CA2125904C - Controlled release formulations coated with aqueous dispersions of ethylcellulose - Google Patents

Controlled release formulations coated with aqueous dispersions of ethylcellulose Download PDF

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Publication number
CA2125904C
CA2125904C CA002125904A CA2125904A CA2125904C CA 2125904 C CA2125904 C CA 2125904C CA 002125904 A CA002125904 A CA 002125904A CA 2125904 A CA2125904 A CA 2125904A CA 2125904 C CA2125904 C CA 2125904C
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Prior art keywords
formulation
active agent
agent
release
substrate
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CA2125904A1 (en
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Benjamin Oshlack
Mark Chasin
Frank Pedi Jr.
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Euro Celtique SA
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Euro Celtique SA
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • A61K31/522Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids

Abstract

A stabilized solid controlled release formulation having a coating derived from an aqueous dispersion of a hydrophobic polymer is obtained by overcoating a substrate including an active agent selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansing agent, a fragrance agent and a fertilizing agent, with an aqueous dispersion of the plasticized hydrophobic polymer and then curing the coated substrate at a temperature above the glass transition temperature of the plasticized hydrophobic polymer, until a curing endpoint is reached at which the coated substrate provides a stabilized dissolution of the active agent which is unchanged after exposure to accelerated storage conditions, the endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37°C and at a relative humidity of 80%.

Description

2~~~~0~

CONTROLLED-RELEASE FORMULATIONS COATED

- WITH ApUEOUS DISPERSIONS OF ETHYLCELLULOSE

BACKGROUND OF THE INVENTION

An important aspect of the manufacture, regulatory review and approval of all dosage forms concerns their stability over extended periods of time. The stability data obtained with regard to a particular dosage form directly affects its shelf-life. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in the regulatory require-ments of the country where approval to market a dosage form is being sought. In the United States, a request to test, and eventually maxket, a drug or a drug formulation may be . made via a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) or an Investigational New Drug Applications (IND).

The agents used in sustained release dosage formula-tions often present special problems with regard to their physical stability during storage. For example, waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing, thus precautions are taken to stabilize them at the time of manufacture or to prevent the change from occurring. Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable 3U variations in availability rates during stability testing at the time of manufacture and during later storage.

It is known that certain strategies can be undertaken to obtain stabilized controlled release formulations in many cases, such as insuring that the individual agents are in a stable form before they are incorporated into the pro-duct, and that processing does not change this condition, -retarding the instability by including additional addi-tives, and inducing the individual agents of the dosage form to reach a stable state before the product is finally completed.

It is also recognized that the moi-sture content of the product can also influence the stability of the product.

Changes in the hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permea-tion and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. However, moisture content of a product can be controlled fairly successfully by controls in the process-ing method and proper packaging of the product.

Hydrophobic polymers such as certain cellulose deriva-tives, zein, acrylic resins, waxes, higher aliphatic alco-hols, and polylactic and polyglycolic acids have been used - in the prior art to .develop controlled release dosage forms. Methods of using these polymers to develop con-trolled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydro-phobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent.

Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage forms for aesthetic reasons such as film coating tablets or beads or for taste-masking. However, these dosage forms are used for immediate release administration of the active drug contained in the dosage form.
The use of organic solvents in the preparation of hydrophobic coatings is considered undesirable because of inherent problems with regard to flammability, carcinogen-icity, environmenta7_ concerns, and safety in general. It ~ considered very desirable in the art, however, to provide a controlled release coating derived from aqueous dispers-ions of a hydrophobic material, such as ethyl cellulose.

Unfortunately, to date, while many formulations have been experimentally prepared which rely upon a hydrophobic l0 coating derived from an aqueous dispersion to provide con-trolled release of an active agent, such formulations have not proven to be commercially viable because of stability problems. Aqueous polymeric dispersions have been used to produce stable controlled release dosage forms, but this has only been possible by other methods such as incorpora-tion of the same into the matrix of the dosage form, rather than via the use of a coating of the aqueous polymeric dispersion to obtain retardant properties.

When coating using aqueous polymeric dispersions to obtain a desired release profile of the active agents) over several hours or longer, it is-known in the art that the dissolution release profile changes on ageing, e.g.

when the final coated product is stored for a.period of time, during which time it may be exposed to elevated temp-erature and/or humidity above ambient conditions. This problem is illustrated, for example, by Dressman, et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991), pp. 654-655, Controlled Release Society, Inc. who reported that phenylpropanolamine HC1 pellets coated with an ethyl cellulose-based film are only stable at room temp-erature under ambient humidity conditions. Munday, et al., Drug Devel. and Indus. Phar., 17 (15) 2135-2143 (1991) sim-ilarly reported that film coated theophylline mini-tablets film coated with ethyl cellulose with PEG (2:1), and ethyl cellulose with Eudragit L (2:1) impeded dissolution upon storage under stress conditions, the degree of slowdown of release being said to be directly proportional to temperature, while the effect of relative humidity (RH) appeared to be insignificant. Munday, et al. concluded that the decreased rate of release was due to the slowing in the rate of molecular diffusion of the drug across the polymeric coating material, and suggested that the change was due to significant alterations in the permeability of the polymer which occurred during the experimental storage.
This instability problem is known to not exist when the polymers are applied from organic solvent solution.
OBJECTS AND SUMMARY OF THE INVENTION
Therefore the present invention can provide a controlled release tablet comprising a core containing an active agent, e.g. a therapeutically active agent, a disinfecting agent, a cleansing agent, a sanitizing agent and a fertilizing agent coated with an aqueous dispersion of a hydrophobic polymer, e.g. alkylcellulose or acrylic polymers such that there is a stable dissolution profile of the active agent when placed in an environment of use.
The present invention can also provide a controlled release formulation comprising a plurality of inert beads comprising an effective amount of an active agent, the beads being coated with an aqueous dispersion of a hydrophobic polymer and providing a reproducible, stable dissolution despite exposure to accelerated storage conditions.
In accordance with another aspect, the present invention can provide a method of preparing a controlled release tablet comprising a core containing an active agent coated with an aqueous dispersion of a hydrophobic polymer such that there is a stable dissolution profile of the active agent when t ....

_ 225904 placed in an environment of use, despite exposure to accelerated storage conditions.
In accordance with still another aspect of the present invention there is provided a controlled release formulation comprising a substrate containing an active agent coated with an aqueous dispersion of a hydrophobic polymer such that there is a stable dissolution profile of the active agent when placed in an environment of use, even after storage for a period of time where the coated formulation may be exposed to storage conditions of temperature and/or humidity elevated above ambient conditions.
The present invention can also provide a controlled release formulation wherein the controlled release is caused by a coating on the formulation of an aqueous dispersion of a hydrophobic polymer such as ethylcellulose which coating provides a stable dissolution of an active agent contained in the formulation, despite exposure to accelerated storage conditions such that the dissolution would be deemed acceptable by a governmental regulatory agency such as the U.S. FDA for purposes of according expiration dating.
The above-mentioned advantage and others are accomplished by the present invention, which relates in part to a controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid. The coated substrate is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 1000 for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides 4~

a stabilized dissolution of said active agent which is .unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions, e.g., of one-three months at a temperature of 37C and at a relative humidity of 80%.

In'certain preferred embodiments, the substrate is coated to a weight gain from about 2% to about 25%.

In other embodiments, the coated substrate is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid, until an endpoint is retched at which the cured coated substrate, . when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 20% of the total amount of active agent released,. when compared to the in-vitro dissolution of said coated substrate prior to curing.

In yet other embodiments of the invention, the cured formulation provides a stabilized dissolution of said active agent which is unchanged after exposure to acceler-ated storage conditions, the stabilized dissolution being deemed appropriate by the United States Food & Drug Admini-stration for the purpose of according expiration dating for said formulation.

other preferred embodiments relate to controlled re-lease dosage formulation comprising a substrate coated with an effective amount of an aqueous dispersion of ethylcell-ulose to obtain a controlled release of an active agent which formulation, after exposure to accelerated storage 7 212'944 conditions of at least one month at 40°C/75% RH, releases an amount of therapeutically active agent which does not vary at any given dissolution time point by more than about 20% of the total amount of therapeutically active agent released, when compared to in-vitro dissolution conducted prior to storage.

In other embodiments, the coated substrate, upon in-vitro dissolution testing; provides a band range after exposure to accelerated storage conditions which is not wider than about 20% at any point of time when compared to the dissolution profile prior to exposure to the accelerated storage conditions.

The active agent may be chosen for a wide variety of uses, including but not limited to systemically active therapeutic agents, locally active therapeutic agents, disinfectants, cleansing agents, fragrances, fertilizers, deodorants, dyes, animal repellents, insect repellents, pesticides, herbicides, fungicides, and plant growth stimulants.

The present invention is further related to a solid controlled release oral dosage formulation, comprising a substrate containing an systemically active therapeutic agent in an amount sufficient to provide a desired thera-peutic effect when said formulation is orally administered.

The substrate is coated with an aqueous dispersion of plas-ticized ethylcellulose and cured at a temperature greater than the glass transition temperature of the aqueous dis-persion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a period of time sufficient to obtain a controlled release of said active agent when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37C from about 5% to about 42.5% (by wt) active agent released after 1 hour, from about 15 % to about 60% (by wt) active agent released after 2 hours, from about 17% to about 75% (by wt) active agent released after 4 hours, and from about 20o to about 90% (by wt) active agent released after 8 hours, said coated substrate being cured to cause individual ethylcell-ulose particles in said coating to coalesce and to gradu-ally slow the release of said active agent when exposed to an environmental fluid until an endpoint is reached at which the release rate (e. g., in-vitro dissolution) obtain-ed after exposing the cured, coated substrate to acceler-ated storage conditions of 37C and 80o relative humidity for one-three months is stable when compared to the release rate obtained immediately after curing. The dosage form preferably provides a therapeutic effect for about 24 hours. The present invention further relates to a method of preparing the dosage form.

The present invention is also related to a method for obtaining a controlled release formulation of an active agent, comprising, preparing a solid substrate comprising an active agent, coating the substrate with a sufficient amount an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of the active agent when the coated substrate is exposed to an environ-mental fluid, and curing the coated substrate at a tempera-ture greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100 til un a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions. The endpoint is determined, e.g., by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of, for example, one-three months at a temperature of 37C and at a relative humidity of 80%.

The present invention is further related to a method -of treating a patient with an oral solid dosage form de-scribed above. In this method, present invention further comprises administering the oral solid dosage form compris-ing the cured, coated substrate to the patient to thereby obtain the desired therapeutic effect for about 12 to about 24, hours. In especially preferred embodiments, the oral solid dosage forms of the present invention provide a desired therapeutic effect for about 24 hours.
The present invention provides many benefits over prior art coatings, including, but not limited to, avoid-ance of organic solvents which have inherent safety con-cerns (flammability, carcinogenicity, environmental con-cerns, safety in general), and extended stability which may result in extended shelf life and expiration dating.
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 A is an SEM of a pharmaceutical bead coated with the controlled release coating of the present inven-tion prior to curing;
Figure B is an SEM of the coated bead depicted in Figure A after curing in accordance with the present invention;
Figure 1 is a graphical representation of the dis-solution stability results obtained with Example 1;
Figure 2 is a graphical representation of the dis-solution stability results of Comparative Example lA;
Figure 3 is a graphical representation of the dis-solution stability results of Comparative Example 1B;
Figure 4 is a graphical representation of the dis-solution stability results of Comparative Example 1C;

to Figure 5 is a graphical representation of the dis-~solution stability results of Example 1, comparing the dissolution profiles obtained under various conditions;

Figure 6 is a graphical representation of the initial dissolution profiles obtained under various curing condi-tions;

Figure 7 is a graphical representation of the results obtained for Comparative Example 18A;

Figure 8 is a graphical representation of the results l0 obtained for Example 18;

Figure 9 is a graphical representation of the results obtained for Example 19;

Figure 10 is a graphical representation of the results obtained for Example 21;

Figure 11 is a graphical representation comparing the in-vitro release of Examples 22 and 23 versus a commerci-ally available.reference (MS Contin);

Figure 12 is a graphical representation of the blood levels obtained for the controlled release formulation of Examples 22 and 23 versus a commercially available refer-ence (MS Contin);

Figure 13 is a graphical representation of the blood levels obtained when two 30 mg capsules of Example 23 are administered, in comparison to one 30 mg MS Contin tablet;

Figure 14 is a graphical representation comparing the in-vitro release of Examples 23 and 24 versus MS Contin;

Figure 15 is a graphical representation of the blood levels obtained for Examples 23 and 24 versus MS Contin;

and Figure 16 is a graphical representation of the blood levels obtained when two 30 mg capsules of Example 24 are administered at the same time, in comparison to one 30 mg MS Contin tablet.

DETAILED DESCRIPTION

- The aqueous dispersions of hydrophobic polymers used as coatings in the present invention may be used to coat substrates such as tablets, spheroids (or beads), micro-s spheres, seeds, pellets, ion-exchange resin beads, and other multi-particulate systems in order to obtain a de-sired controlled release of the active agent. Granules, spheroids, or pellets, etc., prepared in accordance with the present invention can be presented in a capsule or in any other suitable dosage form. The tablets of the present invention may be any suitable shape, such as round, oval, biconcave, hemispherical, any polygonal shape such as square, rectangular, and pentagonal, and the like.

