufacture of the composition, device or excipient of the present invention. Typically, the device can be easily prepared, for instance, by the dry or wet granulation of a mixture containing (a) one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers; and (d) humectant and/or trehalose. Optional components may be added such as, and without being limited thereto, silicone dioxide, one or more excipients, one or more oil components, and/or the like. The granules thus obtained are dried if required and passed through a mill and lubricated. The granules are compressed into a shaped form in a rotary tablet press using a conventional method.
In another embodiment, the device can be prepared by direct compression of a mixture containing (a) one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; (b) one or more superdisintegrants and/or one or more swelling disintegrants; (c) one or more water soluble polymers and/or one or more water insoluble polymers; and (d) humectant and/or trehalose.
Optional components may be added such as, and without being limited thereto, silicone dioxide, one or more excipients, one or more oil components, and/or the like. The controlled release device thus prepared can be used as it is, or further film-coated.

- 9 -=
In the preparation of the device, the device may be cured at a predetermined temperature and relative humidity for a predetermined period of time in order to decrease or increase the rate of release of active pharmaceutical ingredient(s) from the device.
In the device of the present invention, an ideal release rate for individual active pharmaceutical ingredients can be ensured by controlling its release rate by changing the ratio of one or more superdisintegrants and/or one or more swelling disintegrants; to one or more water soluble polymers and/or one or more water insoluble polymers; to humectant and/or trehalose;
and to optional components, if any. In certain embodiments, there is about 0.001 wt% to about 60 wt% of one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; about 1 wt% to about 90 wt% of one or more superdisintegrants and/or one or more swelling disintegrants; about 5 wt% to about 95 wt% of one or more water soluble polymers and/or one or more water insoluble polymers; and about 1 wt% to about 90 wt% of humectant and/or trehalose, based on the weight of the device. Typically, there is about 3 wt% to about 30 wt% of one or more water soluble active pharmaceutical ingredients and/or one or more water insoluble active pharmaceutical ingredients; about 5 wt% to about 50 wt% of one or more superdisintegrants and/or one or more swelling disintegrants; about 5 wt% to about 30 wt% of one or more water soluble polymers and/or one or more water insoluble polymers; and about 5 wt% to about 50 wt% of humectant and/or trehalose, based on the weight of the device.
Swelling disintegrants or superdisintegrants which are used in the present invention may be any suitable swelling disintegrants or superdisintegrants that can improve and modulate the release of the active pharmaceutical ingredient(s). For example and without being limited thereto, sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked N-vinyl-2-pyrrolidone, and alginic acid, a cross-linked cellulose, a cross-linked polymer, a cross-linked starch, ion-exchange resin and combinations thereof,

-10-as well as other conventional Swelling disintegrants or superdisintegrants well known to persons skilled in the art.
Exemplary non-limiting humectants which may be useful according to the present invention may be selected from a wide range of materials such as glycerin (glycerol), propylene glycol (PEG), ethylene glycol, mineral oil, lanolin, sorbitol, maltitol, sodium PCA, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol, lactitol, and triacetin, as well as other conventional humectants well known to persons skilled in the art.
Water soluble polymers which are used in the present invention may be any polymers which are soluble in water and can preferably retard the release of active pharmaceutical ingredients when made into shapes by press-molding. Preferred water soluble polymers are those which can form hydrocolloid when molded into shape, thereby retarding release of pharmaceutically active components. They include naturally occurring or synthetic, anionic or nonionic, hydrophilic rubbers, starch derivatives, cellulose derivatives, proteins, and the like. Specific examples are acacia, tragacanth, xanthan gum, locust bean gum, guar-gum, karaya gum, pectin, arginic acid, polyethylene oxide, Carbomer, polyethylene glycol, propylene glycol arginate, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, carboxyvinyl polymer, sodium polyacrylate, alpha starch, sodium carboxymethyl starch, albumin, dextrin, dextran sulfate, agar, gelatin, casein, sodium casein, pullulan, polyvinyl alcohol, deacetylated chitosan, polyethyoxazoline, poloxamers and the like. Of these, preferable are hydroxyethyl cellulose, xanthan gum, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, polyethylene glycol, poloxamers, polyethylene oxide, starch derivatives and polyvinylpyrrolidone.
These water soluble polymers can be used either singly or in combinations of two or more.
Water insoluble polymers which are used in the present invention may be any polymers which are insoluble in water and can preferably retard the release of active pharmaceutical ingredients. Specific examples of water

