JP2011231121A - Controlled release preparation coated with aqueous dispersion of acrylic polymer and method therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a controlled release solid preparation which can control the release rate of an active ingredient contained in the preparation and can stably elute the active ingredient even after exposed to accelerated storage conditions.SOLUTION: There are provided the method for producing the controlled release solid preparation comprising a step for coating a substrate containing the active ingredient selected from among generalized active medicines, topical active medicines, sterilizing and hygienic agents, cleansers, flavors and fertilizers with an aqueous dispersion of an effective amount of a plasticized hydrophobic acrylic polymer and a subsequent step for curing the coating at a temperature higher than the glass transition point of the dispersion; and the controlled release preparation produced by the method.

Description

The present invention relates to a preparation that enables a stable dissolution rate of an active agent contained therein as a controlled release preparation even after a predetermined storage period.

An important aspect of the 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 pharmaceutical dosage forms is determined when stored, i.e. when stored in special containers and environments.
Related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties. Stability testing requirements include, for example, Good manufacturing Practices (GMPs), USP (the USP), and countries that require market approval of dosage formulations. It is dealt with in the regulatory requirements. In the U.S., testing and ultimately market claims, drugs or drug formulations can be found in New Drug Application (NDA), Simple New Drug Application (Abb
reviated New Drug Application (ANDA)), or Investigational New Drug Application (IND).

Drugs used in sustained release dosage formulations often have special problems with regard to their physical stability during storage. For example, waxes used in such formulations are known to undergo physical alteration upon prolonged exposure, thus preventing them from stabilizing or from alteration. In order to prevent this, we must take precautions. Fat and waxy substances are known to crystallize in an unstable state when used in a purified state, and have a degree of effectiveness during manufacturing and during subsequent storage stability testing. It causes unpredictable fluctuations.

In many cases, it is known that some strategy is taken to obtain stabilized controlled release formulations, where individual reagents are put into a stable form or processed before they are introduced into the product. Does not change this state, or adds additional additives 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 moisture 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 effectiveness. It is also known that binders such as gum arabic have poor solubility when exposed to moisture and heat. However, the moisture content of the product can be controlled fairly well by control in the processing method and proper packaging of the product.

Certain cellulose derivatives, zein, acrylic resins, waxes, higher fatty acid alcohols and hydrophobic polymers such as polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage formulations. Tablets, capsules, suppositories, spheres, beads,
Alternatively, the methods of using these polymers to develop controlled release dosage formulations such as spherules can either introduce those drugs into the controlled release matrix or they can be incorporated into the controlled release coating of the dosage formulation. There are cases of using drugs. It is known in the prior art that the hydrophobic coating is applied from solution, suspension or dry state, respectively. Because many polymers used in controlled release coatings are poorly soluble in water, they usually dissolve the polymer in an organic solvent and apply the solution to individual drug formulations (eg, beads or tablets) And applied by evaporating off the solvent.

Aqueous dispersions of hydrophobic polymers are used in the prior art to coat pharmaceutical dosage formulations for aesthetic reasons such as tablet or bead membrane coating or for seasoning purposes. However, these administration preparations are used for immediate release administration of active agents contained in the administration preparation.

The use of organic solvents in preparing hydrophobic coatings is generally considered undesirable due to inherent problems with flammability, carcinogenicity, environmental issues, cost and safety. However, it is considered highly desirable in the art to provide a controlled release coating derived from an aqueous dispersion of a hydrophobic material such as an acrylic polymer.

Many formulations based on hydrophobic coatings derived from aqueous dispersions have been experimentally prepared to control the release of active agents, but such formulations are commercially available due to stability issues. It has not been proven to be practical. Aqueous polymeric dispersions are used to produce stable controlled release dosage formulations, but the production of this formulation is rather than using a coating of aqueous polymeric dispersion to obtain delayed performance. It is 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 several hours or longer, the dissolution release pattern in the industry varies with aging. For example, the final coated product is stored for a period of time, during which time it is exposed to elevated temperatures and / or humidity above ambient conditions.

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

This instability problem is known not to exist when the polymer is applied in an organic solvent solution, but it is a coating prepared from such an aqueous acrylic polymer dispersion that is stable under various storage conditions. It was impossible to obtain a controlled-release preparation using a membrane.

In particular, commercially available controlled release coatings of acrylic polymers such as those sold under the tradename Eudragit from Rohm Pharma GmbH are recommended curing conditions. It is known that it is not stable when cured at 45 ° C. for 2 hours.

Therefore, the object of the present invention is to accelerate by coating a substrate consisting of an active agent, for example a therapeutic active agent, a bactericide, a detergent, a disinfectant and a fertilizer, with an aqueous dispersion of a hydrophobic acrylic polymer. Even when exposed to various storage conditions, including accelerated storage conditions
It is 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.

Another object of the invention comprises a plurality of inert beads comprising an active agent and a controlled release tablet comprising a core containing the active agent, wherein the bead or tablet core is coated with an aqueous dispersion of a hydrophobic polymer. And to provide a controlled release formulation that is reproducible even when exposed to accelerated storage conditions and provides stable dissolution, as well as a method for its manufacture.

Yet another object of the present invention is that at any point during dissolution when comparing the dissolution pattern of the formulation after exposure to various storage conditions, including “forced” or accelerated storage conditions. Release consisting of a substrate containing an active agent coated with an aqueous dispersion of a hydrophobic polymer that gives a band range in in-vitro dissolution that does not exceed about 15% of the total amount of active agent released It is to provide a controlled formulation.

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

These and other objectives consist, in part, of a substrate composed of an active agent in an amount sufficient to provide the desired effect in the environment of use, when the formulation is exposed to an ambient liquid Coated with a sufficient amount of an aqueous dispersion of a plasticized pharmaceutically acceptable hydrophobic polymer to provide controlled release of the active agent and exposed to accelerated storage conditions Cured at a temperature above the glass transition point of the aqueous dispersion of the plasticized acrylic polymer for a sufficient time to reach the end point of cure reaching the coated substrate which gives a stable dissolution of the active agent which does not change later. This is achieved by the present invention relating to a controlled release formulation. The endpoint is, for example, the dissolution pattern of the formulation immediately after curing and at a temperature of 37 ° C. and a relative humidity of 80%, or 40
Determined by comparing the dissolution pattern of the formulation after exposure to accelerated storage conditions of 1-3 months at a temperature of 0C and 75% relative humidity. In a preferred embodiment, the substrate is coated with a deposition weight of about 2% to about 25%.

In another preferred embodiment, the coated substrate, when subjected to in-vitro lysis,
Compared to the in-vitro dissolution of the coated substrate after curing, the active agent in a non-fluctuating amount along the dissolution curve exceeds about 15% of the total amount of active agent released at any time. To be released.

In yet another embodiment, the cured formulation provides a stable dissolution of the active agent unchanged after exposure to accelerated storage conditions, and the stable dissolution is a United States for the expiration date of the formulation. As deemed appropriate by the United 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 that provides controlled release of the active agent, the formulation being subjected to accelerated storage conditions. Later, release of the therapeutically active agent in an unaltered amount, 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 To do. The acrylic polymer preferably has a permeability that is unaffected by pH conditions prevailing in the gastrointestinal tract.

In other embodiments, the coated substrate has accelerated storage conditions at any time as compared to dissolution patterns prior to exposure to accelerated storage conditions in an in-vitro dissolution test. Which gives a band area no wider than about 20% after exposure to.

Active agents are systemically active therapeutic agents, local active therapeutic agents, disinfectants, detergents, fragrances, fertilizers, deodorants,
Used in a wide range of applications including, but not limited to, dyes, animal repellents, insect repellents, insecticides, herbicides, fungicides, and plant growth stimulants.

The invention further provides an amount sufficient to provide the desired therapeutic effect when the formulation is administered orally,
The present invention relates to a solid controlled release oral dosage formulation comprising a substrate containing a systemic active therapeutic agent. The substrate is coated with an aqueous dispersion of a plasticized acrylic polymer and is a USP paddle.
About 0% to about 42.5% (by weight) of active agent after 1 hour when measured at 100 rpm with 900 ml of aqueous buffer (pH between 1.6 and 7.2) at 37 ° C. by the method or basket method From about 5% to about 60% (by weight) of the active agent after 2 hours and from about 15% to about 4 hours after
Plasticizing for a time sufficient to provide controlled release of the active agent such that 75% (by weight) of the active agent is released and 20% to about 90% (by weight) of the active agent is released after 8 hours. It is effective at a temperature higher than the glass transition temperature of the acrylic polymer aqueous dispersion. The coated substrate provides a stable release when the rate of release of the active agent after exposure of the coated substrate to accelerated conditions is compared to the release rate obtained immediately after curing. The dosage formulation preferably provides about 24 hours of therapeutic cure. The present invention further relates to a method for producing a dosage formulation.

