KR20070017128A - Polymeric compositions and dosage forms comprising the same - Google Patents

Abstract

The present invention provides a dosage form comprising at least one active ingredient (a), a core having an outer surface (b) and a shell (c) present in at least one portion of the core outer surface, wherein at least one portion of the shell is semipermeable, The liquid medium diffuses into the core through the semipermeable shell or shell portion due to the osmotic pressure. The shell also provides a means for contacting the dosage form with the liquid medium and then delivering the active ingredient to the liquid medium outside the shell. One or more portions of the shell may consist of a polymeric composition containing a gelling agent, a film former, which can be dissolved in a multi-solvent system consisting of water and an organic solvent.

Active ingredient, core with outer surface, shell, dosage form, osmotic pressure, semipermeable, multisolvent system, gelling agent, membrane former

Description

Polymeric compositions and dosage forms comprising the same

Background of the Invention

1. Field of Invention

The present invention is directed to dosage forms, such as polymeric compositions and controlled release pharmaceutical compositions, including the same. The invention further relates to a method of providing a predetermined active ingredient concentration, which may or may not be substantially constant over an extended period of time, using the dosage form. More particularly, the present invention relates to controlled release dosage forms for delivering one or more active ingredients in a controlled or delayed manner when the dosage form is contacted with a liquid medium. Dosage forms include one or more active ingredients and have a core and a shell. At least one portion of the shell is semipermeable to a liquid medium, such as a patient's gastrointestinal (GI) fluid, such that the liquid medium diffuses into the core through the semipermeable shell or shell portion, for example due to osmotic pressure. The shell or shell portion also provides for contacting the dosage form with the liquid medium and then delivering the active ingredient to the liquid medium outside the dosage form.

2. Background Information

Controlled release pharmaceutical dosage forms have long been used to optimize drug delivery and improve patient compliance, in particular by reducing the number of doses of drug a patient should consume per day. For this purpose, it is often desirable to control the rate of release of the medicament (one particularly preferred form of the active ingredient) from the dosage form into the GI body fluid of the patient, especially to slow the release to provide prolonged activity of the medicament in the body. .

The rate at which orally delivered pharmaceutically active ingredients reach the active site in the body depends on a number of factors including the rate and extent of drug absorption through the GI mucosa. To be absorbed into the circulatory system (blood), the medicament must first be broken down in GI fluids. For many drugs, diffusion across the GI membrane is relatively rapid compared to dissolution. In such cases, dissolution of the active ingredient is a rate limiting step in drug absorption, and the limitation of the rate of dissolution causes the formulation agent to control the rate of drug absorption into the patient's circulation.

An important purpose of controlled release dosage forms is to provide a desired blood concentration versus time (pharmacokinetic or PK) profile for the medicament. Basically, the PK profile for a drug depends on the rate of absorption of the drug into the blood and the rate of release of the drug from the blood. The type of PK profile desired depends, among other factors, the particular active ingredient and the pharmacological disease to be treated.

Also particularly preferred are pharmaceutical dosage forms for delivering one or more agents at different rates from one another. Since the onset and duration of the therapeutic efficacy of a medicament varies greatly with absorption, distribution, metabolism and release of the medicament, it is possible to control the release of the different medicament in different ways or to have the first active ingredient released immediately out of the dosage form It is often desirable for the active ingredient to be released in a delayed, controlled, sustained, prolonged, elongated or delayed manner.

Well known mechanisms by which dosage forms (or drug delivery systems) can deliver drugs at controlled rates include diffusion, corrosion and osmotic pressure. It is often practical to devise dosage forms that use a combination of the above mechanisms to achieve particularly desirable release profiles for certain active ingredients. Those skilled in the art will appreciate that dosage form constructs that provide multiple compartments, such as multiple core portions and / or multiple shell portions, provide a number of different mechanisms for controlling the release of one or more active ingredients. It is easily recognized as particularly advantageous to.

In various aspects of the invention, the controlled release dosage form of the invention acts as an osmotic controlled drug delivery system. See, eg, Verma et al., "Osmotically Controlled Oral Drug Delivery," Drug Development and industrial Pharmacy, 26 (7), pp. 695-708 (2000), osmotic controlled drug delivery systems provide a number of advantages over conventional controlled release delivery systems. The basic principle of the operation of an osmotic drug delivery system uses the osmotic pressure difference between the outside and inside of a formulation containing the active ingredient. For example, in a basic osmotic pump (EOP) system, the active ingredients and suitable osmotic solutes as discussed by Verma et al. Are contained in the core, such as compressed tablets coated at least to some extent with semipermeable membranes or shells with small pores. It is. When such a dosage form is contacted with a liquid medium, such as the aqueous environment of the GI tract, the active ingredient discharges the liquid through the semipermeable membrane due to the osmotic gradient, forming a saturated solution of the active ingredient in the dosage form. Hydrostatic pressure grows in the dosage form and is relieved by the flow of saturated solution out of the dosage form through the orifice, thereby delivering the active ingredient to the patient until the internal and external pressures of the dosage form become equal. Such a system is illustrated in US Pat. No. 3,845,770, which describes a device having a semipermeable wall surrounded by a compartment containing the active ingredient (see FIG. 1 of that publication). The passageway leads to the exterior of the compartment and the device. The fluid penetrates the wall into the compartment and produces a solution of the active ingredient that is released through the passageway.

Various osmotic drug delivery systems are well known in the art and include, for example, US Pat. No. 3,995,631, US Pat. No. 4,111,202, US Pat. No. 4,327,725, US Pat. No. 4,449,983, US Pat. 4,627,971, US Pat. No. 5,830,501, US Pat. No. 6,342,249, and European Patent Publication No. 0 384 642.

The controlled release dosage forms of the invention employ shells and cores which may optionally include multiple portions having different compositions and / or actions. Dosage forms of the present invention are prepared by novel methods that allow at least one portion of the shell to be semipermeable. On the other hand, current core-shell systems are limited not only by useful methods of making them, but also by materials suitable for use with the current methods. Shells or coatings that give controlled release properties are typically applied by conventional methods such as spray coating in a coating pan. Pan-coating essentially produces a single shell around the core. Single shells are inherently limited in their functionality. It is possible to apply multiple concentric shells, each having a different function via fan-coating, but such a system is limited in that the outer shell must first be dissolved before the function imparted by each continuous layer can be realized. . It is also known to deliver a first dose of active ingredient from the coating and a second dose of active ingredient from the core via pan coating. Dosage forms having a spray coating that provides sustained release are described, for example, in Maffione et al., "High-Viscosity HPMC as a Film-Coating Agent," Orug Development and Industrial Pharmacy (1993) 19 (16), pp. 2043-2053. For example, US Pat. No. 4,576,604 discloses a drug compartment surrounded by a wall (film) where the coating can include an immediate release dose of the drug and the internal drug compartment can contain a sustained release dose of the drug. An osmotic device (dosage form) containing is described. Coating compositions that can be applied through spraying are limited by their viscosity. Highly viscous solutions are difficult or impractical to pump or deliver through spray nozzles. Spray coating is subject to additional restrictions that are time intensive and expensive. Several hours of spraying may be required to spray the coating effective amount to control the release of the active ingredient. Coating times of 8 to 24 hours are not common.

