CA2579382A1 - Controlled release delivery device - Google Patents

Abstract

A controlled release delivery device comprising: (a) two or more polymeric coats substantially enveloping an active ingredient; and (b) at least one transition zone formed between two bordering polymeric coats.

Description

FIELD OF THE INVENTION

The present invention relates to a device for the delivery of active 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 ingredient, and optional binders, lubricants, glidants, fillers, etc.
U.S. Patent No. 6,645,528 teaches porous drug matrices and methods of manufacture thereof.
DE Patent Application No. 3943242 discloses "matrix" type granules comprising an active ingredient and inert excipent(s) compressible into tablets. Each granule consists of a multitude of particles included in a roughly spherical matrix comprising a cellulosic polymer, a vinylic or acrylic polymer, a plasticizer and a lubricating agent.
There are reports in the literature of several tablets which are film-coated with a coating material of, for example, cellulosic, acrylic, starch, polyethylene glycol or gum type, or their derivatives. This coating functions to provide taste masking, protection of an active ingredient, gastro-resistance to physiological fluids, and also to prolong the release of the active ingredient.
For example, U.S. Pat. No. 4,461,759 describes a coated tablet which protects an active ingredient from the harmful effects of the acid pH of the stomach and at the same time releasing the active ingredient at a constant rate in the gastrointestinal tract.
The use of microporous film coating which allows the release of an active ingredient under the effect of an osmotic pressure has also been widely reported. One such report, PCT publication WO 91/16885 (U.S. Pat. No.
5,028,434), teaches the sustained release of an active ingredient irrespective of the solubility of the active ingredient in the medium.
Another practice in the delivery of drugs is the use of micro-particulate pharmaceutical systems giving a sustained release of an active ingredient.
For example, Patent EP 396,425 discloses a system intended for the administration once daily dose of an active ingredient. To this end, the active ingredient is bound to the surface of inert spheruies with a diameter ranging from 250 to 2000 microns, using a known binder. The particles are then fiim-coated with a cellulose compound and a plasticizer, to slow down the release of the active ingredient.
U.S. Pat. No. 5,286,497 describes a formulation based on Diltiazem which is designed to be taken once a day. Diltiazem is bound to the surface of inert granules of sugar or of starch, which are then optionally film-coated.
U.S. Pat. No. 4,869,908 describes floating tablets, characterized by a long residence time in the stomach. This system is more particularly suited to the administration of an active ingredient having a preferential absorption at the gastric level.
Patent FR 2,395,026 teaches a process for the preparation of a system in which the micro-particles containing an active ingredient are in a sustained-release form containing, in their composition, a densifying agent which allows a significant prolongation in the transit time, which may then exceed 24 hours.
This system was developed after observation of the fact that transit in the small intestine is slowed down considerably when the density of the particles exceeds 1.4 grams per cubic centimeter. The same approach of increasing the transit time by elevation of the density is adopted in EP applications 0,080,341 and 0,173,210. However, such systems have the drawback of requiring the introduction of a large amount of densifying agent, of the order of 30 to 80% of the total weight of the form, which limits the content of an active ingredient in the system and constitutes a handicap for the manufacture of forms requiring a large dose of active ingredient.
Another approach for controlled release consists of the development of bioadhesive systems.
EP 0,452,268 claims a bucco-adhesive system in the form of microparticles film-coated with a gel of xanthan/carob gums or with ethylcellulose. The effectiveness of such a system, essentially intended for the mouth, is not established, and all the less so since the particles are coated with a film of wax as an outer layer, which is intended to sustain their release but which makes adhesion improbable, and anyway not demonstrated in vivo.
Application EP 0,516,141 is directed towards the development of a bioadhesive particulate system by overcoating, of any given sustained-release form of an active ingredient, with an adhesive composition based on polymers such as water-soluble derivatives of cellulose, acrylic polymers known under the trade names CarbopolTM or PolycarbophilTM , alginates, gelatin or pectin.
U.S. Pat. No. 6,022,562 discloses an invention which relates to microcapsules for the oral administration of a medicinal and/or nutritional active ingredient, which are smaller than or equal to 1000 micrometer in size.
These microcapsuies consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer.
The invention also relates to a process for the production of the microcapsules.
U.S. Pat. No. 6,022,562 uses multiple film forming polymers in one film forming coating composition, i.e., the polymers are applied as an admixture to form one or more layers of coat.