-11 -insoluble polymers are, ethylcellulose, chitin, chitosan, cellulose esters, aminoalkyl methacrylate polymer, anionic polymers of methacrylic acid and methacrylates, copolymers of acrylate and methacrylates with quaternary ammonium groups, ethylacrylate methylmethacrylate copolymers with a neutral ester group, polymethacrylates, surfactants, aliphatic polyesters, zein, polyvinyl acetate, polyvinyl chloride, and the like. Preferred water insoluble polymers are, ethylcellulose, cellulose acetate, polymethacrylates and aminoalkyl methacrylate copolymer.
Oil components which can be used in the present invention include oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, metal salts of higher fatty acids, and the like. Specific examples of oils and fats include plant oils, such as cacao butter, palm oil, Japan wax (wood wax), coconut oil, etc.; animal oils, such as beef tallow, lard, horse fat, mutton tallow, etc.; hydrogenated oils of animal origin, such as hydrogenated fish oil, hydrogenated whale oil, hydrogenated beef tallow, etc.; hydrogenated oils of plant origin, such as hydrogenated rape seed oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated soybean oil, etc.; and the like. Of these hydrogenated oils are preferred as an oil component of the present invention. Specific examples of waxes include plant waxes, such as carnauba wax, candelilla wax, bayberry wax, auricurry wax, espalt wax, etc.; animal waxes, such as bees wax, breached bees wax, insect wax, spermaceti, shellac, lanolin, etc.; and the like. Of these preferred are carnauba wax, white beeswax and yellow beeswax. Paraffin, petrolatum, microcrystalline wax, and the like, are given as specific examples of hydrocarbons, with preferable hydrocarbons being paraffin and microcrystalline wax. Given as examples of higher fatty acids are caprilic acid, undecanoic acid, lauric acid, tridecanic acid, myristic acid, pentadecanoic acid, palmitic acid, malgaric acid, stearic acid, nonadecanic acid, arachic acid, heneicosanic acid, behenic acid, tricosanic acid, lignoceric acid, pentacosanic acid, cerotic acid, heptacosanic acid, montanic acid, nonacosanic acid, melissic acid, hentriacontanic acid, dotriacontanic acid, and the like. Of these, preferable are myristic acid, palmitic acid, stearic acid, and behenic acid. Specific examples of higher

-12-alcohols are lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachyl alcohol, behenyl alcohol, carnaubic alcohol, corianyl alcohol, ceryl alcohol, and myricyl alcohol. Particularly preferable alcohols are cetyl alcohol, stearyl alcohol, and the like. Specific examples of esters are fatty acid esters, such as myristyl palnnitate, stearyl stearate, myristyl myristate, behenyl behenate, ceryl lignocerate, lacceryl cerotate, lacceryl laccerate, etc.;
glycerine fatty acid esters, such as lauric monoglyceride, myristic monoglyceride, stearic monoglyceride, behenic monoglyceride, oleic monoglyceride, oleic stearic diglyceride, lauric diglyceride, myristic diglyceride, stearic diglyceride, lauric triglyceride, myristic triglyceride, stearic triglyceride, acetylstearic glyceride, hydoxystearic triglyceride, etc.; and the like. Glycerine fatty acid esters are more preferable. Specific examples of metal salts of higher fatty acid are calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, zinc palmitate, zinc myristate, magnesium myristate, and the like, with preferable higher fatty acid salts being calcium stearate and magnesium stearate.
These oil components and water insoluble polymers can be used either singly or in combinations of two or more.
As used herein, the term "active pharmaceutical ingredient" or "active pharmaceutical ingredients" refers to chemical or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo. Non-limiting active pharmaceutical ingredients contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as alternative salt forms, free acid forms, free base forms, and hydrates: analgesics/antipyretics (e.g., aspirin TM, acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline salicylate, butalbital, phenyltoloxamine citrate,

-13-diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, and meprobamate); antiasthamatics (e.g., ketotifen and traxanox); antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, and ciprofloxacin); antidepressants (e.g., nefopam, oxypertine, doxepin, amoxapine, trazodone, amitriptyline, maprotiline, pheneizine, desipramine, nortriptyline, tranylcypromine, fluoxetine, doxepin, imipramine, imipramine pamoate, isocarboxazid, trimipramine, venlafaxine, paroxetine, and protriptyline); antidiabetics (e.g., sulfonylurea derivatives); antifungal agents (e.g., griseofulvin, amphotericin B, nystatin, and candicidin);
antihypertensive agents (e.g., propanolol, propafenone, oxyprenolol, reserpine, trimethaphan, phenoxybenzamine, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine, sodium nitroprusside, rauwolfia serpentina, alseroxylon, and phentolamine);
anti-inflammatories (e.g., (non-steroidal) indomethacin, flurbiprofen, naproxen, ibuprofen, ramifenazone, piroxicam, (steroidal) cortisone, dexamethasone, fluazacort, celecoxib, rofecoxib, hydrocortisone, prednisolone, and prednisone); antiteoplastics (e.g., cyclophosphamide, actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, camptothecin and derivatives thereof, phenesterine, paclitaxel and derivatives thereof, docetaxel and derivatives thereof, vinblastine, vincristine, tamoxifen, and piposulfan); antianxiety agents (e.g., lorazepam, prazepam, chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, and dantrolene); immunosuppressive agents (e.g., cyclosporine, azathioprine, mizoribine, and FK506 (tacrolimus));
antimigraine agents (e.g., ergotamine, divalproex, isometheptene mucate, and dichloralphenazone); sedatives/hypnotics (e.g., barbiturates such as pentobarbital, pentobarbital, and secobarbital; and benzodiazapines such as flurazepam hydrochloride, triazolam, and midazolam); antianginal agents (e.g., beta-adrenergic blockers; calcium channel blockers such as nisoldipine;