It is an object of the present invention to provide novel polymeric compositions suitable for coating dosage forms, such as osmotic lost release dosage forms. It is a further object of the present invention to provide a controlled release dosage form wherein, when contacting the dosage form with a liquid medium, the one or more active ingredients contained therein exhibit a controlled release profile. One feature of the dosage forms of the invention is that they have a semipermeable shell or shell portion. Another feature of the present invention is that the semipermeable shell or shell portion diffuses the liquid medium into the core and permeates into the core through the shell or shell portion, for example due to osmotic pressure. Another feature of the invention is that the shell provides for the delivery of a liquid medium which carries the active ingredient out of the dosage form. Other objects, features and advantages of the present invention will become apparent from the detailed description set forth below to those skilled in the art.

Summary of the Invention

The present invention is based on the total wet weight of the composition, from about 5 to about 50% of the water-insoluble film forming polymer (a), from about 0.05 to about 15% of the gelling agent (b) and from about 40 to about 40 of the multisolvent system (c). A composition comprising and consisting essentially of about 95%,

The multisolvent system provides a composition comprising from about 10 to about 50% water and from about 50 to about 90% water miscible organic solvent, based on the total weight of the multisolvent system.

The present invention further comprises and / or consists essentially of about 40 to about 99% of the water insoluble film forming polymer (a) and about 1 to about 30% of the gelling agent (b) based on the total dry weight of the composition. It provides a composition comprising the.

The invention further provides a dosage form comprising at least one active ingredient (a), a core having an outer surface (b) and a shell (c) present in at least one portion of the core outer surface,

At least one portion of the shell is semipermeable and the shell consists of about 40 to about 99% of the water-insoluble film forming polymer and about 1 to about 30% of the gelling agent, based on its total dry weight, wherein the shell is in dosage form And contacting the liquid medium with the means for providing the active ingredient to the liquid medium outside the shell.

The invention also provides a dosage form comprising at least one active ingredient (a), a core having an outer surface (b) and a shell present in at least one portion of the core outer surface,

The shell comprises a first shell portion semipermeable to the liquid medium and a second shell portion that is different in composition from the first shell portion, wherein the first shell portion and the second shell portion are in substantial contact with the core outer surface, respectively, One portion may be comprised of about 40 to about 99% of the water insoluble film forming polymer and about 1 to about 30% of the gelling agent, based on the total dry weight of the first portion, and the shell may be, for example, For a passage through the first shell portion and / or the second shell portion, there is provided a dosage form comprising contacting the liquid medium with the dosage form and then having means for providing the active ingredient to the liquid medium outside the shell.

The invention further comprises one or more active ingredients (a), an outer surface, a first core portion, a second core portion, and between the first and second core portions and comprising an osmopolymer. A dosage form comprising a core (b) having a third core portion and a shell (c) present in at least one portion of the core outer surface, wherein

The shell is semi-permeable to the liquid medium and comprises, for example, a first shell portion which may consist of about 40 to about 99% of a water insoluble film forming polymer and about 1 to about 30% of a gelling agent based on the total dry weight; A second shell portion, the composition being different from the first shell portion, wherein the first shell portion and the second shell portion are in substantial contact with the core outer surface, respectively; Provided is a dosage form comprising one or more having one or more passageways extending to the core outer surface.

The invention also provides a dosage form comprising at least one active ingredient (a), a core having an outer surface (b) and a shell (c) present in at least one portion of the core outer surface,

The first shell portion and the first shell portion, which is semipermeable to the liquid medium and may consist of about 40 to about 99% of the water insoluble film forming polymer and about 1 to about 30% of the gelling agent, based on the total dry weight. A second shell portion, the composition being optionally different from the portion, wherein the first shell portion and the second shell portion are in substantial contact with the core outer surface, respectively, and the shell and the core have a continuous cavity defining the inner surface, It provides a dosage form comprising none of the first shell portion and the second shell portion substantially extending to the inner surface.

The invention further relates to a third core portion comprising at least one active ingredient (a), an outer surface, a first core portion, a second core portion, and a osmotic polymer located between the first and second core portions. A dosage form comprising a core (b) having and a shell (c) present in at least one portion of the core outer surface, wherein:

The shell is semi-permeable to the liquid medium and comprises, for example, a first shell portion which may consist of about 40 to about 99% of a water insoluble film forming polymer and about 1 to about 30% of a gelling agent based on the total dry weight; A second shell portion having a composition different from the first shell portion, wherein the first shell portion and the second shell portion are in substantial contact with the core outer surface, respectively, wherein the shell and the core define an inner surface; It provides a dosage form having a cavity, wherein either of the first shell portion and the second shell portion substantially extend to the interior surface.

Brief description of the drawings

1A shows a cross-sectional view of one embodiment of a dosage form of the invention.

1B shows a cross-sectional view of another embodiment of a dosage form of the invention.

2 shows a cross-sectional view of another embodiment of a dosage form of the present invention.

3 shows a cross-sectional view of another embodiment of a dosage form of the present invention.

4 shows a cross-sectional view of another embodiment of a dosage form of the present invention.

5 shows a cross-sectional view of another embodiment of a dosage form of the present invention.

6 shows a cross-sectional view of another embodiment of a dosage form of the present invention.

7A and 7B show cross-sectional micrographs of dosage forms coated with prior art coating compositions.

8A and 8B show cross-sectional micrographs of dosage forms coated in embodiments of the present invention.

9 shows the release profile of the active ingredient for one embodiment of the dosage form of the invention as analyzed via the dissolution test described in Example 5. FIG.

10-13 show tensile test results of films formed from the compositions described in Tables E, F, G, and H, respectively.

Detailed description of the invention

It is believed that one skilled in the art will be able to make the best use of the present invention based on the detailed description herein. The following specific embodiments are to be construed as illustrative only, and in no way limit the remainder of the specification.

Unless stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. All percentages, as used herein, are by weight unless otherwise specified.

As used herein, the term “dosage form” applies to any solid object, semisolid or liquid composition designed to include a certain pre-measured amount (dose) of a certain ingredient, eg, the active ingredient as defined below. do. Suitable dosage forms include oral administration, oral administration, rectal administration, systems for topical or mucosal delivery, or subcutaneous implants or other implanted drug delivery systems; Or pharmaceutical pharmaceutical delivery systems comprising compositions for delivering minerals, vitamins and other functional foods, oral care agents, flavoring agents and the like. Dosage forms of the present invention are typically considered to be solid, but may include liquid or semisolid components. In one embodiment, the dosage form is an oral dosage system for delivering a pharmaceutically active ingredient to a human GI tract.

Dosage forms of the present invention represent controlled release of one or more active ingredients contained therein. The active ingredient (s) may be found in the cores, shells, sheaths or parts or combinations thereof. As used herein, the term “controlled release” should apply to compositions that alter the release of the active ingredient in a dosage form, coating, shell, core, portion thereof, or in any manner. The active ingredient (s) released in a controlled manner may be contained in the coating, shell, core, composition, or portion thereof providing the alteration. Alternatively, the controlled release active ingredient may be included in a different part of the dosage form from the coating, shell, core, composition, or part thereof providing the alteration; For example, a controlled release active ingredient can be included in the core portion and modifications can be provided by redundant shell portions. Forms of controlled release include control, prolongation, duration, expansion, smoke, rhythm, repetitive action, and the like. Suitable mechanisms for achieving this form of controlled release include diffusion, corrosion, or surface area control through geometric and / or impermeable barriers, or other mechanisms known in the art. Moreover, the controlled release characteristics of the dosage form can be achieved through the design of the core or part thereof, the shell or part thereof, or a combination of two or more of these parts of the dosage form.