These sustained-release devices have difficulty in controlling the release rate of water soluble or water insoluble active ingredient(s). It is noted that when replacing a multiple times a day 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.
There have been reports in the literature of the use of hydrophobic thermoplastic polymers such as ethylcellulose for the controlled release of pharmaceutical substances. Ethylcellulose is typically applied as a coat. Drug release is by symmetric flow (channel flow) and diffusion through the ethylcellulose layer. Release is controlled by the layer thickness and the rate of channel flow or diffusion flow force. Such systems are at a disadvantage because they allow drug delivery to be controlled via a singular property i.e., coating thickness formed from use of a single film forming admixture. This presents a high risk approach to the optimization of formulations, because the use of coating thickness as an index for controlling rate of input presents a narrow window to work with and limits the applicability of such systems. This is one reason why matrix systems have superceded the use of hydrophobic thermoplastic polymers such as ethyicellulose coats or coats consisting of a mixture of ethylcellulose polymer and a nitrogen-containing polymer such as polyvinylpyrolidone as means for controlling the release of drugs.
Therefore, there is a need to develop a stable drug delivery device that can be reproducibly manufactured and have the desired effect through less administration of the device per day.

SUMMARY OF THE INVENTION
An object of the present invention is to provide a delivery device to control the rate and extent of delivery of an active ingredient, for example, without limitation an active pharmaceutical ingredient, biological, chemical, nutraceutical, agricultural or nutritional active ingredients.
In accordance with an aspect of the present invention, there is provided a controlled release delivery device comprising two or more polymeric coats and at least one transition zone between the polymeric coats, wherein at least two polymeric coats are not applied as an admixture.
In accordance with an aspect of the present invention, there is provided a controlled release delivery device comprising: (a) two or more polymeric coats substantially enveloping an active ingredient; and (b) at least one transition zone formed between a pair of bordering polymeric coats.
In accordance with an aspect of the present invention, there is provided a controlled release delivery device comprising: (a) first, second and third polymeric coats substantially enveloping an active ingredient; (b) a first transition zone formed between a first pair of bordering polymeric coats comprised of the first and second polymeric coats; and (c) a second transition zone formed between a second pair of bordering polymeric coats comprised of the second and third polymeric coats.

In accordance with an aspect of the present invention, there is provided a controlled release delivery device for controlled release of an active ingredient comprising: (a) a core particle comprising the active ingredient; (b) two or more polymeric coats substantially enveloping the core particle comprising the active ingredient; and (c) at least one transition zone between the polymeric coats.

In accordance with an aspect of the present invention, there is provided a controlled release delivery device comprising: (a) a core particle comprising the active ingredient; (b) first, second and third polymeric coats substantially enveloping an active ingredient; (c) a first transition zone formed between a first pair of bordering polymeric coats comprised of the first and second polymeric coats; and (d) a second transition zone formed between a second pair of bordering polymeric coats comprised of the second and third polymeric coats.

In accordance with an aspect of the present invention, there is provided a process for producing a controlled release delivery device for controlled release of an active ingredient comprising:
(a) providing a core particle comprising the active ingredient;
(b) coating the core particle with a first polymeric coat comprised of a first water insoluble polymer to substantially envelope the core particle;
(c) allowing the first polymeric coat to dry; and (d) coating the first polymeric coat with a second polymeric polymeric coat comprised of a second water insoluble polymer to provide a polymeric coat that borders and substantially envelopes the first polymeric coat.