and nitrates such as nitroglycerin, isosorbide dinitrate, pentaerythritol

-14-tetranitrate, and erythrityl tetranitrate); antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine, chlorpromazine, perphenazine, lithium citrate, respiridone, and prochlorperazine); antimanic agents (e.g., lithium carbonate); antiarrhythmics (e.g., bretylium tosylate, esmolol, amiodarone, encainide, digoxin, digitoxin, mexiletine, disopyramide phosphate, procainamide, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide acetate, tocainide, and lidocaine);
antiarthritic agents (e.g., phenylbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamate, gold sodium thiomalate, auranofin, aurothiogiucose, and tolmetin sodium); antigout agents (e.g., colchicine, and allopurinol); anticoagulants (e.g., heparin, heparin sodium, and warfarin sodium); thrombolytic agents (e.g., urokinase, streptokinase, and alteplase); antifibriolytic agents (e.g., aminocaproic acid); hemorheologic agents (e.g., pentoxifylline): antiplatelet agents (e.g., aspirin);
anticonvulsants (e.g., valproic acid, divalproex sodium, phenyloin, phenyloin sodium, clonazepam, primidone, phenobarbitol, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenyloin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, and trimethadione); antiparkinson agents (e.g., ethosuximide);
antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine maleate, methdilazine, loratadine, and); agents useful for calcium regulation (e.g., calcitonin, and parathyroid hormone);
antibacterial agents (e.g., amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, ciprofloxacin, clindamycin, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistimethate sodium, and colistin sulfate); antiviral

-15-agents (e.g., interferon alpha, beta or gamma, zidovudine, amantadine hydrochloride, ribavirin, and acyclovir); antimicrobials (e.g., cephalosporins such as cefazolin sodium, cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, cefuroxime e azotil, cefotaxime sodium, cefadroxil monohydrate, cephalexin, cephalothin sodium, cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, and cefuroxime sodium; penicillins such as ampicillin, amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin G
potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride. cloxacillin sodium, ticarcillin disodium, aziocillin sodium, carbenicillin indanyl sodium, penicillin G procaine, methicillin sodium, and nafcillin sodium; erythromycins such as erythromycin ethylsuccinate, erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin stearate, and erythromycin ethylsuccinate; and tetracyclines such as tetracycline hydrochloride, doxycycline hyclate, and minocycline hydrochloride, azithromycin, clarithromycin) anti-infectives (e.g., GM-CSF);
bronchodilators (e.g., sympathomimetics such as epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate, albuterol, bitolterolmesylate, isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, and epinephrine bitartrate;
anticholinergic agents such as ipratropium bromide; xanthines such as aminophylline, dyphylline, metaproterenol sulfate, and aminophylline; mast cell stabilizers such as cromolyn sodium; inhalant corticosteroids such as beclomethasone dipropionate (BDP), and beclomethasone dipropionate monohydrate; salbutamol; ipratropium bromide; budesonide; ketotifen;
salmeterol; xinafoate; terbutaline sulfate; triamcinolone; theophylline;
nedocromil sodium; metaproterenol sulfate; albuterol; flunisolide; fluticasone proprionate, steroidal compounds and hormones (e.g., androgens such as danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone, testosterone enathate, methyltestosterone, fluoxymesterone, and testosterone

-16-cypionate; estrogens such as estradiol, estropipate, and conjugated estrogens; progestins such as methoxyprogesterone acetate, and norethindrone acetate; corticosteroids such as triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate prednisone, methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate, methylprednisolone sodium succinate, hydrocortisone sodium succinate, triamcinolone hexacetonide, hydrocortisone, hydrocortisone cypionate, prednisolone, fludrocortisone acetate, paramethasone acetate, prednisolone tebutate, prednisolone acetate, prednisolone sodium phosphate, and hydrocortisone sodium succinate; and thyroid hormones such as levothyroxine sodium); hypoglycemic agents (e.g., human insulin, purified beef insulin, purified pork insulin, glyburide, chlorpropamide, tolbutamide, and tolazamide); hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium, probucol, simvastatin, pravastatin, atorvastatin, lovastatin, and niacin); proteins (e.g., DNase, alginase, superoxide dismutase, and lipase); nucleic acids (e.g., sense or anti-sense nucleic acids encoding any therapeutically useful protein, including any of the proteins described herein); agents useful for erythropoiesis stimulation (e.g., erythropoietin); antiulcer/antireflux agents (e.g., famotidine, cimetidine, and ranitidine hydrochloride); antinauseants/antiemetics (e.g., meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, and scopolamine); oil-soluble vitamins (e.g., vitamins A, D, E, K, and the like); as well as other drugs such as mitotane, halonitrosoureas, anthrocyclines, and ellipticine.
A description of these and other classes of useful drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993).
Examples of other drugs useful in the compositions and methods described herein include ceftriaxone, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, fosinopril, acarbose, lorazepan, follitropin, fluoxetine, lisinopril, tramsdol, levofloxacin,