The dissolution profile of each active ingredient from the dosage form depends on the overall contribution from the properties of the various parts. In addition, a single portion, for example a core portion, may have a combination of corrosion and diffusion characteristics. In any case, the rate of dissolution of a particular active ingredient from the dosage form contributes collectively from all the various mechanisms provided by the various parts of the dosage form that influence its release.

Dosage forms of the invention are designed to substantially release all of the active ingredient contained therein within a certain time. As used herein, the total amount of time substantially required for the entirety of the active ingredient (s) released from the dosage form is referred to as the “dosing interval”. During the dosing interval, the amount of medicament released is typically measured at several time points.

As used herein, the term "time interval" refers to the time during the administration interval at which the periodic release rate can be measured. The time interval may be the entire administration interval or a portion thereof.

Drug “release rate” as used herein refers to the amount of drug released from a dosage form per unit time, eg, mg (mg / hr) of drug released per hour. Drug release rates are calculated under in vitro dosage form dissolution test conditions known in the art. The drug release rate obtained at a particular time “after administration” as used herein refers to the in vitro drug release rate obtained at a specific time after the performance of the appropriate dissolution test.

As used herein, a "periodic release rate" refers to a particular periodic interval, i.e., at the end of each periodic interval where the quantity per unit time of drug released, when the measurement is made, represents the periodic release rate during the periodic interval. By amount, the amount of drug released per dosage form during a particular periodic interval as measured. For example, the amount of drug released per hour (h), measured as the difference between the amount of t released between 0 hours and t 2 hours, separated by a 2 hour time interval, is the period for the first 2 hours after administration. The amount of drug released per hour as t is measured from 2 hours to 4 hours, such as a periodic release rate of 2 to 4 hours after administration, and the like.

As used herein, a “constant release rate” is obtained over a predetermined time interval if the periodic release rates measured during two or more portions of the time interval are substantially the same, ie less than 6% different. As used herein, “inconsistent release rate” means that two or more periodic release rates are not equal, ie less than 6%, over the entire period of a particular interval.

As used herein, “rising release rate” means an increased release rate over an immediate preferential release rate. For example, the amount of drug released from the dosage form is measured at a time interval and the amount of drug released during the fifth hour after administration is greater than the amount of drug released from the dosage form during the fourth hour after administration, and the fourth time. Up to a fifth time rise in release rate. The first periodic release rate measured, e.g., the periodic release rate at t for 1 hour (if t is non-zero), is the preferential release, for example, for the time before the dosage form is administered. It is always greater than the speed, so the first periodic release rate becomes a component of the generation of the rising release rate.

As used herein, “rising blood concentration” means that the rate of release of the medicament from the dosage form and also its uptake into the bloodstream exceeds the rate of removal from the mammal's blood over a period of time, and the route of administration interval or portion thereof Increase blood concentration over time.

As used herein, “burst release” refers to a release profile that meets the immediate release criteria during a particular interval. The particular interval arbitrarily performs the scheduled delay time.

As used herein, "gelling agent" refers to those compounds that, when combined with water and heated to any temperature at the approximate gelling temperature for the compound, are those compounds that are water soluble. When cooled, the medium containing the gelling agent becomes relatively harder than when it is heated to any temperature at the approximate gelling temperature. The gelling agent does not include, for example, polyalkylene oxides (such as polyethylene oxide) or polyalkylene glycols (such as polyethylene glycol).

"Water soluble" as used herein in connection with a nonpolymeric material means almost insoluble to highly soluble, i.e., less than 100 parts of water required to dissolve one part of the nonpolymeric water soluble solute. See Remington " The Science and Practice of Pharmacy, "pages 208-209 (2000). As used herein in the context of polymeric materials, "water-soluble" means that the polymer is swollen in water and can be dispersed at molecular weight levels to form a homogeneous dispersion or colloidal "solution".

As used herein, “semipermeable” means that water can permeate, but other molecules, including the active ingredients and salts described herein, are substantially impermeable.

As used herein, "impermeable" means that the composition does not allow passage of aqueous fluids or other molecules such as salts or active ingredients described herein.

As used herein, "diffusion" refers to a molecule, such as a salt and an active ingredient described herein, with a suitable dissolution medium, such as a gastrointestinal fluid or in vitro dissolution medium, in which a dosage form containing such molecule is suitable. When contacted, it is meant to be able to pass through, for example, from a dosage form.

As used herein, “corrosive” means that the composition dissolves through surface corrosion when contacted with a suitable dissolution medium.

The first aspect of the present invention is suitable for preparing components of a dosage form which may contain the active ingredient, for example a corrosive matrix or a shell of the dosage form, in particular as an osmotic release dosage form, the total wetting of the composition. By weight, the water-insoluble membrane blood polymer (a) about 5 to about 50%, for example about 10 to about 40%, the gelling agent (b) about 0.05 to about 15%, for example about 0.1 To about 5%, about 40 to about 95% of the multi-solvent system (c), for example about 55 to about 90%, about 0 to about 30% of the plasticizer (d), for example about 2 to about 25% And a pore former (e) from about 0 to about 10%, for example from about 0.05 to about 5%, comprising and / or consisting essentially of

The multisolvent system is a polymeric composition characterized by consisting of about 10 to about 50% water and about 50% to about 90% water miscible organic solvent, based on its total weight. Such polymeric compositions may be in the form of flowable materials suitable for use as the semipermeable shell or shell portion of the dosage form.

In one embodiment in which the solvent of such a polymeric composition is dried, the polymeric composition is, based on its total dry weight, from about 40 to about 99%, for example about 50, of the water-insoluble film forming polymer (a). To about 80%, gelling agent (b) about 1 to about 30%, for example about 2 to about 10%, plasticizer (c) about 0 to about 60%, for example about 1 to about 40%, and Pore former (d) about 0 to about 15%, for example, about 0.1 to about 10%. Any water-insoluble semipermeable film forming polymer known in the art is suitable for use in the polymeric composition of the present invention. Suitable water insoluble film forming polymers include cellulose esters, cellulose ethers, cellulose ester-ethers, polyvinyl alcohols, polyvinyl acetates, polycaprolactones, polyacrylates, polymethacrylates and derivatives, copolymers and combinations thereof. However, this is not limiting.

Cellulose water insoluble film forming polymers typically have a degree of substitution (D.S.) of inclusions of 0 to 3 in anhydroglucose units. As used herein, “alternate degree” means that the average number of hydroxyl groups is initially present in anhydrous glucose units comprising a cellulose polymer substituted with a substituent. Representative materials include materials selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate and derivatives, copolymers and combinations thereof.