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.
BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims:
FIGURE 1 shows a schematic of a controlled release delivery device comprising three polymeric coats and two transition zones;
FIGURE 2 depicts a proposed or suggested mechanism of controlled release from a transition zone bordered by two poiymeric coats;
FIGURE 3 presents, in accordance with an embodiment of the invention, data regarding the release of an active pharmaceutical ingredient from a coated particle over a sustained-release period.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel composition and to a method of using and preparing same in order to control the rate and extent of delivery of an active ingredient. This is accomplished by the use of two or more polymeric coats having a transition zone between at least two of the polymeric coats. The active ingredient may be, without limitation, an active pharmaceutical ingredient; or biological, chemical, nutraceutical, agricultural or nutritional ingredients. The active ingredient may be in any suitable particle known in the art, for example, without limitation, granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, or crystals.
More specifically, the novel composition of the present invention can be used in any 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, for example, 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.
The 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 in vivo oral, vaginal, anal, ocular, subcutaneous, intramuscular administration or for implantation. The composition may also be used for in vitro or ex vivo delivery of an active ingredient.
In one example, a controlled release delivery device for sustained-release of an active ingredient comprises: (a) a core particle comprising the active ingredient; (b) two or more polymeric coats substantially enveloping the active ingredient; and (c) at least one transition zone between the polymeric coats.
The term "active ingredient" means any compound which has biological, chemical, or physiological utility including, without limitation, pharmaceuticals, drugs, naturally occurring compounds, nucleic acid compounds, peptide compounds, nutraceutical, agricultural or nutritional ingredients or synthetic drugs.
The term "core particle" means a particle comprising an active ingredient and which is substantially surrounded or enveloped by a polymeric coating. The core particle can further comprise other compounds, including, without limitation, binders, buffers, antioxidants, filers or excipients. The core particle can be, without limitation, granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals, or suitable mixtures thereof.
The term "polymeric coating" or "polymeric coat" means any coating which is formed by polymerization of one or more monomers to form linear or branched or cross-iinked macromolecules. The coating may be variously characterized as a coating, layer, membrane, shell, capsule, or the like, and substantially surrounds or envelope a core particle. Where a device of the present invention comprises more than one polymeric coat, a first polymeric coat substantially surrounds or envelopes a core particle, a second polymeric coat substantially surrounds or envelopes the first polymeric coat, and so forth. A subsequent (for example, second) polymeric coat may be applied to a previous (for example, first) polymeric coat in a contiguous or non-contiguous fashion.
The term "transition zone" or "transition boundary" is a region formed and located in between two bordering polymeric coats, where one polymeric coat is directly applied to and substantially surrounds or envelopes another polymeric coat. The transition zone or boundary need not be of uniform thickness or shape along its entirety and may be interrupted by a portion of one bordering polymeric coat leaching into another bordering polymeric coat such that the two bordering polymeric coats appear to be contiguous at this portion. When inspected using microscopic imaging devices portions of the transition zone or boundary will show the polymeric coats bordering the transition zone to be at least partially non-contiguous. The transition zone or boundary may be varied in width or thickness from about 1 angstrom to about millimeter. In one example, the transition zone or boundary may be varied in width or thickness from about 10 angstroms to about 10 micrometer. In another example, the transition zone width or thickness may range from about 1 angstrom, 10 angstrom, 100 angstrom or any number therebetween to 25 about 500 angstrom, 1000 angstrom, 5000 angstrom, 10000 angstrom or any number therebetween.
While not meant to be limiting and for demonstration purposes only, Figure 1 depicts a relationship between 3 polymeric coats (first, second and third polymeric coats) and two transition zones (first and second transition zones). The first and second polymeric coats form a pair of bordering polymeric coats having a first transition zone therebetween, while the second and third polymeric coats form a pair bordering polymeric coats having a second transition zone therebetween. Typically, bordering polymeric coats will not be made of identical components. For example, without limitation, a pair of bordering polymeric coats may comprise two different water insoluble polymers such as an ethylcellulose polymer and a poiyvinyl acetate or an ethylcellulose polymer and a methacrylate copolymer.
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 an active ingredient from a delivery device at such a rate that when a dose of the active ingredient is administered in the sustained release, pulsed release, delayed release or controlled-release device, concentrations (levels) of the active ingredient are maintained within a desired range but below toxic levels over a selected period of time. In the case of in vivo administration, concentrations (levels) of the active ingredient could be measured in blood or plasma, for example. When administered in vivo the sustained release, pulsed release, delayed release or controlled-release device of the present invention allows for useful plasma concentration of an active ingredient to be maintained for longer than in the case of immediate-release forms.
The controlled release profile may be modified on the basis of many factors pertaining to the polymeric coats and transition zones, for example, without limitation, through the types of polymers used, the order in which they are deposited, the number and or width of transition zones or boundaries, the ratios of the polymers in the mix and the nature of their interaction at the transition zones. The co ntro lied- release profile can also be modified by a variety of factors relating to the delivery device and the route of administration as outlined for example, in US Application No. 20070003619, published January 4, 2007. For example, the sustained-release period will vary depending upon the solubility of the active ingredient, the rate of clearance of the active ingredient from the intended site of administration, the size of the core particle, the amount of the active ingredient initially present in the core particle, the presence of other compounds within the core particle that affect the rate of release of the active ingredient, the permeability of the polymeric coating(s) to the active pharmaceutical ingredient, and the rate of degradatioti of the polymeric coating(s), as well as other factors.
Prior art devices that use the singular property of coating thickness to control release are at a disadvantage, because the use of coating thickness as an index for controlling rate of input or drug release presents a narrow window to work with and limits the applicability of such devices.