-17-zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine, fentanyl, flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptan succinate, tacrine, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazole, terbinafine, pamidronate, didanosine, cisapride, venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium bromide.
These drugs are generally considered to be water soluble.
Other drugs include albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, rubitecan, amlodipine besylate/benazepril hydrochloride, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D3 and related analogues, finasteride, quetiapine fumarate, alprostadil, candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbidopa, levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maleate, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquine hydrochloride, chloroquine, trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol.
ursodiol,

-18-nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.
The drug delivery device of the present invention can be used for the treatment of hypertension, angina, diabetes, HIV AIDS, pain, depression, psychosis, microbial infections, gastro esophageal reflux disease, impotence, cancer, cardiovascular diseases, gastric/stomach ulcers, blood disorders, nausea, epilepsy, Parkinson's disease, obesity, malaria, gout, asthma, erectile dysfunction, impotence, urinary incontinence, irritable bowel syndrome, ulcerative colitis, smoking, arthritis, rhinitis, Alzheimer's disease, attention deficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungal infection, herpes, hyperglycemia, hyperlipidemia, hypotension, high cholesterol, hypothyroidism, infection, inflammation, mania, menopause, multiple sclerosis, osteoporosis, transplant rejection, schizophrenia, neurological disorders.
Excipients may also be included in the composition or device of the present invention. Excipients may be selected from diluents, compression agents, extrusion agents, glidants, lubricants, solubilizers, wetting agents, surfactants, penetration enhancers, pigments, colorants, flavoring agents, sweetners, antioxidants, acidulants, stabilizers, antimicrobial preservatives and binders.
These excipients may be chosen from:
(1) diluents such as microcrystalline cellulose, calcium phosphate, mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol;
arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, al lose, dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, and raffinose. Preferred sugars include mannitol, lactose, sucrose, sorbitol, trehalose, glucose, (2) surfactants, wetting agents and solubilisers such as glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan

-19-esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethlylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TVVEENTm), polyoxyethylene stearates, sodium dodecylsulfate, TyloxapolTm (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful solubilisers. Most of these solubilisers, wetting agents and surfactants are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986).
Preferred wetting agents include tyloxapol, poloxamers such as PLURONICTM F68, F127, and F108, which are block copolymers of ethylene oxide and propylene oxide, and polyxamines such as TETRONICTm 908 (also known as POLOXAMINETm 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid such as AEROSOLTM OT, which is a dioctyl ester of sodium sulfosuccinic acid (available from American Cyanimid), DUPONOLTM
P, which is a sodium lauryl sulfate (available from DuPont), TRITONTm X-200, which is an alkyl aryl polyether sulfonate (available from Rohm and Haas), TWEENTm 20 and TWEENTNA 80, which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals), CarbowaxTM 3550 and 934, which are polyethylene glycols (available from Union Carbide), Crodesta TM F-110, which is a mixture of sucrose stearate and sucrose distearate, and Crodesta TM SL-40 (both available from Croda Inc.), and SA9OHCO, which is Cg18H37-CH2 (CON(CH3)CH2(CHOH)4 CF20F1)2.
Wetting agents which have been found to be particularly useful include TetronicTm 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Other useful wetting agents include decanoyl-N-methylglucamide; n-decyl-.beta.-D-glucopyranoside; n-decyl-.beta.-D-maltopyranoside; n-dodecyl-.beta.-D-glucopyranoside; n-dodecyl.beta.-D-maltoside; heptanoyl-N-methylglucamide;
n-heptyl-.beta.-D-glucopyranoside; n-heptyl-.beta.-D-thioglucoside; n-hexyl