Exemplary water insoluble film forming polymers include cellulose acetate having a D.S. of 1 or less and an acetyl content of 21% or less; Cellulose acetates having an acetyl content of 32 to 39.8%; Cellulose acetate having a D.S of 1 to 2 and an acetyl content of 21 to 35%; Cellulose acetate having a D.S. of 2-3 and an acetyl content of 35-44.8%; Cellulose propionate with a D.S. of 1.8, a propyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; Cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; Cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; Cellulose triacylates having a D.S. of 2.9 to 3, such as cellulose trivalaterate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate; Cellulose disylates having a D.S of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate and cellulose dipentanoate; Coesters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate; And derivatives, copolymers and combinations thereof.

Further water insoluble film forming polymers include ethyl cellulose of varying degrees of etherification having an ethoxy content of about 40-55%; Acetaldehyde demethylcellulose acetate; Cellulose acetate ethyl carbamate; Cellulose acetate methyl carbamate; Cellulose acetate diethyl aminoacetate; Semipermeable polyamides; Semipermeable polyurethanes; Semipermeable sulfonated polystyrene; By coprecipitation of polyanions and polycations as described in U.S. Patent Nos. 3,173,876, 3,276,586, 4,541,005, 3,541,006 and 3,546,142 Semipermeable crosslinked optional polymer formed; Semipermeable slightly crosslinked poly (sodium styrene sulfonate); Semipermeable crosslinked poly (vinylbenzyltrimethyl ammonium chloride); The fluid permeability shown for the atmosphere of hydrostatic or osmotic pressure difference along the semipermeable wall as stated in U.S. Patent No. 845,770, U.S. Patent No. 3,916,899 and U.S. Patent No. 4,160,020 is 2.5x10 ^-8 to 2.5 semipermeable polymers that are x10 ^-4 (cm ² / hr atm) and derivatives, copolymers and combinations thereof.

Suitable gelling agents include, but are not limited to, aqueous colloids (also referred to herein as gelling polymers), gelling starches and derivatives, copolymers and mixtures thereof.

Examples of suitable aqueous colloidal gelling agents are alginates, agar, guar gum, soybeans, carrageenan, tara, arabian gum, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, fusthulan, laminarin Hardened glucan, gum arabic, inulin, pectin, wheelan, lactic acid, juglan, methyllan, chitin, cyclodextrin, chitosan, and mixtures thereof.

Examples of suitable gel starch include acid hydrolyzed starch and derivatives and mixtures thereof.

In one embodiment of the invention, the gelling agent comprises gelatin as the gel polymer. Gelatin is a natural thermogelated polymer. It is a tasteless and colorless mixture of derived proteins of the albumin class, usually soluble in hot water. Two types of gelatin are commonly used, Form A and Form B. Type A gelatin is a derivative of acid treated raw materials. Type B gelatin is a derivative of alkali treated raw materials. The moisture content of the gelatin, as well as its Bloom strength, composition and initial gelatin processing conditions, measure the transition temperature between the liquid and the solid. Bloom is a standard measure of gelatin gels and is roughly related to molecular weight. Bloom is defined as the weight in g required to transfer 4 mm of a half inch diameter plastic plunger to a 6.67% gelatin gel maintained at 10 ° C. for 17 hours. In one embodiment, the flowable material is an aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom bone gelatin and about 60% water.

Further suitable thickening aqueous colloids are used to prepare low-moisture polymer solutions, for example mixtures of gelatin and other aqueous colloids with a moisture content of about 30% or less, such as "gummi" sugars and forms. Contains substances that become.

Suitable xanthan gum gelling agents are described in C.P. Materials commercially available from C.P. Kelco Company under the tradename KELTROL 1000, XANTROL 180 or K9B310.

As used herein, “acid hydrolyzed starch” is a form of modified starch produced by treating a starch suspension with dilute acid at a temperature below the gelling point of the starch. During acid hydrolysis, the granular form of starch is maintained in the starch suspension, and the hydrolysis reaction is terminated by neutralization, filtration and drying when the desired degree of hydrolysis is reached. As a result, the average molecular size of the starch polymer is reduced. Acid hydrolyzed starch (also known as "thin film boiling starch") tends not only to a strong tendency to gel upon cooling, but also to a much lower temperature viscosity than the same natural starch.

As used herein, “gelled starch” includes starch that, when combined with water and heated to a temperature sufficient to form a solution, then forms a gel upon cooling to a temperature below the gelling point of the starch. Examples of gelling starch include acid hydrolyzed starches such as those sold by the Grain Processing Corporation under the trade name “PURE-SET B950”; Grain processing corporations include, but are not limited to, hydroxypropyl starch phosphates such as those sold under the trade name “Pure-gel B990” and mixtures thereof.

Multi-solvent systems are miscible, ie homogeneously dispersible at the molecular level, and when combined together consist of two or more solvents that can dissolve both the water-insoluble film forming polymer and the gelling agent. Suitable solvents for use as components of the flowable wet polymeric composition for preparing the shell or part thereof by molding include water (a) and one or more polar organic solvents (e.g. methanol, ethanol, isopropanol and / or acetone) (b ) Combinations.

In embodiments in which increased membrane permeability and flexibility are involved, any plasticizer can be added to the polymeric composition. Suitable plasticizers for preparing the shell or part thereof by molding include polyethylene glycol; Propylene glycol; glycerin; Sorbitol; Triethyl citrate; Tributyl citrate; Dibutyl sebecate; Vegetable oils such as castor oil, grape oil, olive oil and sesame oil; Surfactants such as polysorbate, sodium lauryl sulfate and dioctyl-sodium sulfosuccinate; Monoacetate of glycerol; Diacetate of glycerol; Triacetate of glycerol; Natural gums; Triacetin; Acetyltributyl citrate; Diethyl oxalate; Diethyl maleate; Diethyl fumarate; Diethyl malonate; Dioctyl phthalate; Dibutyl succinate; Glycerol tributyrate; Hydrogenated castor oil; Fatty acids such as lauric acid; Glycerides, such as mono-, di- and / or triglycerides, which may be substituted with the same or different fatty acid groups such as stearic acid, palmitic acid, oleic acid, and the like; And / or mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the polymeric composition for the shell is virtually free of plasticizer, i.e., contains less than about 1% plasticizer, i.e., less than about 0.01% plasticizer.

Pore formers may also optionally be added to the polymeric composition. Suitable pore formers include water soluble organic and inorganic materials. Examples of suitable water-soluble organic materials include water-soluble cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose; Water soluble carbohydrates such as sugars and starches; Water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol; And water-soluble polymers including insoluble swellable polymers such as microcrystalline cellulose. Examples of suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and / or mixtures thereof.

Active ingredients suitable for use in the present invention include, for example, pharmaceuticals, minerals, vitamins and other neutralizing agents, oral care agents, flavoring agents and mixtures thereof. Suitable drugs include analgesics, anti-inflammatory drugs, anti-arthritis agents, anesthetics, antihistamines, cough medicines, antibiotics, anti-infectives, antiviral drugs, anticoagulants, antidepressants, antidiabetic agents, anti-emetic drugs, antiflatulants, antifungal agents, anticonvulsants, appetite suppressants , Bronchodilators, cardiovascular agents, central nervous system preparations, central nervous system stimulants, decongestants, oral contraceptives, diuretics, expectorants, gastrointestinal tracts, migraines, sports disease products, mucolytic agents, muscle relaxants, osteoporosis agents, polydimethylsiloxanes, respiratory agents , Sleep aids, urinary tract preparations and mixtures thereof.