A controlled release delivery device of the present invention, in one example, is formed by combining two or more polymer coats in a transition type assembly in which the layers of coat for a select group of polymers are deposited in a manner such that there is a transition zone from one coat to another. A controlled release delivery device comprising two or more polymeric coats and at least one transition zone between the polymeric coats provides a much wider scope for formulation optimization. Moreover, it has been found that the control of rate of input or drug release can be easier, cost effective or efficient with these systems in comparison to controlling rate of release by polymeric coat thickness alone.
The mechanism of release in the transition type coating as taught in this invention appears to be significantly different from the non-transition type coating taught in the prior art. Without wishing to be bound by theory, by the use of transition coating, cross flow of drug molecules is introduced at the transition boundary or zone as depicted, for example, in Figure 2. It is proposed, that when placed in contact with liquid milieu, systems on which transition coats have been applied may experience diffusion flow followed by cross flow. The net effect may be asymmetric flow which can result in a liquid funnel or funnel flow as drug molecules or materials migrate from the core past a transition zone. It is the present inventors opinion that due to the low tortuosity factor of the pre-transition zone the flow is laminar leading to a diffusion flow force field. Adjacent to this is the transition zone having a h-igher tortuosity factor in which a second force field is generated by the turbulent or funnel flow. This force field is the cross flow force field. The funnel flow that result helps create a velocity gradient. Regardless of mechanism, the delivery device of the present invention comprising at least two polymeric coats and a transition zone between the polymeric coats allows for an improved control of release rate compared to the use of coating thickness aione.
Release control may be effected or optimized through the types of polymers used, the order in which they are deposited, the number and or width of transition zones or boundaries, the ratios of the polymers in the mix and the nature of their interaction at the transition zones.
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 an active ingredient. 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 certain examples granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsuies, or crystals comprising an active ingredient can be prepared by wet or dry granulation, by extrusion spheronization, by powder or solution layering, by microencapsulation techniques, by milling and compression techniques. The transition coating may be carried out using fluid bed coating techniques or by coating using perforated side vented pan coating technique or by microencapsulation technique. These methods have been previously taught in the prior art.
In a particular example, an approach taught by the present inventors, is a multiple wet granulation and drying technique. This involves the granulation of the active ingredient with or without excipients with a first film forming polymer solution or dispersion and drying the granulation in an oven or fluid bed or vacuum drying. The wet granules may be milled or screened before drying. The first polymeric coated dried granules may be milled. The process is repeated using the dried or dried milled granules as starting material and a second film forming polymer solution or dispersion as granulation liquid. This process is repeated as many times as necessary to obtain a desired number of polymeric coats and desired number of transition zones with bordering polymeric coats. The capsules used in this invention may be hard or soft gelatin type or made from cellulose ethers.
In certain examples, different populations of coated particles can be packed together, for example, in a capsule or compressed into a tablet.
Methods of polymeric coating are well known in the art. For example, a core particle may be coated in a fluidized bed or pan, or by spraying or painting a polymeric coat onto a core particle. Another known option is a fluid bed bottom spray coater by having particles suspended in an air stream, and an aqueous dispersion of a polymeric coating composition is sprayed on to the particles. Various conventional coating apparatuses may be employed to facilitate this including, for example, a centrifugal fluidized bed coating apparatus, a pan coating apparatus, or a fluidized bed granulating coating apparatus.
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 ingredient(s) from the device. . A curing process may also be carried out to simply remove a desired amount of solvent from the polymeric coat.
A controlled release delivery device of the present invention, typically, but not always, comprises two or more polymeric coats of water insoluble polymers and at least one transition zone between the polymeric coats of water insoluble polymers.
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 insoluble polymers are, ethyicellulose, 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.
In further specific examples, the acrylic polymer, includes, but is not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolyer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Additionally, the acrylic polymers may be cationic, anionic, or non-ionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or methacrylic acid esters.
The polymers used in the present invention may also be pH insensitive or pH sensitive.
For a delivery device designed to be orally administered to the digestive tract, polymers that are known to be orally ingestible can be used and include, for example, polyvinyl alcohol, hydroxypropyl methyl cellulose, and other cellulose-based polymers. Other known polymers useful for enteral delivery include polymer materials which preferentially dissolve or disintegrate at different points in the digestive tract. Such polymers include, for example, the known acrylic and/or methacrylic acid-based polymers which are soluble in intestinal fluids, e.g. the EudragitTM series of commercially available polymers. Examples of these include Eudragit ETM, such as Eudragit E 100TM
which preferentially dissolves in the more acid pH of the stomach, or enteric polymers such as Eudragit LTM and/or Eudragit STM which preferentially dissolve in the more alkaline pH of the intestine, or polymers which dissolve slowly, e.g. a predetermined rate in the digestive tract, such as Eudragit RLT"", e.g. Eudragit RL 100T"", and/or Eudragit RSTM e.g. Eudragit R100T"", and/or blends of such EudragitT"" polymers.
While the controlled release delivery device of the present invention typically comprises two or more polymeric coats comprised of water insoluble polymers, optional coats or components within a coat may be comprised of water soluble polymers or enteric polymers or any other polymer known to be useful for controlled release.
Water soiuble polymers which may be 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, carboxymethylcell u lose 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 polyvinylpyrrotidone.
These water soluble polymers can be used either singly or in combinations of two or more.
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 camauba 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, maigaric 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 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 palmitate, 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 paimitate, zinc myristate, magnesium myristate, and the like, with preferable higher fatty acid salts being calcium stearate and magnesium stearate.