-20-.beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; and octyl-.beta.-D-thioglucopyranoside. Another preferred wetting agent is p-isononylphenoxypoly(glycidol), also known as Olin-1OG or Surfactant 10-G (commercially available as 10G from Olin Chemicals). Two or more wetting agents can be used in combination.
The pharmaceutical composition or device may further include a pegylated excipient. Such pegylated excipients include, but are not limited to, pegylated phospholipids, pegylated proteins, pegylated peptides, pegylated sugars, pegylated polysaccharides, pegylated block-co-polymers with one of the blocks being PEG, and pegylated hydrophobic compounds such as pegylated cholesterol. Representative examples of pegylated phospholipids include 1,2-diacyl 1-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 2000] ("PEG 2000 PE") and 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[- Poly(ethylene glycol) 5000]("PEG 5000 PE"), where the acyl group is selected, for example, from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and 1-palmitoyI-2-oleoyl.
One skilled in the art can select appropriate excipients for use in the composition of the present invention.
In an embodiment, the device is coated with a non-disintegrating and non-semi-permeable coat. Materials useful for forming the non-disintegrating non-semi-permeable coat are ethylcellulose, polymethylmethacrylates, methacrylic acid copolymers and mixtures thereof.
In yet another embodiment, the device is coated with a non-disintegrating semipermeable coat. Materials useful for forming the non-disintegrating semipermeable coat are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,612,008. The most preferred non-disintegrating semipermeable coating material is cellulose acetate comprising

- 21 -an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine Chemicals.
In an alternative embodiment, the non-disintegrating semipermeable or non-disintegrating non-semi-permeable coat can be formed from the above-described polymers and materials that will form passage ways in the coat.
The passage way forming agents dissolve on contact with fluid and form passages through which fluid and active pharmaceutical ingredient(s) can move through the coat. The passage way forming agent can be a water soluble material or an enteric material. Some examples of the preferred materials are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), polyvinyl pyrolidone, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof. The preferred passage way forming agent is PEG 600, polyvinyl pyrolidone and hydroxypropyl methycellulose.
The active pharmaceutical ingredient(s) that are water soluble or that are soluble under intestinal conditions may also be used to create passage ways in the coat.
The passage way creating agent comprises approximately 0 to about 75% of the total weight of the coating, most preferably about 0.5% to about 25% of the total weight of the coating. The passage way creating agent dissolves or leaches from the coat to form passage ways in the coat for the fluid to enter the core and dissolve the active ingredient.
The coat may also be formed with commonly known excipients such as plasticizers and anti-tacking agents. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol.
10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate,

- 22 -diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like. Depending on the particular plasticizer, amounts of from 0 to about 25%, and preferably about 2% to about 20% of the plasticizer can be used based upon the total weight of the coating polymer. The preferred anti tacking agent is talc. Depending on the coating polymer, amounts of from 0 to about 70%, and preferably about 10% to about 50% of talc can be used based upon the total weight of the coating polymer.
As used herein the term passageway includes an aperture, orifice, bore, hole, weaken area or as created by soluble or leachable materials Generally, the coat around the device will comprise from about 0.5% to about 70% and preferably about 0.5% to about 50% based on the total weight of the device with the coating.
In an alternative embodiment, the dosage form of the device may also comprise an effective amount of the active pharmaceutical ingredient that is available for immediate release as a loading dose. This may be coated onto the coat of the device or it may be incorporated into the coat or it may be press coated into the coated device.
In the preparation of coated device, various conventional well known solvents may be used to prepare the device and apply the external coating to the device. In addition, various diluents, excipients, lubricants, dyes, pigments, dispersants etc. which are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition may be used in the device.
The above disclosure generally describes the present invention. A
more complete understanding can be obtained by reference to the following specific Examples. The Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.

- 23 -A controlled release tablet containing metoprolol succinate and having the following formula is prepared as follows:
% by weight Metoprolol Succinate 20 Trehalose 20 Silicone dioxide 1 Crospovidone 20 Xanthan gum 20 Lactose 18 Magnesium stearate 1 (a) Granulation The metoprolol succinate, trehalose, silicone dioxide, crospovidone, lactose and xanthan is added to fluid bed granulator with a top spray assembly. This is granulated by spraying a 1% binding solution of polyvinyl pyrolidone. Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 5%. The dried granules are passed through a Comil.
(b) Tableting The magnesium stearate is blended with the granules in a V-blender.
After blending, the granules are compressed to tablets on a rotary press.

-24-A controlled release tablet containing venlafaxine hydrochloride and having the following formula is prepared as follows:
% by weight Venlafaxine hydrochloride 20 Trehalose 30 Silicone dioxide 1 Crospovidone 20 Xanthan gum 20 Ethycellulose 10 Lactose 8 Magnesium stearate 1 (a) Granulation The venlafaxine hydrochloride, trehalose, silicone dioxide, crospovidone, lactose, ethylcellulose and xanthan is added to high shear granulator. This is granulated using isopropyl alcohol. The granules are dried in a fluid bed dryer until the loss on drying is less than 5%. The dried granules are passed through a Comil.
(b) Tableting The magnesium stearate is blended with the granules in a V-blender.
After blending, the granules are compressed to caplets on a rotary press.
(c) Curing The tablets are cured by exposing them to a temperature of 40 C and relative humidity of 70% for 3 months.