In order to obtain a controlled release formulation, it is usually necessary to overcoat the substrate compris-ing the active agent with a sufficient amount of the aqueous dispersion of hydrophobic polymer e.g., ethylcell-ulose, to obtain a weight gain level from about 2 to about percent, although the overcoat may be lesser or greater 20 depending upon the physical properties of the active agent and the desired release rate, the inclusion of plasticizes in the aqueous dispersion and the manner of incorporation of the same, for example.

The cured, coated substrates of the present invention 25 provide a stable dissolution profile (e.g., release of the active agent in the environment of use) when stored for extended periods of time at room temperature and ambient humidity (e. g., long term (real time) testing), and when tested under accelerated storage conditions.

The terms "stable dissolution profile" and "curing endpoint" are defined for purposes of the present invention as meaning that the cured, coated substrate reproducibly provides a release of the active agent when placed in an environment of use which is unchanged, even after exposing the cured, coated substrate to accelerated storage condi-tions. Those skilled in the art will recognize that by "unchanged" it is meant that any change in the release of the active agent from the cured, coated formulation would be deemed insignificant in terms of the desired effect.

For pharmaceutical formulations, stability is determined by, e.g, a regulatory agency such as the Food & Drug Administration (FDA) in the U.S., for the purpose of .

according an expiration date for the formulation.

By the phrase "accelerated storage conditions" it is meant, e.g., storage conditions of elevated temperature and/or elevated relative humidity. Preferably, the phrase "accelerated storage conditions" refers to storage condit-ions to which the final drug formulation is subjected for the purpose of obtaining regulatory approval (e.g., FDA

approval in the U.S.) and an expiration date.

The term "expiration date" is defined for purposes of the present invention as the date designating the time dur.-ing which a batch of the product (e. g., the cured, coated substrate) is expected to remain within specification if stored under defined conditions, and after which it should not be used.

The term "band range" for purposes of the present in-vention is defined as the difference in in-vitro dissolu-tion measurements of the controlled release formulations when comparing the dissolution profile (curve) obtained by the formulation upon completion of the manufacturing of the coated product (prior to storage) and the dissolution pro-file obtained after the coated product is exposed to accel-erated storage conditions, expressed as the change in percent of the active agent released from the coated pro-duct at any dissolution time point along the dissolution curves.
In general, the length of the studies and the storage test conditions required by regulatory agencies such as the FDA for pharmaceutical formulations are sufficient to cover 2225~0~

storage, shipment, and subsequent use. Allowable storage test conditions may vary depending upon the particulars of the product. For example, temperature sensitive drug sub-stances should be stored under an alternative, lower temp-s erature condition, which is then deemed to be the long term testing storage temperature. In such cases, it is general-ly, accepted that the accelerated testing should be carried out at a temperature at least 15C above this designated long term storage temperature, together with appropriate l0 relative humidity conditions for that temperature.

A generally accepted accelerated test employed in FDA

guidelines relates to the storage of a drug product (e. g., in its container and package) at 80% Relative Humidity (RH) and 37C (1985 FDA guidelines). If the product holds up 15 for, e.g., three months under these conditions (chemical stability, dissolution, and physical characteristics), then the drug product will be accorded, e.g., a two year expira-tion date. This accelerated test is also now also consid-ered to be acceptable if conducted at 75% RH and 40C (FDA

20 1987 guidelines). It has recently been proposed that long-term storage testing be conducted for.-pharmaceutical formu-lations at 25C 2C at not less than 60% RH 5% for a minimum time period of 12 months. It has been furthe.r_ pro-posed that accelerated testing be conducted for pharmaceu-25 tical formulations at 40C 2C at 75% RH 5% for a min-imum time period of 6 months. All of the above-mentioned accelerated testing criteria and others are deemed equiva-lent for purposes of the present invention, with regard to the determination of stability and the determination of the 30 curing endpoint.

The controlled release coatings of the present inven-tion comprise aqueous dispersions of hydrophobic polymers.

Although ethylcellulose is an especially preferred hydro-phobic polymer for use in the controlled release coatings 35 of the present invention, other hydrophobic cellulosic 2t2~904 derivatives (including other alkyl celluloses) may be also be used, and are deemed to be encompassed by the appended claims.

The inclusion of an effective amount of a plasticizes in the aqueous dispersion of hydrophobic polymer will further improve the physical properties of the film. For example, because ethylceilulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasti-cize the ethylcellulose before using the same as a coating material.

The plasticization of the ethylcellulose may be accomplished either by so-called "internal plasticization"

and "external plasticization." The suitability of a plasticizes depends on its affinity or solvating power for the polymer and its effectiveness at interfering with polymer-polymer.attachments. Such activity imparts the desired flexibility by relieving molecular rigidity. Gen-erally, the amount of plasticizes included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizes, how-ever, can only be properly determined after careful experi-mentation with the particular coating solution and method of application.

An important parameter in the determination of a suitable plasticizes for a polymer is related to the glass transition temperature (Tg) of the polymer. The glass transition temperature is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer.

Below the Tg, the polymer chain mobility is severely restricted. Thus, for a given polymer, if its Tg is above room temperature, the polymer will behave as a glass, being .hard, non-pliable and rather brittle, properties which could be somewhat restrictive in film coating since the coated dosage form may be subjected to a certain amount of 5 external stress.

Incorporation of suitable plasticizers into the poly-mex matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical 10 stress.

ether aspects of suitable plasticizers include the ability of the plasticizes to act as a good "swelling agent" for the ethylcell_ulose, and the insolubility of the plasticizes in water.

15 Examples of suitable plasticizers for the hydrophobic polymers useful in the present inventi.an (e. g., ethylcellu-lose) include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglyc-erides, phthalate esters, castor oil, etc.) may be used.

Triethyl citrate is an especially preferred plasticizes for the aqueous 9ispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispers-ion to stick during processing, and acts as a polishing agent.
In one commercially available product, Aquacoat~
(aqueous dispersion of ethylcellulose available from FMC
Corp., Philadelphia, Pennsylvania, U.S.A.), the ethylcell-ulose is dissolved in a water-immiscible organic solvent and then emulsified in water in the presence of a surfact-ant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizes is not incorporated i.n the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat~ with a suitable plasticizes prior to use. Another aqueous dispersion of ethylcellulose is commercially available as Surelease~

(Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizes into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizes (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.

With respect to handling and storage conditions, FMC

states that Aquacoat~ will undergo a rise in viscosity upon prolonged exposure to temperatures below 15C or above 35C, and that .viscosity can be reduced to less than 100 cps by applying shear (e.g., propeller type mixer). FMC

further states that a continuous film may be formed through a process known as gradual coalescence wherein the individ-ual latex particles coalesce to form a continuous film of plasticized ethylcellulose polymer. After this period, the properties are said to remain constant. Higher coating temperatures, or a high temperature "curing" step is said by FMC to accelerate the process. If the coalescence pro-cess is not complete, FMC states that variability in release rates will result.

The stabilized controlled release formulations of the present invention slowly release the active agent, e.g., when placed in an environmental fluid in an environment of use. By "environmental fluid", it is meant that the formu-lation is placed in an aqueous solution (e. g., in-vitro dissolution), in simulated gastric fluid (e. g., in accord-ance with the USP Basket Method (i.e., 37C, 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at pH 7.5), or in gastrointestinal fluid (in-vivo).

The controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydro-phobic polymer, altering the manner in which the plasti-cizes is added to the aqueous dispersion of hydrophobic polymer, by varying the amount of plasticizes relative to hydrophobic polymer, by the inclusion of additional agents or excipients, by altering the method of manufacture, etc.

In one preferred embodiment of the present invention, the controlled release dosage form comprises pharmaceutic-ally acceptable beads (e.g., spheroids) containing the active ingredient coated with a controlled release coating.

The term spheroid is known in the pharmaceutical art and means, e.g., a spherical granule having a diameter of between 0.2 mm and 2.5 mm especially between 0.5 mm and 2 mm. A suitable commercially available example of such beads are nu pariel 18/20 beads.

A plurality of the cured, coated (stabilized) con-trolled release spheroids may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid.

Spheroids or beads coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeu-tically active agent in water and then spraying the solu-tion onto a substrate, for example, nu pariel 18/20 beads, using a Wurster insert. Optionally, additional agents are also added prior to coating the beads in order to assist the hydromorphone binding to the beads, and/or to color the solution, and the like. For example, a product which in-cludes hydroxypropyl methylcellulose, and the like with or without colorant may be added to the solution and the solu-tion mixed (e.g., for about 1 hour) prior to application of 1~ 2125904 the same onto the beads. The resultant coated substrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coat-s ing. An example of a suitable barrier agent is one which comprises hydroxypropyl methylcellulose (HPMC). However, any film-former known in the art may be used. It is pre-ferred that the barrier agent does not affect the dissolu-tion rate of the final product.

The hydromorphone, HPMC protected (optional) beads may then be overcoated with an aqueous dispersion of the hydro-phobic polymer. The aqueous dispersion of hydrophobic polymer preferably further includes an effective amount of plasticizes, e.g. triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat~ or Sure-lease~, may be used. If Surelease~ is used, it is not necessary to separately add a plasticizes.

The coating solutions of the present invention prefer-ably contain, in addition to the film-former, plasticizes, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic polymer. For example, color can be added to Aquacoat~ via the use of alcohol or propylene glycol based color dispers-ions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aqua-coat~. Alternatively, any suitable method of providing color to the formulations of the present invention may be used. Suitable agents for providing color to the formula-tion when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retardant effect of the coating.

The plasticized aqueous dispersion of hydrophobic polymer may be applied onto the substrate comprising the active agent by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluid-s ized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the hydrophobic polymer coating is sprayed on. A

sufficient amount of the aqueous dispersion of hydrophobic polymer to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environment of use, is preferably applied, taking into account considerations such as the physically character-istics of the active agent, the manner of incorporation of the plasticizer. After coating with the hydrophobic poly-mer, a further overcoat of a film-former, such as Opadry~, is optionally applied to the beads. This overcoat is pro-vided, if at all,. in order to substantially reduce agglom-eration of the beads.

Next, the coated beads are cured in order to obtain a stabilized release rate of the active agent.

The optimum curing values for temperature, humidity and time for the particular formulation is determined experimentally. In certain embodiments of the present invention wherein the substrate is a pharmaceutically acceptable beads having the drug coated thereon, the beads which have been overcoated with the aqueous dispersion of plasticized ethylcellulose are stabilized via an oven curing conducted at a temperature of about 60C and a relative humidity from about 60% to about 100 for a time period from about 48 to about 72 hours. This is demon-strated with respect to the hydromorphone beads described in the examples provided below.

However, one skilled in the art will recognize that necessary curing conditions will be affected by the par-ticular drug incorporated in the formulation, as well as by the thickness of the controlled release coating, the size of the substrate (e. g., beads as compared to tablets).

It is especially contemplated that the time period needed for curing to an endpoint as described above may actually be longer or shorter than the 48-72 hour time period mentioned above. Such curing times which achieve the intended result of a stabilized formulation are consid-ered to be encompassed by the appended claims. Addition-ally, it will be appreciated by those skilled in the art that it may be possible to cure the aqueous dispersion coated substrates of the present invention in other manners in order to reach the endpoint at which the coated sub-strate provides a stable dissolution profile. Such addi-tional curing methods which achieve the intended result of a stabilized formulation are also considered to be encom-passed by the appended claims.

The curing-endpoint may be determined by comparing the dissolution profile of the cured, coated substrate (e. g., the "formulation") immediately after curing (hereinafter referred to as "the initial dissolution profile") to the dissolution profile of the formulat~.on after exposure to accelerated storage conditions. Generally, the curing endpoint may be determined by comparing the dissolution profile of the formulation after exposure to accelerated storage conditions of, e.g., 37C/80% RH or 40C/75% RH for a time period of one month to the initial dissolution profile. However, the curing endpoint may be further con-firmed by continuing to expose the cured, coated formula-tion to accelerated storage conditions for a further period of time and comparing the dissolution profile of the formu-lation after further exposure of, e.g., two months and/or three months, to the initial dissolution profile obtained.

In certain preferred embodiments of the present inven-tion in which the cured coated substrate is a pharmaceu-tical formulation, the curing endpoint is attained when the 21~590~
?. 1 data points plotted along a graph of the dissolution curve obtained after, e.g., exposure to accelerated conditions of 1-3 months, show a release of the active agent which does not vary at any given time point by more than about 20% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage. Such a difference in the in-vitro dissolution curves, referred to in the art as a "band range" or a "band width" of, e.g., 20%. In general, where the in-vitro dissolution prior to storage and after exposure to accelerated conditions varies by not more than, e.g. , about 20 % of the total amount of active agent released, the formulation is considered accep-table when considered by governmental regulatory agencies such as the U.S. FDA for stability concerns and expiration dating. Acceptable band ranges are determined by the FDA

on a case-by-case basis, and any band range for a particu-lar pharmaceutical which would be deemed acceptable by such a governmental regulatory agency would be considered to fall within the appended claims. In preferred embodiments, the aforementioned band range is not more than 15% of the total amount of active agent released. In more preferred embodiments, the band range is not more than 10% of the total amount of active agent released. In the. appended Examples, the band range is often significantly less than 10%.

The release of the active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addi-tion of one or more release-modifying agents, or by pro-viding one or more passageways through the coating.
The release-modifying agents which function as pore-formers can be inorganic or organic, and include materials that can be dissolved, extracted or leached from the coat-ing in the environment of use.