The present invention also provides a plasticized acrylic system so that a predetermined release control of the active agent can be obtained when a solid substrate comprising the active agent is prepared and the coated substrate is exposed to an ambient liquid. Coating endpoint with a sufficient amount of an aqueous dispersion of polymer and the coating substrate giving a stable and unchanged state of solubility of the active agent even after exposure to accelerated storage conditions Until now, it relates to a method for obtaining a controlled release formulation of an active agent comprising curing the coated substrate at a temperature above the glass transition temperature of an aqueous dispersion of a plasticized acrylic polymer.

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

In one preferred embodiment of the present invention, the hydrophobic acrylic polymer comprises a copolymer of an acrylic ester and a methacrylic ester having permeability that is unaffected by pH conditions prevailing in the gastrointestinal tract. Preferably, these copolymers additionally contain small amounts of quaternary ammonium groups which occur as salts and which are related to the permeability of the lacquer material.

The present invention has inherent safety issues (flammability, carcinogenicity, environmental issues, cost, general safety)
Provide many benefits over prior art coatings, including the avoidance of the use of organic solvents with increased safety and would result in extended shelf life and expiration. It is not limited.

In the present invention, an aqueous dispersion of a hydrophobic acrylic polymer used as a coating is used to obtain the desired controlled release of the active agent in tablets, spheres (or beads), spherules, seeds, pellets, Coated substrates such as ion exchange resin beads and other multiparticulate systems are used. Granules, spheres, pellets, or the like made according to the present invention can be present in capsules or other suitable dosage formulations. The tablet of the present invention may have any suitable shape such as a spherical shape, an oval shape, a biconcave shape, a hemispherical shape, a square shape, a rectangular shape, a polygonal shape such as a pentagonal shape, and the like.

To obtain a controlled release formulation, overcoat the substrate comprising the active agent with a sufficient amount of an aqueous dispersion of a hydrophobic acrylic polymer so that an adhesion weight level of about 2 to about 25% is obtained. Is generally necessary, and the overcoat may be less or more depending on, for example, the physical properties of the active agent and the desired release rate, the addition of the plasticizer into the aqueous dispersion and the method of its introduction. In certain embodiments of the invention, the controlled release coating may be applied to the substrate, for example, with a deposition weight of up to 50%.

Cured, coated substrates of the present invention have a stable dissolution pattern when stored at ambient humidity (eg, long term (actual time) testing) at room temperature for extended periods of time, and when tested under accelerated storage conditions. (E.g., release of the active agent into the environment of use).

The terms “stable dissolution pattern” and “curing end point” have been left in use for the purposes of the present invention, even after the cured coated substrate has been exposed to accelerated storage conditions. In that case, the cured coated substrate is defined to mean reproducibly providing unaltered release of the active agent. One skilled in the art recognizes by the word “unchanged” that it means any change that is deemed insignificant with respect to the desired effect, with respect to the release of the active agent from the cured coated matrix formulation. Has been. For pharmaceutical formulations, stability is examined for the expiration date of the formulation, eg, by a standards body such as the Food & Drug Administration (FDA) in the United States.

The phrase “acceleraled storage conditions” means, for example, elevated temperature and / or elevated humidity storage conditions. Preferably, the term “accelerated storage conditions” refers to storage conditions that occur to obtain regulatory approval (eg, US FDA approval) and expiration date of the final drug formulation.

The term “expiration date” is given as the time limit that would remain within the specification when a packaged batch of product (eg, cured coated substrate) is stored under the stated conditions. And should not be used after the deadline.

The term “atmospheric fluid” means that the formulation is an aqueous solution (eg, in-vitro dissolution), simulated gastric fluid (eg, USP basket method (ie, 37 ° C., 100 RPM, first time is 700
ml gastric juice, presence or absence of enzyme, pH 1.2, then 900 ml changed to pH 7.5)) or gastrointestinal fluid (in-vivo).

In the present invention, the term “band range” or “band width” refers to the dissolution pattern obtained by the formulation at the end of manufacture of the coated product (before storage) and the accelerated storage of the coated product. The total (absolute) percentage of active agent released from the coated product at any dissolution point along the dissolution curve when compared to the dissolution pattern obtained after exposure to conditions
It is defined as the difference in the in-vitro dissolution measurement of the controlled release formulation shown as a change.

In general, the length of study and the storage test conditions required by a standards body such as the FDA for pharmaceutical formulations are sufficient to cover storage, shipping, and subsequent use. The storage test conditions that may be permitted may vary depending on the characteristics of the product. For example, a temperature sensitive drug substance should be stored under alternative low temperature conditions where it is considered a long term test storage temperature. In such cases, it is generally the case that accelerated testing should be performed at a temperature of at least 15 ° C above this specified long-term storage temperature and at the same time relative humidity conditions at that temperature. Accepted.

The generally accepted accelerated test employed in the FDA guidelines is
The drug product (e.g. in its container and packaging) is 37 ° C (1985) at 80% relative humidity (RH).
FDA guidelines). If the product lasts for 3 months, for example under those conditions (chemical stability, dissolution, and physical properties) then the drug product is then given an expiration date of eg 2 years . This accelerated test is also now considered acceptable when performed at 40 ° C. (FDA 1987 guidelines) at 75% RH.
Recently, a long-term storage test for pharmaceutical formulations has been conducted at 25 ° C. ± 2 ° C. without exceeding 60% RH ± 5%,
It has been proposed to do so with a minimum time limit of 12 months. In addition, it has also been proposed to perform accelerated testing for pharmaceutical formulations at 40 ° C. ± 2 ° C. and 75% RH ± 5% with a minimum time limit of 6 months. All the accelerated test criteria described above and others are considered equivalent for purposes of the present invention with respect to stability measurements and cure endpoint measurements. All the accelerated test conditions described above and others known to those skilled in the art provide an acceptable basis for determining the endpoint of cure (stability) of the controlled release formulation 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 solubility and permeability that are independent of the pH of the fluid present in the environment of use. In the case of an oral solid dosage formulation, the hydrophobic acrylic polymer of the present invention has solubility and permeability independent of physiological pH values. The hydrophobic acrylic polymer used in the formulations of the present invention is derived from acrylic acid or a derivative thereof. Examples of acrylic acid derivatives include 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 from about 1 to about 8 carbon atoms in the alkyl group. Monomers used in the polymer coating of the present invention also include styrene and its homologs, vinyl acetate,
And vinyl esters such as vinyl chloride. In general, monomers that form hydrophobic water-insoluble polymers are nonionic. In the present invention, the term “nonionic monomer” means not only a monomer having no ionic group (alkali metal carboxylate, sulfonate, quaternary ammonium group, etc.) in the molecule, but also a base, an acid, etc. Monomers that cannot form groups are also included. In many cases, the composition of the hydrophobic acrylic polymer coating may include other monomers.

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

In certain preferred embodiments of the invention, the allyl polymer is also one or more polymerizations that allow release of the active agent contained within the coating at the desired diffusion rate, regardless of the prevailing pH value. Contains compounds that increase permeability by permeability. In the case of oral solid dosage formulations, compounds that increase permeability are the same diffusion rate for the active agent in each region of the digestive (gastrointestinal) tract (regardless of pH) as the dosage formulation passes through the passageway. After being substantially completely extracted, the coating of the present invention is excreted without degradation.

In certain preferred embodiments, the compound that increases permeability comprises at least one polymerizable quaternary ammonium compound. Such compounds are strong bases that exist as stable salts in a wide pH range, for example, throughout all physiological pH ranges, and are readily soluble in water. The nature of the quaternary ammonium compound present in the copolymerizable reagent, and in particular its amount, is an important factor affecting diffusivity.

Suitable polymerizable quaternary ammonium compounds for use in the coating (paint) of the present invention generally have the following general formula:

Wherein R is hydrogen or methyl, A is oxygen or NH, B is a linear or branched alkyl or alicyclic hydrocarbon, preferably having from about 2 to about 8 carbon atoms. And
R ₁ , R ₂ and R ₃ are independently the same or different alkyl or aralkyl, more particularly lower alkyl having from about 1 to about 4 carbon atoms, or benzyl;
Or R ₁ and R ₂ together with a quaternary nitrogen atom are piperidinium or morpholinium and XΘ Is a cation, preferably a cation of an inorganic acid, in particular chloride, sulfate or methosulphate.

Particularly preferred examples of polymerizable quaternary ammonium compounds include quaternized aminoalkyl esters and aminoalkylamides of acrylic acid and methacrylic acid, such as β-methacryloxyethyltrimethylammonium methosulfate, chloride β-acryloxypropyltrimethylammonium, trimethylaminomethylmethacrylamide, etc. 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 It can be bonded to an acrylic acid group or a methacrylic acid group as a group. Further suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles such as methyl vinyl pyridinium salts, vinyl esters of quaternized aminocarboxylic acids, styryl trialkyl ammonium salts and the like.