-25-A controlled release tablet containing divalproex sodium and having the following formula is prepared as follows:
% by weight Divalproex sodium 20 Trehalose 5 Silicone dioxide 1 Sodium starch glycolate 30 Hydroxypropyl methyl cellulose 20 Hydrogenated castor oil 2 Lactose 20 Magnesium stearate 1 (a) Preparation by Wet Granulation Divalproex Na, trehalose, silicone dioxide, sodium starch glycolate, hydroxypropylmethyl cellulose and lactose is granulated in a Hobart low shear mixer using an alcoholic solution of castor oil. The wet granules are dried in a tray dryer oven. The dried granules are lubricated with magnesium stearate in a V-blender.

-26 -, , A controlled release tablet containing Nisoldipine and having the following formula is prepared as follows:
% by weight Nisoldipine 10 Trehalose 10 Silicone dioxide 0.5 Croscarmelose Na 40 Hydroxyethyl cellulose 25 Lactose 10 Sodium lauryl sulphate 9 Magnesium stearate 0.5 Preparation by Direct Compression Nisoldipine, silicone dioxide, lactose, hydroxyethyl cellulose, trehalose and sodium laury sulphate is dry blended in a high shear granulator.
Magnesium stearate is added to the dry blend in a V-blender.
After blending, the dry blended granules from (a) are compressed into tablets.

A controlled release tablet containing Paroxetine HCI and having the following formula is prepared as follows:
% by weight Paroxetine HCI 20 Trehalose 19 Silicone dioxide 0.5 Crospovidone 40 Hydroxypropyl ethyl cellulose 10 Xanthum gum 10 Magnesium stearate 0.5

-27-Preparation by Direct Compression Crospovidone, silicone dioxide, trehalose, paroxetine hydrochloride, hydroxypropylmethyl cellulose, and xanthan gum is dry blended in a Hobart low shear mixer. Magnesium stearate is added to the dry blend in a V-blender. After blending, the dry blended granules from are compressed into tablets.

A controlled release pellets consisting of extruded spheroids containing venlafaxine HCI and having the following formula is prepared as follows:
% by weight Carbedilol HCI 3 Trehalose 50 Crospovidone 20 Microcrystalline cellulose 13 Polysorbate 80 3 Glyceryl monooleate 3 Xanthan gum 8 (a) Preparation of Extrudate and Spheroids Venlafaxine HCI, trehalose, crospovidone, xcipie gum and microcrystalline cellulose is wet granulated in a Hobart low shear mixer. The wet mass is extruded and spheronized.

- 28 -Preparation of controlled release excipients for use as a direct compressible premanufactured excipients to be used for controlling the release of active pharmaceutical ingredients % by weight Crospovidone 30 Trehalose 20 Silicone dioxide 1 Hydroxypropyl methylcellulose 10 Xanthan gum 10 Ethylcellulose 9 Lactose 20 The materials are dry blended in a v-blender.

Optional coating systems that may be used to coat products from examples 1 to 6 are as follows:
1. Non-disintegrating non-semi-permeable Coat type 1 % by weight EudragitTM NE 30 D 41.7 Talc 12.5 Antifoam agent 0.1 Water 45.7 Talc is added to water to which antifoaming agent has been added while stirring with a high shear mixer. The mixture is added slowly to Eudragit NE 30 D solution and stirred. The coating solution is then sprayed onto the tablets or to a theoretical weight gain of about 5% to 50 wt%.

- 29 -2. Using non-disintegrating non-semi-permeable Coat type 2 % by weight Ethylcellulose 80 Hydroxypropylmethylcellulose 20 This is made as a solution in acetone. The coating solution is then sprayed onto the tablets or pellets to a theoretical weight gain of about 2%
to about 15 wtcYo.
3. Non disintegrating non semi-permeable Coat type 3 `)/0 by weight Eudragit RL 30 D 46.3 Triethyl citrate 2.8 Silicone dioxide 4.2 Antifoam agent 0.1 Water 46.6 Silicone dioxide is added to water to which antifoaming agent and triethyl citrate has been added while stirring with a high shear mixer. The mixture is added slowly to Eudragit RL 30 D solution and stirred. The coating solution is then sprayed onto the tablets or pellets to a theoretical weight gain of about 3% to about 20 wt%.
4. Non-disintegrating non-semi-permeable Coat type 4 % by weight Eudragit RL 30 D/Eudragit RS 30 D (1:9) 46.3 Triethyl citrate 2.8 Silicon dioxide 4.2 Antifoam agent 0.1 Water 46.6

