JPH08175977A - Release control type pharmaceutical preparation coated with aqueous dispersion of acrylic polymer and its preparation - Google Patents

Abstract

PURPOSE: To obtain the subject formulation capable of keeping stable dissolution rate of an active agent even after a prescribed storage time by coating a solid substrate comprising a therapeutically active agent with an aqueous dispersion of a plastic acrylic polymer. CONSTITUTION: This formulation is obtained by coating a solid substrate comprising a therapeutically active agent such as hydrohormone with an aqueous dispersion of an acrylic polymer plasticized so as to release the therapeutic agent in controlled state when exposed to gastric juice. The coated substrate releases a definite amount of the therapeutically active agent without changing the dissolution rate even at any point of time of the given dissolution time in an amount of about >=20% based on total amount of the therapeutically active agent released, compared with in vitro dissolution carried out before storage when the in vitro dissolution is carried out after exposure to accelerated storage conditions of >=1 month at 37 deg.C and 75% relative humidity.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a controlled release preparation which enables a stable dissolution rate of an active agent contained therein even after a predetermined storage period.

[0002]

Prior Art and Invention Problems to be Solved An important point of manufacture, regulatory inspection and approval of all formulations is their long-term stability. The stability data obtained for a particular dosage formulation 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, that is, when stored in special containers and environments. To do. Stability testing requirements include, for example, the Good Manufacturing Practices (Goo
d manufacturing Practices (GMPs)), USP
(the USP), as well as regulatory requirements in countries where market approval of dosing formulations is required. In the United States, testing and ultimately market claims, drugs or drug formulations are subject to New Drug Applications.
g Application (NDA), Abbreviated New Drug Application (AND
A)) or the Investigational New Drug Application
replication (IND)).

The drugs used in sustained release dosage formulations often present particular problems with regard to their physical stability during storage. For example, the waxes used in such formulations are known to undergo physical alterations on standing for a long time, thus stabilizing them or preventing alterations from occurring. In order to take precautionary measures. Fats and waxy substances are
It is known to crystallize in an unstable state when used in the purified state, resulting in unpredictable fluctuations in efficacy during stability testing during manufacture and during storage. There is.

It is known that in many cases some strategy is taken to obtain a stabilized controlled release formulation,
The individual reagents are in stable form before they are introduced into the product, the treatment does not change this state, additional additives are added to reduce instability,
There are methods such as by inducing individual drugs in the dosage formulation to reach a stable state before the product is finally complete.

It is also recognized that the water content of the product affects the stability of the product. Changes in the hydration level of polymerizable films such as ethyl cellulose can alter water permeability and drug efficacy. Binders such as gum arabic are also known to have poor solubility when exposed to moisture and heat. However,
The water content of the product can be controlled quite successfully by control in the processing method and proper packaging of the product.

Certain cellulose derivatives, zein, acrylics, waxes, higher fatty acid alcohols and hydrophobic polymers such as polylactic acid and polyglycolic acid have been used in the prior art to develop controlled release dosage formulations. There is. Tablets, capsules, suppositories, spheres, beads,
Alternatively, methods of using those polymers to develop controlled release dosage formulations such as microspheres are described by incorporating the agents into a controlled release matrix or by incorporating them into a controlled release coating of the dosage formulation. For example, it may be used with drugs. It is known in the art that hydrophobic coatings are applied from solution, suspension or dry, respectively. Many polymers used in controlled release coatings have poor solubility in water, so they are usually dissolved in organic solvents and the solution is applied to individual drug formulations (eg beads or tablets). And is applied by evaporating off the solvent.

Aqueous dispersions of hydrophobic polymers have been used in the prior art to coat pharmaceutical dosage formulations for aesthetic reasons such as film coating of tablets or beads, or for flavoring purposes. However, these dosage formulations are used for immediate release administration of the active agent contained in the dosage formulation.

The use of organic solvents in preparing hydrophobic coatings is generally considered unfavorable due to the inherent problems of flammability, carcinogenicity, environmental concerns, cost and safety. However, it is considered in the art to provide controlled release coatings derived from aqueous dispersions of hydrophobic materials such as acrylic polymers.

Many formulations based on hydrophobic coatings derived from aqueous dispersions have been experimentally prepared for controlled release of active agents, but such formulations have been found to suffer from stability problems. It has not been proven commercially viable.
Aqueous polymerizable dispersions are used to produce stable controlled release dosage formulations, but the production of this formulation is rather delayed by using a coating of aqueous polymerizable dispersions. Only possible by other methods such as introducing it into the matrix of the formulation.

When coated using an aqueous polymerizable dispersion to obtain the desired release pattern of the active agent over a period of hours or longer, in the art, the dissolution release pattern is dependent on aging. It is known to change, for example, the final coated product is stored for a period of time during which it is exposed to elevated temperature and / or humidity above ambient conditions.

Recently, this is due to Mandy et al.
al., Drug Devel. and Indus. Phar., 17 (15) 2135.
-2143 (1991)), in which the release rate of the drug by varying temperature and relative humidity, ethyl cellulose and PEG (2: 1 ratio; total coverage = 3% w / w). ), Ethylcellulose and Eudragit L (trade name) (2: 1 ratio; total coating = 3% w / w) and Eudragit RL (Eudragit).
The effect of storage of theophylline small tablet film coated with RL (trade name) (coating amount = 1.5% by weight / weight) has been reported. Samples were stored isothermally at 28 ° C, 35 ° C and 45 ° C, with relative humidity (RH) maintained between 55-60% and 45 ° C, 55%.
RH for 24 hours, then 28 ° C and 20% RH for 24 hours,
And cycled at 5 ° C. and 10% RH for 24 hours, and after repeating the cycle, conditions were 24 hours at 45 ° C. and 55% RH and 28 ° C. and 0% R, respectively.
It changes to H and is performed. The aging treatment resulting from storage under forced conditions as described above prevented dissolution regardless of the nature of the polymerizable film. The greatest reduction in release rate is said to occur within the first 21 days (isothermal storage) after painting.

This instability problem is known not to exist when the polymer is applied in organic solvent solution, but is prepared from such aqueous acrylic polymer dispersions which are stable under various storage conditions. It was impossible to obtain a controlled release preparation using the coated film.

In particular, Rohm Pharma (Rohm Pharma Gmb
Controlled release coatings of commercially available acrylic polymers, such as those marketed under the trade name Eudragit by H) are recommended curing conditions, 45
It is known that it is not stable when it is cured at 2 ° C. for 2 hours.

[0014]

SUMMARY OF THE INVENTION It is therefore an object of the present invention to coat a substrate consisting of active agents such as therapeutically active agents, bactericides, detergents, disinfectants and fertilizers with an aqueous dispersion of a hydrophobic acrylic polymer. Accelerated by
) To provide a controlled release formulation that results in a stable dissolution or other release pattern of the active agent when placed in the environment of use, even when exposed to various storage conditions, including storage conditions. .

Another object of the invention consists of a controlled release tablet consisting of a plurality of inert beads of active agent and a core containing the active agent, the beads or tablet core being an aqueous dispersion of a hydrophobic polymer. It is an object of the invention to provide a controlled-release formulation that is coated and that is reproducible even when exposed to accelerated storage conditions and that provides stable dissolution, as well as a method of making the same.

Yet another object of the invention is "forced".
Or when comparing the dissolution patterns of the formulations after exposure to various storage conditions, including accelerated storage conditions, at no point during dissolution does not exceed about 15% of the total amount of active agent released. It is intended to provide a controlled release formulation consisting of a matrix containing an active agent coated with an aqueous dispersion of a hydrophobic polymer that provides a band range for in-vitro dissolution.

It is a further object of the present invention to provide controlled release such that the shelf life of a dissolution is approved by a government regulatory agency such as the US Food and Drug Administration (FDA) even when exposed to accelerated storage conditions. To provide a controlled release formulation as obtained by coating a formulation with an aqueous dispersion of a hydrophobic polymer, such as an acrylic polymer, which is a coating that provides a stable dissolution of the active agent contained in the formulation. Is.

[0018] For their and other purposes, some of them consist of a matrix which, in the environment of use, consists of an amount of active agent sufficient to give the desired effect, the matrix being exposed to the ambient liquid of the formulation. Coated with an aqueous dispersion of a plasticized pharmaceutically acceptable hydrophobic polymer in an amount sufficient to provide controlled release of the active agent when exposed to accelerated storage conditions. A temperature above the glass transition temperature of the aqueous dispersion of plasticized acrylic polymer for a sufficient time to reach the end of cure reaching a coated substrate that provides a stable dissolution of the active agent that does not change after exposure. It is achieved by the present invention for a controlled release formulation which has been cured with. The endpoint may be, for example, the dissolution pattern of the formulation immediately after curing, at a temperature of 37 ° C and 80% relative humidity, or
It is determined by comparing the dissolution pattern of the formulation after exposure to accelerated storage conditions of 1-3 months at a temperature of ° C and 75% relative humidity. In a preferred embodiment, the substrate is coated with a build up weight of about 2% to about 25%.

In another preferred embodiment, the coated substrate is subjected to in-vitro dissolution for any period of time as compared to in-vitro dissolution of the coated substrate after curing. Also, the active agent is released in an invariable amount along the dissolution curve which exceeds about 15% of the total amount of the active agent released.

In yet another embodiment, the hardened formulation provides a stable dissolution of the active agent unchanged after exposure to accelerated storage conditions, the stable dissolution being the expiry date of the formulation. About the United States Food and Drug Administration
States Food & Drug Administration).

Another preferred embodiment relates to a controlled release dosage formulation comprising a substrate coated with an effective amount of an aqueous dispersion of an acrylic polymer which provides controlled release of the active agent, the formulation comprising accelerated storage conditions. After exposure to the active ingredient, the therapeutic activity was unchanged at up to about 20% of the total amount of therapeutically active agent released at any time, compared to in-vitro lysis performed prior to storage. It releases the agent. The acrylic polymer preferably has a permeability that is unaffected by the pH conditions prevailing in the gastrointestinal tract.

In another embodiment, the coated substrate is accelerated in the in-vitro dissolution test at any time when compared to the dissolution pattern prior to exposure to accelerated storage conditions. It provides a band area no wider than about 20% after exposure to different storage conditions.

The active agent is a systemically active therapeutic agent, local active therapeutic agent, disinfectant, cleaning agent, fragrance, fertilizer, deodorant, dye, animal repellent, insect repellent, insecticide, herbicide, fungicide, And used in a wide range of applications including plant growth stimulants,
It is not limited to these.

The present invention further relates to a solid, controlled release oral dosage form which comprises a matrix containing a systemically active therapeutic agent in an amount sufficient to provide the desired therapeutic effect when orally administered. The substrate is coated with an aqueous dispersion of a plasticized acrylic polymer, USP Paddle
100 rpm with 900 ml of aqueous buffer (pH between 1.6 and 7.2) at 37 ° C by the method or basket method
Measured at about 0% to about 42.5% (by weight) of active agent after 1 hour, about 5% to about 60% (by weight) of active agent after 2 hours, and about 4% after about 4 hours. Sufficient controlled release of the active agent is obtained such that it releases 15% to about 75% (weight) of the active agent and after 8 hours releases 20% to about 90% (weight) of the active agent. It is effective for a time longer than the glass transition temperature of the aqueous dispersion of the plasticized acrylic polymer. The coated substrate provides a stable release when the rate of release of the active agent after exposing the coated substrate to accelerated conditions is compared to the release rate obtained immediately after curing.
The dosage formulation preferably provides a therapeutic cure of about 24 hours. The invention further relates to a method of making a dosage formulation.