Other polymerizable quaternary ammonium compounds useful in the present invention include acrylic- and methacryl-oxyethyltrimethylammonium chloride and methosulfate, benzyldimethylammonium methylmethacrylate chloride, diethylmethylammonium ethyl-acrylate and methacrylate methosulfate, N -Trimethylammoniumpropylmethacrylamide chloride and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

More information on suitable hydrophobic acrylic polymers can be found in US Pat. Nos. 3,520,970 and 4
, 737,357 (both assigned to Rohm GmbH), both of which are hereby incorporated by reference.

One skilled in the art may substitute other quaternary ammonium compounds in the present invention for other polymerizable permeability increasing compounds. Compounds that increase such additional polymerizable permeability are intended to be within the scope of the above claims.

In one preferred embodiment, the hydrophobic acrylic polymer used in the coating of the present invention consists of a copolymer of acrylic and methacrylic acid esters with a small amount of quaternary ammonium groups. Such copolymers are often referred to as ammonio methacrylate copolymers and are commercially available from Rohm Pharma AG, for example, under the tradename Eudragit. Ammonio methacrylate copolymers are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic esters with small amounts of quaternary ammonium groups.

In certain particularly preferred embodiments of the present invention, the acrylic coatings are Eudragit RL 30 D and Eudragit RS 30 D, respectively.
) Derived from a mixture of two acrylic resin lacquers used in the form of an aqueous dispersion, commercially available from Rohm Pharma. Eudragit RL 30 D and Eudragit RS 30 D are copolymers of acrylic and methacrylic esters with a small amount of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth) acrylic esters being 1:20 in Eudragit RL 30 D and 1:40 in Eudragit RS 30 D. The average molecular weight is about 150,
000. The code designation represents the permeation performance of those reagents, RL is highly permeable and RS is less permeable. The Eudragit RL / RS mixture is insoluble in water and is a digestible fluid. However, the coatings formed therefrom are swellable and are permeable to aqueous solutions and digestible fluids.

The Eudragit RL / RS dispersions of the present invention may ultimately be mixed together in any desired ratio to obtain a controlled release formulation with the desired dissolution pattern. Desired controlled release formulations are, for example, 100% Eudragit RL, 50% Eudragit RL and 50%
% Eudragit RS, and 10% Eudragit RL and 90% Eudragit RS, and 100% Eudragit RS derived from delayed goods coatings.

The hydrophobic acrylic polymer used in the present invention can be produced by any method known in the art, but bulk polymerization in the presence of an initiator that forms dissolved free radicals in the monomer mixture. Alternatively, there may be mentioned a method in which solution or precipitation polymerization is carried out in an organic solvent, and the polymer thus formed is then isolated 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 vinyl pyrrolidone. When such materials are used, the amount is as small as 20% by weight of the copolymer. It may also contain small amounts of ionic monomers such as acrylic acid or methacrylic acid, or an amino monomer that is the basis of the quaternized monomer.

In another embodiment of the invention, the hydrophobic acrylic polymer coating further comprises a polymer whose permeability is pH dependent, such as an anionic polymer synthesized from methacrylic acid and methyl methacrylate. Also good. Such polymers are commercially available from Rohm Pharma GmbH under the trade names Eudragit L and Eudragit S. The ratio of free carboxyl groups to ester is 1: 1 in Eudragit L and 1: 2 in Eudragit S. Eudragit L is insoluble in acid and pure water, but its permeability increases when the pH exceeds 5.0. Eudragit S is similar except that the permeability increases when it exceeds pH 7. Hydrophobic acrylic polymer coatings include dimethylaminoethyl methacrylate and neutral methacrylate (Eudragit E (Eu, commercially available from Rohm Pharma).
It may contain polymers whose properties based on dragit E) etc. are cationic. The hydrophobic acrylic polymer coating in the present invention is further made of poly (meth) such as Eudragit NE (NE = neutral ester) commercially available from Rohm Pharma.
A neutral polymer based on acrylic acid may be contained. Eudragit NE 30 D (Eu
dragit NE 30D) Lacquer coating is a digestible fluid that is insoluble in water, but is permeable and swellable.

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

The release of the active agent from the controlled release formulation of the present invention may be inorganic or organic and contains one or more substances containing substances that can be dissolved, extracted or filtered from the coating in the environment of use. It is further influenced, i.e. adjusted to the desired rate, by two or more pore formers. By exposing the fluid to the environment of use, the pore-forming agent is dissolved, for example, to form grooves or pores that are filled with the environmental fluid.

For example, the pore former may consist of one or more water-soluble hydrophilic polymers to alter the release characteristics of the formulation. Examples of suitable hydrophilic polymers include hydroxypropyl methylcellulose, cellulose esters, and protein derivatives. Of these polymers, hydroxyalkyl cellulose and carboxyalkyl cellulose are particularly preferred as the cellulose ester. As synthetic water-soluble polymers, polyvinyl pyrrolidone, crosslinked polyvinyl pyrrolidone, polyethylene oxide and the like are used, and water-soluble polydexrose such as pullulan, dextran, sucrose, glycolose, fructose, mannitol, lactose, mannose, galactose and sorbitol. , Saccharides and polysaccharides are also used. In certain preferred embodiments of the invention, the hydrophilic polymer is hydroxypropyl methylcellulose.

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

Semipermeable polymers may be incorporated into the controlled release coating as a pore former to alter the release characteristics of the formulation. Such semipermeable polymers include, for example, cellulose acrylate, acetate, and other semipermeable polymers such as those disclosed in US Pat. No. 4,285,987 (incorporated herein by reference), and the United States. Patent Nos. 3,173,876, 3,276,58
And selectively permeable polymers formed by the polycation and polyanion coprecipitation method disclosed in US Pat. No. 6,3,541,005, 3,541,006 and 3,546,142 (incorporated herein by reference).

Other pore formers useful in the formulations of the present invention include starch, modified starch, and starch derivatives; xanthan gum, alginic acid, other alginates, bentonite, bee gum, agar, guar, carob gum, arabic Rubber, quince silium (psyllium)
), Flaxseed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin rubber, etc .; cross-linked polyvinyl pyrrolidone; Examples thereof include ion exchange resins such as biosynthetic rubber. Other pore forming agents include substances useful for forming microporous thin films in the environment of use,
For example, polycarbonate consisting of a linear polyester of carbonic acid with repeating carbonate groups in the polymer chain; bisphenol, microporous poly (vinyl chloride), microporous polyamide, microporous modacrylic copolymer, microporous styrene-acrylic and its co-polymer Coalesced, porous polysulfone, halogenated poly (vinylidene), polychloroether, acetal polymer, polyether produced by esterification of dicarboxylic acid or anhydride and alkylene polyol, poly (alkylene sulfide), phenolic resin, polyester, Asymmetric porous polymer, cross-linked olefin polymer, hydrophilic microporous homopolymer, copolymer or intercopolymer with reduced bulk density, and other similar materials, poly (urethane), cross-linked chain extended poly (Urethane), Li (imide), poly (benzimidazole), collodion, refolded protein, although microporous material such as crosslinked semi-solid poly (vinyl pyrrolidones), are not limited to are not.

Generally, the amount of 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 passages are described in U.S. Pat.Nos. 3,845,770, 3,916,889, 4,063,064, and 4,
088,864 (all of which are incorporated herein by reference). The passage may take any shape such as a circle, a triangle, a rectangle, an ellipse, and an irregular shape. Instead of or in addition to including compounds that increase permeability, hydrophilic monomers, pH-sensitive polymers, and / or pore formers, the passageway provides for release of the active agent contained in the formulation. It may be included.

In one embodiment of the present invention, the hydrophobic polymer contained in the aqueous polymer coating dispersion is insoluble in water (such as a copolymer of acrylate and methacrylate without quaternary ammonium compounds). Yes, the release of the active agent is substantially controlled only through the presence of one or more passages through the coating.

Examples of suitable controlled release formulations according to the present invention include administration as measured in USP paddle method or basket method at 37 ° C. in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 100 rpm. The in vitro dissolution rate of the formulation, for example, for a 12 hour formulation (dose twice a day) releases about 0% to about 42.5% (by weight) of the therapeutically active agent after 1 hour, Releases about 25% to about 55% (weight) after 2 hours and about 45% to about 75% (weight) after 4 hours
And give a value of releasing more than about 55% (by weight) after 6 hours. Another example of a suitable controlled release formulation according to the invention is USP paddle method or basket method at 37 ° C. in 900 ml aqueous buffer (pH between 1.6 and 7.2).
When measured at rpm, the dissolution rate of the administered formulation in vitro is, for example, 2
For a 4-hour formulation (once daily), about 0% to about 42.5 (by weight) of active agent is released after 1 hour and about 5% to about 60% (by weight) of active agent is released after 2 hours. About 15% to about 75 after 4 hours
% (By weight) of the active agent is released, and after about 8 hours, from about 20% to about 90% (by weight) of the active agent is released. These examples of acceptable dissolution rates are that the formulation is an oral solid dosage formulation,
It relates to certain preferred embodiments of the invention and is not intended to be limiting in any way.