- 30 -Silicone dioxide is added to water to which antifoaming agent and triethyl citrate has been added while stirring with a high shear mixer. The mixture is added slowly to a mixture of Eudragit RL 30 D and RS 30 D
solution and stirred. The coating solution is then sprayed onto the tablets and pellets to a theoretical weight gain of about 3% to about 15 wt%.
5. Using non disintegrating semi-permeable Coat type 1 % by weight Cellulose acetate 80 Triacetin 5 PEG 600 14.5 Red Iron oxide 0.5 The cellulose acetate is dissolved in acetone while stirring with a high shear mixer. The red iron oxide, polyethylene glycol 600 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear coating solution is then sprayed onto the tablets or pellets to a theoretical weight gain of about 1 /0 to about 15 wt%.
6. Using disintegrating coat type 1 The tablets or pellets may be coated with an OpadryTM or LustreClearTM material or other suitable water-soluble material by first dissolving the opadry material, preferably Opadry Clear, in purified water.
The Opadry solution is then sprayed onto the tablets or pellets to a theoretical coating level of about 2% to about 15 wt%.

- 31 -7. Using disintegrating coat type 2 % by weight Eudragit L 30 D 46.3 Polyethylene glycol 600 2.8 Talc 7.0 Antifoam agent 0.1 Water 50.8 Talc is added to water to which antifoaming agent and polyethylene glycol 600 has been added while stirring with a high shear mixer. The mixture is added slowly to a mixture of Eudragit L 30 D solution and stirred. The coating solution is then sprayed onto the tablets and pellets to a theoretical weight gain of about 3% to about 15 wt%.
8. Using disintegrating coat type 2 % by weight Eudragit L and/or Eudragit S 10.0 Polyethylene glycol 600 2.0 Talc 5.0 Antifoam agent 0.1 Water 5.0 Ethanol 77.9 Talc is added to ethanol and water to which antifoaming agent and polyethylene glycol 600 has been added while stirring with a high shear mixer.

The mixture is added slowly to a mixture of Eudragit L and or Eudragit S in Ethanol and stirred. The coating solution is then sprayed onto the tablets and pellets to a theoretical weight gain of about 3% to about 20 wt%.

- 32 -

Claims (36)

WE CLAIM:

1. A controlled release device, comprising a homogenous blend of:
(a) a disintegrant selected from a swelling disintegrant and a super-disintegrant, (b) a water soluble polymer, in an amount of from about 20% to about 60% by weight based on the total amount of material in the device, (c) an active pharmaceutical ingredient selected from a water soluble active pharmaceutical ingredient and a water insoluble active pharmaceutical ingredient, and (d) trehalose, in an amount of from about 5% to about 50% by weight based on the total amount of material in the device.

2. The controlled release device according to claim 1, further comprising silicon dioxide.

3. The controlled release device according to claim 1 or 2, further comprising an oil component.

4. The controlled release device according to claim 3, wherein the oil component is used in the amount of 1% or more by weight based on the total amount of material in the device.

5. The controlled release device according to any one of claims 1 to 4, further comprising a water-insoluble polymer that is used in the amount of 1%
or more by weight based on the total amount of material in the device.

6. The controlled release device according to claim 5, wherein said water-insoluble polymer is selected from ethylcellulose, chitin, chitosan, cellulose esters, aminoalkyl methacrylate polymer, anionic polymers of methacrylic acid and methacrylates, copolymers of acrylate and methacrylates with quaternary ammonium groups, ethylacrylate methylmethacrylate copolymers with a neutral ester group, polymethacerlates, surfactants, aliphatic polyesters, zein, polyvinyl acetate, and polyvinyl chloride.

7. The controlled release device according to any one of claims 1 to 6, wherein the water-soluble polymer is selected from the group consisting of naturally occurring or synthetic, anionic or nonionic, hydrophilic rubbers, cellulose derivatives, starch derivatives, polysaccharides, hydrogels, gelling agents, gums, alginates, surfactants, polyethylene glycols, polyethylene oxides, polyvinyl alcohols, crosslinked polymers and proteins.

8. The controlled release device according to any one of claims 1 to 7, wherein the disintegrant is chosen from the group consisting of a cross-linked cellulose, a cross-linked polymer, a cross-linked starch, an ion-exchange resin and a combination thereof.

9. The controlled release device according to any one of claims 1 to 8, wherein the disintegrant is chosen from the group consisting of sodium starch glycolate, sodium croscarmellose, homopolymer of cross-linked N-viny1-2-pyrrolidone, and alginic acid.

10. The controlled release device according to any one of claims 1 to 9, wherein the disintegrant is present in the amount of 1% by weight or more.

11. The controlled release device according to any one of claims 1 to 10, wherein the active pharmaceutical ingredient is present in the amount of 0.001% or more by weight.

12. The controlled release device according to any one of claims 1 to 11, wherein the water-soluble polymer is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, xanthan gum, carrageenan, carbomer, polyvinylpyrrolidone, locust bean gum, guar-gum, karaya gum, pectin, arginic acid, and propylene glycol arginate.