The present invention also provides that when a solid substrate comprising an activator is prepared and the coated substrate is exposed to an ambient liquid,
The substrate was coated with a sufficient amount of an aqueous dispersion of a plasticized acrylic polymer to obtain the desired controlled release of the active agent, and the coated substrate was subjected to accelerated storage conditions. After curing the coated substrate at a temperature above the glass transition temperature of the aqueous dispersion of plasticized acrylic polymer until the end of curing, which gives a stable and unchanged solubility of the activator. To a controlled release formulation of the active agent.

The present invention further relates to a method of treating a patient with the oral solid dosage formulation described above. In this method, the invention further comprises for therapeutically administering to the patient an oral solid dosage formulation comprising a hardened coated matrix to obtain the desired therapeutic effect for about 12 to about 24 hours. . In a particularly preferred embodiment, the oral solid dosage formulations of the invention provide the desired therapeutic effect for about 24 hours.

In one preferred embodiment of the invention,
Hydrophobic acrylic polymers consist of copolymers of acrylic and methacrylic acid esters, which have a permeability that is not affected by the pH conditions prevailing in the gastrointestinal tract. Preferably, these copolymers also occur as salts and are involved in the permeability of the lacquer material,
It contains a small amount of quaternary ammonium groups.

The present invention has inherent safety issues (flammability,
Prior art, including the avoidance of the use of organic solvents with carcinogenicity, environmental concerns, costs, general safety, and the increased safety that would lead to extended shelf life and shelf life Provides many benefits over, but is not limited to.

[0029]

DETAILED DESCRIPTION OF THE INVENTION In the present invention, an aqueous dispersion of a hydrophobic acrylic polymer used as a coating is a tablet, a sphere (or a bead), a small sphere to obtain a desired controlled release of an active agent. Coated substrates such as agents, seeds, pellets, ion exchange resin beads, and other multiparticulate systems are used. The granules, spheres, pellets or the like produced according to the present invention can be present in capsules or in other suitable dosage formulations. The tablet of the present invention has a spherical shape,
It may be any suitable shape such as an oval, a biconcave, a hemisphere, a square, a rectangle, a polygon such as a pentagon, and the like.

About 2 to about 25 to obtain a controlled release formulation
It is generally necessary to overcoat the substrate comprising the activator with a sufficient amount of an aqueous dispersion of a hydrophobic acrylic polymer so that a% deposit weight level is obtained, the overcoat being, for example, the activator. Depending on the physical properties of the and the desired release rate, the addition of the plasticizer into the aqueous dispersion and the method of its introduction, it may be more or less. In one embodiment of the invention, the controlled release coating is, for example, 50
It may be applied to the substrate with a weight coverage of up to%.

The cured, coated substrates of the present invention are stable when stored at room temperature in ambient humidity (eg, long term (actual time) testing) for extended periods of time, and when tested in accelerated storage conditions. Gives a good dissolution pattern (eg release of the active agent into the environment of use).

For the purposes of the present invention, the terms "stable dissolution pattern" and "end-of-cure" refer to the environment of use even after exposure of the cured coated substrate to accelerated storage conditions. When placed, it is defined to mean that the cured coated substrate reproducibly gives an unchanged release of the active agent. Those skilled in the art will recognize by the term "unchanged" that it means any change in the release of the active agent from the cured coated matrix formulation that is considered insignificant with respect to the desired effect. Has been done.
For pharmaceutical formulations, stability refers to the expiration date of the formulation, for example, the Food & Drug Administration in the United States.
It is inspected by a standard organization such as ministration (FDA).

By the phrase "acceleraled storage conditions" is meant, for example, elevated temperature and / or elevated humidity storage conditions. Preferably, the term "accelerated storage conditions" refers to storage conditions that are undertaken to obtain regulatory approval (eg, US FDA approval) and expiration date for the final drug formulation.

The term "expiration date" refers to the time period during which a packaged batch of product (eg, cured coated substrate) will remain within specifications if stored under the conditions described. And should not be used after that deadline.

The term "ambient fluid" refers to the formulation in aqueous solution (eg, in-vitro dissolution), simulated gastric fluid (eg, USP basket method (ie, 37 ° C., 100 RP).
M, first time 700 ml gastric juice, with or without enzyme, pH 1.2, then changed to pH 7.5 at 900 ml) or gastrointestinal fluid (in-vivo) Means that.

In the present invention, the “band region” (band ran)
ge) or "bandwidth" refers to the dissolution pattern obtained by the formulation at the end of manufacture of the coated product (before storage) and the dissolution pattern obtained after subjecting the coated product to accelerated storage conditions. When compared to the pattern, shown as the total (absolute) change in percentage of active agent released from the coated product at any time of dissolution along the dissolution curve,
Defined as the difference in in-vitro dissolution measurements of controlled release formulations.

In general, the length of study and the storage test conditions required by a regulatory agency such as the FDA for pharmaceutical formulations are sufficient to cover storage, shipping, and subsequent use. Acceptable storage test conditions may vary depending on the characteristics of the product. For example, a temperature sensitive drug substance is considered a long term test storage temperature,
Instead, it should be stored under low temperature conditions. In such cases, it is generally accepted that accelerated testing should exceed this specified long-term storage temperature at a temperature of at least 15 ° C and at the same time be carried out under suitable relative humidity conditions at that temperature. Is accepted.

The generally accepted accelerated test adopted in the FDA guidelines is that the drug product (eg, in its container and packaging) is at 37% (1985 FDA) at 80% relative humidity (RH). Guideline). If the product withstands, for example, 3 months under those conditions (chemical stability, dissolution, and physical properties), then the drug product is, for example, 2
Annual expiration date is given. This accelerated test is also currently considered acceptable when conducted at 40 ° C. (FDA 1987 guidelines) at 75% RH. Recently, a long-term storage test of pharmaceutical preparations was conducted at 25 ° C ± 2 ° C.
It has been proposed to do this with a minimum time limit of 12 months, not exceeding% RH ± 5%. In addition, accelerated testing
For pharmaceutical formulations, at 40 ° C ± 2 ° C and 75% RH ± 5%,
It is also proposed to do it with a minimum time limit of 6 months. All of the accelerated test criteria mentioned above, and others, are considered equivalent for purposes of this invention in terms of stability measurements and cure endpoint measurements. All of the accelerated test conditions described above and others known to those of skill in the art provide an acceptable basis for determining the cure (stability) endpoint of the controlled release formulations of the present invention. .

The controlled release coating of the present invention comprises an aqueous dispersion of a hydrophobic (water insoluble) acrylic polymer. In certain preferred embodiments, the hydrophobic acrylic polymer coatings of the present invention have a solubility and permeability that is independent of the pH of the fluid present in the environment of use. In the case of oral solid dosage formulations, the hydrophobic acrylic polymer of the present invention is
It has a solubility and permeability that is independent of the pH value. The hydrophobic acrylic polymer used in the formulations of the present invention is derived from acrylic acid or its derivatives. Examples of the acrylic acid derivative include respective esters of acrylic acid and methacrylic acid, and alkyl esters of acrylic acid and methacrylic acid. In certain preferred embodiments, each alkyl ester of acrylic acid and methacrylic acid has about 1 to about 8 carbon atoms in the alkyl group. Monomers used in the polymer coatings of the present invention also include styrene and its homologs, vinyl acetate, and vinyl esters such as vinyl chloride. Generally, the monomers that form hydrophobic, water-insoluble polymers are non-ionic. The term "nonionic monomer" in the present invention means not only a monomer having no ionic group (such as alkali metal carboxylate or sulfonate or quaternary ammonium group) in the molecule, but also a base or acid. Also included are monomers that cannot form groups. In many cases, the hydrophobic acrylic polymer coating composition may include other monomers.

Those skilled in the art will appreciate that the hardness and extensibility of the paint coating and the lowest temperature at which the coating can be formed from the aqueous dispersion are affected by the particular monomer contained in the hydrophobic acrylic polymer used in the present invention. I understand that. It is known that lower alkyl esters of methacrylic acid form relatively stiff homopolymers, and acrylic acid esters and higher alkyl esters of methacrylic acid give relatively soft homopolymers. Alkyl or aryl groups with more than 4 carbon atoms have a hydrophobizing effect, which reduces the swelling capacity and the diffusion permeability.

In one preferred embodiment of the invention,
Arlyl polymers also include one or more polymerizable, permeability-increasing compounds that permit release of the active agent contained within the coating at the desired diffusion rate, regardless of the predominant pH value. contains. In the case of oral solid dosage formulations, a compound that enhances permeability provides the active agent with the same diffusion rate in each region of the digestive (gastrointestinal) tract (regardless of pH) during passage of the dosage formulation. After being allowed to be released and extracted substantially completely, the coating of the invention is excreted without decomposition.

In one preferred embodiment, the permeability-increasing compound comprises at least one polymerizable quaternary ammonium compound. Such compounds have broad p
In the H region, for example, it is a strong base that exists as a stable salt throughout all physiological pH regions and is readily soluble in water. The nature of the quaternary ammonium compound present in the copolymerizable reagent, and especially its amount, is an important factor affecting diffusivity.

Suitable polymerizable quaternary ammonium compounds used in the coatings (coatings) of the present invention generally have the general formula:

[0044]

Embedded image

Wherein R is hydrogen or methyl, A is oxygen or NH, B is a linear or branched alkyl or cycloaliphatic hydrocarbon, preferably from about 2 to about 8 carbon atoms. And R ₁ , R ₂ and R ₃ are independently
R ₁ and R ₂ which are the same or different alkyl or aralkyl, more particularly lower alkyl having from about 1 to about 4 carbon atoms, or benzyl, or together with a quaternary nitrogen atom. Is piperidinium or morpholinium, and X ^Θ is a cation,
Preference is given to cations of inorganic acids, especially chlorides, sulphates or methosulfates.

Particularly preferred examples of the polymerizable quaternary ammonium compound include quaternary acrylic acid and methacrylic acid.
Examples thereof include quaternized aminoalkyl esters and aminoalkylamides, such as β-methacryloxyethyltrimethylammonium methosulfate, β-acryloxypropyltrimethylammonium chloride and trimethylaminomethylmethacrylamide methosulfate.
The quaternary ammonium atom can form part of a heterocycle, as in methacryloxyethylmethylmorpholinium chloride or its corresponding piperidinium salt, or contains a heteroatom, such as a polyglycol ether group. As a group, it can be bonded to an acrylic acid group or a methacrylic acid group. Further suitable polymerizable quaternary ammonium compounds include quaternized vinyl substituted nitrogen heterocycles such as methylvinylpyridinium salts, quaternized aminocarboxylic acid vinyl esters, and styryltrialkylammonium salts.

Other polymerizable quaternary ammonium compounds useful in the present invention include acryl- and methacryl-oxyethyl trimethyl ammonium chloride and methosulfate, benzyl dimethyl ammonium methyl methacrylate chloride, diethyl methyl ammonium ethyl acrylate and methacrylate meth. Sulphate,
N-trimethylammoniumpropyl methacrylamide chloride, and N-trimethylammonium-2,2-
Dimethylpropyl-1-methacrylate chloride may be mentioned.

Further information regarding suitable hydrophobic acrylic polymers can be found in US Pat. Nos. 3,520,970 and 4,737,357.
No. (both assigned to Rohm GmbH), both incorporated herein by reference.

Those skilled in the art may substitute other polymerizable, permeability-increasing compounds in the present invention with the quaternary ammonium compounds described above. Such additional polymerizable, permeability-increasing compounds are intended to be within the scope of the following claims.

In one preferred embodiment, the hydrophobic acrylic polymer used in the coating of the present invention comprises acrylic and methacrylic acid esters and a small amount of a fourth carboxylic acid ester.
It is composed of a copolymer with a primary ammonium group. Such copolymers are often referred to as ammoniomethacrylate copolymers and are available from Rohm Pharma.
Ruma AG), for example, under the trade name of Eudragit. Ammonio methacrylate copolymers are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with small amounts of quaternary ammonium groups.