212.59 0 ~

For example, the pore-formers may comprise one or more water-soluble hydrophilic polymers in order to modify the release characteristics of the formulation. Examples of suitable hydrophilic polymers include hydroxypropylmethyl-cellulose, cellulose ethers, acrylic resins and protein-derived materials. Of these polymers, the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkyl-celluloses, are preferred. Also, synthetic water-soluble polymers may be used, such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, etc., and polysaccharides, e.g., pullulan, dextran, etc. In certain preferred embodiments of the present invention, the hydro-philic polymer comprises hydroxypropylmethylcellulose.
In addition, a water-soluble polydextrose that dis solves to a level of at least about 1% (W/W) in water at 25°C may be incorporated into the controlled release coat ing.
The pore-formers further include alkali metal salts, polysaccharides, such as lithium carbonate, sodium chlor-ide, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, and the like. Suitable polysaccharides include sucrose, glu-cose, fructose, mannitol, lactose, mannose, galactose, sorbitol and the like. The pore-forming solids may also be polymers which are soluble in the environment of use, such as Carbowaxes~, Carbopol~, and the like. The pore-formers embrace diols, polyols, polyhydric alcohols, polyalkylene glycols, polyglycols, poly(a-w)alkylenediols, and the like.
The pore-formers are non-toxic and on their removal from lamina, channels and pores are formed through the lamina that fill with fluid present in the environment use.
Semipermeable polymers may also be incorporated in the controlled release coating to change the release character istics of the formulation. Such semipermeable polymers in clude, for example, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, beta-glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate chloracetate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate, cellulose acetate valerate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, and other semipermeable polymers such as those described in U.S. Patent No. 4,285,987, as well as the selectively permeable polymers formed by the coprecipitation of a polycation and a polyanion as disclosed in U.S. Pat.
Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142.
The controlled release coatings of the present invention can also include other release-modifying agents such as cellulose acetate phthalate, such as those disclosed in U.S.
Patent No. 2,196,768. Other suitable release-controlling agents which may be included in the controlled release coating of the present invention include shellac, zero, hydroxypropylmethyl cellulose phthalate, sandarac, modified shellac, etc.
The controlled release coatings of the present invention can also include released modifying agents which promote erosion (i.e., erosion promoting agents), such as starch (including, but not limited to corn starch, rice starch, a starch, carboxymethyl starch, potato starch, and other vegetable starches), modified starch, and starch derivatives. This category is also intended to include other erosion-promoting agents such as gums, including but not limited to xanthan gum, alginic acid, other alginates,_ bentonite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylo-pectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins, such as potassium polymethacrylate, carrageenan, kappa-carrageenan, lambdacarrageenan, gum karaya, biosynthetic gum, etc.

The controlled release coatings of the present inven-tion can also include release-modifying agents which are useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain, microporous materials prepared by the phos-genation of a dihydroxyl aromatic such as bisphenol, a microporous poly(vinylchloride), microporous polyamides such as polyhexamethylene adipamide, microporous modacrylic copolymers including those formed from poly(vinychloride) and acrylonitrile, microporous styrene-acrylic and its copolymers, porous polysulfones having a diphenylene sul-fone in a linear chain thereof, halogenated poly(vinyl-idene), polychloroethers, acetal polymers, polyesters pre-pared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics, polyesters, microporous polysaccharides having substituted an hydroglucose units exhibiting a decreased permeability to the passage of water and biological fluids, asymmetric porous polymers, cross-linked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or in-terpolymers having a reduced bulk density, and materials de-scribed in U.S. Pat. Nos. 3,595,752; 3,643,178; 3,654,066;

3,709,774; 3,718,532; 3,803,601; 3,852,224; 3,852,388; and 3,853,601; in British Patent No. 1,126,849; and in Chem.

Abst. Vol. 71, 427F, 22573F, 1969. _ um Additional microporous materials for forming micropor-ous lamina include poly(urethane), cross-linked chain-extended poly(urethane), poly(imides), poly(benzimida-zoles), collodion, regenerated proteins, semi-solid cross-5 linked poly(vinylpyrrolidone), microporous materials pre-pared by diffusion of multivalent cations into polyelectro-lyte sols, microporous derivatives of polystyrene) such as poly(sodium-styrenesulfonate), polyvinyl benzyl trimethyl-ammonium chloride), microporous cellulosic acrylates and 10 the like microporous polymers such as those described in U.S. Pat. Nos. 3,524,753; 3,565,259; 3,276,589; 3,541,055;

3,541,006; 3,546,142; 3,615,024; 3,646,178; and 3,852,224.

In certain preferred embodiments of the present in-15 vention, the release-modifying agent is hydroxypropyl-methylcellulose, lactose, metal stearates, or mixtures thereof.

In general, the amount of release-modifying agent included in the controlled release coatings of the present 20 invention may be from about 0.1% to about 80%, by weight, relative to the combined weight of hydrophobic polymer (e.g., ethylcellulose) and release-modifying agent. In general, the ratio of hydrophobic polymer to hydrophilic polymer is from about 99:1 to about 20:80, by weight. In 25 certain preferred embodiments, the controlled release formulations of the present invention include from about 0.1% to about 50%, and in most preferred embodiments from about 0.1% to about 25%, by weight, relative to the combined weight of the hydrophobic polymer and release-modifying agent.

The controlled release coatings of the present inven-tion may also include an exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864.

1 r~

The passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
The active agents) included in the controlled release formulations of the present invention include systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents, chemical impregnants, cleans-ing agents, deodorants, fragrances, dyes, animal repel-lents, insect repellents, a fertilizing agents, pesticides, l0 herbicides, fungicides, and plant growth stimulants, and the like.

A wide variety of therapeutically active agents can be used in conjunction with the present invention. The thera-peutically active agents (e. g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs.

Examples of such therapeutically active agents include antihistamines (e. g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analge-sics (e. g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (e. g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e. g., metoclopramide), anti-epileptics (e. g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e. g., codeine phosphate), anti-asthmatics (e. g. theophylline), antacids, anti-spasmodics (e. g. atropine, scopolamine), antidiabetics (e. g., insulin), diuretics (e. g., ethacryni.c acid, bendrofluazide), anti-hypotensives (e. g., propran-olol, clonidine), antihypertensives (e. g, clonidine, methyldopa), bronchodilators (e. g., albuterol), steroids (e. g., hydrocortisone, triamcinolone, prednisone),_ anti-biotics (e. g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, de-~, v 2~
congestants, laxatives, vitamins, stimulants (including .appetite suppressants such as phenylpropanolamine). The above list .is not meant to be exclusive.

In certain preferred embodiments, the therapeutically active agent comprises hydromorphone, oxycodone, dihydro-codeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, mixtures of any of the foregoing, and the like.

In another preferred embodiment of the present inven-tion, the active agent is a locally active therapeutic agent and the environment of use may be, e.g., the gastro-intestinal tract, or body cavities such as the oral cavity, periodontal pockets, surgical wounds, the rectum or vagina.

The locally active pharmaceutical agents) include antifungal agents (e. g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline', aminoglycosides, etc.), antiviral agents (e. g, acyclovir, idoxuridine, etc.), breath fresheners (e. g. chlorophyll), antitussive agents (e. g., dextromethorphan hydrochloride), anti-cariogenic compounds (e. g. metallic salts of fluor-ide, sodium mvnofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e. g., methylsalicylate, sali-cylic acid, etc.), local anesthetics (e. g., benzocaine), oral antiseptics (e. g., chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-flammatory agents (e. g., dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), anti-plaque agents (e. g, chlorhexidine and salts thereof, octen-idine, and mixtures of thymol, menthol, methysalicylate, eucalyptol), acidity reducing agents (e. g., buffering agents such as potassium phosphate dibasic, calcium car-bonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), and tooth desensitizers (e. g., potassium nitrate).

This list is not meant to be exclusive.

When the controlled release coating of the present invention is to be applied to tablets, the tablet core (e. g. the substrate) may comprise the active agent along with any pharmaceutically accepted inert pharmaceutical filler (diluent) material, including but not limited to sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures thereof and the like.

l0 Also, an effective amount of any generally accepted pharma-ceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned agents of the excipient prior to compression of the tablet core agents.

Most preferred is magnesium stearate in an amount of about 0.2-3% by weight of the solid dosage form.

In another preferred embodiment of the present inven-tion, the active agent is disinfecting agent, e.g. a chlorine compound such as calcium hypochlorite, and the environment of use is a surrounding body of water, e.g. a recreational pool.

In still another preferred embodiment of the present invention, the active agent comprises at least one of a cleansing agent, a germicide, a deodorant, a surfactant, a fragrance, a perfume, a sanitizer, and/or a dye, and the environment of use is an aqueous solution, e.g. a urinal or toilet bowl.

In yet another preferred embodiment of the present in-vention, the active agent is a chemical impregnant, e.g.

fertilizer, animal repellents, insect repellents, pesti-cides, herbicides, fungicides, plant growth stimulants, and the environment of use is, e.g., anywhere around the home, e.g. soil, trees etc. The fertilizer may be, for example, a nitrogen containing compound such as urea, urea formalde-hyde composites, potassium nitrate, potassium sulfate, potassium chloride, ammonium nitrate, ammonium sulfate, monoammonium phosphate, dibasic ammonium phosphate, ammon-iated super-phosphoric acid, micronutri_ent ingredients such as trace elements of iron, zinc, manganese, copper, boron, molybdenum, and mixtures of any of the foregoing. The fertilizer may be, e.g., in granular form.
For example, when the coated substrate is a coated chlorine tablet for combatting bacterial and algaecidal contamination of swimming pools and the like, the substrate may comprise commercial grade calcium hypochlorite, with or without trichloroisocyanuric acid, sodium dichlorocyan-urate, lithium hypochlorite, powdered lime, and/or the like.
For example, the substrate may comprise about 98.5%
commercial grade calcium hypochlorite and about 1.5%
powdered lime, by weight. The substrate may also comprise commercial granular calcium hypochlorite, up to 20% by weight chloride of lime, and 1% zinc stearate having an available chlorine percentage of about 69% and a mass of about 57 g and a diameter of about 40 mm, as described in U.S. Patent No. 4,192,763. The substrate is then coated with the aqueous dispersion of plasticized hydrophobic polymer to a weight gain from about 3 to about 30 percent, depending upon the desired rate of dissolution, and the coated tablet is then cured in accordance with the present invention until an endpoint is reached at which the cured coated tablet provides a reproducibly stable dissolution profile.
When the active agent comprises a composition suitable for cleaning and preventing the staining of toilet bowls, the substrate may include a well-known disinfectant such as calcium hypochlorite and/or trichloroisocyanuric acid. The active agent may alternatively comprise an alkali metal salt of dichloroisocyanuric acid and a chloride salt such as calcium chloride and barium chloride, such as that which 'd 21259Q~
is described in U.S. Patent No. 4,654,341.
One possible example of such a product might include a substrate comprising 0.5-5% fragrance, 1-10% dye, 10-40%

5 surfactant (which may be nonionic, cationic, anionic or zwitterion surfactants), and other optional components such as germicides, disinfectants, processing aids, and other commonly included ingredients known to those skilled in the art. Such active agents may be incorporated into a sub-10 strate comprising a tablet, along with other well-known ingredients such as detergents, surfactants, perfumes, dyes, and any necessary fillers.

The substrate may alternatively comprise a pellet which is prepared by homogenously mixing together, e.g., 1 g of 15 azure blue dye 65% (dye commercially available from Hilton David), 1 g Pluronic F-127T"' (a nonionic surfactant comprising the condensation products of ethylene oxide with the product resulting from the reaction of propylene oxide and ethylene diamine; commercially available from BASF-20 Wyandote Chemicals), 38 g Carbowax 8000T'" (a solid polyethylene glycol, molecular weight 8000; commercially available from Union Carbide), and 40 g Kemamide UT"' (a oleylamide surfactant; commercially available from Witco) and an optional fragrance (e. g., 0.5% by weight citrus pine 25 fragrance), and thereafter processing the above ingredients into a pellet by conventional methods such as noodling, plodding, extruding and cutting and stamping the mass to form the pellets. Optionally, the pellets may also include a suitable amount of an inorganic salt to cause the pellet 30 to settle to the tank bottom, and one or binding agents such as guar gum. The pellet is then coated with the aqueous dispersion of plasticized hydrophobic polymer to a weight gain from about 2 to about 30 percent, depending upon the desired rate of dissolution, and the coated pellet is then cured in accordance with the present invention A.

21 2590' until an endpoint is reached at which the cured coated pellet provides a reproducibly stable dissolution profile.

Another example of a substrate useful for the treat-ment of the flush water of toilets is one which comprises an iodophor such as povidone iodine, as described in U.S.

Patent No. 5,043,090.

When the substrate comprises a fragrance, the frag-rance may be any conventional commercially available per-fume oil, e.g., volatile compounds including esters, ethers aldehydes, alcohols, unsaturated hydrocarbons, terpenes, and other ingredients which are well known in the art.

Their type and compatibility is limited only by their compatibility and desirability, as may be determinable by those skilled in the art.

When the active agent comprises a composition suitable for use as a fertilizer, the active agent may comprise granular urea which is coated with the aqueous dispersion of plasticized hydrophobic polymer to a weight gain from about 2 to about 30 percent and then cured in accordance with the present invention. In urea pill production, urea at 70% solids concentration in water is heated to remove substantially all of the water. The molten urea is then injected as droplets to an air cooling tower where crystal-line urea is formed as a hard pill or bead, which is then coated and cured in accordance with the present invention.