The coating formulations of the present invention are smooth and precise, can support pigments and other coating additives, are non-toxic, inert and non-sticky. It is possible to produce a tough 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 a plasticizer further improves the physical life of the coating. For example, the use of a plasticizer improves the elasticity of the coating and lowers the film forming temperature of the dispersion. Plasticization of the acrylic resin is achieved by any of so-called “internal plasticization” and “external plasticization”.

Internal plasticization is usually directly related to the molecular modification of the polymer in its manufacturing process, for example, copolymerization, modification and / or substitution of functional groups, adjustment of the number of side chains, or adjustment of the length of the polymer. Etc. Such techniques are usually not possible with coating solution formulations.

External plasticization is the addition of a substance to the membrane solution, thereby achieving the required change in membrane performance of the dried coating.

The suitability of a plasticizer depends on the affinity or solvency for the polymer and the impact that inhibits polymer-polymer adhesion. Such activity imparts the desired flexibility by reducing the rigidity of the molecule. In general, the amount of plasticizer contained in the coating solution is based on the concentration of the film former, for example, most often from about 1 to about 50% by weight film former. However, the concentration of the plasticizer can only be determined properly after careful experimentation with special coating solvents and methods of application.

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

An important parameter for determining an appropriate plasticizer for a polymer is the glass transition temperature (Tg) of the polymer. The glass transition point is the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not show a change in state, but rather a change in the polymer's macromolecular mobility. Below the Tg, the polymer chain mobility is severely limited. Thus, for a given polymer, if its Tg is above room temperature, the polymer behaves like glass and is not hard and flexible, but rather brittle, and the properties are somewhat limited in film coating. This is because the coated dosage formulation 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 atmospheric conditions the coating becomes softer, more flexible, and often tougher and resistant to mechanical stress. It becomes more possible to do.

Other aspects of suitable plasticizers include the ability of plasticizers to function as good “swelling agents” for acrylic resins.

Examples of suitable plasticizers for the acrylic polymers of the present invention include triethyl citrate
Examples include, but are not limited to, NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Eudragit RL / RS (trade name)
Other plasticizers that have proven 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 the acrylic polymers of the present invention.

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

The dissolution pattern of the final product can be determined, for example, by increasing or decreasing the thickness of the retarder coating, by changing the method of adding the plasticizer to the acrylic resin, and / or, for example, by the manufacturing method It can be changed by changing other aspects.

In certain preferred embodiments of the invention, the controlled release dosage formulation consists of pharmaceutically acceptable beads (eg, spherical) containing the active ingredients coated with a controlled release coating. The term spherical is known in the pharmaceutical field 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. A suitable such commercially available bead is the nu pariel 18/20 bead.

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

When an acrylic resin dispersion is used to coat inert pharmaceutical beads such as nu parei 18/20 mesh beads, the resulting stabilized solid controlled release beads are then When taken and contacted with gastric juice, it may be placed in a gelatin capsule in an amount sufficient to provide an effective amount of controlled release. In this embodiment, the beads coated with the therapeutically active agent can be prepared, for example, by dissolving the therapeutically active agent in water and then dissolving the solution, eg,
Wurster insert on a substrate such as Pariel 18/20 mesh beads
). If desired, additional components may be added prior to coating the beads, such as to help attach the active agent to the beads and / or to color the solution. For example, hydroxypropylmethylcellulose or the like, with or without a colorant, is added to the product containing it and mixed (eg, about 1 hour) before applying the solution to the beads. The resulting coated substrate may then optionally be overcoated with a barrier layer to separate the therapeutically active agent from the acrylic coating in the beads of this example. An example of a suitable barrier layer is that comprised 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 consisting of the active agent (and the 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. Pre-prepared dispersions of acrylic resins, such as various commercial forms of Eudragit, include Eudragit RS30S and Eudragit RL30D.

The coating solution of the present invention preferably contains a colorant for elegance and product distinction, in addition to the film former, plasticizer and solvent system (ie, water). 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 colored pigments such as titanium dioxide and iron oxide pigments. The introduction of pigments, however, increases the effect of hindering coating. Alternatively, any suitable method for coloring the formulations of the present invention may be used.

The plasticized coating of the acrylic polymer (and any optional permeabilizing compound and / or pore former) can be applied to the substrate comprising the therapeutically active agent using any suitable spray device known in the art. It may be applied by spraying. In a preferred method, a Wurster fluidized bed system is used, which fluidizes the material cored by an air jet injected from below and performs drying while the acrylic polymer coating is being sprayed. When the coated substrate is exposed to an aqueous solution, such as gastric juice, a sufficient amount of coating to obtain a predetermined controlled release of the therapeutically active agent is sufficient for the physical properties, plasticity of the therapeutically active agent. It is preferably applied in consideration of the method of introducing the agent. After application with an acrylic resin, a further overcoat of a film forming agent such as Opadry (trade name) may optionally be applied to the beads. This overcoat is made to substantially reduce the agglomeration of the beads, even if slightly agglomerated.

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

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

In accordance with the present invention, the curing step is performed with the coated substrate, eg, beads, at a temperature above the Tg of the coated formulation, and dissolution that is substantially unaffected by exposure of the coated formulation to elevated temperature and / or humidity storage conditions. Continue curing until the end point is reached, giving the pattern. In general,
The curing time is about 24 hours or more, 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 that exceeds ambient conditions during the curing process to achieve a stabilized end product.

One possible mechanism for changing the dissolution pattern of prior art products cured by standard methods is that they continue to cure during storage, so that the product has a substantially constant dissolution pattern. Is to never reach a stabilized endpoint. For it,
The cured product of the present invention provides 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 an oven at a temperature in excess of the Tg of the plasticized acrylic polymer for the required time. Optimum values of temperature and time for this formulation are determined experimentally.

In certain embodiments of the invention, the stabilized product is obtained by performing oven curing at a temperature of about 45 ° C. for about 24 to about 48 hours. In some embodiments,
The product is preferably cured, for example, for about 36 hours. In certain preferred embodiments, the product is cured for about 48 hours. It is contemplated that certain products coated with the controlled release coating of the present invention may require curing times longer than 48 hours, for example 60 hours or longer. Those skilled in the art will appreciate that the curing conditions depend on the particular drug introduced into the formulation, as well as the film thickness of the controlled release coating, and the size of the substrate (eg, tablets compared to beads).
We recognize that it is influenced by.

It is particularly conceivable that the time required to cure to the end point described above may actually be longer or shorter than the time described above. Such cure times that achieve the intended result of the stabilized formulation are encompassed by the above claims. Furthermore, those skilled in the art will also appreciate that the aqueous dispersion coated substrate of the present invention can be cured by other methods to reach an end point that gives a stable dissolution pattern of the coated substrate. . Additional curing methods (such as sonication) that achieve the intended results of the stabilized formulation are also considered to be encompassed by the above claims.

The endpoint of cure is the dissolution pattern of the cured coated substrate (eg, “substrate”) immediately after curing (hereinafter referred to as the “initial dissolution pattern”) and dissolution of the formulation after exposure to accelerated storage conditions. It is determined by comparing with the pattern. Generally, the end point of curing is, for example, 37
Determined by comparing the dissolution pattern of the formulation after exposure to accelerated storage conditions to an initial dissolution pattern for a period of one month at 0 ° C / 80% RH or 40 ° C / 75% RH. However, the endpoint of cure continues to expose the cured coating formulation to accelerated storage conditions for an additional period of time, and further, for example, the dissolution pattern of the formulation after exposure for 2 months and / or 3 months Further confirmation may be made by comparison with the initial dissolution pattern obtained.

In certain preferred embodiments of the invention in which the cured coated substrate is a pharmaceutical formulation, the endpoint of cure is a graph of the dissolution curve obtained after exposing the data points, for example, for 1-3 months at accelerated conditions. In-virto obtained when drawn along and performed prior to storage
), The release of active agent remains unchanged at any given time until it exceeds about 15% of the total amount of active agent released. Such differences in dissolution curves in-vitro are referred to in the industry as, for example, 15% “band area” or “band width”. Generally, after exposure to in-vitro dissolution and accelerated conditions prior to storage, for example, when the total amount of active agent released changes in an amount not greater than about 20% The formulation can be approved by government regulatory agencies such as the US FDA, considering stability issues and expiration dates. The acceptable band region is F
Any band areas for specific drugs that are determined on a case-by-case basis by the DA and deemed acceptable to such government regulatory bodies are considered to fall within the scope of the above claims. . In a preferred embodiment, the band region described 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 region is often less than 5%.