In one particularly preferred embodiment of the invention, the acrylic coatings are each Eudragit RL 3
0 D (Eudragit RL 30 D) and Eudragit RS 30
It is derived from a mixture of two acrylic resin lacquers used in the form of an aqueous dispersion, marketed by Rohm Pharma under the trade name D (Eudragit RS 30 D). Eudragit RL 30 D and Eudragit RS 30 D are copolymers of acrylic acid ester and methacrylic acid ester with a small amount of quaternary ammonium group, and the molar ratio of the ammonium group to the residual neutral (meth) acrylic acid ester is , 20 in Eudragit RL 30 D and 1:40 in Eudragit RS 30 D. The average molecular weight is about 15
It is 0,000. The code notation represents the permeation performance of those reagents, where RL is high permeability and RS is low permeability. The Eudragit RL / RS mixture is insoluble in water and is a digestible fluid. However, the coating formed therefrom is swellable and permeable to aqueous solutions and digestive fluids.

The Eudragit RL / RS dispersions of the present invention may be mixed together in any desired ratio to ultimately obtain a controlled release formulation having the desired dissolution pattern. The desired controlled release formulation is, for example, 100%
Eudragit RL, 50% Eudragit RL and 50
% Eudragit RS and 10% Eudragit R
Obtained from a delayed film coating derived from L and 90% Eudragit RS as well as 100% Eudragit RS.

The hydrophobic acrylic polymer used in the present invention can be prepared by any method known in the art, but in the presence of an initiator that will form free radicals dissolved in the monomer mixture. Or a method of performing solution or precipitation polymerization in an organic solvent, and then isolating the polymer thus formed from the solvent.

The hydrophobic acrylic polymer coating of the present invention may contain a hydrophilic monomer whose solubility does not depend on pH. Examples include acrylamide and methacrylamide, hydroxyalkyl esters of acrylic acid and methacrylic acid, and vinylpyrrolidone. When using such materials, the amount is small, up to 20% by weight of the copolymer. It may also contain small amounts of ionic monomers such as acrylic acid or methacrylic acid or amino monomers on which the quaternized monomers are based.

In another embodiment of the invention, the hydrophobic acrylic polymer coating is an anionic polymer synthesized from methacrylic acid and methyl methacrylate,
It may further contain a polymer whose permeability is pH-dependent. Such polymers are available in Eudragit L and Eudragit S.
Rohm Pharma Gm
bH). The ratio of free carboxyl groups to ester is 1: 1 for Eudragit L and 1: 2 for Eudragit S. Eudragit L is insoluble in acid and pure water, but its permeability increases when the pH exceeds 5.0. Eudragit S also has a pH
It is the same except that when it exceeds 7, the permeability is increased. The hydrophobic acrylic polymer coating contains dimethylaminoethyl methacrylate and a polymer whose properties are cationic based on neutral methacrylic acid esters (such as Eudragit E commercially available from Rohm Pharma). May be. The hydrophobic acrylic polymer coating of the present invention further comprises a loam
Eudragit NE (Eu
poly (meta) such as dragit NE) (NE = neutral ester)
It may contain a neutral polymer based on acrylic acid. The Eudragit NE 30D lacquer coating is a water-insoluble digestible fluid, but permeable and swellable.

The dissolution pattern of any formulation provided by the present invention can be altered by varying the relative amounts of the different acrylic resin lacquers contained in the coating. In addition, the permeability (and dissolution pattern) of the resulting coating can also be changed by changing the molar ratio of the neutral (meth) acrylic acid ester compound that increases the polymerizable permeability (for example, a quaternary ammonium compound). Can be changed.

The release of the active agent from the controlled release formulations of the present invention may be inorganic or organic and contains substances capable of dissolving, extracting or filtering from the coating in the environment of use. It is further influenced, ie adjusted to the desired rate, by one or more pore-forming agents. By exposing the fluid to the operating environment,
Pore formers are, for example, dissolved to form grooves or pores that are filled with environmental fluid.

For example, the pore-forming agent may consist of one or more water-soluble hydrophilic polymers to modify the release characteristics of the formulation. Examples of suitable hydrophilic polymers include hydroxypropyl methylcellulose,
Cellulose esters and protein inducers are mentioned. Of those polymers, hydroxyalkyl cellulose and carboxyalkyl cellulose are particularly preferable as the cellulose ester. As the synthetic water-soluble polymer, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide and the like are used, and water-soluble polydexrose such as pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose and sorbitol. , Saccharides, and polysaccharides are also used. In one preferred embodiment of the present invention the hydrophilic polymer is hydroxypropyl methylcellulose.

Other examples of the pore-forming agent include lithium carbonate, sodium chloride, sodium bromide, potassium chloride,
Examples thereof include alkali metal salts such as potassium sulfate, potassium phosphate, sodium acetate and sodium citrate. The pore-forming solids are Carbowaxes (trade name, Carbowaxes),
It is a polymer that dissolves in the usage environment such as Carbopol (trade name, Carbopol). The pore-forming agent contains diol, polyol, polyhydric alcohol, polyalkylene glycol, polyglycol, poly (α-ω) alkylene diol and the like.

The semipermeable polymer may be incorporated into the controlled release coating as a pore-forming agent to modify the release characteristics of the formulation. Such semipermeable polymers include:
For example, cellulose acrylate, acetate, and other semipermeable polymers as disclosed in US Pat. No. 4,285,987 (incorporated herein by reference), as well as US Pat. Nos. 3,173,876, 3,276,586, 3,541,005
Nos. 3,541,006 and 3,546,142 (incorporated herein by reference) and include selectively permeable polymers formed by the coprecipitation method of polycations and polyanions.

Other pore-forming agents useful in the formulations of the present invention include starch, modified starch, and starch derivatives; xanthan gum, alginic acid, other alginates,
Bentonite, vegan, agar, guar, locust bean gum, gum arabic, quince psyllium (psylliu
m), flaxseed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin and other rubbers; crosslinked polyvinylpyrrolidone; potassium polymethacrylate, carrageenan, κ-carrageenan, λ-carrageenan, karaya gum , Ion-exchange resins such as biosynthetic rubber, and the like. Other pore-forming agents include materials useful for forming microporous thin films in the environment of use, for example, polycarbonates consisting of linear polyesters of carbonic acid with repeating carbonate groups in the polymer chain; bisphenols. , Microporous poly (vinyl chloride), microporous polyamide, microporous modacrylic copolymer,
Microporous styrene-acrylic and its copolymers, porous polysulfones, poly (vinylidene) halides, polychloroethers, acetal polymers, polyethers produced by esterification of dicarboxylic acids or anhydrides with alkylene polyols, poly ( Alkylene sulfide), phenolic resin, polyester, asymmetric porous polymer, crosslinked olefin polymer, hydrophilic micropore homopolymer, copolymer with reduced bulk density or intercopolymer,
And other similar substances, poly (urethane), crosslinked chain extended poly (urethane), poly (imide), poly (benzimidazole), collodion, regenerated protein, semi-solid crosslinked poly (vinylpyrrolidone), etc. , But not limited thereto.

Generally, the amount of the pore-forming agent contained in the controlled-release coating of the present invention is about 0.1% to about 80% by weight based on the total amount of the hydrophobic acrylic polymer and the pore-forming agent.

The controlled release coating of the present invention may include outlet means comprising at least one passage, hole or the like.
The passageway is described in U.S. Pat.Nos. 3,845,770, 3,916,889, and
No. 4,063,064 and No. 4,088,864, all of which are incorporated herein by reference. The passages are circular, triangular, square, oval,
It can have any shape, such as an irregular shape. The passageway, instead of or in addition to containing a permeability-enhancing compound, a hydrophilic monomer, a pH-sensitive polymer, and / or a pore-forming agent, to obtain release of the active agent contained in the formulation, May be included.

In one embodiment of the present invention, the hydrophobic polymer contained in the aqueous polymer coating dispersion is water-insoluble (such as a copolymer of acrylic and methacrylic acid esters containing no quaternary ammonium compound). The release of the active agent is substantially controlled only through the presence of one or more passageways through the coating.

Examples of suitable controlled release formulations according to the present invention include the USP paddle or basket method at 37 ° C. in 900 ml of aqueous buffer (pH between 1.6 and 7.2) at 100 rpm. In addition, the dissolution rate of the administered preparation in vitro is about 0% to about 1 hour after 1 hour for a 12-hour preparation (administered twice a day).
Releases 42.5% (by weight) of therapeutically active agent, about 25 hours later
% To about 55% (by weight) is released and after 4 hours about 45% to about 75%
% (Weight) is released and after 6 hours about 55% (weight)
It gives the value of releasing more. Other examples of suitable controlled release formulations according to the present invention include US
900 ml at 37 ℃ by P paddle method or basket method
100 in the aqueous buffer solution (pH between 1.6 and 7.2)
In vitro (in virt
The dissolution rate in o) is, for example, 24 hours formulation (1 day per day).
Dose), about 1% to about 42.5% by weight of the active agent is released after 1 hour, about 5% to about 60% by weight of the active agent is released after 2 hours, and about 15% after about 15 hours. % To about 75% (by weight) of active agent is released and after 8 hours about 20% to about 90%.
% (By weight) of active agent is released. These examples of acceptable dissolution rates relate to certain preferred embodiments of the invention in which the formulation is an oral solid dosage formulation, and are not intended to be limited in any way.

The coated preparation of the present invention is smooth and precise,
It is possible to support pigments and other coating additives,
Non-toxic, inert and non-greasy. It is possible to produce a strong and continuous film.

The acrylic coating used in the present invention preferably contains an effective amount of a suitable plasticizer. This is because the use of plasticizers further improves the physical life of the coating. For example, the use of plasticizers improves the elasticity of the coating and reduces the film forming temperature of the dispersion. The plasticization of acrylic resin is so-called
It is achieved by either "internal plasticization" or "external plasticization".

Internal plasticization is usually directly related to the molecular modification of the polymer in its manufacturing process, eg copolymerization, modification and / or substitution of functional groups, adjustment of the number of side chains, or polymer length. Adjustment of the height. Such techniques typically cannot be performed with coating solution formulations.

External plasticization is the addition of substances to the membrane solution, which achieves the required changes in the membrane performance of the dry coating.

The suitability of a plasticizer depends on its affinity or solubility for the polymer and its ability to inhibit the adhesion of the polymer to the polymer. Such activity imparts the desired flexibility by softening the rigidity of the molecule. Generally, the amount of plasticizer contained in the coating solution is based on the concentration of the film forming agent, eg, most often from about 1 to about.
50% by weight film former. The concentration of plasticizer, however, can only be determined properly after careful experimentation with the particular coating solvent and method of application.

Most preferably, about 20% plasticizer is included in the aqueous dispersion of acrylic polymer.

An important parameter for determining the appropriate plasticizer for a polymer is the glass transition temperature (Tg) of the polymer. The glass transition point is the temperature or temperature range in which there is a fundamental change in the physical properties of the polymer. This change does not indicate a change in state, rather it is a change in the macromolecular mobility of the polymer. If it is lower than Tg,
The mobility of polymer chains is severely limited. Therefore,
For a given polymer, if its Tg is above room temperature, the polymer behaves like glass, is not stiff, flexible, but rather brittle, and its properties are somewhat limited in coating applications. This is because the coated dosage form may be subject to a certain amount of external stress.

Introducing a suitable plasticizer into the polymer matrix can effectively reduce the Tg so that under ambient conditions the coating becomes softer, more flexible and often tough and mechanical. It becomes more possible to resist stress.