When the substrate comprises plant food formulations, the substrate can be pelleted, ball-shaped, particulate, or in stick form, and may additionally contain growth promot-ing substances such as gibberellic acid along with soil fungistats such as formaldehyde and paraformaldehyde, etc.

In certain embodiments of the present invention, the coated substrate includes an additional dose of active agent included in either the controlled release coating comprising the aqueous dispersion of hydrophobic polymer, or in an additional overcoating coated on the outer surface ,~ ~;

of the controlled release coating. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid.

Figure A is a Scanning Electron micrograph (sEM) of a theophylline bead coated in accordance with the present invention prior to curing, taken at a magnification of 18,000. The coating is an aqueous dispersion of ethyl-cellulose coated to a weight gain of 5%. The SEM shows the distinct particles of ethylcellulose on the coating. Due to cracks or pores in the coating, the coating allows the environmental fluid to pass through to the underlying core where the active agent is found.

Figure B is an SEM of the theophylline bead shown in Figure A, taken after the bead has been cured in an oven at 60C and at a relative humidity of about 85~ for a time period of 72 hours. The SEM of Figure B is taken at a magnification of 15,000. The individual ethylcellulose particles have coalesced and fused to such an extent that further exposure to temperatures above the glass transition temperature of the aqueous dispersion and a relative humid-ity from about 60% to about 100% do not cause a further coalescence or fusion which would further change the dissolution profile of the coated substrate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever. In the follow ing tablets which report the results of dissolutions tests, the underlined numerals specify hours and the figures pro-vided in the columns beneath these underlined numerals specify the percent active ingredient dissolved.

Hydromorphone beads were prepared by dissolving hydro-morphone HC1 in water, adding Opadry~ Y-5-1442, light pink (a product commercially available from Coloron, West Point, Pennsylvania, which contains hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 Aluminum Lake), 20% w/w, and mixing for about 1 hour, and then spraying onto nu pariel 18/20 beads using a bluster insert. The resultant coated beads were then overcoated with Opadry~ Y-5-1442 light pink (15% w/w). The resultant preparation had the formula set forth in Table 1 below:

Ingredient Percent AmtJUnit Hydromorphone HC1 4.75% 4 mg Nu Pariel 18/20 87.9% 74 mg Opadry~ Lt. Pink Y-5-1442 2.4% 2 mg Opadry'~ " (overcoat) 5.0% 4.2 ma 100.0% 84.2 mg The hydromorphone, HPMC protected beads were then overcoated with 15o w/w Aquacoat~ (including triethyl citrate), and then overcoated with Opadry~ Light Pink 5%
w/w after curing (see Table 2). The beads cured at high humidity were dried in a fluid bed before the final overcoat.
TABLE 2 - Composition After Coating Ingredient Percent Hydromorphone beads 80.570 Aquacoat~ ECD 30 12.060 Triethyl citrate 2.390 Opadry~ Lt. Pink 4.98-°s Y-5-1442 (Overcoat) 100%
The product was then divided into four portions. In Example 1, the coated beads were placed in a 30 cc amber glass vial and cured in an oven for 72 hours at 60°C/85~

21~5~04 relative humidity. In Comparative Example lA, the coated beads were cured for 24 hours at 60°C under dry conditions.
In Comparative Example 1B, the coated beads were cured for 72 hours at 60°C under dry conditions. In Comparative Example 1C, the coated beads were cured for 24 hours at 60°C at 85% relative humidity.
All products cured at the four above-mentioned differ-ent conditions were then tested for stability under the following conditions: Room Temperature; 37°C dry; 37°C/85%
Relative Humidity (RH); 50°C dry; 60°C dry: and 60°C/85%
RH.
The relative humidity in a water-filled desiccator in a 60°C oven was determined as follows. First, about 500 grams of purified water is poured into a plastic desiccator and the metal guard inserted. A hygrometer/temperature indicator is placed on top of the guard and the desiccator covered and placed in the 60°C oven for 24 hours. After 24 hours the relative humidity in the desiccator was 85% while the temperature was still 60°C. On placing the hygrometer alone in the 60°C oven for 24 hours, the relative humidity was 9% at 60°C.
The dissolution tests were carried out via the USP
Basket Method, 37°C, 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. In each instance, the dissolution was conducted by placing an open capsule containing the specified amount of cured beads (8 mg hydromorphone HC1, 209 mg beads ~ 10%) into a vessel.
It was observed that the dissolution of Example 1 did not change under these accelerated conditions, except that changes were seen with respect to the extreme conditions of 60°C/85% RH.
The results for Example 1 are set forth in Tables 3-8 below:

-Hydromor-Time phone HC1 Dissolution wks ~Amount~ 1 2 4 8 12 18 24 5 Initial 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 7.95 mg 0 5.1 30.3 55.0 67.4 79.8 88.9 4 7.80 mg 1.3 8.2 33.5 57.4 70.0 82.8 90.9 8 , 7.78 mg 0.7 6.0 30.5 54.0 66.4 78.0 88.2 Hydromor-Time phone HC1 Dissolution wks Amounts 1 2 4 8 12 18 24 Initial 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 15 1 7.96 mg 0 6.0 30.8 55.3 68.0 81.6 ~.7 4 7.91 mg 2 8.1 33.2 56.6 70.2 82.0 91.3 8 7.73 mg 1 5.8 31.3 57.5 64.6 82.7 9L6 TABLE 5 - 37C,/80%RH

20 Hydromor-Time phone HC1 Dissolution wks (Amount) 1 2 4 8 12 18 24 Initial 8.19 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 7.85 mg 0 5.6 31.0 55.1 68.5 80.3 89.1 25 4 8.16 mg 2.4 7.6 32.3 52.8 64.4 75.4 82.7 8 8.22 mg 2.9 7.9 33.5 53.3 64.5 73.6 81.3 TABLE 6 - 50C dry, Hydromor-30 Time phone HC1 Dissolution wks (Amount) 1 2 4 8 12 18 24 Initial 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 8.14 mg 0 6.3 32.7 56.3 68.3 80.8 4 7.81 mg 2.3 10 37.0 59.6 72.0 84.5 35 8 7.74 mg 2 10.4 35.8 59.2 71.3 82.3 90.5 2~2590~
3c TABLE 7 - 60C (dry Hydromor-Time phone HC1 Dissolution wks Amount 1 2 4 8 12 18 24 Initial 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 8.13 mg 0 6.7 34.6 57.8 70.3 82.1 90.5 4 8.30 mg 2.7 10.6 36.6 56.8 68.7 80.4 85.6 8 ~ 7.94 mg 3.6 11.9 37.4 58.4 71.1 80.6 89.3 TABLE 8 - 60C/100%
RH

Hydromor-Time phone HC1 Dissolution wks Amount) 1 2 4 8 12 18 24 Initial 8.14 mg 0 4.6 29.5 52.6 64.7 76.6 82.8 1 7.26 mg 6.1 9.9 23.4 42.4 53.3 63.1 72.5 4 6.64 mg 19 23.7 32.5 41.4 46.7 53.0 51.7 8 5.38 mg 25.1 28.4 33.2 40.0 44.1 47.7 52.0 The data provided in Table 5 shows that despite expo-sure to accelerated conditions, the change in amount of hydromorphone released at each time point was insignifi-cant. The largest band range occurred at 24 hours (after 2 month storage), where the difference in amount released is 1.50.
In contrast, the dissolution profiles of Comparative Examples lA, 1B and 1C continued to slow down (e. g., cure) at all accelerated conditions. The results are set forth in Tables 9, 10 and 11, respectively. The widest point of the band range for Comparative Example lA was 22.4 (at 4 hours dissolution). The widest point of the band range for Comparative Example 1B is 17.3% (at 12 hours dissolution).
The widest point of the band range for Comparative Example 1C is, in contrast, only 9.10 (at 18 hours dissolution).
The fact that the results of Comparative Example 1C repre-sent substantial improvement as compared to the results of Comparative Examples lA and 1B is not surprising, as this was the only comparative example which utilized curing at high relative humidity conditions.
TABLE 9 - Comparative Example lA
Hydromor-Time phone HC1 Dissolution wks (Amount) 1 2 4 8 12 18 24 Initial 9.03 mg 17.8 43.6 63.6 78.8 86.7 94.7 94.2 Room Temp.
8 wks 8.79 mg 18.4 35.9 58.2 76.3 88.7 97 l0 37°C (dry) 8 wks 8.50 mg 14 36.5 59.1 81.1 91.4 99.4 37°C 80oRH
8 wks 8.15 mg 6.6 23.6 41.2 60.7 72.3 83.1 50°C (dry) 8 wks 8.45 mg 17.3 36 56.1 78.1 89.1 97.1 102.6 60°C (dry) 8 wks 8.65 mg 7.3 28.5 48.9 64.4 82 92.3 99.1 60°C/100%RH
8 wks 5.81 mg 17.5 22.6 28.8 36.5 41.7 46.5 50.3 TABLE 10 - Comparative Example 1B
Hydromor-Time phone HCl Dissolution wks (Amount) 1 2 4 8 12 18 24 Initial 8.82 mg 4.7 35.5 58.3 75.6 87.3 96.0 98.2 Room Temp.
8 wks 8.29 mg 8.7 34.6 59.3 80.8 92.1 99.2 105.7 37°C ~dryZ
8 wks 8.34 mg 8.3 36.1 55.9 77.4 87.3 97.8 103.1 37°C/80%RH
8 wks 8.86 mg 4.9 25.4 43.6 61.7 70 80 87.2 50°C (dry) 8 wks 8.71 mg 10.8 35.4 55.9 77.2 88.9 99.5 103.2 60°C (dry) 8 wks 8.30 mg 5.3 32 54.1 76.6 87.2 99.8 105.5 60°C/100%RH
8 wks 6.22 mg 16.3 21.2 27.4 35.9 40.5 46.2 49.4 212~~04 TABLE 11 - Comparative Example 1C
Hydromor-Time phone HC1 Dissolution wks _ _ - -(Amount) 1 2 4 8 12 18 24 Initial 8.71 mg 0.7 15.3 41.9 60.7 71.2 82.4 86.7 Room Temp.
8 wks 8.40 mg 1 14.2 39.8 58.8 69.1 79.1 87.2 37'C ydry) 8 wks 8.84 mg 2.7 14.5 40.5 60.4 71 81.3 89.8 37°C/80%RH
8 wks 8.78 mg 2.5 12.4 37.8 54.6 63.8 73.3 50°C (dry) 8 wks 8.71 mg 3.2 17.5 42.3 61.1 70.8 81 87.9 60°C (dry) 8 wks 8.57 mg 2.9 18.2 43.4 62.5 73.6 84.3 60°C/100%RH
8 wks 6.10 mg 15.7 20.3 26.4 33.8 38.3 43.1 46.7 Figure 1 is a graphical representation of the dissolu-tion results obtained with Example 1, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37°C/80%RH.
Figure 2 is a graphical representation of the dissolu tion profile of Comparative Example lA, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37°C/80%RH.
Figure 3 is a graphical representation of the dissolu-tion profile of Comparative Example 1B, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37°C/80%RH.
Figure 4 is a graphical representation of the dissolu-tion profile of Comparative Example 1C, comparing the initial dissolution profile with the dissolution profile after 8 weeks storage at 37°C/80%RH.
Comparing the results depicted in Figure 1 (Example 1) with the results depicted in Figures 2-4 (the comparative examples), it is readily apparent that only in Example 1 were the initial and 8 week dissolution profiles substan-tially identical under storage conditions of 37°C/80%RH.
Figure 5 is a graphical representation of the dissolu-tion profiles of Example 1, comparing the initial dissolu-tion profile with the dissolution profiles obtained after 8 weeks storage under various conditions {room temperature;
37°C/80%RH; and 60°C dry). The dissolution profiles of Example 1 after 8 weeks under these various conditions is seen to be substantially identical.
Finally, Figure 6 is a graphical representation of the initial dissolution profiles obtained after various curing conditions (curing of 2 hrs at 60°C dry (the prior art); 72 hrs at 60°C/85%RH (Example 1): 24 hrs at 60°C dry (Compara-tive Example lA); 72 hrs at 60°C dry (Comparative Example 1B): and at 60°C at 85% RH for 24 hours (Comparative Example 1C)).
EXAMPLE 2 - Curing at 60°C Dry Heat - Longer Drying In Example 2, hydromorphone HC1 beads were prepared in accordance with Example 1 in order- to determine if the stabilized initial dissolution achieved after curing at 60°C/85%RH could instead be achieved by a longer drying period without humidity. After coating with Aquacoat~, a further overcoat of Opadry~ Y-5-1442, light pink is applied to~the beads. The coated product had the composition set faith in Table 12 below:
TABLE 12 - Composition After Coating Ingredient Percent Amt/Unit Hydromorphone beads 80.57% 84.2 mg Aquacoat~ ECD 30 12.06% 12.6 mg Triethyl citrate 2.39% 2.5 mg Opadry~ Lt. Pink (Overcoat) 4.98% 5.2 ma 100.0% 99.3 mg ~1~.5904 The Aquacoat~ coated hydromorphone HC1 beads were then cured in a 60°C dry oven, and stored at 60°dry heat. The cured beads were placed in open gelatin capsules containing the specified amount of cured beads (about 8 mg hydromor-5 phone HC1), and dissolution studies were then conducted in the manner set forth in Example 1 on three samples at the following time points: initial, 1 day, 2 days, 7 days, and 21 days in order to determine the stability of the dissolu-tion profile. Dissolution studies were conducted as de-10 tailed above on the three samples. The mean results are set forth in Table 13 below:

Dissolution lTime) Time Wt Hours 15 Da s lmct) 1 2 4 8 12 18 24 Initial 196.7 15.6 43.8 68.7 89.9 101.0 109.2 113.8 1 196.3 3.7 37.5 63.5 84.9 97.5 107.2 112.3 ' 2 196.3 4.8 .37.0 62.9 84.8 95.1 104.7 111.8 7 197.3 13.5 37.8 63.3 84.9 98.8 108.6 115.9 20 21 197.3 17.4 36.5 58.4 77.9 88.9 98.2 103.1 From the results set forth in Table 13 above, it is apparent that a profound slow down in release rate of the samples of Example 2 did not occur, as compared with the 25 high temperature/high humidity condition of Example 1.
This profound slow down is apparent when comparing, e.g.
the initial dissolution of the drug in Tables 3-8 (Example 1) versus the initial dissolution of the drug in Table 13 (Example 2) (e. g., 0% vs. 15.6% release after one hour:
30 4.6% vs. 43.8% released after two hours; 29.5% vs. 68.7%
released after four hours; etc.). The release rate for the drug in Example 2, however, would eventually slow down to a more similar rate to Example 1 after exposure to acceler-ated storage conditions. In other words, an endpoint was 35 not reached at which the dissolution profile matches the base level of Example 1.