The oil components and water insolubie 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 altemative salt forms, free acid forms, free base forms, and hydrates: analgesics/antipyretics (e.g., aspirin, 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, 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 hydrochlo(de, 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 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, respirid.one, 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, aurothioglucose, 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, divatproex 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 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;
saimeterol; xinafoate; terbutaline sulfate; triamcinolone; theophylline;
nedocromil sodium; metaproterenol sulfate; albuteroi; flunisolide; fluticasone proprionate, steroidal compounds and hormones (e.g., androgens such as danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone, testosterone enathate, methyltestosterone, fluoxymesterone, and testosterone 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, methylpred n iso lone 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, zafirlukast, interferon, growth hormone, interieukin, 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, amiodipine 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, nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.
A controlled release delivery device of the present invention may be used for treatment of a patient, for example, an animal and more particularly, a mammal. By mammal, is meant any member of the class of mammalia that is characterized by being a vertebrate having hair and mammary glands.
Examples include, without limitation, dog, cat, rabbit, horse, pig, goat, cow, human being. The delivery device of the present invention may be administered to any animal patient or mammalian patient that is in need of treatment with a site specific, timed, pulsed, chronotherapeutic, extended, or controlled release of an active ingredient. In one example, a delivery device of the present invention is used for treating a horse. In another example, a delivery device of the present invention is used for treating a human being.
The controlled release delivery device of the present invention may be used for the treatment of many human diseases, for example, without limitation, 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 esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethlylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TWEENTM), polyoxyethylene stearates, sodium dodecylsulfate, Tyloxapol (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 TWEENTM 80, which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals), Carbowax 3550 and 934, which are polyethylene glycols (available from Union Carbide), Crodesta F-110, which is a mixture of sucrose stearate and sucrose distearate, and Crodesta SL-40 (both available from Croda Inc.), and SA90HCO, which is Cg18H37-CH2 (CON(CH3)CH2(CHOH)4 CF20H)2.
Wetting agents which have been found to be particularly useful include Tetronic 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-ma ltopyra noside; 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-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-10G or Surfactant 10-G (commercialiy 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-phosphoethano lam i ne- N-[Po ly(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-paimitoyl-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 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 or channels in the coat. The passage way forming agents or channeling 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 or channeling agent can be a water soluble material or an enteric material. Some general examples of passageway forming agents or channeling agents are watersoluble materials and/or wicking agents such as cellulose ethers, polyethylene glycols or microcrystalline cellulose. Some further examples of passageway forming agents or channeling agents are sodium chloride, potassium chloride, lactose, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), for example PEG 600, polyvinyl pyrolidone, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.
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 passageway 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.
As used herein the term passageway includes an aperture, orifice, bore, channel, hole, weaken area or as created by soluble or leachable materials.
Polymeric coats 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, dibutyl 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, oiive oil, sesame oil, acetyltributylcitrate, acetyltriethyicitrate, glycerin sorbitol, diethyloxalate, diethylmalate, d iethyifu ma rate, 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. It will be understood that some polymeric coats may be formed without the use of a plasticizer, for example, without limitation, a polymeric coat of Eudragit NE30DTM (methacrylate copolymer).
An example of an 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.
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 altemative 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.
In order to illustrate, and without limitation several typical forms of controlled release devices can be considered, for example, granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsuies, crystals or other types of particles known to the skilled person comprising one or more of the following; active pharmaceutical ingredient; biological, chemical, nutraceutical, agricultural or nutritional materials; surrounded by two or more polymer coats in which: (I) polymers are chosen from the group comprised of ethyicellulose polymer, polyvinyl acetate polymer, ammonio methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, or their derivatives (II) polymeric coats are deposited in a such a way as to transition from one or more layers of coat of one polymer type to one or more layers coat of another polymer type moving from the inside to the outside of the controlled release device(III) a transition zone or boundary in the region of first contact between the respective polymers of thickness of about 1 angstrom to about 25 millimeter (IV) polymers are applied separately and not in the same admixture. In certain examples there may be granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsuies, crystals or particles other types of particles known to the skilled person in which there is one transition zone or boundary, while in other examples there are more than one transition zones or boundaries. When considering some examples of the ordering of polymeric coats in more detail: coats may be deposited in a such a way as to transition from one or more layers of coat of ethylcellulose to one or more layers of coat of methacrylate copolymer to one or more layers of coat of polyvinyl acetate polymer moving from the inside to the outside of the controlled release device; coats may be deposited in a such a way as to transition from one or more layers of coat of polyvinyl acetate to one or more layers of coat of methacrylate copolymer to one or more layers of coat of ethylcellulose moving from the inside to the outside of the device;
coats may be deposited in a such a way as to transition from one or more layers of coat of polyvinyl acetate to one or more layers of coat of ethylcellulose to one or more layers of coat of methacrylates copolymer moving from the inside to the outside of the device; coats may be deposited in a such a way as to transition from one or more layers of coat of methacrylate copolymer to one or more layers of coat of ethylcellulose to one or more layers of coat of polyvinyl acetate moving from the inside to the outside of the device; or coats may be deposited in a such a way as to transition from one or more layers of coat of inethacrylate copolymer to one or more layers of coat of polyvinyl acetate to one or more layers of coat of ethylcellulose moving from the inside to the outside of the device. When considering examples, of polymers that may be used to deposit coats a polymer may be selected from one or a mixture of, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poty(acrytic acid), poly(methacrylic acid), methacrylic acid alkylamide copolyer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copotymers. In certain examples, the polymers are thermoplastic polymers, while in other examples the polymer may be a pH insensitive water insoluble polymer, while in still other examples polymeric coats may comprises pH insensitive polymers, pH sensitive polymers, or both pH insensitive polymersand pH sensitive polymers.
In certain examples, a pharmaceutical dosage form prepared according to a controlled release delivery device may be usedfor treatment of medical conditions or disease states. In other examples, the pharmaceutical dosage form may be for providing a patient with site specific, timed, pulsed, chronotherapeutic, extended, or controlled release of active pharmaceutical ingredients.
In other examples, of controlled release delivery devices according to the present invention, there may be granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or any other suitable particle known to the skilled person containing one or more of the following; active pharmaceutical ingredients; biological, chemical, nutraceutical, agricultural or nutritional materials; surrounded by two or more polymer coats in which: (I) coats are made from water insoluble film forming polymers and or their derivatives (II) coats are deposited in a such a way as to transition from one or more layers of coat of one type of polymer to one or more layers of coat of another type of polymer moving from the inside to the outside (III) a transition zone or boundary is formed in the region of first contact between the respective polymers of thickness of about 1 angstrom to about 25 millimetre (IV), optionally channeling agents are present.
Channeling agents may optionally be present in one or more of the transition coats. Other optional components include, without limitation, filler, lubricant, antioxidant, anti-tacky or plasticizer agent, 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.