Other aspects of suitable plasticizers include the plasticizer's ability to function as a good "swelling agent" for acrylics.

Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to, triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. . Eudragit RL / RS (trade name)
Other plasticizers that have been found suitable for increasing the flexibility of coatings formed from acrylic films such as lacquer solutions include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, And triacetin. Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of acrylic polymers of this invention.

It is further known that the addition of small amounts of talc reduces the tendency of the aqueous dispersion to stick during processing and acts as a polish.

The dissolution pattern of the final product is, for example,
Modified by increasing or decreasing the thickness of the retarder coating, by changing the method of adding the plasticizer to the acrylic resin, and / or by changing other aspects of the manufacturing process, for example. can do.

In one preferred embodiment of the invention,
Controlled release dosage formulations include pharmaceutically acceptable beads containing the active ingredient coated with a controlled release coating (eg,
Spherical). The term spherical is known in the pharmaceutical art and means, for example, spherical particles having a particle size of between 0.2 mm and 2.5 mm, in particular between 0.5 mm and 2 mm. Suitable commercially available such beads are:
There is nu pariel 18/20 beads.

The plurality of hardened coated (stabilized) controlled release beads may then be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release when ingested and in contact with gastric fluid. Good.

When the acrylic resin dispersion is used to coat inert pharmaceutical beads, such as nu parei 18/20 mesh beads, a plurality of the resulting stabilized solid controlled release beads are obtained. , Then ingested and placed in a gelatin capsule in an amount sufficient to provide an effective controlled release when contacted with gastric juices. In this embodiment, the beads coated with the therapeutically active agent are
For example, a therapeutically active agent is prepared by dissolving it in water and then spraying the solution onto a substrate such as Nupariel 18/20 mesh beads using a Wurster insert. If desired, additional components may be added prior to coating the beads, to help adhere the active agent to the beads, and / or to color the solution, and the like. For example, hydroxypropyl methylcellulose, with or without colorants,
The containing product is added to the solution and mixed (eg, about 1 hour) before the solution is applied to the beads. The resulting coated substrate may then optionally be overcoated with a barrier layer in the beads of this example to separate the therapeutically active agent from the acrylic coating. Examples of suitable barrier layers include those composed of hydroxypropyl methylcellulose. However, any film forming agent known in the art may be used. The blocking reagent is preferably one that does not affect the dissolution rate of the final product.

The beads of activator (and desired protective coating) may then be overcoated with an acrylic polymer. The acrylic polymer dispersion preferably further contains an effective amount of a plasticizer such as triethyl citrate. Eudragit RS30S and Eudragit RL include pre-prepared dispersions of acrylic resins, such as various commercial forms of Eudragit.
30D is mentioned.

The coating solution of the present invention preferably contains, in addition to the film-forming agent, the plasticizer and the solvent system (ie water), a colorant for the sake of elegance and product distinction. Alternatively or in addition to the overcoat, the solution of therapeutically active agent may be colored. Suitable ingredients that impart color to the formulation include color pigments such as titanium dioxide and iron oxide pigments. The introduction of pigments, however, has an increased effect of impeding the coating. Alternatively, any suitable method of coloring the formulations of the present invention may be used.

A plasticizing coating of an acrylic polymer (and optionally with a permeability-increasing compound and / or a pore-forming agent) is applied onto a substrate of therapeutically active agent by any suitable spraying device known in the art. May be applied by spraying. In the preferred method, a Wurster fluidized bed system is used in which an air jet injected from below fluidizes the cored material and provides drying while the acrylic polymer coating is being sprayed. A sufficient amount of coating to obtain a predetermined controlled release of the therapeutically active agent when the coated substrate is exposed to an aqueous solution, such as gastric juice, is determined by the physical properties of the therapeutically active agent, plasticity, and plasticity. Taking into consideration the method of introducing the agent,
It is preferably applied. After applying with acrylic resin,
A further overcoat of a film forming agent such as Opadry may be optionally applied to the beads. This overcoating is done to substantially reduce bead aggregation, if at all.

The coated beads, tablets, etc. are then hardened to obtain a stabilized release rate of the therapeutically active agent.

Traditionally, curing is carried out on Eudragit-coated formulations after application in a fluidized bed at 45 ° C. for 2 hours. Such a standard cure is recommended by Rohm Pharma. This is because the 20% level of solids exceeds the glass transition temperature of Eudragit RS 30 D plasticized with triethyl citrate. This recommended cure does not stabilize the dissolution pattern of the formulation on storage as described in the examples.

According to the invention, the curing step is carried out at a temperature above the Tg of the coating formulation of the coating substrate, eg beads,
The coating formulation is then allowed to cure until it reaches an end point, which gives a dissolution pattern that is virtually unaffected by exposure to elevated temperature and / or humidity storage conditions. In general,
The curing time is about 24 hours or longer, and the curing temperature is, for example, about 45 ° C. It has further been discovered in the present invention that it is not necessary to place the coated substrate at a humidity level above atmospheric conditions during the curing process to achieve a stabilized end product.

One possible mechanism for the change in the dissolution pattern of prior art products cured by standard methods is that they continue to cure during storage, resulting in a substantially constant product. It never reaches a stabilized endpoint giving a dissolution pattern of In contrast, the cured products of the present invention provide a release rate of the therapeutically active agent that is substantially unaffected during storage by increasing temperature and humidity.

In a preferred embodiment of the invention, the stabilized product is obtained by curing the coated substrate in the oven at a temperature above the Tg of the plasticized acrylic polymer for the required time. The optimum temperature and time values for a particular formulation are determined empirically.

In one embodiment of the invention, the stabilized product is obtained by oven curing at a temperature of about 45 ° C. for a period of about 24 to about 48 hours. In one embodiment, the product is preferably cured, for example, for about 36 hours. In one preferred embodiment, the product is cured for about 48 hours. It is believed that certain products coated with the controlled release coatings of the present invention require cure times greater than 48 hours, for example 60 hours or more. Those skilled in the art will appreciate that the curing conditions will be influenced by the particular drug introduced into the formulation, as well as by the controlled release coating thickness, and by the size of the substrate (eg, tablets compared to beads, etc.). It has recognized.

It is specifically contemplated that the time required to cure to the above endpoints may in fact be longer or shorter than the above times. Such cure times that achieve the intended results of stabilized formulations are included in the claims above. Furthermore, one of ordinary skill in the art will appreciate that the aqueous dispersion coated substrates of the present invention may be cured by other methods to reach an endpoint that provides a stable dissolution pattern for the coated substrate. . Additional curing methods (such as sonication) that achieve the intended result of the stabilized formulation are also considered to be within the scope of the above claims.

The end point of cure is the dissolution pattern (hereinafter hereafter) of the cured coated substrate (eg, "substrate") immediately after curing.
"Initial dissolution pattern") and the dissolution pattern of the formulation after exposure to accelerated storage conditions. Generally, the end point of curing is, for example,
37 ° C / 80% RH or 40 ° C / 75% RH for 1 month,
It is determined by comparing the dissolution pattern of the formulation after exposure to accelerated storage conditions with the initial dissolution pattern. However, the cure endpoint continues to expose the cured coating formulation to accelerated storage conditions for additional periods of time, and further, for example, 2 months and / or 3
Further confirmation may be made by comparing the dissolution pattern of the formulation after exposure for a month with the initial dissolution pattern obtained.

In one preferred embodiment of the invention where the cured coated substrate is a pharmaceutical formulation, the endpoint of cure is the dissolution curve obtained after exposing the data points to, for example, 1-3 months at accelerated conditions. The in-virt (in-virt
It shows the release of active agent unchanged at any given time up to about 15% of the total amount of active agent released when compared to dissolution in o). Such in-vitro dissolution curve differences are referred to in the art as, for example, 15% "band area" or "bandwidth". Generally, in vitro (in-v
If the total amount of active agent released changes, for example, not more than about 20%, after exposure to accelerated dissolution and accelerated conditions in itro), the formulation may be administered by a government such as the US FDA. It is considered that the regulatory body may grant permission if stability issues and effective dates are taken into consideration. Acceptable band areas are determined on a case-by-case basis by the FDA, and any band area for a particular drug that may be considered acceptable to such government regulatory agencies,
It is considered to be within the scope of the above claims. In a preferred embodiment, the band region mentioned above is not more than 10% of the total amount of active agent released. In a more preferred embodiment, the band region is no more than 7% of the total amount of active agent released. In the examples described below, the band area is often less than 5%.

When the controlled release coating of the present invention is applied to a tablet, the tablet core (eg, matrix) is aligned with any pharmaceutically acceptable inert pharmaceutical filler (diluent) material. Active agent, sucrose, dextrose,
Examples include lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, and mixtures thereof, but are not limited thereto. Also, an effective amount of a generally acceptable pharmaceutical lubricant including calcium or magnesium soap may be added as an excipient for the reagents described above prior to compression of the tablet core reagent. Most preferred is magnesium stearate in an amount of about 0.2-5% by weight in solid dosage form.

In one embodiment of the invention, the coated substrate is added to a controlled release coating consisting of an aqueous dispersion of a hydrophobic polymer, or an additional overcoat coated on the outer surface of the controlled release coating. Contains an amount of active agent.
This is done, for example, to give therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric juice,
It is desirable when a loading dose of therapeutically active agent is required.
In such cases, additional protective coatings (eg HP
MC) may be included to separate the immediate release coating from the controlled release coating.

The active agent contained in the controlled release preparation of the present invention includes a systemically active therapeutic agent, a locally active therapeutic agent, a disinfectant, a chemical impregnating agent, a detergent, a deodorant, an aromatic agent, a dye, and an animal. Examples include repellents, insect repellents, fertilizers, insecticides, herbicides, fungicides, plant growth stimulants and the like.

A wide range of therapeutically active agents can be used with the present invention. Therapeutically active agents (eg, pharmaceutical formulations) that can be used in the compositions of the present invention include both water-soluble and water-insoluble drugs. Examples of such therapeutically active agents are antihistamines (eg dimenhydrinate, diphenhydrinate, chlorpheniramine and chlorpheniramine d-maleate), analgesics (eg aspirin, codeine, morphine, dihydromorphine). , Oxycodone, etc., non-steroidal anti-inflammatory agents (eg naproxine, diclofenac, indomethacin, ibuprofen, sulindac), antiemetics (eg metoclopramide), antiepileptic agents (eg phenytoin, meprobamate and nitrezepam), vasodilators (eg , Nifedipine, papaverine, diltiazem and nicardilin), antitussives and expectorants (eg codeine phosphate), anti-asthma agents (eg theophylline), antacids, anticonvulsants (eg atropipine). , Scopolamine), antidiabetic agents (eg insulin), diuretics (eg ethacrynic acid, bendrofluazide), antihypertensive agents (eg propranolol, clonidine), antihypertensive agents (eg clonidine, methyldopa), qi Governmental dilators (eg albuterol), steroids (eg hydrocortisone, triamcinolone, prednisone), antibiotics (eg tetracycline), anti-hemorrhoids, sleeping pills, psychotropics, antidiarrheals, mucolytics, analgesics. Agents, decongestants, laxatives, vitamins, stimulants (including appetite suppressants of phenylpropanolamines), and their salts,
Hydrates and solvates are mentioned. The above list is not meant to be limiting.

In certain preferred embodiments, the therapeutically active agent is hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts, hydrates and solvates of any of the above.
It consists of a mixture or the like of any of the above.

In another preferred embodiment of the present invention,
The active agent is a locally active therapeutic agent and the environment of use is, for example, the gastrointestinal tract or body cavity, such as the oral cavity, periodontal pocket, surgical wound, rectum or vagina.