EXAMPLE 3 - Increased Mixing Time In Example 3, another attempt to stabilize Aquacoat~
coated hydromorphone HC1 beads using the premise that high temperature is not enough to insure complete coalescence of the ethylcellulose film. Normal time of mixing (and bond-ing) plasticizer and Aquacoat~ is recommended by FMC to be 30.minutes. In Example 3, the contact time of the plasti-cizer (triethyl citrate) with the ethylcellulose polymer dispersion (Aquacoat~) was increased to 24 hours.
The coated beads were prepared in accordance with Example 1 and then placed in a 30 cc amber glass vial and cured in a 60°C dry oven. Dissolution studies were then conducted on three samples at the following time points: 1 day, 2 days, 7 days and 11 days. Mean results are set forth in Table 14 below:

Dissolution (Time) Time Wt Hours Da s (mg) 1 2 4 8 12 18 24 1 210.7 27.7 53.3 77.3 95.7 103.4 108.2 110.4 2 209.7 25.9 50.3 74.3 94.2 101.9 106.4 110.2 7 209.7 24.8 48.3 73.1 95.2 102.7 108.5 112.6 11 210.3 24.0 45.4 70.5 94.9 103.9 113.3 115.9 From the results set forth in Table 14 above, it is apparent that a profound slow down in release rate of the samples of Example 3 did not occur, as compared with the release rates both initially and under the high tempera ture/high humidity conditions of Example 1. In other words, an endpoint was not reached at which the dissolution pro file gets down to the base level of Example 1. This pro-found slow down in release rate is apparent when comparing, e.g., the initial dissolution of the drug in Tables 3-8 (Example 1) versus the dissolution of the drug after one day storage (e. g., 0% vs. 27.7% release after one hour:
4.6% vs. 53.3% after two hours; 29.5% vs. 77.3% after four hours; etc.).

EXAMPLE 4 - Recommended Curina (Prior Art) Hydromorphone beads were prepared by dissolving hydro-morphone Hcl in water, adding Opadry°, and mixing for about 1 hour, and then spraying onto nu pariel 18/20 beads using a Wurster insert. The resultant coated beads were then overcoated with Opadry° Y-5-1442 light pink (15o w/w). The beads were then overcoated with an aqueous dispersion of Aquacoat° to a 15% weigtht gain according to Table 15 below:

Ingredient % wt Amt/Unit Hydromorphone beads 84.7 80 mg Aquacoat~ CD 30 12.7 12 mg Citroflex~2A (Triethylcitrate) 2.5 2.4 ma 99.9 94.4 mg After the resin was applied to the beads, the beads were cured in a fluid bed for about 2 hours at 60°C, as suggested in the literature and as recommended by FMC, since it is above the Tg for Aquacoat~ plasticized with triethyl citrate at 200 level of solids.
The cured beads were then stored at room temperature, with dissolution studies being conducted initially and at 3 months.
Samples were also stored at 37°C/80o RH. The mean results are provided in Table 16:

Time Mean wt 1 2 4 8 12 18 24 Initial 283.2 30.4 44 70.2 89.1 97.0 101.3 102.1 3 mos 282.3 36.2 57.8 76.9 89.0 93.4 96.6 98.5 37C/80o RH

1 mo 288.4 0.5 26.7 50.5 69.6 80.7 90.7 97.0 2 mos 287.3 0.6 25.1 50.7 70.3 81.6 92.2 98.8 3 mos 293.7 1.2 23.7 48.6 65.6 74.5 80.2 83.5 From the results provided in Table 16 above, it can be seen that the dissolution profile of the samples stored at room temperature were acceptable. However, the dissolution of the samples slowed dramatically when stored at 37C/80%

RH. The band range for this example was unacceptably wide at, e.g., the one hour dissolution point (storage at 37C/

80% RH), as well as numerous other points.

Samples from the batch of Example 4 were repackaged, stored and thereafter subjected to heat under dry condi-tions at 37C and moisture (37C/80% RH). The dissolution results are provided in Table 17 below:

Hours Time Mean wt 1 2 4 8 12 18 24 Initial 283.2 30.4 49.0 70.3 89.1 97.0 101.3 102.1 37 Drv 2 wks 283.2 25.0 44.4 65.0 84.5 92.9 100.7 104.4 4 wks 280.7 21.5 28.0 63.5 84.3 95.6 - -37C/80% RH

2 wks 283.2 16.6 39.1 60.5 80.1 89.8 99.8 103. 4 4 wks 281.3 4.6 26.6 53.7 71.4 82.1 - -From the results set forth above, it is apparent that under dry conditions at 37C, the dissolution of Example 4 did not come to the same endpoint as at 37C/80% RH. Thus, the combination of both moisture and heat was required to complete the curing.

To test the effectiveness of high temperature (60°C), high humidity curing as an effective process of stabilizing plasticized ethylcellulose controlled release films, Exam ples 5-7 were manufactured at different levels of Aquacoat~
load.
In each of Examples 5-7 , hydromorphone beads were made according to Example 1. Thereafter, overcoatings of 5%
w/w, lo% w/w, and 15% w/w were applied to Examples 5-7 respectively, according to the formulas set forth in Tables 18-20:

212~g04 TABLE 18 - Composition of Ex. 5 After Coatina Ingredient Percent AmtLUnit Hydromorphone beads 84.2% 84.2 mg Aquacoat~ ECD 30 4.7% 4.2 mg Triethyl citrate 0.9% 0.84 ma 100% 89.24 mg TABLE 19 - Composition of Ex. 6 After Coatina Ingredient Percent Amt/Unit Hydromorphone beads 89.3% 84.2 mg Aquacoat~ ECD 30 8.9% 8.4 mg Triethyl citrate 1.8% 1.7 ma 100% 94.3 mg TABLE 20 - Composition of Ex. 7 After Coating I nq_red Tent Percent AmtJUn it Hydromorphone beads 84.8% 84.2 mg Aquacoat~ ECD 30 12.7% 12.6 mg Triethyl citrate 0.9% 2.5 ma 100% 99.3 mg All three batches were cured in~water loaded desicca-tors in a 60°C oven. These batches were placed on screen trays in these desiccators after the Aquacoat~. film was applied to the HPMC overcoated hydromorphone HC1 bead. The desiccators containing the Aquacoat~-coated beads were then placed in a 60°C oven for 72 hours. Thereafter, the batches were removed from the ovens. The beads appeared moist and therefore were dried in a lab line fluid bed dryer for one hour. They were then overcoated with 5% w/w Opadry~ Y-5-1442 light pink in a wurster insert.
Stability studies on Examples 5-7 show the initial dissolutions to be the same as dissolutions done on samples placed at 37°C/80% RH conditions. The results are provided in Tables 21-23 below:

TABLE 21 - Dissolution (Time) - 5o Aquacoat~
Hours Time Mean wt 1 2 4 8 12 18 24 Initial 190 39.8 57.4 73.0 88.0 93.8 98.0 95.6 28 191 33.4 54.6 71.9 84.2 89.8 94.6 96.4 TABLE 22 - Dissolution (Time) - 10% Aauacoat~
Hours Time Mean wt 1 2 4 8 12 18 24 Initial 200.3 7.5 27.9 48.5 68.1 76.2 90.3 88.9 28 210 9.9 32.4 52.6 67.8 77.9 85.9 90.9 TABLE 23 - Dissolution (Time) - 15°s Aquacoat~
Hours Time Mean wt 1 2 4 8 12 18 24 Initial 210 5.4 13.9 38.0 57.8 68.4 78.6 81.3 28 207.3 9.5 23.8 43.4 58.8 67.8 77.0 81.3 In Example 8, Hydromorphone beads overcoated with l00 of the Aquacoat~ are prepared in accordance with Example 6. The hydromorphone beads of Example 8 have the following formula set forth in Table 24 below:

Inaredient Percent Amt/Unit Hydromorphone beads 89.30 84.2 mg Aquacoat~ ECD30 8.90 8.4 mg Triethyl citrate 1.8a 1.7 ma 1000 94.3 mg To test the effectiveness of curing at a lower relative humidity compared to Example 6, the above beads were cured for 72 hours at 37°C at 60% relative humidity (rather than 85oRH).
Similar initial results were obtained for Example 8 as compared to Example 6, thus indicating that the curing step can also be completed at a lower relative humidity. The results are set forth in Table 25 below:
TABLE 25 - Dissolution (Time) - 10% Aquacoat~
Example 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 24 hr Ex. 6 7.5 27.9 48.5 68.1 76.2 90.3 88.9 Ex. 8 1.1 18.9 45.0 65.0 76.0 85.8 91.5 Hydromorphone HC1 beads were prepared made by spraying a suspension of Hydromorphone HC1 and Opadry~ Y-5-1442 light pink (20%w/w) onto nu-pariel 18/20 beads, in accord ance with the method set forth in Example 1. These beads were then further coated with Opadry~ Y-5-1442 light pink (15% w/w). These beads were then further coated with the Surelease~ at a level of 10% weight gain. The formula of the coated bead is set forth in Table 26:

Incxredient mct/dose Percent Hydromorphone HC1 4.0 mg 4.32%
NuPariel beads 18/20 74.0 mg 79.91%
Opadry light pink 6.2 mg 6.70%
Surelease 8.4 mct 9.07%
92.6 mg 100%
The batch was then divided into two portions. Example 9 was cured at 60°C/85% RH for 3 days (72 hours), and then dried in a fluid bed dryer for 30 minutes at 60°C to dry off the excess moisture. These beads were then overcoated with 5% Opadry light pink. Example 10 was left uncured.
Both Examples 9 and 10 were then filled into hard gelatin capsules at a strength of 4 mg hydromorphone per capsule and stored for 3 months at 37° C/100% RH. Dissolu-tion studies were conducted (pursuant to the method set forth for Example 1) initially for both Examples 9 and 10 zlz~9o~

and again after the 3 month storage at 37° C/100o RH. The results are set forth in Tables 27 and 28 below:
TABLE 27 - Example 9 Time Initial 3 Months at 37° C/100% RH
1 4.7 6.5 4 42.3 56.0 g 64.9 75.0 12 77.2 83.19 TABLE 28 - Example 10 Time Initial 3 Months at 37° C/100%. RH
1 1.6 4.5 4 12.0 61.9 8 47.8 79.0 12 66.7 87.7 The results indicate that despite the expected differ-ences in initial release rates caused by the use of a diff-erent aqueous dispersion of ethylcellulose (Surelease~ as compared to Aquacoat~), the curing step as described above for Example 9 still significantly stabilized the product in comparison to the uncured product of Example 10. The rela-tively faster controlled release rate of the Examples using Aquacoat~ as compared to Surelease~ may be due to the lesser degree of plasticization during the preparation of the coating formulation. However, products using either coating may be modified to obtain satisfactory results.