Controlled Release Venlafaxine HCI Tablets This is a two step process. In the first step, immediate release tablets are manufactured by dry granulation process followed by direct compression into tablets. In step two, three coats consisting of one or more layers of Aquacoat 30ECD (ethylcellulose polymer), Kolicoat SR 30D (polyvinyl acetate) and Eudragit NE 30D (acrylic polymer) are applied one after the other such that there is a transition from one coat to another. Note that the film forming polymers are administered separately and not as an admixture.

(1) Manufacture of Tablet TABLE-1 Venlafaxine formulation (%) Venlafaxine HCI 20, Lactose 59, Microcrystalline cellulose 20, Silicone dioxide 0.5, Magnesium stearate 0.5.
% by weight Venlafaxine hydrochloride 20 Lactose 59 Microcrystalline cellulose 20 Silicone dioxide 0.5 Magnesium stearate 0.5 The materials with exception of the magnesium stearate were charged into a planetary mixer and blended for 5 minutes. The homogeneous blend was charged into a V-Blender. Magnesium stearate was added and the content blended for about 5 minutes. The blended materials were compressed into tablets in a rotary press.

(2) Coating of Tablets The tablets were coated with an aqueous dispersion composed of ethylcellulose (Aquacoat 30ECD) plasticized with dibutyl sebacate to a 2%
weight gain. This was immediately followed with a coat of polyvinyl acetate (Kolicoat SR 30D) plasticized with triethyl citrate to a weight gain of 2%.
Finally a coat of Eudragit NE 30D (methacrylate copolymer) was applied to a weight of 2%. Coating was carried out in a side vented coating pan. The inlet and outlet temperature was 62 and 40 degrees Centigrade respectively.
Relative humidity of the coating room was 45%. The transition coated tablets were cured by drying in a tray dryer oven for 2 hours at 60 degree Centigrade.

Controlled Release Metoprolol Succinate Tablets This is a two step process. In the first step, immediate release tablets are manufactured by dry granulation process followed by direct compression into tablets. In step two, three coats consisting of one or more layers of Aquacoat 30ECD (ethylcellulose polymer), Kolicoat SR 30D (polyvinyl acetate) and Eudragit NE 30D (methacrylate copolymer) are applied one after the other such that there is a transition from one coat to another.
(1) Manufacture of Tablet TABLE-2 Metoprolol formulation (%) Metoprolol succinate 30 Lactose 49 Microcrystalline 20 cellulose Silicone dioxide 0.5 Magnesium stearate 0.5 % by weight Metoprolol succinate 30 Lactose 49 Microcrystalline cellulose 20 Silicon dioxide 0.5 Magnesium stearate 0.5 The materials with exception of the magnesium stearate were charged into a planetary mixer and blended for 5 minutes. The homogeneous blend was charged into a V-Blender. Magnesium stearate was added and the content blended for about 5 minutes. The blended materials were compressed into tablets in a rotary press.

(2) Coating of Tablets The tablets were coated with Eudragit NE 30D to a 2% weight gain.
This was immediately followed with a coat of polyvinyl acetate (Kolicoat SR
30D) plasticized with triethyl citrate to a weight gain of 2%. Finally a coat of an aqueous dispersion composed of ethylcellulose (Aquacoat 30ECD) plasticized with dibutyl sebacate was applied to a weight of 3%. Coating was carried out in a side vented coating pan. The inlet and outlet temperature was 62 and 40 degrees Centigrade respectively. Relative humidity of the coating room was 45%. The transition coated tablets were cured by drying in a tray dryer oven for 2 hours at 60 degree Centigrade.