As the locally active agents, antibacterial agents (for example, amphotericin B, clotrimazole, nystatin, ketoconazole, miconazole, etc.), antibiotics (penicillin, cephalosporins, erythromycin, tetracycline, aminoglycoside, etc.), antiviral agents ( For example, acyclovir, idoxuridine, etc., fresh breath agent (eg, chlorophyll), antitussive (eg, dextromethorphan hydrochloride), anti-caries agent (eg, metal salt of fluoride, sodium monofluorophosphate, tin fluoride). , Fluorinated amines), painkillers (eg,
Methyl salicylate, salicylic acid, etc.), local anesthetics (eg benzocaine), oral preservatives (eg chlorohexidine and its salts, hexyl resorcinol,
Dequalinium chloride, cetylpyridinium chloride), anti-inflammatory agents (for example, dexamethasone, β-methasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (estriol), antiplaque agents (chlorohexidine and its salts, octenidine, And thymol, menthol, methisalicylate, eucalyptol), acidity reducing agents (eg buffering agents such as dibasic potassium phosphate, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), and teeth. Examples include desensitizing agents (eg, potassium nitrate). This list is not meant to be limiting.

In another preferred embodiment of the present invention,
The activator is a disinfectant such as a chlorine compound such as calcium hypochlorite, and the use environment is water surrounding the human body such as a recreation pool.

Yet another preferred embodiment of the present invention is
The active agent comprises at least one detergent, germicide, deodorant, surfactant, fragrance, fragrance, disinfectant, and / or dye, and the environment of use is, for example, a toilet or a toilet.

In yet another preferred embodiment of the present invention, the activator is a chemical impregnating agent such as fertilizer, animal repellent, insect repellent, insecticide, herbicide, fungicide, plant growth stimulant. Yes, and the environment of use is somewhere around the house, such as on the ground, trees, etc. Fertilizers include, for example, urea, urea-formaldehyde complex, potassium nitrate, potassium sulfate, potassium chloride, ammonium nitrate, ammonium nitrate, monoammonium phosphate, dibasic ammonium phosphate, ammonified perphosphate; iron, zinc, manganese, copper, Trace elements such as trace elements such as boron and molybdenum, and mixtures of any of the above. The fertilizer may be in granular form, for example. In those embodiments, the controlled release coating thickness will depend, among other things, on the desired rate and total time of release of the effective amount of the active agent. In some circumstances where a relatively long cure time is desired, the substrate may be coated with a relatively high build weight, eg, 50% or more. In other situations, it may be desirable to obtain the desired cure by utilizing coated substrates coated with different coat weights, or by including different components in the coating, so that the desired percentage of coated substrate is It provides a faster release of active agent as compared to other coated substrates, thereby providing a total release of active agent within the desired effective level, even over an extended period of time.

For example, if the coated substrate is a coated chlorine tablet to combat bacteria and algicidal contaminants such as swimming pools, the substrate may be from commercially available calcium hypochlorite, as well as trichloroisocyanuric acid, dichloro. It may consist of sodium cyanurate, lithium hypochlorite, powdered lime, and / or the presence or absence of others.

For example, the substrate may consist of about 98.5% by weight of commercial calcium hypochlorite and about 1.5% powdered lime. The substrate is also commercially available granular calcium hypochlorite, up to 20% by weight lime chloride, and about 69% effective as described in US Pat. No. 4,192,763, which is incorporated herein by reference. It may consist of 1% zinc stearate having a chlorine percentage and a mass of about 57 g and a diameter of about 40 mm. The substrate is then
The aqueous dispersion of plasticized hydrophobic polymer is coated at the desired deposit weight and the coated tablets are then, according to the invention,
Hardened until an end point is reached, which results in a hard coated tablet that gives a reproducibly stable dissolution pattern.

When the active agent comprises a composition suitable for cleaning and preventing toilet bowl soiling, the substrate may also contain known disinfectants such as calcium hypochlorite and / or trichloroisocyanuric acid. Good. The activator, on the other hand, consists of an alkali metal salt of dichlorocyanuric acid and chloride salts such as calcium chloride and barium chloride, as described in US Pat. No. 4,654,341, which is hereby incorporated by reference. Good.

Some possible examples of such products are 0.5 to 5% fragrance, 1 to 10% dye, 10 to
40% surfactant (it is nonionic, cationic,
A substrate, which may be anionic or zwitterionic surfactants) and other optional ingredients such as bactericides, disinfectants, processing aids, and other commonly contained ingredients known to those skilled in the art. It may be contained. Such active agents may be incorporated into a matrix consisting of tablets together with other known ingredients such as delaying agents, surfactants, flavors, dyes, and any required fillers.

The substrate is, for example, 1 g azul.
65% azure blue dye (a dye commercially available from Hilton David) and 1 g of Pluronic F-127 (a product obtained by the reaction of ethylene oxide with propylene oxide and ethylenediamine). Nonionic surfactant consisting of condensation products of Basuf Wyandoot Chemicals (BA
(Commercially available from SF-Wyandote Chemicals)), 38 g
Carvowasque 8000 (solid polyethylene glycol, molecular weight 8000; Union Carb
ide)), 40 g of Kemamide (Kema
mide) U (oleylamide surfactant; Witc
o) commercially available) and an optional fragrance (eg 0.5% by weight of citrus pine fragrance) are mixed homogeneously together, and then a mass of the above ingredients is mixed into noodles to form pellets. It may consist of pellets produced by forming into pellets by conventional methods such as sizing, extruding, extruding and cutting and punching. If desired, the pellets may contain suitable amounts of inorganic salts and one or more binders such as guar gum to set the pellets at the bottom of the tank. The pellets are then coated with an aqueous dispersion of plasticized hydrophobic polymer at a build up weight of about 2 to about 30%, depending on the desired rate of dissolution,
The coated pellets are then cured according to the present invention until the end point is reached, which is a cured coated pellet that gives a reproducible and stable dissolution pattern.

Other examples of substrates useful in the treatment of toilet flush water are described in US Pat.
It is composed of iodine holes such as povidone iodine as described in 5,043,090.

When the substrate comprises a fragrance, the fragrance may be a commercially available volatile compound such as an ester, ether, aldehyde, alcohol, unsaturated hydrocarbon, terpene, and other components known in the art. It may be any of the perfume oils mentioned.

When the activator comprises a composition suitable as a fertilizer, the activator is coated with an aqueous dispersion of a plasticized hydrophobic polymer to a deposit weight of about 2 to about 30% and then It may consist of granular urea, cured according to the invention. In the manufacture of urea granules, 70% solids concentration of urea in water is heated to remove substantially all water.
Molten urea was then injected as droplets into the air cooling tower,
There, crystalline urea is formed as hard granules or beads, which are then coated and cured according to the invention.

If the substrate consists of a botanical food preparation, the substrate can be in the form of pellets, spheres, particles or rods, together with soil fungicides such as formaldehyde and paraformaldehyde, with gibberellic acid. It may further contain a substance whose growth is accelerated.

FIG. 1 is a split screen scanning electron micrograph (SEM) of theophylline beads coated according to the present invention before curing. The left side magnification is 77 times and the right side magnification is 540 times. The coating is an aqueous dispersion of Eudragit. SEM shows clear particles of acrylic polymer in the coating. For example, cracks or pores in the coating cause the coating to pass into the environmental liquid from the underlying core, which contains the active agent.

FIG. 2 shows the beam of FIG. 1 with S after curing the beads in an oven at 45 ° C. for 48 hours.
EM. The left side magnification is 77 times and the right side magnification is 1100 times. The SEM in FIG. 2 exhibits an apparent morphological change in the coating on the bead surface. This cure is
It is considered to play an important role in stabilizing the dissolution pattern of the coated substrate.

When the controlled release coatings of the present invention are applied to tablets, the tablet core (eg, substrate) is the active agent, including, but not limited to, sucrose, dextrose, lactose, microcrystalline cellulose, xylitol. , Fructose, sorbitol, mixtures thereof and the like, and any pharmaceutically acceptable inert pharmaceutical filler (diluent) substance. Also, an effective amount of any of the commonly accepted pharmaceutical lubricants, including calcium or magnesium soaps, may be added as an excipient for the above ingredients prior to compression of the tablet core ingredients. Most preferably, magnesium stearate is added to the solid dosage formulation at about 0.2-
It is to be added at a weight of 5%.

A tablet coated with a sufficient amount of a coating of acrylic resin to achieve a controlled release formulation according to the invention is
It may be prepared and cured in a manner similar to that described above for the manufacture of beads. Those skilled in the art will recognize that the curing conditions that require a particular, elevated temperature, elevated humidity and time range to obtain a stabilized product will depend on the particular formulation. Will do.

[0116]

Detailed Description of the Preferred Embodiments The following examples describe various aspects of the invention. They do not limit the scope of the invention in any way.

Example 1 Production of hydromorphone beads Hydromorphone beads were dissolved in water with hydromorphone hydrochloride, and Opadry Y-5-1442, light pink (color-on, waist point, Pennsylvania (Co
Product commercially available from loron, Westpoint, Pennsylvania, hydroxypropyl methylcellulose (HPM
C), hydroxypropyl cellulose, titanium dioxide,
Polyethylene glycol and D & C Red No. 30 aluminum lake) were added at 20% w / w and mixed for about 1 hour, then Wurster inserts (Wurster inserts on nu pariel 18/20 mesh beads). inse
rt) and sprayed. The obtained product had the composition shown in Table 1 below.

[0118]

[Table 1]

Example 2 Coating with Retarder-No Curing Step In Example 2, the hydromorphone beads prepared in Example 1 were treated with Eudragit RS to give a 5% deposition weight as shown in Table 2. Overcoated with 30D. No drying was done to the end point.

[0120]

[Table 2]

The initial solubility of the hydromorphone beads was tested and then stored for 1 month under accelerated conditions of 37 ° C./80% RH (RH = relative humidity). After one month, the beads had aggregated.

The dissolution test was carried out by the USP basket method at 37 ° C. at 100 RPM with an initial time of 700 ml.
The gastric juice was treated at pH 1.2, then 900 ml, pH 7.5. Dissolution was carried out in open capsules containing the appropriate amount of beads in the container. The results are listed in Table 3 below.

[0123]

[Table 3]

The above results indicate that the hydromorphone hydrochloride dissolves slowly from the coated beads when the beads are placed under accelerated storage conditions.

Example 3 Protection of Retardant Coating To investigate whether the slow dissolution of the hydromorphone beads of Example 2 was due to stability issues between hydromorphone and the retarder, Example 3 In, Nupariel hydromorphone beads were prepared as in Example 1, then overcoated with 5% HPMC and tested without forming the retarder layer. Dissolution test
First, and after storage at 37 ° C. dried and 37 ° C./80% RH accelerated conditions.

The results of the dissolution test of Example 3 are shown in Table 4 below.

[0127]

[Table 4]

The results of Example 3 show that coated beads without a coating of retarder are stable.

To quantify the relative humidity under "drying conditions" in the oven, 60 in a desiccator filled with water.
The relative humidity in a ° C oven was quantified as follows. First, about 500 grams of purified water was poured into a plastic desiccator and a metal guard was inserted. A hygrometer / temperature indicator was placed on top of the guard, covered with a desiccator and left in an oven at 60 ° C for 24 hours. 24 hours later,
The relative humidity in the desiccator was 85%, but the temperature was still 60 ° C. When the hygrometer alone was placed in an oven at 60 ° C for 24 hours, the relative humidity was 9% at 60 ° C.