13. The controlled release device according to any one of claims 3 to 12, wherein the oil component is one or more compounds selected from the group consisting of oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, and metal salts of higher fatty acids.

14. The controlled release device according to claim 13, wherein said wax is selected from carnauba wax, cethyl esters wax, white beeswax or white wax, yellow beeswax, and bees wax.

15. The controlled release device according to claim 13, wherein said oil is selected from a hydrogenated oil, vegetable oil, and combinations thereof.

16. The controlled release device according to claim 13, wherein said hydrocarbon is selected from paraffin, microcrystalline wax, and combinations thereof.

17. The controlled release device according to claim 13, wherein said higher fatty acid is selected from myristic acid, palmitic acid, stearic acid, and behenic acid.

18. The controlled release device according to claim 13, wherein said higher alcohol is selected from cetyl alcohol and stearyl alcohol.

19. The controlled release device according to claim 13, wherein said esters are glycerine fatty acid esters.

20. The controlled release device according to any one of claims 1 to 19, further comprising an excipient selected from diluents, compression agents, extrusion agents, glidants, lubricants, solubilizers, wetting agents, surfactants, penetration enhancers, pigments, colorants, flavoring agents, sweeteners, antioxidants, acidulants, stabilizers, antimicrobial preservatives and binders.

21. The controlled release device according to any one of claims 1 to 20, wherein there is a lag phase prior to the release of the active pharmaceutical ingredient.

22. The controlled release device according to any one of claims 1 to 20, wherein said device is a sustained release device.

23. The controlled release device according to any one of claims 1 to 20, wherein said device is a pulsed release device.

24. The controlled release device according to any one of claims 1 to 20, wherein said device is a delayed release device.

25. The controlled release device according to any one of claims 1 to 20, wherein said device modulates the release of the active pharmaceutical ingredient in order to produce multiple peaks.

26. The controlled release device according to any one of claims 1 to 20, wherein said device is a chronotherapeutic delivery device.

27. Use of the controlled release device according to any one of claims 1 to 26 for treatment of a condition selected from hypertension, angina, diabetes, HIV AIDS, pain, depression, psychosis, microbial infections, gastro esophageal reflux disease, impotence, cancer, cardiovascular diseases, gastric/stomach ulcers, blood disorders, nausea, epilepsy, Parkinson's disease, obesity, malaria, gout, asthma, erectile dysfunction, impotence, urinary incontinence, irritable bowel syndrome, ulcerative colitis, smoking, arthritis, rhinitis, Alzheimer's disease, attention deficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungal infection, herpes, hyperglycemia, hyperlipidemia, hypotension, high cholesterol, hypothyroidism, infection, inflammation, mania, menopause, multiple sclerosis, osteoporosis, transplant rejection, schizophrenia, and neurological disorders.

28. A method of making a universal tableting granulated excipient, which is free-flowing and directly compressible, for controlled release of a therapeutically active medicament selected from a water soluble or an insoluble therapeutically active medicament comprising:
homogenously blending said therapeutically active medicament with a premanufactured granulated controlled release excipient comprising from about 5 to about 50 percent by weight of trehalose, from about 5 to about 95 percent by weight of a super-disintegrant, about 20 to about 60 percent by weight of a water soluble polymer material, from about 5 to about 75 percent by weight of an inert pharmaceutical filler and silicone dioxide, and;
thereafter directly compressing the resulting blend to form a tablet.

29. The method of claim 28, further comprising making a controlled release device using the excipient, wherein the device is made by wet or dry granulation of the components and tableted.

30. The method of claim 28, further comprising making a controlled release device using the excipient, wherein the device is made by direct tableting.

31. The method of claim 28, further comprising making a controlled release device using the excipient, wherein the device is made by extrusion-spheronization.

32. The method of any one of claims 28 to 31, further comprising making a controlled release device using the excipient, wherein the device is coated by one or more layers of enteric or non-enteric coat or both.

33. The method of any one of claims 28 to 32, further comprising making a controlled release device using the excipient, wherein the device is cured at predetermined temperature and relative humidity over a predetermined period in order to decrease or increase the rate of release of active pharmaceutical ingredient from the device.

34. A universal tableting granulated excipient, which is free-flowing and directly compressible, for controlled release of a therapeutically active medicament selected from a water soluble therapeutically active medicament or an insoluble therapeutically active medicament, comprising a homogenous blend of:
from about 5 to about 50 percent by weight of trehalose, from about 5 to about 95 percent by weight of a super-disintegrant, from about 20 to about 60 percent by weight of a water soluble polymer material, from about 5 to about 75 percent by weight of an inert pharmaceutical filler, and from 0 to about 35 percent by weight of silicon dioxide.

35. The universal tableting granulated excipient of claim 34, further comprising a water insoluble polymer.

36. The controlled release device of claim 3 or 35, wherein the water insoluble polymer comprises more two or more different water insoluble polymers.