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

In certain embodiments of the present invention, the coated substrate comprises an additional amount of active in a controlled release coating comprising an aqueous dispersion of a hydrophobic polymer or an additional overcoat coated on the outer surface of the controlled release coating. Contains agents. This is desirable, for example, when a loading of therapeutically active agent is required to provide a therapeutically effective blood level of the active agent when the formulation is first exposed to gastric fluid. In such cases, an additional protective coating (eg HPMC)
It may be included to separate the immediate release coating layer from the controlled release coating layer.

Active agents contained in the controlled release preparation of the present invention include systemically active therapeutic agents, locally active therapeutic agents, disinfectants, chemical impregnants, detergents, deodorants, fragrances, dyes, animal repellents, Insect repellent,
Examples include fertilizers, insecticides, herbicides, fungicides, and plant growth stimulants.

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 include antihistamines (eg, dimenhydrinate, diphenhydrinate, chlorpheniramine and chlorpheniramine d-maleate), analgesics (eg, aspirin, codeine, morphine, dihydromorphine). , Oxycodone, etc.), non-steroidal anti-inflammatory agents (eg naproxin, diclofenac, indomethacin, ibuprofen, sulindac), antiemetics (eg metoclopramide), antiepileptics (eg phenytoin, meprobamate and nitrezepam)
Vasodilators (eg nifedipine, papaverine, diltiazem and nicardiline)
Antitussives and expectorants (eg, codeine phosphate), antiasthmatic agents (eg, theophylline), antacids, anticonvulsants (eg, atropine, scopolamine), antidiabetic agents (eg, insulin), diuretics (eg, For example, ethacrynic acid, bendrofluazide), antihypertensive drugs (eg, propranolol, clonidine), antihypertensive drugs (eg, clonidine, methyldopa), gastroscals (eg, albuterol), steroids (eg,
Hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), antiepileptic drugs, hypnotics, psychotropic drugs, antidiarrheal drugs, mucolytic agents, analgesics, decongestants, laxatives, vitamins, stimulants (phenyl) Propanolamine appetite suppressants), and their salts, hydrates and solvates. The above list is not intended to be limiting.

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

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

Topically active agents include antibacterial agents (eg, amphotericin B, clotrimazole,
Nystatin, ketoconazole, miconazole, etc.), antibiotics (penicillin, cephalosporin, erythromycin, tetracycline, aminoglycoside, etc.), antiviral agents (eg, acyclovir, idoxuridine, etc.), fresh breath agents (eg, chlorophyll)
, Antitussives (eg, dextromethorphan hydrochloride), anti-caries agents (eg, fluoride metal salts, sodium monofluorophosphate, tin fluoride, fluorinated amines), analgesics (eg, methyl salicylate, salicylic acid, etc.) Local anesthetics (eg benzocaine),
Oral preservatives (eg, chlorhexidine and its salts, hexyl resorcinol, dequalinium chloride, cetylpyridinium chloride), anti-inflammatory agents (eg, dexamethasone, β
-Methasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.)
Hormonal agents (estriol), anti-plaque agents (chlorohexidine and its salts, octenidine, and thymol, menthol, methisalicylate, eucalyptol), acidity reducing agents (eg, dibasic potassium phosphate Buffering agents, calcium carbonate, sodium bicarbonate, sodium hydroxide and potassium, etc.), and tooth desensitizers (eg, potassium nitrate). This list is not intended to be limiting.

In another preferred embodiment of the present invention, the active agent is a disinfectant such as a chlorine compound such as calcium hypochlorite and the environment of use is water surrounding the human body such as a recreational pool. is there.

Yet another preferred embodiment of the present invention is that the active agent is at least one detergent, disinfectant,
It consists of deodorants, surfactants, fragrances, fragrances, disinfectants, and / or dyes, and the usage environment is, for example, a urinal or toilet.

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

For example, if the coated substrate is a coated chlorine tablet to combat bacterial and algicidal contaminants such as swimming pools, the substrate can be from commercially available calcium hypochlorite, as well as trichloroisocyanuric acid, sodium dichlorocyanurate. , Lithium hypochlorite, powdered lime, and / or
Or it may consist of something else present or absent.

For example, the substrate comprises about 98.5% by weight of commercial calcium hypochlorite and about 1.5% by weight.
May be made of powdered lime. The substrate can also be about 69% effective, as described in US Pat. No. 4,192,763, which is incorporated by reference, commercially available granular calcium hypochlorite, up to 20% by weight lime chloride, and incorporated herein by reference. It may consist of 1% zinc stearate having a percent chlorine and a mass of about 57 g and a diameter of about 40 mm. The substrate is then coated with an aqueous dispersion of the plasticized hydrophobic polymer with the desired adhesion weight, and the coated tablets are then endpoints according to the present invention that are cured coated tablets that give a reproducibly stable dissolution pattern. Until it reaches

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

Some possible examples of such products include 0.5-5% fragrance, 1-10% dye, 10-40% surfactant (which can be nonionic, cationic, anionic or zwitterion And a substrate composed of other optional ingredients such as disinfectants, disinfectants, processing aids, and other commonly contained ingredients known to those skilled in the art. Good.
Such active agents may be introduced into the substrate consisting of tablets together with other known ingredients such as retarders, surfactants, fragrances, dyes, and any fillers required.

The substrate, on the other hand, is, for example, 1 g azure blue dye 65% (Hilton.
1 g Pluronic (a dye available from Hilton David)
ic) F-127 (nonionic surfactant consisting of condensation products of ethylene oxide and products obtained by reaction of propylene oxide and ethylenediamine; commercially available from BASF-Wyandote Chemicals) ), 38 g of Carboisk 8000 (solid polyethylene glycol, molecular weight 8000; Union Carbide (Unio)
n commercially available from Carbide), 40 g of Kemamide U (oleylamide surfactant; commercially available from Witco) and optional fragrances (eg,
0.5% by weight of citrus pine fragrance) together, and then the above-mentioned masses of ingredients are mixed by conventional methods such as noodle formation, extrusion, extrusion and cutting and punching to form pellets. It may be made of pellets produced by making pellets.
If desired, the pellets may contain an appropriate amount of inorganic salt and one or more binders such as guar gum to place the pellets at the bottom of the tank. The pellets are then coated with an aqueous dispersion of a plasticized hydrophobic polymer with an adhesion weight of about 2 to about 30%, depending on the desired dissolution rate, and the coated pellets are then reproducible according to the present invention. Cured until reaching an end point that results in a cured coated pellet giving a stable dissolution pattern.

Other examples of substrates useful for the treatment of toilet sink water, introduced here by reference,
It consists of iodophors such as povidone iodine as described in US Pat. No. 5,043,090.

Where the substrate consists of a fragrance, the fragrance can be, for example, an ester, ether, aldehyde,
It can be any commercially available perfume oil such as volatile compounds including alcohols, unsaturated hydrocarbons, terpenes, and other ingredients known in the art.

When the active agent comprises a composition suitable as a fertilizer, the active agent is coated with an aqueous dispersion of a plasticized hydrophobic polymer such that the adhesion weight is from about 2 to about 30% and then cured according to the present invention. It may be made of granular urea. In the production of urea granules, 70% solids concentration urea is heated in water to remove substantially all of the water. The molten urea is then injected as droplets into an air cooling tower where crystalline urea is formed as hard granules or beads, which are
It is then coated and cured according to the present invention.

When the substrate consists of a vegetable food formulation, the substrate can be in the form of pellets, spheres, particles or rods, such as gibberellic acid, along with soil fungicides such as formaldehyde and paraformaldehyde It may further contain a substance accelerated in growth.

FIG. 1 is a split screen scanning electron micrograph (SEM) of a theophylline bead coated according to the present invention prior to curing. The magnification on the left is 77x and the magnification on the right is 540
Is double. The coating is an aqueous dispersion of Eudragit. SEM shows clear particles of acrylic polymer in the coating. For example, due to cracks or holes in the coating, the coating causes the active agent to pass from the underlying nuclei containing the active agent into the environmental liquid.

FIG. 2 is a SEM after the beads shown in FIG. 1 have been cured for 48 hours in a 45 ° C. oven. The magnification on the left is 77x and the magnification on the right is 1100x. FIG.
The SEM of the company favors obvious morphological changes in the bead surface coating. This cure is
It is thought to play an important role in stabilizing the dissolution pattern of the coated substrate.

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

Tablets coated with a sufficient amount of acrylic resin coating to achieve a controlled release formulation according to the present invention may be manufactured 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 range of elevated temperatures, elevated humidity and time to obtain a stabilized product will depend on the particular formulation. Will do.

The following examples describe various aspects of the present invention. They are not intended to limit the scope of the invention in any way.