Example 4 Prior Art Curing (Recommended in the Literature) In Example 4, the hydromorphone beads prepared according to Example 3 were coated with Eudragit RS for a 5% build up weight. . After application of the coating, the beads were dried (cured) in a fluid bed drier for 2 hours at 45 ° C. This temperature is above the Tg of Eudragit RS 30 D plasticized with triethyl citrate at 20% solids level. Dissolution tests were performed initially and after drying at 37 ° C. and storage at 37 ° C./80% RH. The results are shown in Table 5 below.
Shown in

[0131]

[Table 5]

From the above results, the dissolution of hydromorphone from the tested beads changed drastically on storage and was recommended by the literature and the shortened curing step utilized in Example 4 showed stability / curing It was found that it did not help the problem.

Examples 5-7 Optimization of Curing and Ingredients for Delayed Coating The results obtained from Examples 2-4 show that dissolution of beads overcoated with retarder coating slows to a certain point, The above does not seem to change. However, dissolution at the endpoint achieved was too slow.

In Examples 5-7, additional tests were conducted to determine the processing conditions required during manufacture to cure the product to its endpoint dissolution.

In order to obtain a formulation with a more suitable dissolution curve, and more than a coating with less than 5% deposited weight, the more soluble Eudragit RL (methacrylic acid ester 1:20 quaternary ammonium group). ) Was included in the delay coat.

In Examples 5-7, hydromorphone beads were treated with 5% H 2 to protect the retarder coating from the environment.
The one manufactured in the same manner as in Example 4 was used except that it was overcoated with PMC. In Example 5, the retarder coating consisted of 100% Eudragit RL. Example 6
In, the retarder coating is 50% Eudragit RL and
Consists of 50% Eudragit RS. Finally, Example 7
In, the retarder coating is 10% Eudragit RL and
Consists of 90% Eudragit RS. Each of Examples 5-7 was coated for a 5% total deposit weight.

Each of the HPMC-protective coatings of Examples 5-7 was tested in the dry environment at 45 ° C. for 1, 2, 7, 10, 21 and 3.
Cured for 0 days and the dissolution test for each time was carried out as described in Example 2.

Only Example 7 showed the desired release pattern, the cure being complete after 1 day. The solubility studies of the products of Examples 5 and 6 are comparable to those obtained with the immediate release product, and even after curing the formulation, the amount / type of retarder used was similar to that of the drug. Not sufficient to prevent release (ie, about 100% of the drug is released in about 1 hour). Example 7 was further tested under accelerated conditions as follows. After curing for 21 days,
Place the sample of Example 7 in an oven at 37 ° C./80% RH,
Dissolution tests were carried out as described in Example 2 for 7 and 3
It went 0 days later. Representative dissolution pattern of Example 7 (3
The average results of the samples) are shown in Table 6 below.

[0139]

[Table 6]

The results shown in Table 6 show that the dissolution pattern after one month is comparable to the initial cured sample even after the sample was tested under accelerated conditions. . Therefore, after curing at 45 ° C for 24 hours, the methacrylic acid ester controlled release coating was substantially stabilized.

Examples 8-10 Optimization of Retarder Film Thickness In Examples 8-10, to determine the optimum weight of methacrylate polymer for use in the desired release pattern, and at 45 ° C. Additional tests were performed to determine the reproducibility and effectiveness of the 48 hour curing process in a dry environment. Three batches were made with different levels of methacrylic acid ester and cured in a 45 ° C. drying oven.

In Example 8, hydromorphone beads were prepared as in Example 3 as described in Table 7 below.

[0143]

[Table 7]

The hydromorphone beads were then further processed as in Example 5. In Example 7, the retarder coating was Eudragit RS and Eudragit RL.
Of 90:10 (5% w / w coating). The formulation of Example 7 is set forth in Table 8 below.

[0145]

[Table 8]

Examples 9 and 10 were prepared by the same procedure as in Example 7. In Example 9, the retarder coating had Eudragit RS and Eudragit RL 90:10 (8% w /
w coating). In Example 10, the retarder coating had Eudragit RS and Eudragit RL 90:10.
(12% w / w coating). The formulations for Examples 9 and 10 are set forth in Tables 9 and 10 below, respectively.

[0147]

[Table 9]

[0148]

[Table 10]

Examples 9 and 10 were each coated with a Eudragit controlled release coating and an HPMC 5% overcoat and then cured for 2 days in a 45 ° C. oven on a paper-coated dish. Solubility studies were conducted for Examples 8-10.

Initial dissolution pattern of Example 8 (after curing)
Was shown to be similar to that of Example 7 (the products of both Examples were both overcoated with a 5% w / w Eudragit coating). Example 8 after curing for 2 days
Sample at room temperature, 37 ℃ / 80% RH, 37 ℃ dry and 50
Subjected to further testing under accelerated conditions of ° C drying.
A representative dissolution pattern of Example 8 (average result for 3 samples) is shown in Table 11 below.

[0151]

[Table 11]

As is apparent from the dissolution results provided by Example 8, the dissolution pattern of the sample after 1 day of curing was not taken, but the result obtained after 2 days of curing was that of Example 7-1.
The results were essentially the same as those obtained after curing for 2 days and 2 days. Therefore, it is assumed that the product of Example 8 is stable one day after curing.

After curing for 2 days, the sample of Example 9 was tested for solubility and then the sample of Example 9 was exposed to accelerated conditions of 37 ° C./80% RH for 1 month. Representative initial dissolution pattern for Example 9 (average result of 3 samples)
Is shown in Table 12 below.

[0154]

[Table 12]

As is evident from the solubility results provided by Example 9 above, the results obtained after 2 days of curing are:
It is virtually identical to the results obtained under accelerated storage conditions of 37 ° C./80% RH, thus indicating that Example 2 is stable after 2 days of curing. Moreover, the solubility results obtained according to Example 9 indicate a slow release of hydromorphone, which is expected to give a thicker retarder coating.

After curing for 2 days, the sample of Example 10 was tested for solubility, then the sample of Example 10 was tested at room temperature, and at 37 ° C.
Further tests were carried out after storage under accelerated conditions of C / 80% RH, 37 C and 50 C drying. Representative dissolution pattern for Example 10 (average result of 3 samples)
Is shown in Table 13 below.

[0157]

[Table 13]

As can be seen from the above solubility results provided by Example 10, the solubility results obtained by Example 10 are as predicted by the thinner retarder coatings of Examples 8 and 9. In comparison, it showed a slower release rate of hydromorphone. All the results obtained after 2 days of curing are in comparison with the results obtained under accelerated conditions of 37 ° C./80% RH, the amount of drug dissolved (%) at 8 and 12 hours Other than that is substantially the same. The results show that if a high amount of retarder coating is deposited, it may take a long time to cure the coating in order to obtain a stabilized formulation.

Example 11 Morphine Sulfate Coated Beads In Example 11, the curing step of the present invention was applied to a formulation in which morphine sulfate was substituted as the drug.

Morphine Sulfate and HPMC (Opadry.
Clear Y-5-7095) suspension onto 18/20 mesh Nupariel beads at a temperature of 60 ° C in a fluid bed dryer.
And applied using a Wurster insert. Opadry Lavender YS-1-4729 HPMC-based film coating suspension was then applied as a protective coating at a 5% coat weight after drug application.

After the overcoating step was completed, the morphine sulfate beads were then overcoated with a retarder mixture of Eudragit RS 30D and Eudragit RL 30D at a RS to RL ratio of 90:10 at an adhesion level of 5% by weight. Coated This mixture of Eudragit RS 30 D and Eudragit RL 30 D together with talc (included as an anti-sticking agent) and triethyl citrate (plasticizer),
It was carried out in a Wurster insert with an introduction temperature of 35 ° C.

Once the retarder overcoat is finished, the Morphine Sulfate Beads will become Opadry Lavender YS.
-1-4729 was final overcoated with a 5 wt% deposition level.

After the final film coating step was completed, the morphine sulfate beads were cured at 45 ° C. for 2 days on a paper-coated dish. After curing, the beads were filled into gelatin capsules at a strength of 30 mg morphine sulfate. The final composition is shown in Table 14 below.

[0164]

[Table 14]

Next, for the sample of Example 11, a solubility stability test was conducted at room temperature and 37 ° C. after the curing step described above.
/ 80% RH, dried at 37 ° C and dried at 50 ° C under accelerated conditions, and after 1 month and 2 months. The results are shown in Table 15 below.

[0166]

[Table 15]

The results set forth in Table 15 demonstrate that the curing step stabilizes the dissolution pattern of morphine sulphate even when the sample is stored under accelerated conditions, resulting in a substantially constant dissolution rate to the end point. Shows to keep.

Example 12 Controlled Release Hydromorphone Hydrochloride 8 mg Formulation-Acrylic Poly
Mar coating Example 12 was prepared as follows.

1. Drug formulation: Hydromorphone beads,
Dissolve hydromorphone hydrochloride in water and use Opadry Y-5-144
2. Light pink (Colorcon, Westpoint, PA) products, including hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, polyethylene glycol and D & C Red No. 30 aluminum lake. ) Is added and mixed for about 1 hour 20% w / w
A suspension of This suspension is then Nupariel
Sprayed using a Wurster insert on 18/20 mesh beads.

2. First overcoat: The coated hydromorphone beads were then overcoated with a Wurster insert to give 5% w / w of Opadry Light Pink. This overcoat was applied as a protective coating.

3. Retarder coating: After forming the first overcoat, the ratio of RS to RL of Eudragit RS 30 D and Eudragit RL 30 D is 90:10, so as to adhere to the hydromorphone beads, then 5% by weight. Was coated with the retarder coating mixture. Triethyl citrate (plasticizer) and talc (anti-sticking agent) were also added to the Eudragit suspension. A Wurster insert was used to apply the paint suspension.

4. Second overcoat: After the retarder coating was finished, the hydromorphone beads were applied as a final overcoat with Opadry Light Pink using a Wurster insert for a 5 wt% deposit. This overcoat was also applied as a protective coating.

5. Curing: After the final overcoat was finished, the hydromorphone beads were cured in a 45 ° C oven for 2 days. The hardened beads were then filled into gelatin capsules to a hydromorphone strength of 8 mg. The complete formulation for the beads of Example 12 is set forth in Table 16 below.

[0174]

[Table 16]

For Eudragit-coated hydromorphone beads of Example 12, solubility studies were conducted at the initial and after 28 days, respectively. The results are shown in Table 17 below.

[0176]

[Table 17]

The solubility studies of Eudragit-coated hydromorphone beads set forth in Table 17 above show that the initial solubilities are comparable to those conducted when the samples were placed at 37 ° C./80% RH. It is shown that.

Example 13 In Example 13, 12 patients were subjected to a randomized crossover test (washout in 1 week) of 6 methods at a single dose to obtain an immediate release formulation. Compared to the results obtained at equal doses. Blood samples were used to quantify plasma levels at post-dose, 0.25, 0.5, 0.75,
1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 1
Harvested at 2, 18, 24, 30, 36 and 48 hours.
Comparative Example 13A is an 8 mg hydromorphone immediate release formulation (2 tablets of Dilaudid 4 mg tablets, commercially available from Knoll). Example 13 is the 8 mg dose of Example 1
2 of the encapsulated hydromorphone beads.

The results obtained according to Comparative Example 13A are shown in FIG. The results obtained according to Example 13 are listed in FIG. FIG. 5 shows the plasma levels of Example 13 as Comparative Example 13A.
The results are plotted as follows. The results for Example 13 are further set forth in Table 18 below. The data relate to the area under the curve (bioavailability), the maximum plasma concentration (C _max ) and the time to reach maximum plasma concentration (T _max ).

[0180]

[Table 18]

The results obtained for Example 13 show that at 12 hours post-dose, the blood level of hydromorphone was 500 p
It is above g / ml hydromorphone, and plasma levels at 24 hours post-dose are well above 300 pg / ml. Therefore, this product is considered suitable for once daily administration.