Chrontherapeutic Paroxetine HCI Tablets This is as in Example 2 except for the following; paroxetine is substituted for metoprolol, and hydroxypropylmethyl cellulose 5% by weight of polymer is added to the transition coat. The tablets are cured by drying in a tray dryer oven for 2 hours at 60 degree Centigrade. To obtain chronotherapeutic release a final coat of methacrylic acid copolymer type A (Eudragit L) is applied to 4% weight gain.

Venlafaxine HCI Granules (1) Manufacture of Tablet TABLE-3 Venlafaxine formulation (%) Venlafaxine HCI 20 Lactose 59 Microcrystalline 20 cellulose Silicone dioxide 1.0 % by weight Venlafaxine hydrochloride 20 Lactose 59 Microcrystalline cellulose 20 Silicone dioxide 1.0 The materials were charged into a high shear granulator and blended for 5 minutes. The homogeneous blend was granulated using Eudragit NE30D.
The wet granules were screened through a 1.4 millimetre sieve using a co-mill and dried in a tray dryer oven. The dried granules were wet granulated in a planetary mixer using polyvinyl acetate (Kolicoat SR 30D) plasticized with triethyl citrate. The wet granules were dried and milled. The milled granules were filled into capsules.

Venlafaxine granules with a transition zone were prepared according to the process described in Example 4 and tested in a dissolution experiment against a comparable Venlafaxine preparation without a transition zone.

The dissolution experiment was done in a USP dissolution apparatus at a acid media of pH 1.5 for 3 hours and the media was changed to phosphate buffer pH 7.5 until an asymptote was reached or 24 hours had elapsed. Results shown in Figure 3 indicate that the Venlafaxine granules with a transition zone are more effective at controlling release than the comparable Venlafaxine preparation without a transition zone.

Claims (42)

1. A controlled release delivery device comprising:
(a) two or more polymeric coats substantially enveloping an active ingredient; and (b) at least one transition zone formed between a pair of bordering polymeric coats.

2. A controlled release delivery device comprising:
(a) first, second and third polymeric coats substantially enveloping an active ingredient;
(b) a first transition zone formed between a first pair of bordering polymeric coats comprised of the first and second polymeric coats; and (c) a second transition zone formed between a second pair of bordering polymeric coats comprised of the second and third polymeric coats.

3. The controlled release delivery device according to claim 1 or 2, wherein at least two of the polymeric coats comprise a water insoluble polymer.

4. The controlled release delivery device according to any one of claims 1 to 3, wherein at least two of the polymeric coats comprise a water insoluble polymer selected from the group consisting of ethylcellulose polymer, polyvinyl acetate polymer, ammonio methacrylate copolymer, ethyl acrylate, methyl methacrylate copolymer, and their derivatives.

5. The controlled release delivery device according to any one of claims 1 to 4, wherein at least two the polymeric coats comprise a water insoluble polymer selected from the group consisting of ethylcellulose polymer, polyvinyl acetate polymer, methacrylate copolymer.

6. The controlled release delivery device according to any one of claims 1 to 5, wherein each polymeric coat within the pair of bordering polymeric coats comprises at least one different water insoluble polymer.

7. The controlled release delivery device according to any one of claims 1 to 5, further comprising a polymeric coat comprised of an enteric polymer.

8 The controlled release delivery device according to any one of claims 1 to 5, wherein at least one polymeric coat is comprised of multiple layers.

9. The controlled release delivery device according to any one of claims 3 to 7, wherein the amount of said water insoluble polymer is at least about 1 %

by weight based on the total weight of the device.

10. The controlled release delivery device according to any one of claims 1 to 8, further comprising a water soluble polymer 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.

11. The controlled release delivery device according to any one of claims 1 to 10, further comprises excipients selected from the group consisting of diluents, filler, anti-tacky agent, plasticizer, compression agents, extrusion agents, glidants, lubricants, solubilizers, wetting agents, surfactants, penetration enhancers, pigments, colorants, flavoring agents, sweeteners, antioxidants, acidulants, stabilizers, antimicrobial preservatives, and binders.

12. The controlled release delivery device according to any one of claims 1 to 10, wherein at least one polymeric coat comprises a channeling agent.

13. The controlled release delivery device according to any one of claims 1 to 10, wherein at least one polymeric coat comprises a channeling agent selected from the group consisting of sodium chloride, potassium chloride, lactose, 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.

14. The controlled release delivery device according to any one of claims 1 to 13, wherein the transition zone has a thickness of about 1 angstrom to about 25 millimeters.

15. The controlled release delivery device according to any one of claims 1 to 14, wherein the transition zone has a thickness of about 10 angstroms to about 10 micrometers.

16. The controlled release delivery device according to any one of claims 1 to 15, wherein each polymeric coat is applied separately and not in the same admixture.

17. The controlled release delivery device according to any one of claims 1 to 16, wherein the device is formulated as granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, or crystals.