The following example illustrates the stabilization of morphine beads in accordance with the present invention.
A suspension of morphine sulphate and HPMC (Opadry~
Clear Y-5-7095) was applied onto 18/20 mesh Nu-pariel beads in a fluid bed granulator with a Wurster insert, at 60°C.
A HPMC purple color suspension (Opadry~ lavender YS-1-4729) was then applied as an overcoat at the same temperature.
The beads were then overcoated to a 5% weight gain with Aquacoat~ and triethyl citrate as a pJ_asticizer at 60°C
inlet. The beads were then cured in an oven at 60°C/100%
relative humidity for three days. The beads were then dried in the fluid bed granulator at 60°C, and an overcoat of HPMC with a purple color was then applied using the bluster insert.
The beads were then filled into hard gelatin capsules l0 at a strength of 30 mg morphine sulphate per capsule. The final formula, set forth in Table 29 thus became:

Ingredient mgJcapsule Percent Morphine sulphate 5Hz0 30.0 8.51%
Nu-pariel beads 18/20 255.0 72.36%
Opadry~ Clear Y-5-7095 15.0 4.26%
Opadry~ Lavender,YS-1-4729 15.8 4.48%
- Aquacoat~ ECD30 (solids). 15.8 4.48%
Triethyl citrate 3.2 0.91%
Opadry Lavender Y-S-1-4729 17.6 4.99%
352.4 100%
An initial dissolution of the capsules was conducted using the USP paddle method at 100 rpm in 900 ml of water, and again after storage at 37°C/100% relative humidity, and at 60°C dry for one month. It was observed that a stable product was made. The results are set forth in Table 30:
TABLE 30 - Percent Morphine Dissolved Time 37°C/100% RH 60°C
Hrs Initial After 1 Mo After 1 Mo 1 15.7 16.6 15.3 4 53.0 51.4 54.9 8 84.4 83.3 90.4 12 96.5 94.4 96.9 212.904 A second experiment was conducted with morphine as described in Example 11; however, the retardant Aquacoat~

layer was applied to a 15% weight gain to develop a slower releasing morphine product. The final formulation is set forth in Table 31:

Ingredient Ma/capsule Percent Morphine sulphate 5Fiz0 30. 0 7 65%

Nu-pariel beads 18/20 255.0 65.0%

Opadry~ Clear Y-5-7095 15.0 3.82%

Opadry'~ Lavender YS-1-4729 15.8 4.03%

Aquacoat~ ECD30 (solids) 47.4 12.08%

Triethyl citrate 9.5 2.42%

Opadry~ Lavender Y-S-1-4729 19.6 5.00%

392.3 100%

An initial-dissolution of the 30 mg morphine sulphate capsules was conducted as described in Example 10 and again after storage at 37C/100% relative humidity and 60C dry for one month. It was again observed that a stable product was made. The results are set forth.-in Table 32 below:

Percent Morphine Dissolved Time 37C/100%RH 60C

Hrs Initial After 1 Mo After 1 Mo 1 0 3.1 0 4 18.1 19.4 178 8 49.2 49.4 45.7 12 66.3 68.2 65.9 In Example 13, the applicability of another medica-ment, theophylline, having very different physical prop-erties compared to hydromorphone is demonstrated.
Theophylline hydrous and colloidal silicon dioxide were first mixed together in a high shear mixer, then sieved using a Jet sieve to enhance flowability. Using a fluid bed granulator equipped with a rotor processor, ~ sugar spheres were layered with the theophylline/colloidal sili-con dioxide mixture using a PVP (C-90) solution. Layering 5 was continued until an approximately 78 % load was obtained.
The formula of the 400 mg theophylline beads when filled into capsules is set forth in Table 33 as follows:

Mcr/unit capsules 10 Theophylline hydrous (equivalent to 400 mg anhydrous theophylline) 440.0 Colloidal silicon dioxide 0.4 Sugar spheres 30/35 mesh 110.0 PVP (C-30) 13.5 15 563.9 These spheres were then overcoated with a dibutylsebe-cate plasticized Aquacoat~ ECD 30 retardant to a 5% weight gain in the Wurster column in a fluid bed granulator. A

portion of the spheres was not cured, and another portion 20 was stored at 60C and 100% relative humidity for 72 hours.

The following results set forth in Table 34 were obtained:

Hours Time 1 2 4 8 12 18 24 25 Initial (uncured) 9.0 92.8 94.6 95.4 97.8 98.0 100.0 72 hours at 60C/100% RH 3.2 5.3 7.0 7.9 11.0 14.1 35.8 From the above, it was determined that theophylline spheroids coated with Aquacoat~ also are not stable and 30 need to be cured. After storage at 72 hours at 60C and 100% relative humidity, a dramatic drop in dissolution rate occurred; however, such conditions may, in some instances, represent "ideal" curing conditions to form a stable pro-duct. In view of this goal, the dissolution data after 72 212~90~

hours at 60%C/100%RH provides a dissolution profile too slow for theophylline.

Therefore, Example 14 was prepared in order to attempt to improve the dissolution profile of the formulation via incorporation of this new curing step, and the coating was altered in order to increase the dissolution rate to 100%

theophylline dissolved in 12 hours.

Example 14 was prepared as follows. Theophylline powder layered beads were made as described in Example 13 and were then overcoated with a plasticized Aquacoat~ ECD

30 retardant, which, and for this example, included 10%

HPMC (hydroxypropyl methyl cellulose). This was done so that the release of theophylline would be faster than Example 13. The inclusion of HPMC to speed up dissolution is known in the prior art. The retardant layer was also coated to a 6% weight gain in the Wurster column of the fluid bed granulator.

The coated beads were then cured for 72 hours at 60C/

100% relative humidity. A dissolution study was conducted initially, and once again after the beads were stored at 37C/80% relative humidity for three. months. It was ob-served that the stability of the dissolution of the the-ophylline from the formulation of Example 14 improved dram-atically compared to Example 13. It was further observed that by inclusion of HPMC in the retardant layer in the pro-portions of Aquacoat~ ECD 30 (solids):HPMC of 9:1, coated to a 6% weight gain, the dissolution rate of the formula-tion was increased to 100% theophylline dissolved in 12 hours. The results are set forth in detail in Table 35 below:

Hours: 1 2 4 8 12 Cured Initial 17 38 68 97 100 Storage at 37C/80%RH for 3 months 13 31 60 94 100 Controlled Release Hydromorphone HC1 8 ma Formulations - Once-a-Day Preparation Examples 15 - 17 were prepared as follows:

1. Drug Loading. Hydromorphone beads were prepared by dissolving hydromorphone HC1 in water, adding Opadry Y-5-1442, light pink (a product commercially available from Colorcon, West Point, PA, which contains hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol and D&C Red No. 30 aluminum lake) and mixing for about 1 hour to obtain a 20% w/w suspension.

This suspension was then sprayed onto Nu-Pareil 18/20 mesh beads using a Wurster insert.

2. First Overcoat. The loaded hydromorphone beads were then overcoated with a 5o w/w gain of Opadry Light Pink using a Wurster insert. This overcoat was applied as . a protective coating and provides immediate release hydromorphone beads. See Table 36 below:

Table 36 - Immediate Release Beads 2o Processing Step Ingredient % mg per Unit Drug Loading Hydromorphone HC1- 4.7 4.0 Nu-Pareil 18/20 87.9 74.0 Opadry Lt Pink 2.4 2.0 First Overcoat Opadry Lt Pink 5.0 4.2 Total 100.0 84.2 mg 3. Retardant Coat. After the first overcoat, the hydromorphone beads were then coated with a retardant coat-ing of Aquacoat ECD 30 and Triethyl Citrate (a plasticizer) to a 5%, 10% and 15% weight gain (based on dry wt. of Aqua-coat). A Wurster insert was used to apply the coating suspensions.
4. Curing. After the application of the retardant coating, the beads were placed in a 60°C oven containing a tray of water to maintain about a 100% relative humidity level. All three batches were allowed to cure for 72 hours.

5. Second Overcoat. The cured beads we re removed from the humid oven, and dried in a fluid bed dryer for about one hour. The dried cured beads were then overcoated with a 5% w/w gain of Opadry Light P ink using a Wurster insert. This overcoat was applied as a protective coating.

The final formulations for beads havi ng 5%, %, and 10 15%

Aquacoat coatings are set forth in Tables 38 and 37, 39 below, respectively:

Table 37 - Beads with 5% Coating Processing Step Ingredient % ma per Unit Drug Loading Hydromorphone HCl 4.2 4.0 Nu-Pareil 18/20 78.8 74.0 Opadry Lt Pink 2.1 2.0 First Overcoat Opadry Lt Pink 4.5 4.2 Retardant Coat Aquacoat ECD '30 (dry wt.) 4.5 4.2 Triethyl Citrate 0.9 0.8 Second Overcoat Opadry Lt Pink 5.0 4.7 Total 100.0 93.9 mg Table 38 - Beads with 10% Coating Processing Step Ingredient % m a per Unit Drug Loading Hydromorphone HC1 4.0 4.0 Nu-Pareil 18/20 74.5 74.0 Opadry Lt Pink 2.0 2.0 First Overcoat Opadry Lt Pink 4.2 4.2 Retardant Coat Aquacoat ECD 30 (dry wt.) 8.5 8.4 Triethyl Citrate 1.7 1.7 Second Overcoat Opadry Lt Pink 5.1 5.0 Total 100.0 99.3 mg Table 39 Beads with 15% Coating Processing Step Ingredient % mg per Unit Drug Loading Hydromorphone HC1 3.8 4.0 Nu-Pareil 18/20 70.8 74.0 Opadry Lt Pink 1.9 2.0 First Overcoat Opadry Lt Pink 4.0 4.2 Retardant Coat Aqu acoat ECD 30 (dry wt.) 12.1 12.6 Triethyl Citrate 2.4 2.5 Second Overcoat Opadry Lt Pink 5.0 5.2 Total 100.0 104.5 mg 7. Encapsulation. The hydromorphone beads were then filled into hard gelatin capsules to a total of 8 mg Hydro-morphone HC1 per capsule using the following combinations:
Example 15: All beads have 5% Aquacoat coating;
Example 16: 75% beads having 10% Aquacoat coating and 25% immediate release beads;
Example 17: 75% beads having 15% Aquacoat coating and 25% immediate release beads.
Dissolution studies were conducted on the Aquacoat-coated hydromorphone beads of Examples 15-17 both initially and after 28 days. The results are set forth in Tables 40-42 below:
Table 40 - Dissolution 15 of Example Hours Time 1 2 4 8 12 18 24 Initial 33.8 54.6 71.2 85.7 92.997.3 99.9 28 days 34.0 53.1 70.8 86.1 93.198.2 100.7 Table 41 - Dissolution 16 of Example Hours Time 1 2 4 8 12 18 24 Initial 31.6 43.4 59.2 72.3 79.285.7 90.3 28 days 32.3 43.7 59.2 72.6 80.786.8 91.5 Table 42 - Dissolution of Example 17 Hours Time 1 2 4 8 12 18 24 Initial 29.3 37.2 52.1 66.4 73.9 80.4 85.4 5 28 days 31.1 37.0 51.4 66.0 73.7 81.3 86.2 Stability studies of the Aquacoat-coated hydromorphone beads of Examples 15 -17, as set forth above, show the initial dissolutions to be the same as dissolutions done on 10 samples placed at 37°C/80% RH conditions.

In Examples 18 - 20, a single dose six-way randomized cross-over study (one week wash-out) was conducted in 12 15 patients and compared to the results obtained with an equivalent dose of an immediate release preparation. Blood samples were taken initially, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 48 hours after administration in order to determine plasma levels.

20 Comparative Example 18A is 8 mg of a hydromorphone immedi-ate release formulation (two tablets of Dilaudid~ 4 mg tablets, commercially available from Knoll). Example 18 is an 8 mg dose of the encapsulated hydromorphone beads of Example 15. Example 19 is an 8 mg dose of the encapsulated 25 hydromorphone beads of Example 16. Example 20 is an 8 mg dose of the encapsulated hydromorphone beads of Example 17.

The results obtained for Comparative Example 18A are set forth in Figure 7. The results obtained for Example 18 are set forth in Figure 8. The results obtained for Example 30 19 are set forth in Figure 9. The results obtained for Example 20 are set forth in Figure 10. The results for Examples 18-20 are further set forth in Table 43 below, which provides data regarding area under the curve (bio-availability), the peak plasma concentration (Cmax), and the 35 time to reach peak plasma concentration (tmax) 2I25ga4 Product AUC Cmax Tmax Comparative Example 18A

2 Dilaudid Tablets 12427 3013 1.10 Example 18 6718 1070 2.58 Example 19 9933 1265 2.39 Example 20 8695 1138 0.88 Dilaudid is known to be effective for about 6 hours.
Blood levels for 8 mg Dilaudid at 6 hours were about 300 pg/ml hydromorphone. Therefore, a circulating concentra-tion of about 300 pg/ml should be an effective analgesic concentration in the blood.
The results obtained for Example 19 showed that at the 12th hour after administration, the blood levels of hydro morphone were over 500 pg/ml hydromorphone, and at the 24th hour after administration, the blood levels were well over 300 pg/ml. Therefore, this product is considered to be suitable for once a day administration.
Example 20, on the other hand, provided levels of over 300 pg/ml at the 12th hour after -administration, with levels of about 250 pg/ml at the 24th hour after admini-stration. Therefore, this product is considered to be suitable for twice a day administration, and possibly suitable for once a day administration.

In Example 21, morphine sulfate controlled release beads with a 5% w/w controlled release of which 7% of the coating includes HPMC as a pore former are prepared as follows.
First, a starting bead product is manufactured using a rotor processing technique. The base morphine sulfate bead formula to which the controlled release coating is applied to is set forth in Table 44 below:

57 a 21 2590 Table 44 Ingredient Amt/Unit Morphine Sulfate Powder 30 mg Lactose Hydrous Impalpable 42.5 mg PVP 2.5 mg Sugar Beads 18/20 125 mg Purified Water qs Opadrv Red YS-1-1841 10.5 ma Total 210.5 mg The controlled release coating is manufactured as follows. The pore former Methocel E5T"~ Premium (HPMC), is dispersed and dissolved in enough purified water to yield a 2°s w/w solution.
An Aquacoat dispersion is plasticized with triethyl citrate for approximately 30 minutes. After 30 minutes the HPMC dispersion is mixed into the plasticized Aquacoat dispersion, and blended for an additional 15-30 minutes. A
load of the morphine sulfate beads is charged into a Uniglatt Wurster Insert equipped with a 1.2 mm fluid nozzle.
The beads are then filmcoated with the Aquacoat/HPMC
dispersion (in a ratio of 93:7) to a weight gain of 5%.
The controlled release coating formula used in Example 21 is set forth in Table 45 below:
Table 45 Ingredient Amt/Unit MorphineSulfate Base Beads 210.5 mg AquacoatECD 30 (solids) 9.8 mg MethocelE5 Premium 0.7 mg TriethylCitrate 2.1 mg PurifiedWater qs Opadry 11.7 mg Red PurifiedWater qs Total 234.8 mg B

21~59D4 After completion of the controlled release coating process, the coated beads are discharged from the Wurster Insert into a curing tray and cured in a temperature/

humidity chamber at 60C/80% RH for 72 hours. Upon com-pletion of this curing step, the beads are dried to a LOD

of 4% or less and are given a final overcoat of Opadry Red YS-1-1841 (15% w/w solution) using the Uniglatt Wurster Insert. The beads are then filled into hard gelatin cap-sules using a capsule filling machine to obtain the finished product.