Examples 14-15 In Examples 14-15, four randomized crossover tests at a single dose were conducted on 10 subjects. Example 14 was tested with 8 mg of hydromorphone beads of Example 13-fasted, and Example 15 was tested with 8 mg of hydromorphone beads of Example 13-diet. In Comparative Example 14A, 8 mg of immediate release hydromorphone (Dilauzide
did) 2 4 mg tablets were administered to a fasted person. In Comparative Example 15A, 8 mg of immediate release hydromorphone (2 Dilaudid 4 mg tablets) was administered to the fed person.

The plasma levels of Comparative Example 14A and Comparative Example 15A are shown in FIG. 6, and the plasma levels of Examples 14 and 15 are shown in FIG. The results of Examples 14-15 and Comparative Examples 14A and 15A are further shown in Table 19. This is the area under the curve and the percent absorption (bioavailability), the maximum plasma concentration (C _max ) and the time to reach maximum plasma concentration (T _max ) compared to the immediate release ones. Provide data.

[0184]

[Table 19]

Examples 14 to 15 and Comparative Examples 14A and 1
As can be seen from the results obtained with 5A, both the immediate release tablet and the controlled release beads of Examples 14 and 15 had little food effect, and the biology of the controlled release beads of Examples 14 and 15 The usefulness is slightly increased. Plasma levels again confirmed that this product was suitable for once daily dosing. Within 24 hours, this controlled release product gave plasma levels close to 600 pg / ml and at 12 hours plasma levels above 700 pg / ml.

Examples 16 to 17 In Examples 16 to 17, three kinds of crossing tests were conducted in a steady state for 4 days. In Comparative Example 16A, the subject was administered 8 mg of immediate-release hydromorphone (2 tablets of dilauzide 4 mg tablets) every 6 hours. In Example 16, 8 mg of the hydromorphone beads of Example 15 were administered every 12 hours. In Example 17, 8 mg of hydromorphone beads of Example 13
Was administered every 24 hours. Blood samples were taken on day 4.

The plasma levels of Examples 16 and 17 relative to the plasma level of Comparative Example 16A are set forth in FIG. Comparative Example 1
The plasma levels of Examples 16 and 17 versus the 6A valley level are listed in Figure 9 (values for Example 17 were doubled in Figure 9). The results for Examples 16-17 and Comparative Example 16A are further listed in Table 20. It is the area under the curve and the data on percent absorption (bioavailability), maximum plasma concentration (C _max ) and time to reach maximum plasma concentration (T _max ) compared to the immediate release ones. I will provide a.

[0188]

[Table 20]

From the data shown in Table 20, for the area under the curve (AUC) as an indicator for biological activity, Comparative Example 16A and Examples 16 and 17 all increased over the dosing interval. , Has almost equivalent AUC, and it can be confirmed that all administration methods are biologically useful.

Further, in this study, Example 17, which was dosed only 8 mg every 24 hours, showed that this formulation was dosed with an immediate release formulation (4 mg every 6 hours) with doubling the amount of beads. If a 16 mg dose is given once a day, which is equivalent to that of hydromorphone, it provides an excellent 24-hour formulation. For Example 17, the minimum or trough concentrations shown in Figure 9 would be equivalent to 4 mg of the immediate release formulation of this product (dosed every 6 hours), which is therefore an excellent daily dose. This indicates that the product will be given twice.

Example 18 Controlled Release Morphine Sulfate 30 mg Formulation-Acrylic Polymer Coated
Cover Example 18 was prepared in the same manner as the above example. The complete formulation for the beads of Example 18 is set forth in Table 21 below.

[0192]

[Table 21]

The ratio of Eudragit RS 30 D to Eudragit RL 30 D is 98: 2. After the final overcoat was completed, the morphine beads were cured in a 45 ° C oven for 2 days. The hardened beads are then placed in gelatin capsules 30
Filled with mg strength.

Final product, initial; 3 months at room temperature and 6
Months storage; and accelerated storage conditions (40 ° C / 75
% RH) for 1 month, 2 months and 3 months. The results are shown in Table 22 below.

[0195]

[Table 22]

The solubilities listed in Table 22 show that the beads of Example 18 are stable.

A double-blind, single-dose, crossover study was then carried out on 12 subjects, for the dosage form of Example 18, standard commercial controlled release morphine sulfate tablets (Comparative Example 18A, MS Contin (trade name), manufactured by Purdue Fredrick). The results are shown in Table 23.

[0198]

[Table 23]

The data obtained from Example 18 show that the product is suitable for once-daily administration.

Examples 19 to 20 In Examples 19 to 20, the high loading base beads were prepared so that the loading of morphine sulfate was high, and therefore,
High doses can be easily administered once a day. Highly loaded beads are the Glatt Rotor Processo
Produced by layering the powder in r). The formulations of Examples 19-20 are set forth in Table 24 below.

[0201]

[Table 24]

Since the base beads are different compared to the low loading beads used in Example 18, more of the relatively soluble Eudragit RL was included in the loading and the Eudragit and morphine immediate release layers were included. Stability is further enhanced by providing an extra HPMC protective coating between.

The formulation for administration of 69 mg is listed in Table 25.

[0204]

[Table 25]

The beads were then placed in an oven at 45 ° C for 2 hours.
It was cured for a day and then split in two. The first part was filled in a hard gelatin capsule with a strength equivalent to 60 mg and the second part was filled in a hard gelatin capsule with a strength equivalent to 30 mg.

Solubility studies were performed on two strength capsules. The data show that the percentage of morphine dissolved is the same for both intensities. Stability testing was performed on 60 mg capsules. The results for the 60 mg capsules are set forth in Table 26 below.

[0207]

[Table 26]

A bioavailability test was then performed on 30 mg strength capsules (Example 19 = fasting, Example 20 = diet).
Was fasted with 30 mg MS Contin (Example 19
A) was used as a control.

The results are shown in Table 27.

[0210]

[Table 27]

FIG. 10 is a graph showing plasma levels obtained in Comparative Example 19A versus plasma levels in Examples 19-20 (both fed and fasted). The data obtained show that the product is suitable for once-daily administration.

Example 21 Controlled Release Acetaminophen (APAP) tablets were prepared according to the present invention as follows.

First, by compressing the immediate release APAP nucleus on the Compap coarse L,
The core was produced as a tablet weighing 555.6 mg. Compup Course L contains approximately 90% APAP and pharmaceutical grade excipients including binders, disintegrants and lubricants, and is commercially available from Mallinckrodt, Inc., St. Louis, MO. It is a material that can be directly compressed. APAP
The tablet core contains about 500 mg APAP. The Compap Course L is compressed using a rotary tablet press with a 7/16 ″ circular standard concave lid and a smooth molding tool. The core has a theoretical weight of 555.6 mg and a hardness of about 8-9 Kp. Compressed with.

The APAP tablet cores produced as described above are then coated with the controlled release coating of the invention as follows.

Approximate amount of Eudragit RS-30D
And Eudragit RL-30D are mixed and purified water is added. The amount of purified water is such that the final coating suspension is a solid polymer,
Calculated to have plasticizer and talc at a concentration of about 20%. Triethyl citrate was then added and mixed for 15 minutes. Then talc was added and mixed for an additional 15 minutes. Appropriate amounts of APAP tablet cores were compounded into an Accela Cota coat-ing pan. Coating suspension, polymer coating, 4% per tablet
It sprayed using the suitable spraying device (spray gun) until it became the adhesion weight of.

After the functional coating has been sprayed, the tablets are sprayed with an Opadry film coating. This coating is sprayed in the same way as the functional coating.

Additional information regarding control coated APAP tablets is set forth in Table 28 below.

[0218]

[Table 28]

After the coating process is completed, the functional coated tablets are discharged into a curing tray and stored in a chamber at 45 ° C for 48 hours.
Allowed to cure for hours. The results of solubility tests on the cured tablets are shown in Table 29 below.

[0220]

[Table 29]

Example 22 In Example 22, controlled release acetaminophen (A
PAP) tablets were produced. If it is desired to provide rapid dissolution, the amount of Eudragit RL-30 D is increased and the amount of Eudragit RS-30 D is decreased. Thus, a controlled release APAP tablet containing only Eudragit RL-30D and no Eudragit RS-30D was prepared. APAP nuclei were prepared as in Example 4. The APAP tablet cores prepared as described above were then coated with a controlled release coating of the invention as follows: Purified water was added to Eudragit RL-30D. The amount of purified water was calculated so that the concentration of the final coating suspension was about 20% solid polymer, plasticizer and talc. Then triethyl citrate was added and stirred for 15 minutes. Then
Talc was added and stirred for 15 minutes. Appropriate amount of APAP
Tablet cores were added to an Accela Cota coating tank. The coating suspension was sprayed from a suitable spray gun until the polymer had a 4% coating weight per tablet.

After the spraying of the functional coating was completed, the tablets were sprayed with Opadry coating to prevent sticking of the tablets. The coating was sprayed in the same manner as the functional coating.

Additional information regarding controlled release coated APAP tablets is set forth in Table 30 below.

[0224]

[Table 30]

After the coating process was completed, the functional coated tablets were placed in a curing tray and cured in a tank at a temperature of 45 ° C. for 48 hours.
The coated tablets were subjected to a solubility test and the data set forth in Table 31 below was obtained.

[0226]

[Table 31]

The embodiments described above are not meant to be exclusive. Many other variations of this invention will be apparent to those of skill in the art and are expected to be within the scope of the following claims.

[Brief description of drawings]

The following drawings describe embodiments of the invention,
It is not meant to limit the scope of the invention covered by the claims.

FIG. 1 is a split screen scanning electron micrograph (SEM) of pharmaceutical beads coated with a controlled release coating prior to curing according to the present invention.

2 is a split screen scanning electron micrograph (SEM) of the coated pharmaceutical beads of FIG. 1 after curing according to the present invention.

FIG. 3 is a graph showing the dissolution results of Comparative Example 13A.

FIG. 4 is a graph showing the dissolution results of Example 5.

FIG. 5 is a graph comparing plasma levels obtained in Example 13 to plasma levels obtained in Comparative Example 13A.

FIG. 6 is a graph showing plasma levels obtained in Examples 14A and 15A.

FIG. 7 is a graph showing plasma levels obtained in Examples 14 and 15.

FIG. 8 is a graph comparing the plasma levels obtained in Examples 16 and 17 to the plasma levels obtained in Comparative Example 16A.

FIG. 9 graphically illustrates the results obtained in Examples 16 and 17 against the trough levels obtained in Example 16A.