Suitable oral care agents include respiratory fresheners, tooth brighteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, local anesthetics, mucus protectants and the like.

Suitable flavoring agents include menthol, peppermint, mint flavor, fruit flavor, ultramollet, vanilla, balloon gum flavor, coffee flavor, liqueur flavor, combinations thereof, and the like.

Examples of suitable gastrointestinal tract preparations include calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate, irritant laxatives such as bisacrylyl, cascara sagrada, dantron Senna, phenolphthalein, aloe, castor oil, ricinolic acid and dihydrobile acid and mixtures thereof; H2 receptor antagonists such as pamotadine, ranitidine, cimetadine, nizatidine; Proton pump inhibitors such as omeprazole or lansoprazole; Gastrointestinal cytoprotective agents such as sucralate and microprostol; Gastrointestinal motility promoters such as frucallopride, antibiotics for H, pylori such as clarithromycin, amoxicillin, tetracycline and metronidazole; Laxatives such as diphenoxylate and loperamide; Glycopyrrolate; Antiemetic agents, such as ondansetron, analgesics such as mesalamine.

In one embodiment of the invention, the active ingredient is bisaccordyl, pamotadine, ranitidine, cimetidine, fruclopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, anthase and pharmaceutically Acceptable salts thereof, esters thereof, isomers thereof and mixtures thereof.

In another embodiment, the active ingredient may be an analgesic, anti-inflammatory and antipyretic agent such as nonsteroidal anti-inflammatory agents (NSAIDs) including propionic acid derivatives such as ibuprofen, naproxen, ketoprofen and the like; Acetic acid derivatives such as indomethacin, diclofenac, sulindac, tolmetin and the like; Phenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid and the like; Biphenylcarbodiic acid derivatives such as diflunisal, flufenical and the like; And oxycams, for example, piroxicam, westoximcam, isoxiccam, meloxycam and the like. In one specific embodiment, the active ingredient is a propionic acid derivative NSAID, such as ibuprofen, naproxen, plovifene, fenbufen, phenofene, indopropene, ketoprofen, flupropene, fipropene , Caprophene, oxaprozin, pranopropene, suprofen and pharmaceutically acceptable salts thereof, derivatives thereof and combinations thereof. In another specific embodiment of the present invention, the active ingredient is aceminophene, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flubiprofen, diclofenac, cyclobenzaprine, meloxycamp, forrecoxib, celecock Sieves and pharmaceutically acceptable salts thereof, esters thereof, isomers thereof and mixtures thereof.

In another embodiment of the present invention, the active ingredient is pseudoepinephrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenylhydramine, asemizole, terpenadine, fexofenadine, loratadine, desloratadine , Cetirizine, mixtures thereof, and pharmaceutically acceptable salts thereof, esters thereof, isomers thereof, and mixtures thereof.

Examples of suitable polydimethylsiloxanes, including but not limited to dimethicone and simethicone, are the compounds described in US Pat. No. 4,906,478, US Pat. No. 5,275,822 and US Pat. No. 6,103,260. The term "cimethicone" as used herein refers to a broad class of polydimethylsiloxanes including, but not limited to, simethicone and dimethicone.

The polymeric composition of the present invention comprises the steps of (a) combining water with all other organic solvents to form a multicomponent solvent mixture under ambient conditions, and adding a water-insoluble membrane to form the polymer (s) with stirring under ambient conditions ( b), increasing the temperature of the mixture of step (b) to a temperature greater than the gelling temperature of the desired gelling agent (s), and then stirring the gelling agent (s) with stirring until the mixture is homogeneous while maintaining a constant temperature Can be prepared by step (c). In embodiments in which plasticizers and / or pore formers are included in the composition, these components are typically added to the mixture at any time after step (a). Alternatively, the polymeric composition of the present invention may comprise the step (a), gelling agent (s) of combining an organic solvent with the desired film forming agent (s) to form a first premix in a first container under ambient conditions. (B) combining the gelling agent (s) with water in a second vessel at a temperature above the gelling temperature to form a second premix (b), at or above the gelling temperature of the gelling agent (s) until the resulting mixture is homogeneous It can be prepared by the step (c) of combining the first premix and the second premix at a temperature.

Another aspect of the invention is shown in FIG. 1A, which is a cross sectional view of a dosage form 2 comprising a core 4 and a shell 5. In another aspect of the invention, the shell 5 may be present in part of the core 4 without completely surrounding the core 4. In this aspect of the invention, the shell 5 is semipermeable to the liquid medium, at least one part of which is composed of the polymeric composition described above. The core 4 comprises one or more active ingredients. In this aspect of the invention, the shell 5 comprises a passage 12 extending from the outer surface of the shell 5 to at least the outer surface of the core 4, as shown. In other aspects of the invention, multiple passageways may be used. Thus, when contacting the dosage form 2 with the liquid medium, the liquid medium penetrates the shell 5 and the core 4 (which contains the active ingredient and any osmotic agent or osmotic polymer). In this case, the liquid medium containing the active ingredient is osmotically “pumped” from the dosage form 2 into the liquid medium enclosed through the passage 12.

Another aspect of the invention is shown in FIG. 1B, which is a dosage form comprising a core 24 and a first shell portion 25 and a second shell portion 26 surrounding the core 24 in this embodiment ( 22) is a cross-sectional view. In another aspect of the invention, the first shell portion 25 or the second shell portion 26 may be present in a portion of the core 24 without completely surrounding the core 24. The first shell portion 25 is semipermeable to a liquid medium consisting of the polymeric composition mentioned above, and the second shell portion 26 is different in composition from the first shell portion 25. In the embodiment shown in FIG. 1B, the second shell portion 26 is diffusible. Core 24 includes one or more active ingredients. Thus, upon contacting the dosage form 22 with the liquid medium, the liquid medium penetrates the first shell portion 25, reaches the core 24 (which contains the active ingredient), and the active ingredient. The liquid medium containing is osmotically “pumped” from the dosage form 22 into the liquid medium enclosed through the diffusable second shell portion 26. In another embodiment, the second shell portion 26 is corrosive such that the active ingredient is released from the core 24 as the second shell portion 26 to expose the core 24 to the liquid medium.

Another embodiment of the present invention is shown in FIG. 2, which is semipermeable to a liquid medium and has a second composition different from the first shell portion 208 and the first shell portion 208 composed of the above-described polymeric composition. A cross sectional view of a dosage form 202 including a shell 206 having a shell portion 210 and a core 204. For example, the second shell portion 210 can be diffuse, impermeable or corrosive. Core 204 includes one or more active ingredients. In a first aspect of the invention, the first shell portion 208 includes a passage 212 extending from the outer surface of the first shell portion 208 to the outer surface of the core 204, as shown. . In another aspect of the invention, the first shell portion 208 may comprise a plurality of passages. In this embodiment, the first shell portion 208 is semipermeable and the second shell portion 210 is impermeable. Thus, upon contacting the dosage form 202 with the liquid medium, the liquid medium penetrates the first shell portion 9288 and contains the core 204 (here containing the active ingredient and any osmotic or osmotic polymer). And the liquid medium containing the active ingredient is osmotically “pumped” from the dosage form 202 into the liquid medium enclosed through the passage 212. In another aspect of the invention (not shown in FIG. 2), the second shell portion 210 includes one or more passageways extending from the outer surface of the second shell portion 210 to the outer surface of the core 204. One or more of the first shell portion 208 and the second shell portion 210 may extend from the first shell portion 208 and the second shell portion 210 to the outer surface of the core 204, respectively. Each may include.