Example 1
Manufacture of hydromorphone beads Hydromorphone beads are dissolved in water, hydromorphone hydrochloride, and Opadry Y
-5-1442, Light Pink (Color On, West Point, Pennsylvania (Coloron, W
estpoint, Pennsylvania) products, including hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, titanium dioxide, polyethylene glycol and D & C Red No. 30 aluminum lake) at 20% w / w, about 1 Mix for hours and then spray using a Wurster insert onto nu pariel 18/20 mesh beads. The obtained product had the composition shown in Table 1 below.

Example 2
No retarder coating-curing step In Example 2, the hydromorphone beads produced in Example 1 were overcoated with Eudragit RS 30 D to give a 5% adhesion weight as shown in Table 2. .
Drying to the end point was not performed.

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

The dissolution test was performed according to the USP basket method at 37 ° C. at 100 RPM, with the first time being 700 ml of gastric juice at pH 1.2, then 900 ml and pH 7.5. Dissolution was performed in open capsules containing the appropriate amount of beads in a container. The results are shown in Table 3 below.
It describes.

The above results indicate that the dissolution of hydromorphone hydrochloride from the coated beads is slow when the beads are placed under accelerated storage conditions.

Example 3
Protection of retarder coating To examine whether the slow dissolution of the hydromorphone beads of Example 2 is due to stability problems between the hydromorphone and the retarder, in Example 3, Nupariel Hydro Morphone beads were prepared as in Example 1 and then overcoated with 5% HPMC and tested without forming a retarder layer. Dissolve test first and then at 37 ° C
After drying and storage at accelerated conditions of 37 ° C./80% RH.

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

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

In order to quantify the relative humidity under “drying conditions” in the oven, the relative humidity in a 60 ° C. oven in a desiccator filled with water 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 the desiccator and left in an oven at 60 ° C. for 24 hours. After 24 hours, the relative humidity in the desiccator was 85%, but the temperature was still 60 ° C. When only the hygrometer 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 produced according to Example 3 were coated with Eudragit RS to a 5% adhesion weight. After applying the coating, the beads were dried (cured) for 2 hours at 45 ° C. in a fluid bed dryer. This temperature is above the Tg of Eudragit RS 30 D, plasticized with triethyl citrate at a solids level of 20%. Dissolution tests were performed initially and after storage at 37 ° C. and 37 ° C./80% RH. The results are shown in Table 5 below.

From the above results, the dissolution of hydromorphone from the tested beads changed drastically upon storage and was recommended by the literature and the shortened curing process utilized in Example 4 is:
It has been found that it does not help stability / curing problems.

Examples 5-7
Optimization of Curing and Delay Coating Components The results obtained from Examples 2-4 show that dissolution of beads overcoated with a retarder coating is
It seems to slow down to a certain point, but no further change. However, the end point dissolution achieved was too slow.

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

Eudragit RL (methacrylic acid ester 1:20, which is more soluble than to obtain a formulation with a more appropriate dissolution curve, and than to reduce the coating to less than 5% weight of attachment.
Quaternary ammonium groups) were included in the delayed coating.

In Examples 5-7, hydromorphone beads were used that were prepared in the same manner as Example 4 except that they were overcoated with 5% HPMC to protect the retarder coating from the environment. In Example 5, the retarder coating consists of 100% Eudragit RL. Example 6
The retarder coating consists of 50% Eudragit RL and 50% Eudragit RS. Finally, in Example 7, the retarder coating consists of 10% Eudragit RL and 90% Eudragit RS. Each of Examples 5-7 was coated to a total weight of 5%.

Each of the HPMC-protective coatings of Examples 5 to 7, was 1, 2, 7, 10,
It was cured for 21 and 30 days and subjected to dissolution testing for each time as described in Example 2.

Only Example 7 showed the desired release pattern and the cure was also complete after 1 day. The solubility studies of the products of Examples 5 and 6 are equivalent to those obtained with the immediate release product, and even after the formulation is cured, the amount / type of retarder used is the speed of the drug. Not enough to prevent release (
That is, about 100% of the drug is released in about 1 hour). Example 7 was further tested as follows under accelerated conditions. After curing for 21 days, the sample of Example 7 was placed in a 37 ° C./80% RH oven and dissolution tests were performed after 7 and 30 days in the same manner as described in Example 2. A typical dissolution pattern of Example 7 (average result of 3 samples) is shown in Table 6 below.

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

Examples 8-10
Optimizing the retarder coating thickness In Examples 8-10, to determine the optimum weight of the methacrylate polymer for use in the desired release pattern, as well as a 48 hour curing step in a dry environment at 45 ° C. Additional tests were performed to determine reproducibility and efficacy at Three batches were produced 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.

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

Examples 9 and 10 were prepared in the same manner as Example 7. In Example 9, the retarder coating consists of Eudragit RS and Eudragit RL 90:10 (8% w / w coating). In Example 10, the retarder coating had a Eudragit RS and Eudragit RL of 90:10 (
12% w / w coating). The formulations of Examples 9 and 10 are shown in Tables 9 and 10 below, respectively.

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

The initial dissolution pattern (after curing) of Example 8 was shown to be similar to that of Example 7 (both products of both examples were overcoated with 5% w / w Eudragit coating). ). After curing for 2 days, the sample of Example 8 was room temperature and 37 ° C / 80% RH, 37 ° C dried and 50 ° C.
It was subjected to further testing under accelerated drying conditions. Typical dissolution pattern of Example 8 (
The average results for three samples) are shown in Table 11 below.

As is apparent from the dissolution results given by Example 8, the dissolution pattern of the sample after 1 day of curing was not taken, but the results obtained after 2 days of curing were obtained after 1 day and 2 days of curing in Example 7. The results were virtually identical. Therefore, the product of Example 8 is assumed to be stable even after 1 day of cure.

After curing for 2 days, the sample of Example 9 was tested for solubility and then the sample of Example 9 was
Exposed for 1 month under accelerated conditions of 80% RH. A typical initial dissolution pattern (average result of 3 samples) for Example 9 is shown in Table 12 below.

As is apparent from the solubility results given by Example 9 above, the results obtained after 2 days of curing are substantially identical to the results obtained under accelerated storage conditions of 37 ° C./80% RH. Therefore, Example 9 shows that it is stable after 2 days of curing. Furthermore, the solubility results obtained with 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, and then the sample of Example 10 was then subjected to accelerated conditions of room temperature and 37 ° C / 80% RH, 37 ° C drying and 50 ° C drying. Further tests were carried out after storage. Typical dissolution pattern for Example 10 (average results for 3 samples)
Is shown in Table 13 below.

As is apparent from the above solubility results given by Example 10, the solubility results obtained by Example 10 are in comparison with the thinner retarder coatings of Examples 8 and 9, as expected. Showed a slower release rate of hydromorphone. All results obtained after 2 days of cure are 8 hours and 1 in comparison to the results obtained under accelerated conditions of 37 ° C./80% RH.
Except for the amount of drug dissolved (%) at 2 hours, it is substantially the same. Those results are
A high amount of retarder coating indicates that a long time may be required to cure the coating to obtain a stabilized formulation.

Example 11
Morphine sulfate coated beads In Example 11, the curing process of the present invention was applied to a formulation in which morphine sulfate was substituted as a drug.

A suspension of morphine sulfate and HPMC (Opadry Clear Y-5-7095) on 18/20 mesh Nupariel beads in a fluid bed drier at a temperature of 60 ° C, using a Wurster insert And applied. Opadry lavender YS-1-4729 HPMC-based suspension for film coating was then applied at a 5% adhesion weight as a protective coating after drug application.

After the overcoat process is complete, morphine sulfate beads, then Eudragit RS
A mixture of 30D and Eudragit RL 30 D retarder with a ratio of RS to RL of 90:10 and 5
The overcoat was at a weight percent adhesion level. This mixture of Eudragit RS 30 D and Eudragit RL 30 D was carried out in a Wurster insert at an introduction temperature of 35 ° C. with talc (contained as an anti-blocking agent) and triethyl citrate (plasticizer).

Once the retarder overcoat was finished, the morphine sulfate sulfate was finally overcoated with Opadry Lavender YS-1-4729 at a 5 wt% adhesion level.

After the final membrane coating process is complete, the morphine sulfate beads can be
Cured for 2 days at ° C. After curing, the beads were filled into gelatin capsules with a strength of 30 mg morphine sulfate. The final composition is shown in Table 14 below.

Next, for the sample of Example 11, a solubility stability test was performed after the curing step described above.
After storage under accelerated conditions of room temperature, 37 ° C./80% RH, 37 ° C. drying and 50 ° C. drying, one month later and two months later. The results are shown in Table 15 below.