FIG. 10 is a graph showing the plasma levels obtained in Examples 19 and 20 against the plasma levels obtained in Comparative Example 19A.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mark Chaisin, Waynecourt, Manarapan, 07726 NJ, United States, 07726 3 (72) Inventor Frank Pedy United States, 10598 New York, Yorktown Heights, Hyatt Street 2773

Claims (41)

[Claims] 1. A solid substrate comprising an effective amount of a therapeutically active agent, the solid substrate being plasticized in an effective amount to provide controlled release of the therapeutically active agent when the coated substrate is exposed to gastric fluid. Coated with an aqueous dispersion of an acrylic polymer, the coated substrate being subjected to in vitro dissolution after being placed under accelerated storage conditions of 40 ° C. and 75% relative humidity for at least 1 month. In some cases, greater than about 20% of the total amount of therapeutically active agent released compared to in vitro lysis performed prior to storage, the concentration of the therapeutic agent was unchanged at any given dissolution time. A controlled release formulation comprising releasing a fixed amount of a therapeutically active agent. 2. The coating is for at least about 12 hours,
An amount sufficient to provide an effective blood level of the therapeutically active agent, the coated substrate being at 40 ° C in an in vitro dissolution test.
Of the dissolution pattern before exposure to the accelerated conditions when compared to the dissolution pattern after exposure to accelerated storage conditions for at least 1 month at a temperature of 75% and relative humidity of 75%. The formulation of claim 1 which provides a band area no greater than about 15% of the total active agent released at that time. 3. Plasticizing to gradually slow the release of the active agent when the individual acrylic polymer particles in the coating coalesce and are exposed to ambient liquid until the band region is obtained. The formulation according to claim 1, wherein the coated substrate is cured at a temperature higher than the glass transition point of the aqueous dispersion of the acrylic polymer thus prepared. 4. A substrate containing a systemically active therapeutic agent in an amount sufficient to provide the desired therapeutic effect when the formulation is administered orally, said substrate having an adherence of from about 2% to about 25%. Is coated with an aqueous dispersion of a weight-plasticized acrylic polymer at 37 ° C. according to the USP paddle method.
10 with 900 ml of aqueous buffer (pH between 1.6 and 7.2)
About 12.5% to about 42.5 after 1 hour when measured at 0 rpm
% (By weight) of active agent is released and after 2 hours from about 25% to about 55%
% (Weight) of active agent is released and after 4 hours, about 45% to about 75%
% (By weight) of active agent is released and after about 8 hours about 55% to about 85%
% (By weight) of active agent is released and the coated substrate is at 40 ° C./75
% Of relative amount of therapeutically active agent released in vitro compared to in vitro lysis prior to storage when subjected to in vitro lysis following accelerated storage conditions of at least 1 month. An oral dosage formulation which controls the release of solids, which comprises releasing an amount of the therapeutically active agent without fluctuation at any given dissolution time at an amount greater than about 20%. 5. A formulation according to any one of claims 1 to 4 which, when administered orally, provides a therapeutically effective blood level for at least 24 hours. 6. The formulation of any one of claims 1-5, wherein the substrate is coated with a build up weight of about 2% to about 25%. 7. The therapeutically active agent is an antihistamine, an analgesic, a nonsteroidal anti-inflammatory, a gastrointestinal preparation, an antiemetic, an antiepileptic, a vasodilator, an antitussive, an expectorant, an antiasthmatic, a hormone, a diuretic. Agents, antihypertensive agents, antihypertensive agents, bronchodilators, antibiotics, antiviral agents, antihemorrhoid agents, steroids, sleeping agents, psychotropic agents, antidiarrheal agents, mucolytic agents, analgesics, decongestants, The formulation according to any one of claims 1 to 6, which is selected from the group consisting of laxatives, vitamins and stimulants. 8. The substrate is a pharmaceutically acceptable bead, wherein a plurality of the coating-cured beads are for providing an effective controlled release dosage when contacted with an aqueous solution. A sufficient amount to be contained in a capsule.
7. The formulation according to any one of 7. 9. The formulation according to claim 1, wherein the substrate is a tablet core. 10. The therapeutically active agent is hydromorphone, oxycodone, morphine, levorphanol, methadone,
Meperidine, heroin, dihydrocodeine, codeine,
9. An opioid analgesic selected from the group consisting of dihydromorphine, buprenorphine, any salt thereof, and any mixture thereof.
The formulation according to paragraph. 11. The coating is for about 24 to about 48 hours,
The formulation of claim 3, which is cured. 12. The coating further comprises a permeability-enhancing compound in an amount effective to control the rate of release of the therapeutically active agent from the cured coating substrate.
The formulation according to any one of 1 to 11. 13. The preparation according to claim 1, wherein the compound increasing the permeability is a monoethylenically unsaturated quaternary ammonium compound capable of free radical polymerization. 14. The formulation of any one of claims 1-4, wherein the coated substrate comprises at least one passageway through the coating that regulates the release of the systemically active therapeutic agent. 15. It provides a stable dissolution of the activator after exposure to accelerated storage conditions at a temperature of 40 ° C. and a relative humidity of 75% for 3 months without change. 1
5. The formulation according to any one of 4 to 4. 16. A formulation as claimed in any one of claims 4, 5, 7 or 10 wherein a portion of the amount of the active agent contained in the formulation is incorporated into the coating of the substrate. 17. A dissolution pattern after exposure to accelerated storage conditions for at least 1 month at a temperature of 40 ° C. and 75% relative humidity, prior to exposure to accelerated conditions as described above. The formulation of claim 2, wherein the band area does not change by more than about 10% when compared. 18. A dissolution pattern after exposure to accelerated storage conditions at a temperature of 40 ° C. and 75% relative humidity for at least 1 month prior to exposure to accelerated conditions as described above. 3. The formulation of claim 2, wherein the band area does not change by more than about 7% when compared. 19. A method of treating a human patient, which comprises orally administering an oral solid formulation according to claims 1-18. 20. A matrix containing a sufficient amount of an active agent to provide a desired effect in a use environment, the active agent being a topically active therapeutic agent, a disinfectant, a detergent, a fragrance, a fertilizer, Deodorant, dye, animal repellent, insect repellent, insecticide,
Selected from the group consisting of herbicides, fungicides, and plant growth stimulants, the substrate being a plasticizer in an amount sufficient to inhibit release of the active agent when the formulation is exposed to the surrounding liquid. Is coated with an aqueous dispersion of an acrylated acrylic polymer, the coated substrate reaching a cure endpoint that provides stable solubility of the activator that does not change after exposure to accelerated storage conditions. Cured at a temperature above the glass transition temperature of the aqueous dispersion of the plasticized acrylic polymer for at least 24 hours, the endpoints mentioned above being the dissolution pattern of the formulation immediately after curing and 37 ° C.
Controlled release formulation, which is determined by comparing the dissolution pattern of the formulation after exposure to accelerated storage conditions for at least 1 month at 80% relative humidity at 80 ° C. 21. The formulation of claim 20, wherein the substrate is coated with a build up weight of about 2 to about 50%. 22. The locally active therapeutic agent is an antibacterial agent, an antibiotic agent, an antiviral agent, a fresh breathing agent, an antitussive agent, an anti-caries agent, an analgesic agent, a local anesthetic agent, an antiseptic agent, an antiinflammatory agent, a hormonal agent, The formulation according to claim 20, which is selected from the group consisting of anti-plaque agents, acidity-reducing agents, and tooth desensitizing agents. 23. The formulation of claim 20, wherein the substrate is a tablet core. 24. The coating is for a period of about 24 to about 48 hours.
The formulation of claim 20, which is cured. 25. The coating further comprises a permeability-enhancing compound in an amount effective to modulate the rate of release of the therapeutically active agent from the cured coating substrate.
The preparation according to 0. 26. The preparation according to claim 25, wherein the compound that increases the permeability is a monoethylenically unsaturated quaternary ammonium compound capable of free radical polymerization. 27. A solid substrate comprising a therapeutically active agent in an amount sufficient to provide a patient with a therapeutically effective blood level for about 12 to about 24 hours and exposing the coated substrate to an ambient liquid. In some cases, the substrate was coated with a sufficient amount of an aqueous dispersion of plasticized ethylcellulose so that a predetermined controlled release of the active agent was obtained, and the coated substrate was accelerated. A temperature above the glass transition temperature of the aqueous dispersion of plasticized acrylic polymer for at least 24 hours before reaching the end point of cure, which gives a stable solubility of the activator that does not change after exposure to storage conditions. The above-mentioned end points are the dissolution pattern of the formulation immediately after curing and 37 ° C.
Oral solids consisting of the cured coated substrate as determined by comparison with the dissolution profile of the formulation after exposure to accelerated storage conditions of 80% relative humidity and 80% relative humidity for at least 1 month. Is administered to a patient, thereby providing an effective blood level of the therapeutically active agent for a predetermined time period, which results in the desired therapeutic effect for about 12 to about 24 hours, controlling release. A method of treating a patient with an oral solid dosage formulation comprising: 28. A plasticized acrylic resin is used to obtain a predetermined controlled release of the active agent when a solid substrate of the active agent is prepared and the coated substrate is exposed to an ambient liquid. Coating with a sufficient amount of an aqueous dispersion of the system polymer and reaching a cure endpoint that provides stable solubility of the activator that does not change after exposure of the coated substrate to accelerated storage conditions. Curing the coated substrate at a temperature above the glass transition temperature of the aqueous dispersion of plasticized acrylic polymer for at least 24 hours, the endpoints mentioned above being the dissolution pattern of the formulation immediately after curing and 37 ° C.
A formulation for controlling the release of the active agent, which is determined by comparing with the dissolution pattern of the formulation after exposure to accelerated storage conditions of 80% relative humidity at 80% relative temperature for at least 1 month. How to get. 29. The active agent is a systemically active therapeutic agent,
Topically active therapeutic agent, disinfectant, detergent, fragrance, fertilizer, deodorant, dye, animal repellent, insect repellent, insecticide, herbicide,
29. The method of claim 28, selected from the group consisting of fungicides, and plant growth stimulants. 30. The locally active therapeutic agent is an antibacterial agent, an antibiotic, an antiviral agent, a fresh breathing agent, an antitussive agent, an anti-caries agent, an analgesic agent, a local anesthetic agent, an antiseptic agent, an antiinflammatory agent, a hormonal agent, 30. The method of claim 29, selected from the group consisting of antiplaque agents, acidity reducing agents, and tooth desensitizing agents. 31. The substrate comprises inert pharmaceutically acceptable beads, wherein the surface of the inert beads is coated with the therapeutically active agent, and a sufficient amount of cured coated beads is encapsulated. 29. The method according to claim 27 or 28, characterized in that the method comprises the step of preparing the oral administration preparation. 32. The method according to claim 27 or 28, further comprising: the substrate for oral administration being prepared by incorporating the therapeutically active agent into a tablet. 33. The method of claim 27 or 28, wherein the coated substrate is cured for about 24 to about 48 hours until the endpoint is reached. 34. The method of claim 27 or 28, wherein the substrate is coated at a build up weight of about 2% to about 25%. 35. The active agent is an antihistamine, an analgesic, a nonsteroidal anti-inflammatory, a gastrointestinal preparation, an antiemetic, an antiepileptic, a vasodilator, an antitussive, an expectorant, an antiasthmatic, a hormone, a diuretic. , Antihypertensive agent, antihypertensive agent, bronchodilator, antibiotic, antiviral agent, antihemorrhoid agent, steroid agent, sleeping agent, psychotropic agent, antidiarrheal agent, mucolytic agent, painkiller, decongestant, laxative 29. The method according to claim 27 or 28, which is selected from the group consisting of a vitamin preparation and a stimulant. 36. The active agent is hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, any salt thereof, and any mixture thereof. 29. The method according to claim 27 or 28, which is an opioid analgesic selected from the group consisting of: 37. The method of claim 27 or 36, wherein the active agent is released for at least about 24 hours. 38. Furthermore, a permeability-increasing compound is incorporated into an aqueous dispersion of an acrylic polymer in an amount effective to control the rate of release of the therapeutically active agent from the cured coated substrate described above. Claim 27 or 28 which consists of
The described method. 39. A mixture of copolymers wherein the acrylic polymer has a molar ratio of acrylic acid ester or methacrylic acid ester having an ammonium group to (meth) acrylic acid ester of about 1:20 to about 1:40. A formulation according to claims 1 to 32 consisting of: 40. The acrylic polymer has a first copolymer having a molar ratio of an acrylic ester or methacrylic ester having an ammonium group to a (meth) acrylic ester having an ammonium group, and an ammonium group. The molar ratio of acrylic or methacrylic acid ester to (meth) acrylic acid ester is about 1:40.
A mixture of second copolymers, wherein the ratio of the first copolymer to the second copolymer is from about 0: 100 to about 10:
The formulation according to claims 1 to 32, which is 0: 0. 41. The acrylic polymer comprises a monomer selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and a mixture of any of the above. Paragraphs 1 to 32.