Another aspect of the present invention is shown in FIG. 3, which is a core 304 having a first core portion 303 and a second core portion 305, and first and second core portions 303 and from an outer surface. A cross-sectional view of a dosage form 302 including a shell 306 having a plurality of passages 312 extending to the outer surface of 305. In another aspect of the invention, the shell 306 may have a single passage. Core 304 includes one or more active ingredients. At least one shell 306 portion is semipermeable to the liquid medium and consists of the aforementioned polymeric composition, wherein at least about 30% of the cross-sectional area of the semipermeable portion of the shell is non-stripe. When contacting the dosage form 302 with the liquid medium, the liquid medium penetrates the shell 306 and reaches the first and second core portions 303 and 305, respectively, wherein the active ingredient (s) and any Osmotic agents or osmotic polymers), the liquid medium containing the active ingredient (s) is osmotically “pumped” from the dosage form 302 into the enclosed liquid medium through the passage 312. In one embodiment, the first core portion 303 comprises a first active ingredient and the second core portion 305 comprises a second active ingredient, which may be the same as or different from the first active ingredient. In another embodiment, the first and second core portions 303 and 305 comprise different doses or concentrations of the first and second active ingredients, which may each be the same or different active ingredients. In yet another aspect, the passage 312 in the shell 306 exposes different surface areas of each of the underlined core portions 303 and 305 to allow different release rates for the first and second active ingredients, or first and second If the two active ingredients have different solubilities, the same release rate for the first and second active ingredients can be tolerated.

Another aspect of the invention is shown in FIG. 4, which is a core 404 having a first core portion 403, a second core portion 405, and a third core portion 407, and first and second portions. A cross-sectional view of a dosage form 402 including a shell 406 that includes shell portions 408 and 410, respectively. The plurality of passages 412 extend from the outer surface of the shell 406 to the outer surfaces of the first and second core portions 403 and 405. In another aspect of the invention, the shell 406 may have a single passage located in either the first shell portion 408 or the second shell portion 410. In this embodiment, the first shell portion 408 and the second shell portion 410 are each semipermeable to the liquid medium, and one or more portions of the first shell portion 408 or the second shell portion 410 are mentioned above. It consists of one polymeric composition. The second shell portion 410 may be different in composition from the first shell portion 408. For example, in other embodiments, the first shell portion 408 may be semipermeable and consists of the aforementioned polymeric composition, and the second shell portion 410 may be diffuse, impermeable, or corrosive. Core 404 includes one or more active ingredients. In the embodiment shown in FIG. 4, the first core portion 403 comprises a first active ingredient, and the second core portion 405 comprises a second active ingredient, which may be the same as or different from the first active ingredient. The third core portion 407 includes an osmotic polymer that provides an osmotic pressure when in contact with the liquid medium, and presses the active ingredient through the passage 412 to the surface of the shell 406. In the embodiment shown in FIG. 4, when contacting the dosage form 402 with a liquid medium, the liquid medium penetrates the first and second shell portions 408 and 410 and respectively the first and second core portions 403. And 405) a third core portion containing an osmotic polymer, which swells to compress the first and second core portions 403 and 405, as well as wherein the active component (s) is contained) 407, the liquid medium containing the active ingredient is osmotically “pumped” from the dosage form 402 into the enclosed liquid medium through passage 412. In addition, passages 412 in the first and second shell portions 408 and 410 expose different surface areas of the underlined core portions 403 and 405, respectively, allowing different release rates for the first and second active ingredients. Alternatively, where the first and second active ingredients have different solubility, the same release rate can be allowed for the first and second active ingredients.

Another aspect of the invention is shown in FIG. 5, which may be different in composition from the first shell portion 508 and the first shell portion 508, which are semipermeable to the liquid medium and consist of the polymeric composition mentioned above. A cross sectional view of a dosage form 502 including a shell 506 with a second shell portion 510 and a core 504. For example, second shell portion 510 may be semipermeable, diffuse, impermeable, or corrosive, although in this embodiment it is semipermeable. Core 504 includes one or more active ingredients. As shown in FIG. 5, the cavity 501 extends through the core 504, the first shell portion 508, and the second shell portion 510. The inner surface 513 of the core 504 is defined by the cavity 501, so that none of the first shell portion 508 and the second shell portion 510 substantially extends to the inner surface 513, Allow the active ingredient to be contained in the core 504 which is only released through the inner surface 513. The diameter of the continuous cavity typically ranges from about 15 to about 90% of the thickness of the dosage form, and the diameter of the continuous cavity typically ranges from about 5 to about 30% of the core diameter. The length of the continuous cavity is typically about 25 to about 40 of the diameter of the dosage form. When contacting the dosage form 502 with a liquid medium, the liquid medium penetrates not only the inner surface 513 but also the first and second shell portions 508 and 510, and the core 504 (where the active ingredient is And the active medium containing the active ingredient passes through the inner surface 513 to the central cavity 501 and to the enclosed liquid medium from the dosage form 502. In this embodiment, the main mechanism for liquid release is corrosion.

Another aspect of the invention is shown in FIG. 6, which is semipermeable to a core 604 having a first core portion 603, a second core portion 605, and a third core portion 607, and a liquid medium. Is a cross-sectional view of a dosage form comprising a shell 606 having a first shell portion 608 composed of the aforementioned polymeric composition and a second shell portion 610 that is different in composition from the first shell portion 608. . For example, the second shell portion 610 may be semipermeable, diffusive, impermeable or corrosive, although semipermeable in this embodiment. Core 604 includes one or more active ingredients. As shown in FIG. 6, the cavity 601 extends through the core 604, the first shell portion 608, and the second shell portion 610. The inner surface 613 of the core 604 is defined by the cavity 601, and neither of the first shell portion 608 nor the second shell portion 610 substantially extends to the inner surface 613, Thus active ingredients contained in the core 604 are only released through the inner surface 613. In one embodiment, the first core portion 603 contains a first active ingredient, the second core portion 605 contains a second active ingredient, which may be the same as or different from the first active ingredient, The third core portion 607 contains an osmotic polymer that provides an osmotic pressure upon contact with the liquid medium to urge the active ingredient through the inner surface 613 into the liquid medium. The diameter of the continuous cavity typically ranges from about 15 to about 905 of the thickness of the dosage form, and the diameter of the continuous cavity typically ranges from about 5 to about 30% of the core diameter. The diameter of the continuous cavity is typically about the same as the thickness of the dosage form, and the length of the continuous cavity is typically about 25 to about 40 of the diameter of the dosage form. When contacting the dosage form 602 with a liquid medium, the liquid medium penetrates not only the inner surface 613 but also the first and second shell portions 608 and 610, respectively, and the first and second core portions ( 603 and 605 (where the active ingredient (s) is contained), as well as a third osmotic polymer, which swells to compress the first core portion 603 and the second core portion 605. Reaching each of the core portions 603, the liquid medium containing the active ingredient (s) passes through the inner surface 613 to the central cavity 601 and to the liquid medium enclosed from the dosage form 602. In this embodiment, the main mechanism for drug release is corrosion.