18. A controlled release delivery device for controlled release of an active ingredient comprising:
(a) a core particle comprising the active ingredient;
(b) two or more polymeric coats substantially enveloping the core particle comprising the active ingredient; and (c) at least one transition zone between the polymeric coats.

19. A controlled release delivery device comprising:
(a) a core particle comprising the active ingredient;
(b) first, second and third polymeric coats substantially enveloping an active ingredient;
(c) a first transition zone formed between a first pair of bordering polymeric coats comprised of the first and second polymeric coats; and (d) a second transition zone formed between a second pair of bordering polymeric coats comprised of the second and third polymeric coats.

20. The controlled release delivery device according to claim 18 or 19, wherein at least two of the polymeric coats comprise a water insoluble polymer.

21. The controlled release delivery device according to any one of claims 18 to 20, wherein at least two of the polymeric coats comprise a water insoluble polymer selected from the group consisting of ethylcellulose polymer, polyvinyl acetate polymer, ammonio methacrylate copolymer, ethyl acrylate, methyl methacrylate copolymer, and their derivatives.

22. The controlled release delivery device according to any one of claims 18 to 21, wherein at least two the polymeric coats comprise a water insoluble polymer selected from the group consisting of ethylcellulose polymer, polyvinyl acetate polymer, methacrylate copolymer.

23. The controlled release delivery device according to any one of claims 18 to 22, wherein each polymeric coat within the pair of bordering polymeric coats comprises at least one different water insoluble polymer.

24. The controlled release delivery device according to any one of claims 18 to 22, further comprising a polymeric coat comprised of an enteric polymer.

25. The controlled release delivery device according to any one of claims 18 to 22, wherein at least one polymeric coat is comprised of multiple layers.

26. The controlled release delivery device according to any one of claims 20 to 24, wherein the amount of said water insoluble polymer is at least about 1% by weight based on the total weight of the device.

27. The controlled release delivery device according to any one of claims 18 to 25, further comprising a water soluble polymer 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.

28. The controlled release delivery device according to any one of claims 18 to 27, further comprises excipients selected from the group consisting of diluents, filler, anti-tacky agent, plasticizer, compression agents, extrusion agents, glidants, lubricants, solubilizers, wetting agents, surfactants, penetration enhancers, pigments, colorants, flavoring agents, sweeteners, antioxidants, acidulants, stabilizers, antimicrobial preservatives, and binders..

29. The controlled release delivery device according to any one of claims 18 to 27, wherein at least one polymeric coat comprises a channeling agent.

30. The controlled release delivery device according to any one of claims 18 to 27, wherein at least one polymeric coat comprises a channeling agent selected from the group consisting of sodium chloride, potassium chloride, lactose, 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.

31. The controlled release delivery device according to any one of claims 18 to 30, wherein the transition zone has a thickness of about 1 angstrom to about 25 millimeters.

32. The controlled release delivery device according to any one of claims 18 to 31, wherein the transition zone has a thickness of about 10 angstroms to about 10 micrometers.

33. The controlled release delivery device according to any one of claims 18 to 32, wherein each polymeric coat is applied separately and not in the same admixture.

34. The controlled release delivery device according to any one of claims 18 to 33, wherein the device is formulated as granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, or crystals.

35. The controlled release delivery device according to any one of claims 1 to 34, wherein the device is made by wet or dry granulation of the components and tableted.

36. The controlled release delivery device according to any one of claims 1 to 34, wherein the device is made by direct tableting.

37. The controlled release delivery device according to any one of claims 1 to 34, wherein the device is made by extrusion-spheronization.

38. Use of the controlled release delivery device of any one of claims 1 to 37 for site specific, timed, pulsed, chronotherapeutic, or extended delivery of an active ingredient.

39. Use of the controlled release delivery device according to any one of claims 1 to 37 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.

35. A process for producing a controlled release delivery device for controlled release of an active ingredient comprising:
(a) providing a core particle comprising the active ingredient;
(b) coating the core particle with a first polymeric coat comprised of a first water insoluble polymer to substantially envelope the core particle;
(c) allowing the first polymeric coat to dry; and (d) coating the first polymeric coat with a second polymeric polymeric coat comprised of a second water insoluble polymer to provide a polymeric coat that borders and substantially envelopes the first polymeric coat.

36. The process of claim 35, wherein at least one polymeric coat comprises a plasticizer.

37. A process according to claim 35 wherein coating is carried out using fluid bed coating techniques or perforated side vented pan coating technique or microencapsulation technique.

38. A process according to claim 35 wherein coating is carried out using multiple wet granulation and drying technique.

39. The process of claim 38 wherein a milling step is introduced before and or after drying of the wet granules.

40. The process of any one of claims 35 to 39, further comprising a curing step after all coating steps are completed.

41. A medicament comprising the controlled release delivery device of any one of claims 1 to 37 for site specific, timed, pulsed, chronotherapeutic, or extended delivery of an active ingredient.

42. A medicament comprising the controlled release delivery device according to any one of claims 1 to 37 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.