The results listed in Table 15 show that the curing process stabilizes the dissolution pattern of morphine sulfate even when the sample is stored under accelerated conditions and maintains the dissolution rate to the end point substantially constant. Is shown.

Example 12
Controlled release hydromorphone hydrochloride 8 mg formulation-acrylic polymer coating Example 12 was prepared as follows.

1. Drug formulation: Hydromorphone beads, Hydromorphone hydrochloride dissolved in water, Opadry Y-5-1442, Light pink (Colorcon, West Point, Pennsylvania (Color on
Product commercially available from Westpoint, PA), hydroxypropyl methylcellulose,
Hydroxypropylcellulose, titanium dioxide, polyethylene glycol and D & C red No. 30 aluminum lake) were added and mixed for about 1 hour to give a 20% w / w suspension. This suspension was then sprayed onto a Nupariel 18/20 mesh bead using a Wurster insert.

2. First overcoat: The coated hydromorphone beads are then
Light pink was overcoated with a Wurster insert so that 5% w / w adhesion was achieved. This overcoat was applied as a protective coating.

3. Retarder coating: after forming the first overcoat, to hydromorphone beads, then
Eudragit RS 30 D and Eudragit RL 30 D R to adhere to 5% by weight
A retarder coating mixture was coated with a 90:10 ratio of S to RL. Triethyl citrate (plasticizer) and talc (anti-adhesive) 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 coated with 5% by weight of Opadry Light Pink as a final overcoat using a Wurster insert. 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 cured beads were then filled into gelatin capsules to 8 mg hydromorphone strength. The complete formulation of Example 12 beads is listed in Table 16 below.

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

The solubility studies of the Eudragit-coated hydromorphone beads listed in Table 17 above show that the initial solubility is comparable to that performed when the sample was placed at 37 ° C./80% RH. ing.

Example 13
In Example 13, a cross-over study (washout in one week) randomized six methods at a single dose was performed on 12 patients and obtained with an equal dose of immediate release formulation. Compared with the results. Blood samples are initially 0.25, 0.5 after administration to quantify plasma levels.
, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 18, 24, 30
, 36 and 48 hours. Comparative Example 13A is an 8 mg hydromorphone immediate release formulation (2 Dilaudid 4 mg tablets, commercially available from Knoll). Example 13
8 mg dose of the encapsulated hydromorphone beads of Example 12.

The results obtained by Comparative Example 13A are shown in FIG. The results obtained in Example 13 are described in FIG. FIG. 5 shows the plasma levels of Example 13 plotted against the results of Comparative Example 13A. The results for Example 13 are further described in Table 18 below. The data is the area under the curve (bioavailability), the maximum plasma concentration (C _max )
And the time to reach maximum plasma concentration (T _max ).

The results obtained for Example 13 show that at 12 hours after administration, the blood level of hydromorphone exceeds 500 pg / ml hydromorphone and the plasma level at 24 hours after administration is well above 300 pg / ml. ing. This product is therefore considered suitable for once daily administration.

Examples 14-15
In Examples 14-15, four randomized crossover studies were performed on 10 subjects at a single dose. Example 14 was tested with 8 mg hydromorphone beads from Example 13-fasted and Example 15 was tested with 8 mg hydromorphone beads from Example 13-diet. Comparative Example 1
In 4A, 8 mg immediate release hydromorphone (two Dilaudid 4 mg tablets)
Was administered to those who fasted. In Comparative Example 15A, 8 mg immediate release hydromorphone (two Dilaudid 4 mg tablets) was administered to those who had a meal.

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 to 15 and Comparative Examples 14A and 15A are further described in Table 19. This is the area under the curve and the percentage of absorption compared to that of immediate release (biological utility), the maximum plasma concentration (C _max ), and the time to reach the maximum plasma concentration (T
data on _max ).

As can be confirmed from the results obtained in Examples 14 to 15 and Comparative Examples 14A and 15A, both the immediate release tablets and the controlled release beads of Examples 14 and 15 have little food effect. The biological utility of 14 and 15 controlled release beads is slightly increased. The plasma level confirmed again that this product is suitable for once daily administration. 24
In time, this controlled release product gave plasma levels close to 600 pg / ml, and in 12 hours 700 pg / ml
Plasma levels above ml were given.

Examples 16-17
In Examples 16 to 17, three kinds of crossing tests were performed for 4 days in a steady state. Comparative Example 16A
, Subject to immediate release hydromorphone every 6 hours (2 tablets of Giraudide 4 mg) 8
mg was administered. In Example 16, 8 mg of hydromorphone beads of Example 15 were administered every 12 hours. In Example 17, 8 mg of the hydromorphone beads of Example 13 were administered every 24 hours. A blood sample was taken on the fourth day.

The plasma levels of Examples 16 and 17 relative to the plasma levels of Comparative Example 16A are listed in FIG. The plasma levels of Examples 16 and 17 relative to the valley levels of Comparative Example 16A are listed in FIG. 9 (the values for Example 17 were doubled in FIG. 9). The results for Examples 16 to 17 and Comparative Example 16A are further shown in Table 20. It is the data for the area under the curve and the percentage of absorption compared to that of immediate release (biological utility), maximum plasma concentration (C _max ), and time to reach maximum plasma concentration (T _max ). I will provide a.

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

Furthermore, in this study, Example 17, which was only administered 8 mg every 24 hours, showed that this formulation doubled the amount of beads and hydromorphone administered as an immediate release formulation (4 mg every 6 hours). If given the same amount of 16 mg once a day, it provides an excellent 24 hour formulation. For Example 17, the minimum or trough concentration shown in FIG.
It would be equivalent to mg immediate release formulation (administered every 6 hours), thus indicating that it would give an excellent once-daily product.

Example 18
Controlled release morphine sulfate 30 mg formulation-acrylic polymer coating Example 18 was prepared in the same manner as the above example. The complete formulation of the beads of Example 18 is listed in Table 21 below.

The ratio of Eudragit RS 30 D to Eudragit RL 30 D is 98: 2. After completion of the final overcoat, the morphine beads were cured in an oven at 45 ° C. for 2 days. The hardened beads were then filled into gelatin capsules with a strength of 30 mg.

The final product was done initially; after storage at room temperature for 3 and 6 months; and after exposure to accelerated storage conditions (40 ° C / 75% RH) for 1 month, 2 months and 3 months . The results are shown in Table 22 below.

  The solubility listed in Table 22 indicates that the beads of Example 18 are stable.

A double-blind, single-dose crossover study, followed by a standard commercially available controlled-release morphine sulfate tablet (comparative example 18A, MS Contin ( (Trade name) and Purdue Fredrick). The results are shown in Table 23.

From the data obtained from Example 18, it can be seen that the product is suitable for once daily administration.

Examples 19-20
Examples 19 to 20 are highly formulated base beads manufactured so that the blending amount of morphine sulfate is large. Therefore, a large dose can be easily administered once a day. Highly loaded beads are produced by layering the powder in a Glatt Rotor Processor. The formulations of Examples 19-20 are listed in Table 24 below.

Since the base bead is different compared to the low-blend bead used in Example 18, more and more soluble Eudragit RL is included in the blend, between the Eudragit layer and the morphine immediate release layer. By providing an extra HPMC protective coating, the stability is further enhanced.

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

The beads were then cured in an oven at 45 ° C. for 2 days and then divided into two. The first part was filled into hard gelatin capsules with a strength equivalent to 60 mg, and the second part was filled into hard gelatin capsules with a strength equivalent to 30 mg.

The solubility of the two strength capsules was examined. The data shows that the percentage of dissolved morphine is the same for both intensities. A stability test was performed on 60 mg capsules. The results for the 60 mg capsule are listed in Table 26 below.

The bioavailability test was then performed with a 30 mg strength capsule (Example 19 = Fast, Example 2
0 = food) was fasted with 30 mg of MS contin (Example 19A) as a control.

  The results are listed in Table 27.

FIG. 10 shows Comparative Example 19A versus plasma levels of Examples 19-20 (both diet and fast).
It is a graph which shows the plasma level obtained by this. From the data obtained it can be seen that the product is suitable for administration once a day.

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

First, an immediate release APAP core was prepared as a tablet with a core weight of 555.6 mg by compressing Compap coarse L. Compass Course L is about 90%
Is a directly compressible material commercially available from Mallinckrodt, Inc., St. Louis, MO, containing pharmaceutical grade excipients including the following APAP and binders, disintegrants and lubricants is there. The APAP tablet core contains about 500 mg of APAP. COMPUP Course L
Is compressed using a rotary tablet press equipped with a smooth molding tool with a 7/16 ″ circular standard concave lid. The core is compressed at a theoretical weight of 555.6 mg and a hardness of about 8-9 Kp. .

Next, the APAP tablet core produced as described above is coated with the controlled release coating of the present invention as follows.