In an aspect of the invention wherein the shell comprises two or more shell portions, the inner surface of each shell portion may be substantially as shown, for example, in FIGS. 1B, 2, 4, 5 and 6. Must be in contact with the outer surface of the core. Thus, in this aspect, the inner surface of any shell portion is not present on the outer surface of any other shell portion.

The active ingredient is present in a therapeutically effective amount of dosage form, which is the amount that results in the desired therapeutic response upon oral administration and can be readily determined by those skilled in the art. In determining this amount in which a particular active ingredient is administered, the bioavailability characteristics of the active ingredient, the method of administration, the age and weight of the patient and other factors should be considered as known in the art. Typically, the dosage form comprises about 2 to about 75 weight percent of a combination of one or more active ingredients, for example, the dosage form may include about 5 to about 50 weight percent, and about 7 to about 25 weight percent Means. In one embodiment, the core comprises at least one active ingredient in total of at least about 25% by weight, such as from about 25 to about 75% by weight (based on the weight of the core).

The active ingredient may be in any form of dosage form. For example, the active ingredient may be present in the form of particles which may be dispersed, for example melted or dissolved, at the molecular level within the dosage form, or may be coated or uncoated sequentially. When the active ingredient is in particle form, the particles (whether coated or uncovered) typically have an average particle size of about 1 to about 2000 μm. In one embodiment, such particles are crystals having an average particle size of about 1 to about 300 μm. In another embodiment, the particles are granules or pellets having an average particle size of about 50 to about 2000 μm, such as about 50 to about 1000 μm, or about 100 to about 800 μm.

In embodiments in which the active ingredient is contained in the core, at least one portion of the active ingredient may optionally be coated with a release controlling coating, as is known in the art. This advantageously provides additional tools for controlling the release profile of the active ingredient from the dosage form. For example, the core may comprise coated particles of one or more active ingredients, and the particle coating imparts a release controlling function as is well known in the art. Examples of suitable controlled release coatings for particles include U.S. Patent No. 4,173,626, U.S. Patent 4,863,742, U.S. Patent 4,980,170, U.S. Patent 4,984,240, U.S. Patent 5,286,497, U.S. Patent 5,912,013. , US Pat. No. 6,270,805 and US Pat. No. 6,322,819. Controlled release coated active particles which are commonly used may also be used. Thus, all or part of one or more active ingredients in the core may be coated with a release modulating material.

In a preferred embodiment for the active ingredient absorbed into the systemic circulation of the animal, the active ingredient (s) are typically soluble upon contact with fluids such as water, gastric juice, intestinal fluid and the like. In one embodiment, the dissolution properties of one or more active ingredients can be adjusted: eg, controlled, sustained, extended, delayed, extended, delayed, and the like. In one embodiment in which one or more active ingredients are released in a controlled manner, the controlled release active ingredient (s) is contained in the core. In one particular such embodiment, the dosage form releases one or more active ingredients contained in the core at substantially constant rates over a particular time interval.

In one embodiment, the dissolution properties of the one or more active ingredients meet the USP specification for immediate release tablets containing the active ingredient. For example, for acetaminophen tablets, USP 24 is used in USP device 2 (paddle) at 50 rpm in phosphate buffer at pH 5.8, with at least 80% acetaminophen contained in the dosage form within 30 minutes of administration. In the case of ibuprofen tablets, USP 24 was used in a phosphate buffer at pH 7.2 using USP Apparatus 2 (paddle) at 50 rpm, with at least 80% of ibuprofen contained in the dosage form within 60 minutes of administration. From USP 24, 2000 Version, 19-20 and 856 (1999) c. In an embodiment in which one or more active ingredients are released immediately, the immediate release active ingredient is typically contained in the shell or on the surface of the shell, for example in an additional coating surrounding one or more portions of the shell. .

In a particular embodiment, the core or core portion acts as a corrosion matrix in which the active ingredient dispersed by the dissolution of the continuous layer of the matrix surface is released. In this embodiment, the rate of release of the active ingredient from the core or core portion depends on the rate of dissolution of the matrix material. Particularly useful corrosion matrix materials for providing surface corrosion include materials which first absorb liquid and then swell and / or gel before dissolution. In this particular embodiment, the corrosion matrix core or core portion is controlled release compressible or moldable selected from swellable corrosive hydrophilic materials, pH dependent polymers, insoluble corrosive materials and combinations thereof, based on their total dry weight. About 5 to about 50% excipient. In one embodiment, the release-controlling excipient suitable for preparing the core or shell or part thereof by molding is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylate copolymer Form B , Shellac and combinations thereof.

Suitable swellable corrosive hydrophilic materials for use as release-controlled excipients for preparing cores or parts thereof by compression include water swellable cellulose derivatives, polyalkylene glycols, polyalkylene oxides, acrylic polymers, aqueous colloids, gelled starches. Swellable crosslinked polymers, derivatives, copolymers and combinations thereof.

Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxy Hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose and hydroxypropylethylcellulose.

Examples of suitable polyalkylene glycols include polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include poly (ethylene oxide).

Examples of suitable acrylic polymers include potassium methacrylate divinylbenzene copolymers, polymethylmethacrylates, CARBOPOLs (high molecular weight crosslinked acrylic acid homopolymers and copolymers) and the like.

Examples of suitable aqueous colloids include the compounds mentioned above.

Examples of suitable clays include smectites such as bentonite, kaolin and laponite; Magnesium trisilicate, magnesium aluminum silicate and the like and derivatives thereof and mixtures thereof.

Examples of suitable gelled starch include acid hydrolyzed starch, swelled starch such as sodium starch glycolate and derivatives thereof.

Examples of suitable swellable crosslinked polymers include crosslinked polyvinyl pyrrolidone, crosslinked agar and crosslinked carboxymethylcellulose sodium.

Insoluble edible materials suitable for use as release-controlled excipients for preparing the core or portions thereof by compression include water insoluble polymers and low melting hydrophobic materials.

Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers; And the like and derivatives thereof, copolymers and combinations thereof.

Suitable low melting hydrophobic materials include fats, fatty acid esters, phospholipids and waxes. Examples of suitable fats include hydrogenated vegetable oils such as cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower seed oil and hydrogenated soybean oil; And free fatty acids and salts thereof. Examples of suitable fatty acid esters are sucrose fatty acid esters, mono, di and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurate, glyceryl Myristate, GLYCOWAX-932, lauroyl macrogol-32 glycerides and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl srene, phosphotidyl enositol and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, wax, candelia wax, shellac wax, microcrystalline wax and paraffin oak; Fat-containing mixtures such as chocolate and the like.