The finished product is then subjected to dissolution testing via USP Apparatus II (paddle method), 100 rpm, 37C, 700 ml simulated gastric fluid (without enzyme) for one hour, and then 900 ml simulated gastric fluid (without enzymes) after first hour.

The finished product is also subjected to dissolution testing after being stored for 3 months and 6 months at room temperature; as well as under accelerated storage conditions (40C/75% RH) for one month, two months and three months. The results are set forth in Table 46 below:

Table 46 Morphine Sulfate 30 mg Capsules 5a Controlled Release Coating 93:7 Ratio Storage Morphine Conditions Sulfate & Testing 5H20 Dissolution (Hours) Time m ca 1 2 4 8 12 18 24 Initial 29.75 25.9 42.7 71.1 96.8 105.3 105.6 107.0 RT

3 months 29.63 25.0 41.2 68.2 93.0 102.7 6 months 29.64 22.8 40.4 65.7 91.5 102.9 40C/75% RH

1 month 29.33 21.9 39.1 65.9 92.9 103.0 2 months 29.76 23.1 39.2 67.4 93.3 103.3 3 months 29.16 21.5 37.6 67.5 92.8 109.2 As can be seen from the dissolution results provided ~in Table 46, the capsules of Example 21 provide a stable dissolution profile even after exposure to accelerated conditions for 3 months.

In Example 22, morphine sulfate controlled release beads with a controlled release coating of 5% w/w (includ-ing 5% HPMC as a pore former, by weight of the coating), is l0 prepared.

A batch of approximately 892.4 g of morphine sulfate controlled release beads is manufactured with a 5% w/w controlled release coating and a 5% HPMC overcoat. The morphine sulfate bead formula to which the controlled re-lease coating is applied are prepared as described in Example 21. Thereafter, the controlled release coating is prepared and applied to the beads. Further information concerning the formulation of Example 22 is provided in Table 47 below:

Table 47 Ingredient Amt/Unit Morphine Sulfate Base Beads 210.5 mg Aquacoat ECD 30 (solids) 10.0 mg Methocel E5 Premium 0.5 mg Triethyl Citrate 2.1 mg Purified Water qs Opadry Red YS-1-1841 11.7 mg Purified Water qs Total 234.8 mg The manufacturing process and curing and encapsulation technique used is the same for Example 22 as per Example 21, the difference being that the morphine sulfate beads are filmcoated with an Aquacoat/HPMC (95:5) dispersion in Example 22.

e_ 212904 The results of dissolution testing conducted in the same manner as per Example 21 are set forth in Table 48 below:
Table 48 5 Morphine Sulfate 30 mg Capsules 5% Controlled Release Coating 95:5 Ratio Storage Morphine Conditions Sulfate & Testing 5H20 Dissolution (Hours) 10 Time m ca 1 2 4 8 12 18 24 Initial 30.38 16.9 29.6 52.3 79.8 92.8 101.4 104.7 RT 30°C
3 months 30.20 14.5 28.2 50.4 77.2 90.3 6 months 30.3 15.7 28.9 49.7 78.6 92.1 15 40°C,/75% RH
1 month 29.84 15.9 27.1 47.7 73.8 87.4 2 months 30.72 15.5 27.4 49.6 76.6 89.0 3 months 29.95 13.9 27.4 49.8 76.6 88.9 20 As can be seen from the dissolution results provided in Table 48, the capsules of Example 22 provide a dissolu-tion which is slower than that of Example 21. The capsules once again provide a stable dissolution profile despite exposure to accelerated conditions.

In Example 23, morphine sulfate controlled release beads with a controlled release coating of 5~ w/w (in cluding 3o HPMC as a pore former, by weight of the coat ing), are prepared.
A batch of approximately 892.4 g of morphine sulfate controlled release beads is manufactured with a 5o w/w controlled release coating and a 5o HPMC overcoat. The morphine sulfate beads to which the controlled release coating was applied are prepared as described in Example 21. Thereafter, the controlled release coating is prepared and applied to the beads to a weight gain of 5%. Further information concerning the formulation of Example 23 is provided in Table 49 below:
Table 49 Ingredient Amt~Unit Morphine Sulfate Base Beads 210.5 mg Aquacoat ECD 30 (solids) 10.2 mg Methocel E5 Premium 0.3 mg Triethyl Citrate 2.1 mg Purified Water qs Opadry Red YS-1-1841 11.7 mg Purified Water gs Total 234.8 mg The manufacturing process and curing and encapsulation technique used is the same for Example 23 as per Example 21, the difference being that the beads are filmcoated with an Aquacoat/HPMC,(97:3) dispersion in Example 23.
The results of dissolution testing conducted in the same manner as per Example 21 are set forth in Table 50 below:
Table50 MSCR 30 mg 5% CCI (Ratio 97:3 ) sules of Cap Specifications Storage Morphine Conditions Sulfate & Testing 5H2o 30 Dissolution urs) (Ho Time m ca 1 2 4 8 12 18 Initial 17.8 28.4 46.7 73.1 86.0 99.0 RT 30C 60%RH 31.60 3 months 17.9 27.3 44.6 71.1 86.0 99.8 40C/75% RH 28.0 1 month 25.64 18.3 26.4 46.9 77.0 92.9 109.7 2 months 29.83 17.1 29.3 47.2 75.8 92.4 104.7 3 months 31.63 14.3 23.9 40.8 67.2 81.1 96.3 As can be seen from the dissolution results provided in Table 50, the capsules of Example 23 provide a dissolu-tion which is slower than that of Example 22. The capsules once again provide a stable dissolution profile despite exposure to accelerated conditions.

Human bioavailability studies were conducted to com pare the 30 mg morphine sulfate controlled release capsules produced in Examples 21 and 22 to a reference standard, MS
Contin 30 mg tablets, which are marketed commercially for twice-a-day administration. The study was a three-way crossover study using normal male volunteers with a one week wash-out period with the doses being administered under fasting conditions. Fifteen (15) volunteers com-pleted the study.
A summary of the results obtained in this study are set forth in Table 51 below:
Table 51 Measurement MS Contin Example 21 Example 22 AUC 89.31 96.24 93.85 Tmax 2 . 6 2 2 . 9 0 3 . 8 7 C",~x 10.09 7.02 5.89 PW@HH* 5.25 9.00 10.50 *Peak Width at Half-Height Figure 11 is a graphical representation of the in-vitro percent dissolved of each of the formulations (MS
Contin, Example 21 and Example 22). Figure 12 is a graphical representation of the blood levels obtained in the volunteers for each of the formulations.
Figure 13 is a plot of the blood level curve obtained with MS Contin to a theoretical blood level curve which would be obtained if two 30 mg morphine sulfate controlled release capsules of Example 22 (ratio of Aquacoat/HPMC is 212~90~

95:5) are administered simultaneously. The theoretical plot of Example 22 (wherein the blood level obtained with one capsule of Example 22 is doubles at each time point) indicate that the capsules of Example 22 appear suitable for administration to human patients on a once-a-day basis.
This is a most surprising result because the in-vitro dissolution tests appeared to indicate that the formulation would be suitable only for twice-a-day administration (see Figure 11 showing in-vitro dissolution curves).

From the data in Example 24, it was apparent that the capsules of Example 22 (in which the beads are coated with a 5% coating of Aquacoat (HPMC in a 95:5% ratio)) gave blood profiles that looked suitable for once-a-day admini-stration. However, the data indicated that with a slight decrease in the quantity of pore former (HPMC), an even better dosage formulation for a once-a-day product might be obtained. Therefore, a human bioavailability study was conducted using the capsule produced in Example 23 which contained a 3% pore former with the capsules of Example 22 and MS Contin 30 mg as the reference. In the same study the effect of dosing with food was also investigated.
Table 52 provides a summary of the results obtained.
Table 52 Study Group AUC T ,X C ax Ex. 24 (97:3 Fasted) 101 5.6 5.9 Ex. 28 (95:5 Fasted) 93 3.6 7.0 Ex. 24 (97:3 Fed) 96 7.8 5.9 MS Contin (Fasted) 103 2.3 13.0 -- ~ 27 2590 Figure 14 provides comparative in-vitro dissolution curves obtained with Example 23, Example 22 and MS ContinT"".
Figure 15 provides representative blood levels obtained after administration of Example 23 (both fed and fasted) versus MS Contin (fasted).
Figure 16 is a plot of the blood level curve obtained with MS Contin to a theoretical blood level curve which would be obtained if two 30 mg morphine sulfate controlled release capsules of Example 23 (ratio of Aquacoat/HPMC is 95:5) are administered simultaneously. The theoretical plot of Example 23 (wherein the blood level obtained with one capsule of Example 23 is doubled at each time point) indicate that the capsules of Example 23 appear suitable for administration to human patients on a once-a-day basis. This is a most surprising result because the in-vitro dissolution tests appeared to indicate that the formulation would be suitable only for twice-a-day administration (see Figure 11 showing in-vitro dissolution curves).

Controlled release acetaminophen (APAP) controlled release tablets are prepared in accordance with the present invention as follows. First, immediate release APAP cores are prepared by compressing CompapT"~ coarse L into tablet cores weighing approximately 555.6 mg. Compap coarse L
contains approximately 90% APAP, along with pharmaceutical grade excipients including a binder, disintegrant and lubricant, and is a directly compressible material commercially available from Mallinckrodt, Inc., St. Louis, MO. The APAP tablet cores include approximately 500 mg of APAP. The Compap coarse L is compressed using a rotary tablet press equipped with a 7/16" round, standard concave cup, plain, tooling. The cores were compressed at a theoretical weight of 555.6 mg and at a hardness of about 8-9 kg.
O !
:i 112590~~~
Next, the APAP tablet cores prepared above are coated with the controlled release coating of the present invention as follows. Methocel E5T"' premium is dispersed in three times its weight of hot purified water using a mixer.

5 Thereafter, purified water at ambient temperature is added and mixed for approximately 1 hour. The mixture is allowed to cool. The amount of the ambient temperature purified water added is calculated such that the final coating sus-pension will have a concentration of about 20% of solids 10 polymer and plasticizer.

In a separate container, triethyl citrate is mixed with Aquacoat ECD-30T"" for about 15 minutes. The Aquacoat/

triethyl citrate suspension is then added to the methocel dispersion and mixed thoroughly. The appropriate quantity of 15 APAP tablet cores are loaded into an Accella CotaTM coat-ing pan. The Aquacoat/triethyl citrate coating suspension is sprayed from an appropriate spray gun until a weight gain of 10% per tablet is attained.

Further information concerning the controlled release 20 coated APAP tablets is set forth in Table 53 below:

Table 53 Inctredients m tab APAP IR tablet cores 555.6 Aquacoat ECD-30 (solids) 27.78 25 Methocel E5 premium 27.78 Triethyl Citrate 11.11 Purified water gs Total: 622.27 30 After completion of the coating process, the coated tablets are discharged into a curing tray and cured in a temperature/ humidity chamber at 60°C/80% RH for 72 hours in order to obtain a stabilized controlled release formu-lation. In vitro dissolution is carried out in a simulated ~n 1 ;. , intestinal fluid at 37'C using the USP basket method at 100 RPM. The results are set forth in Table 54 below:
Table 54 Hour % APAP Dissolved 1 2.7 2 6.3 4 13.9 8 27.1 12 36.4 18 47.7 24 58.4 In Example 27, controlled release APAP tablets having a slower dissolution than those of Example 26 are prepared.
First, immediate release APAP tablet cores are pre pared in accordance with Example 26. Thereafter, APAP con-trolled release tablets are manufactured by coating the immediate release APAP tablet cores with a controlled re-lease coating obtained from an aqueous dispersion of ethyl-cellulose containing 50% HPMC as a pore former to a 15%
weight gain. The formula for the coated APAP tablet cores is set forth in Table 55 below:
Table 55 Ingredients mg/tab APAP IR tablet cores 555.6 Aquacoat ECD-30 (solids) 41.67 Methocel E5 premium 41.67 Triethyl Citrate 16.67 Purified water gs Total: 655.61 The method of manufacture of the coating suspension and its application to the cores are the same as set forth in Example 26. The coating suspension is applied until the requisite weight gain per tablet is attained. Thereafter, the coated tablets are cured in accordance with the proced-ures set forth with regard to Example 26. Next, in-vitro dissolution of the cured coated APAP controlled release formulation is carried out in the same manner as in Example 26. The results are set forth in Table 56 below:
Table 56 Hour % APAP Dissolved 1 2.3 2 5.3 4 10.6 8 20. 1 12 28.6 18 39.5 In Example 28, the release rate of the controlled re-lease APAP tablet formulation of Example 26 is increased by increasing the quantity of the pore former. In this Ex-ample, immediate release APAP tablet cores are prepared according to the manufacturing procedure set forth in Example 26. Thereafter, a controlled release coating com-prising an aqueous dispersion of ethylcellulose containing 60~ HPMC as a pore former is applied to the immediate re-lease APAP tablet cores.
Thereafter, the coating suspension is applied to the tablet cores in the manner set forth with regard to Example 26. The coating suspension is applied until the requisite weight gain per tablet is attained. Further information concerning the formulation of Example 28 is set forth in Table 57 below:

Table 57 Ingredients mqJtab APAP IR tablet cores 555.6 Aquacoat ECD-30 (solids) 22.224 Methocel E5 premium 33.336 Triethyl Citrate 11.112 Purified water QS .-Total: 622.272 Thereafter, the tablets of Example 28 are cured in the same manner as those of Example 26. In-vitro dissolution of the cured, coated tablets of Example 28 is set forth in Table 58 below:
Table 58 Hour ~ APAP Dissolved 1 3.1 2 22.4 ' 4 79.4 8 100.1 In Example 29, the dissolution rate of the tablets of Example 26 is increased by virtue of increasing the amount of pore former contained in the controlled release coating to 70%.
In Example 29, immediate release tablet cores are pre-pared in accordance with the procedure set forth with re-gard to Example 26. Thereafter, the immediate release cores are coated with a controlled release coating comprising an aqueous dispersion of ethylcellulose containing 70°s HPMC as the pore former. The coating is contained until a weight gain of 10% is achieved. The formula for the coated APAP
tablet cores is set forth in Table 59 below:

212 ~~~4 Table 59 I~redients m tab APAP IR tablet cores 555.6 Aquacoat ECD-30 (solids) 16.668 Methocel E5 premium 38,892 Triethyl Citrate 11.112 Purified water gs Total: 622.272 Thereafter, the coated tablets are cured under the same conditions set forth in Example 26. In vitro dissolu-tion is then carried out as set forth in Example 26. The results are set forth in Table 60 below:
Table 60 Hour % APAP Dissolved 1 97.2 2 102.8 The examples provided above are not meant to be exclu-sive. Many other variations of the present invention would be obvious to those skilled in the art.

Claims (96)

1. A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said active agent selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 1000 for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions.
2. The formulation of claim 1, wherein said substrate is coated to a weight gain from 2% to 30%.
3. The formulation of claim 1, wherein said substrate is a bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.
4. The formulation of claim 1, wherein said substrate is a tablet core.
5. The formulation of claim 3, wherein said beads are coated with said aqueous dispersion of ethylcellulose to a weight gain from 2% to 25%.
6. The formulation of claim 5, wherein said coating is cured for a time period from 48 to 72 hours, until said endpoint is reached.
7. The formulation of claim 6, wherein said coating is cured at a relative humidity of 85%.
8. A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, wherein said coating further includes a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.
9. The formulation of claim 8, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semipermeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former and mixtures of any of the foregoing.
10. The formulation of claim 8, wherein said coating comprises from 0.1% to 70% of said release-modifying agent.
11. The formulation of claim 8, wherein said coating comprises from 0.1% to 50% of said release-modifying agent.
12. The formulation of claim 8, wherein said coating comprises from 0.1% to 25% of said release-modifying agent.
13. The formulation of claim 8, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates and mixtures of any of the foregoing.
14. The formulation of claim 1, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40°C. and a relative humidity of 75% for 3 months.
15. The formulation of claim 1, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions which are deemed appropriate by the United States Food & Drug Administration for the purpose of according expiration dating for said formulation.
16. The formulation of claim 8, wherein said cured coated substrate, when subjected to in-vitro dissolution after exposure to said accelerated conditions, releases an amount of said active agent which does not vary at any given time point by more than 20% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage.
17. The formulation of claim 1, wherein a portion or the amount of said active agent included in said formulation is incorporated into a coating on said substrate.
18. A method for obtaining a controlled release formulation of an active agent, comprising:
preparing a solid substrate comprising an active agent, said active agent being selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant;
coating said substrate with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions.
19. The method of claim 18, wherein said coated particles are cured for 48 to 72 hours, until said endpoint is reached.
20. The method of claim 18, further comprising coating said substrate to a weight gain from 2% to 25%.
21. A method for obtaining a controlled release formulation of an active agent, comprising:
preparing a solid substrate comprising an active agent;
coating said substrate with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and with a release-modifying agent in an amount effective to modify the rate of release of said active agent from said coated substrate;
curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37°C. and at a relative humidity of 80%.
22. The method of claim 21, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.
23. The method of claim 21, wherein said coating comprises from 0.1% to 70% of said release-modifying agent.
24. The method of claim 21, wherein said coating comprises from 0.1% to 5% of said release-modifying agent.
25. The method of claim 21, wherein said coating comprises from 0.1% to 25% of said release-modifying agent.
26. The method of claim 21, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
27. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid, until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 20% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing, wherein said active agent is selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.
28. The formulation of claim 27, wherein said cured, coated substrate provides the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 37°C and at a relative humidity of 80%.
29. The formulation of claim 27, wherein said cured, coated substrate provides the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 40°C. and at a relative humidity of 75%.
30. The formulation of claim 27, wherein said substrate is coated to a weight gain from 2% to 25%.
31. The formulation of claim 27, wherein said substrate is a bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.
32. The formulation of claim 27, wherein said substrate is a tablet core.
33. The formulation of claim 27, wherein said coating is cured for a time period from 48 to 72 hours, until said endpoint is reached.
34. The formulation of claim 27, wherein said coating is cured at a relative humidity of 85%.
35. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid, until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than 20% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing, wherein said coating further includes a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.
36. The formulation of claim 35, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semipermeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.
37. The formulation of claim 36, wherein said coating comprises from 0.1% to 70% of said release-modifying agent.
38. The formulation of claim 36, wherein said coating comprises from 0.1% to 50% of said release-modifying agent.
39. The formulation of claim 36, wherein said coating comprises from 0.1% to 25% of said release-modifying agent.
40. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid, until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than 20% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing, wherein said coated substrate includes at least one passageway through said coating which modifies the release of said active agent.
41. The formulation of claim 37, wherein said release-modifying agent comprises hydroxypropylmethylcellulose.
42. A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a therapeutic effect when said formulation is orally administered, said substrate being coated with a cured aqueous dispersion of plasticized ethylcellulose to a weight gain from 2% to 25%, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37°C. and at a relative humidity of 80% and said coating being sufficient to obtain a controlled release of said active agent when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37°C. from 5% to 42.5% (by wt) active agent released after 1 hour, from 15% to 55% (by wt) active agent released after 2 hours, from 17% to 75% (by wt) active agent released after 4 hours and from 20% to 90% (by wt) active agent released after 8 hours, said coated substrate, when subjected to accelerated storage conditions of at least one month at 40°C./75% RH, releasing an amount of said therapeutically active agent upon in-vitro dissolution which does not vary at any given time point by more than 20% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage.
43. The formulation of claim 42, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastrointestinals, anti-emetics, anti-epileptics, vasodilators, antitussive agents, expectorants, anti-asthmatics, hormones, diuretics, antihypotensives, antihypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
44. The formulation of claim 43, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.
45. The formulation of claim 43, wherein said substrate is selected from the group consisting of a tablet core and a pharmaceutically acceptable bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when said capsule is orally administered.
46. The formulation of claim 44, which is a once-a-day formulation.
47. The formulation of claim 43, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.
48. The formulation of claim 47, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semipermeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former and mixtures of any of the foregoing.
49. The formulation of claim 47, wherein said coating comprises from 0.1% to 70% of said release-modifying agent.
50. The formulation of claim 47, wherein said coating comprises from 0.1% to 50% of said release-modifying agent.
51. The formulation of claim 47, wherein said coating comprises from 0.1% to 25% of said release-modifying agent.
52. The formulation of claim 47, wherein said release-modifying agent comprises up to 10% of said coating, by weight.
53. The formulation of claim 42, wherein said coated substrate includes at least one passageway through said coating which modifies the release of said systemically active therapeutic agent.
54. The formulation of claim 47, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
55. The formulation of claim 42, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40°C. and a relative humidity of 75% for 3 months.
56. The formulation of claim 42, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions which are deemed appropriate by the United States Food & Drug Administration for the purpose of according expiration dating for said formulation.
57. The formulation of claim 42, wherein a portion of the amount of said active agent included in said formulation is incorporated into a coating on said substrate.
58. The formulation of claim 42, which provides therapeutically effective blood levels of said systemically active therapeutic agent when administered orally for 12 hours.
59. The formulation of claim 42, which provides therapeutically effective blood levels of said systemically active therapeutic agent when administered orally for 24 hours.
60. The formulation of claim 44, which provides therapeutically effective blood levels of said opioid analgesic when administered orally for 24 hours.
61. The use of a controlled release oral solid dosage form comprising a cured coated substrate to provide an effective blood level of a therapeutically active agent in a patient for a period of time of from 12 to 24 hours, the solid dosage form being prepared by:
preparing a solid substrate comprising a sufficient amount of a therapeutically active agent to provide therapeutically effective blood levels in the patient for 12 to 24 hours;
coating said substrate with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid; and curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said coating including a release-modifying agent in said aqueous dispersion of ethylcellulose in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.
62. The use of claim 61, wherein said coated substrate is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100%.
63. The use of claim 61, wherein said substrate comprises pharmaceutically acceptable inert beads, further comprising coating said therapeutically active agent onto the surface of said inert beads, and preparing said oral dosage form by placing a sufficient quantity of cured coated beads into a capsule.
64. The use of claim 61, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.
65. The use of claim 63, wherein said coated substrate is cured for 48 to 72 hours, until said endpoint is reached.
66. The use of claim 61, further comprising coating said substrate to a weight gain from 2% to 25%.
67. The use of claim 61, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, antitussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
68. The use of claim 61, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.
69. The use of claim 67, wherein said oral solid dosage form provides a desired therapeutic effect for 24 hours.
70. The use of claim 68, wherein said oral solid dosage form provides a desired therapeutic effect for 24 hours.
71. The use of claim 61, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.
72. The use of claim 61, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
73. An oral solid dosage form comprising:
a solid substrate comprising an effective amount of a therapeutically active agent, a coating covering said substrate, said coating comprising a cured aqueous dispersion of ethylcellulose in an amount required to provide effective blood levels of said therapeutically active agent for at least about 12 hours, said coating including from 0.1% to 70% by weight of a release-modifying agent, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37°C. and at a relative humidity of 80% and said coated substrate upon in-vitro dissolution testing providing a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40°C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, which is not wider than 20% of total active agent released at any point of time.
74. The oral solid dosage form of claim 73, wherein said coating includes at least one passageway running from an exterior surface of said coating to said solid substrate, said passageway causing a desired modification of the release rate of said therapeutically active agent when said oral solid dosage form is exposed to aqueous fluids or gastrointestinal fluid.
75. The oral solid dosage form of claim 73, wherein the band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40°C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, does not differ by more than 15%.
76. The oral solid dosage form of claim 73, wherein the band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40°C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, does not differ by more than 10%.
77. The oral solid dosage form of claim 73 which provides effective blood levels of said therapeutically active agent for 24 hours.
78. The dosage form of claim 73, wherein said substrate comprises a pharmaceutically acceptable inert bead upon which said therapeutically active agent is coated and a plurality of said coated beads are placed in a capsule to provide said effective amount of said therapeutically active agent.
79. The oral solid dosage form of claim 73, which is a coated tablet.
80. The controlled release dosage form of claim 73, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.
81. A controlled release dosage form, comprising:
a solid substrate comprising an effective amount of a therapeutically active agent, said solid substrate being coated with a cured aqueous dispersion of ethylcellulose in an amount effective to provide a controlled release of said therapeutically active agent when said coated substrate is exposed to gastrointestinal fluid, said coating including a release-modifying agent in an amount effective to modify the rate of release of said therapeutically active agent from said coated substrate, said coated substrate when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40°C./75% RH releasing an amount of said therapeutically active agent which does not vary at any given dissolution time point by more than 20% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from 60% to 100% for 48 to 72 hours.
82. The controlled release dosage form of claim 81 which is administered once a day.
83. The controlled release dosage form of claim 81 which is administered twice a day.
84. The controlled release dosage form of claim 81, wherein said substrate comprises a pharmaceutically acceptable inert bead upon which said therapeutically active agent is coated and a plurality of said coated beads are placed in a capsule to provide said effective amount of said therapeutically active agent.
85. The controlled release dosage form of claim 81 which is a coated tablet.
86. The controlled release dosage form of claim 81, wherein said substrate is coated with said aqueous dispersion of ethylcellulose to a weight gain from 2%
to 25%.
87. The controlled release dosage form of claim 82, wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.
88. The formulation of claim 27, wherein said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than 15% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.
89. The formulation of claim 27, wherein said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than 10% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.
90. The use of an orally administered oral solid dosage form of claim 73, to treat a human patient.
91. The use of an orally administered controlled release dosage form of claim 81, to treat a human patient.
92. The use of an orally administered solid controlled release oral dosage formulation of claim 42, to treat a human patient.
93. The use of an orally administered formulation of claim 8, to treat a human patient.
94. The formulation of claim 8, wherein said active agent is selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.
95. The formulation of claim 21, wherein said active agent is selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.
96. The formulation of claim 35, wherein said active agent is selected from the group consisting of a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.
CA002125904A 1993-06-23 1994-06-15 Controlled release formulations coated with aqueous dispersions of ethylcellulose Expired - Lifetime CA2125904C (en)

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