Approximate amounts of Eudragit RS-30 D and Eudragit RL-30 D are mixed and purified water is added. The amount of purified water is such that the final coating suspension is about solid polymer, plasticizer and talc.
Calculated to have a concentration of 20%. Then triethyl citrate was added and mixed for 15 minutes. Then talc was added and mixed for an additional 15 minutes. An appropriate amount of APAP tablet core was blended into Accela Cota coat-ing pan. The coating suspension was sprayed using a suitable spraying device (spray gun) until the polymer coating was 4% attached weight per tablet.

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

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

After the coating process is finished, the functionally coated tablets are discharged into the curing tray and are indoors.
Cured for 48 hours at 0C. The results of the solubility test for the cured tablets are shown in Table 29 below.

Example 22
In Example 22, controlled release acetaminophen (APAP) tablets were prepared. If required to provide rapid dissolution, increase the amount of Eudragit RL-30 D and decrease the amount of Eudragit RS-30 D. Thus, controlled release APAP tablets containing only Eudragit RL-30 D and no Eudragit RS-30 D were produced. APAP
The core was produced in the same manner as in Example 4. Next, the APAP tablet core produced as described above was coated with the release control coating of the present invention as follows: purified water with Eudragit RL-30 D
Added to. The amount of purified water was calculated so that the final coating suspension concentration was about 20% with solid polymer, plasticizer and talc. Then triethyl citrate was added and stirred for 15 minutes. Then talc was added and stirred for 15 minutes. An appropriate amount of APAP tablet core was added to the Accela Cota coating tank. The coating suspension was sprayed from a suitable spray gun until the polymer had a 4% adhesion weight per tablet.

After the spraying of the functional coating was completed, the tablet was sprayed with Opadry coating paint to prevent the tablets from sticking. This 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.

After the coating process was completed, the functional coated tablet was placed in a curing tray and cured in a bath at a temperature of 45 ° C. for 48 hours. The solubility test of the coated tablet was performed, and the data described in Table 31 below was obtained.

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

Claims (21)

A controlled release formulation comprising a solid substrate comprising an effective amount of a therapeutically active agent, wherein the solid substrate controls the therapeutically active agent when exposed to gastric juice after the substrate is coated. Coated with an aqueous dispersion containing a plasticized acrylic polymer and a compound that increases permeability in an amount effective to release and provide a formulation suitable for once daily administration And the coated substrate has a predetermined dissolution time when subjected to in vitro dissolution after being exposed to accelerated storage conditions at 40 ° C. and 75% relative humidity for at least one month after curing. About 2% of the total amount of therapeutically active agent released compared to the in vitro dissolution performed prior to storage at any point in time.
Until an endpoint is reached that releases an amount of the therapeutically active agent that does not change more than 0%,
A controlled release formulation characterized in that it is cured at a temperature above the glass transition temperature of the aqueous dispersion and the coating provides a therapeutically effective blood level for at least 24 hours. A solid controlled release oral dosage formulation comprising a substrate containing a sufficient amount of a systemically active therapeutic agent to provide a desired therapeutic effect when administered orally, the substrate comprising about 2% to about 25
% Coated weight with an aqueous dispersion containing a plasticized acrylic polymer and a compound that increases permeability, the coating being 900 m at 37 ° C. according to the USP Baddle Method
When measured at 100 rpm with 1 aqueous buffer (pH 1.6-7.2), 12.5-42.5% (by weight) of active agent is released after 1 hour and 25%- The activity of releasing 55% (by weight) of active agent, releasing 45% to 75% (by weight) of active agent after 4 hours and releasing 55% to 85% (by weight) of active agent after 8 hours Sufficient to obtain controlled release of the agent, and when the coated substrate is subjected to accelerated storage conditions of at least 1 month at 40 ° C. and 75% relative humidity after curing, in vitro dissolution Release any amount of the therapeutically active agent that does not change by more than about 20% of the total amount of the therapeutically active agent released at any point in time compared to the in vitro dissolution performed prior to storage. A temperature higher than the glass transition temperature of the aqueous dispersion until the end point is reached A solid controlled release oral dosage form characterized in that it is cured with a coating and the coating provides a therapeutically effective blood level for at least 24 hours. A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide the desired effect in the environment of use, wherein the active agent is a disinfectant, detergent, fragrance, fertilizer, deodorant Selected from the group consisting of agents, dyes, animal repellents, insect repellents, insecticides, herbicides, fungicides, and plant growth stimulants, the substrate when the formulation is exposed to the surrounding liquid Coated with an aqueous dispersion comprising a plasticized acrylic polymer and a compound that increases permeability in an amount sufficient to obtain a controlled release of the active agent, the coated substrate comprising: A temperature higher than the glass transition temperature of the aqueous dispersion for at least 24 hours, until the end of cure is reached, which gives a stable solubility of the active agent that does not change after exposure to accelerated storage conditions The end point is cured. Determined by comparing the dissolution pattern of the subsequent formulation with the dissolution pattern of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37 ° C. and a relative humidity of 80%, wherein the coating is at least A controlled release formulation characterized in that it provides a therapeutically effective blood level for 24 hours. The accelerated condition of the coated substrate after being exposed to at least one month of accelerated storage conditions at a temperature of 40 ° C. and a relative humidity of 75% during an in vitro dissolution test. Providing a band region that is not broader than about 15% of the total active agent released at any point in time when compared to the dissolution pattern prior to exposure to water.
The preparation described in 1. The coated substrate coalesces the individual acrylic polymer particles in the coating until the band region is obtained and gradually slows down the release of the active agent when exposed to the surrounding liquid. The preparation according to claim 3 or 4, which is cured at a temperature higher than the glass transition temperature of the aqueous dispersion. 4. A formulation according to claim 1 or 3, characterized in that the substrate is coated with an adhesion weight of about 2% to about 25%. The therapeutically active agent is an antihistamine, an analgesic, a non-steroidal anti-inflammatory agent, a gastrointestinal agent, an antiemetic,
Antiepileptics, vasodilators, antitussives, expectorants, antiasthmatics, hormones, diuretics, antihypertensives, antihypertensives, bronchodilators, antibiotics, antivirals, antiepileptics, steroids The composition is selected from the group consisting of a sleeping agent, a psychotropic agent, an antidiarrheal agent, a mucolytic agent, a sedative, a decongestant, a laxative, a vitamin agent and a stimulant. 6. The preparation according to any one of 6. The substrate is a pharmaceutically acceptable bead and a plurality of the coated hardened beads in the capsule in an amount sufficient to provide an effective dosage with controlled release when contacted with an aqueous solution. The preparation according to any one of claims 1 to 7, wherein the preparation is contained. 9. The preparation according to any one of claims 1 to 8, characterized in that the substrate is a tablet core. The therapeutically active agent is an opioid selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, any salt thereof, and mixtures thereof. The preparation according to any one of claims 1 to 8, wherein the preparation is an analgesic. The coating is cured for about 24 to about 48 hours.
The preparation of any one of -3. 12. A compound according to any of claims 1 to 11, characterized in that the compound which increases the permeability is contained in an amount effective to modulate the release rate of the therapeutically active agent from the cured coated substrate. 1. The preparation according to item 1. The compound that increases permeability is a monoethylenically unsaturated compound capable of free radical polymerization.
The preparation according to any one of claims 1 to 3, which is a quaternary ammonium compound. 4. The coated substrate of claim 1, wherein the coated substrate comprises at least one passage through the coating that alters the release of the systemically active therapeutic agent. The preparation according to item. 4. A stable dissolution of the active agent which does not change after 3 months exposure to accelerated storage conditions at a temperature of 40 [deg.] C. and 75% relative humidity. 1. The preparation according to item 1. The preparation according to any one of claims 1 to 3, characterized in that a part of the amount of the active agent contained in the preparation is blended in the coating of the substrate. When the dissolution pattern after exposure to accelerated storage conditions for at least 1 month at a temperature of 40 ° C. and 75% relative humidity is compared to the dissolution pattern before exposure to the accelerated conditions described above, 6. A formulation according to claim 5, characterized in that the band area does not change by more than about 7%. 4. A formulation according to claim 1 or 3, characterized in that the substrate is coated with an adhesion weight of about 2% to about 50%. The acrylic polymer comprises a mixture of a copolymer of an acrylic ester and a methacrylic ester having a molar ratio of ammonium group to (meth) acrylic ester of about 1:20 to about 1:40. The preparation according to any one of claims 1 to 16. The preparation according to any one of claims 1 to 3, further comprising a pH-dependent plasticized acrylic polymer. The plasticized acrylic polymer is non-pH-dependent plasticized acrylic polymer, pH-dependent plasticized acrylic polymer, and non-pH-dependent plasticized acrylic polymer and pH-dependent 4. The formulation according to any one of claims 1 to 3, characterized in that it is selected from the group consisting of a mixture with a plasticized acrylic polymer.