Suitable pH dependent polymers for use as release-controlled excipients for preparing cores or parts thereof by compression include enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, Cellulose acetate phthalate; Natural resins such as shellac and zein; Enteric acetate derivatives such as polyvinyl acetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; And enteric acrylate derivatives, for example polymers based on polymethacrylates, such as Rphm Pharma GmbH, which is usually marketed under the trade name “EUDRAGIT S”. Poly (methacrylic acid, methyl methacrylate) 1: 2, and poly (methacrylic acid, methyl methacrylate) 1: 1 commercially marketed by Jean Parma Geembeha under the trade name “EUDRAGIT L” 1: 1 And the like, derivatives thereof, salts thereof, copolymers thereof, and combinations thereof.

In certain other embodiments, the core or core portion acts as a diffuse matrix. In this embodiment, the core portion comprises an active ingredient dispersed through an insoluble porous matrix, which includes pores or channels through which body fluid can be introduced into the core or core portion, which active ingredient must diffuse to release from the dosage form. do. In this embodiment, the release rate of the active ingredient from the core or core portion depends on the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and the torsion (T) of the matrix; Release of the active ingredient from the core or core portion may be described as being controlled, extended, sustained or extended. In this embodiment, the contribution of active ingredient dissolution from the main core portion depends on the square root of zero rank, first order or time kinetics. In this particular embodiment, the diffusive matrix core or core portion may comprise a pore former as mentioned above.

In embodiments in which the core or core portion acts to regulate the release of the active ingredient contained therein, the release of the active ingredient may be further controlled by the action of the enclosed shell or shell portion, as described above. In this embodiment, the release of the active ingredient from the dosage form is governed by the sum of all the contributions acting on it, for example from the core or the core portion and the shell or the shell portion, respectively, and can be adjusted, extended, sustained, extended, It may be described as delayed or beated. In this embodiment, the dissolution of the active ingredient from the dosage form depends on the square root of zero rank, first rank or time kinetics.

In embodiments in which the core comprises multiple parts, these parts comprise different materials and are prepared by both different methods. In one particular embodiment, the first core portion can be made by compression and the second core portion can be made by molding.

In certain embodiments, the core comprises multiple portions comprising different active ingredients or different release-modulating properties or both, and the shell controls or adds release of one or more active ingredients contained within each core portion. It includes multiple parts of the corresponding number to cover a particular core part for adjustment. In this aspect, it is important to have a manufacturing method capable of maintaining the orientation of the core before and during the application of the shell or each shell portion. Advantageously, the orientation of the components of the dosage forms of the present invention can be precisely adjusted when prepared using a heat cycle or thermoset device and described below.

In one such embodiment, the dosage forms differ in composition and at least one of the first or second core portions comprises a core comprising a first core portion and a second core portion comprising the active ingredient, and a composition differing in composition At least one of the first or second shell portions includes a shell surrounding the core and comprising a first shell portion and a second shell portion that modulate the release of the active ingredient contained in the underlined core portion.

The core or core portion of the present invention is prepared by any suitable method, including, for example, compression and molding, and depends on the method being prepared, and typically the active ingredient and various excipients (physical properties desired for the core) Inert components, which may be useful for imparting).

In embodiments in which the core or portion thereof is produced by compression, suitable excipients include fillers, binders, disintegrants, lubricants, lubricants, and the like, as known in the art. In embodiments in which the core further provides controlled release of the active ingredient prepared by compression and contained therein, the core may further comprise a release-controlled extrudable excipient as described above.

Suitable fillers for use in the manufacture of the core or parts thereof by compression include dextrose, sucrose, maltose, lactose, sugar-alcohol, mannitol, sorbitol, maltitol, xylitol, starch hydrolyzate Water-insoluble plastic vesicles such as dextrins and maltodextrins, such as dextrins, such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle grinding materials, such as dicalcium phosphate, tricalcium phosphate Water-soluble compressible carbohydrates such as sugars, including the like and mixtures thereof.

Suitable binders for preparing the core or portions thereof by compression include anhydrous binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose and the like; Wet binders, for example, aqueous colloids such as acacia, alginate, agar, guar gum, soybeans, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin , Maltodextrin, lactomannan, fusthulan, laminarin, hardened glucan, inulin, wheelan, lactic acid, juglan, methyllan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulose compounds, sucrose, starch, etc. Water soluble polymers comprising; Derivatives thereof and mixtures thereof.

Disintegrants suitable for preparing the core or portions thereof by compression include sodium starch glycolate, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose and the like.

Lubricants suitable for producing the core or part thereof by compression include long chain fatty acids and salts thereof, such as magnesium stearate and stearic acid, talc, glycerides and waxes.

Glidants suitable for producing the core or portions thereof by compression include colloidal silicon dioxide and the like.

Other suitable pharmaceutically acceptable auxiliaries for producing the core or portions thereof by compression include preservatives; High intensity sweeteners such as aspartame, acesulfame potassium, sucralose and saccharin; Flavoring agents; coloring agent; Antioxidants; Surfactants; Wetting agents and the like and mixtures thereof.

In one embodiment, the core or portion thereof forms a push member homogeneously or heterogeneously combined with the core component to act as an osmotically effective solution that is soluble in the liquid medium absorbed into the core and One or more osmotic agents, also known as osmotically effective compounds or osmotically effective solutes, which may exhibit osmotic inclination across the semipermeable shell or shell portion with respect to the external liquid medium. Osmotic agents useful in the present invention include solid compounds selected from the group consisting of lithium chloride, magnesium sulfate, potassium sulfate, magnesium chloride, sodium chloride, sodium sulfate, sorbitol, mannitol, urea, inositol, sucrose, glucose and mixtures thereof However, this is not limiting. The osmotic pressure in the atmosphere of osmotic preparations suitable for the present invention is greater than zero ATM, and generally from zero ATM to 500 ATM or more. The amount of osmotic agent combined with the core component is about 0 to about 65%, for example about 0.01 to about 40%, based on the total dry weight of the core.

In another embodiment, the core or portion thereof comprises one or more osmotic polymers. Osmotic polymers, when used, exhibit bodily fluid absorption and / or bodily fluid inhalation properties. Osmotic polymers include hydrophilic polymers that can be brought into contact with water and aqueous biological body fluid and then expanded to swelling or equilibrium. Osmotic polymers exhibit the ability to retain a significant portion of body fluids that have been inhaled or absorbed. Examples of suitable osmotic polymers include poly (hydroxyalkyl methacrylates) having a molecular weight of 20,000 to 5,000,000; Poly (vinylpyrrolidone) having a molecular weight of about 10,000 to 360,000; Poly (vinyl alcohol) having a low acetate content, slightly crosslinking with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of 2,000 to 30,000; Poly (ethylene oxide) having a molecular weight of 10,000 to 7,800,000; Acidic carboxy polymers known as carboxypolymethylene or carboxyvinyl polymers and mixtures thereof, including but not limited to. Examples of suitable acidic carboxypolymers include polymers consisting of polyalkyl sucrose and acrylic acid slightly crosslinked with a solid of the trade name “CARBOPOL”; Acidic carboxy polymers having a molecular weight of 200,000 to 6,000,000, including sodium acidic carboxyvinyl hydrogel and potassium acidic carboxyvinyl hydrogel; Polyacrylamide solids with the trade name "CYANAMER"; And mixtures and copolymers thereof, but is not limited thereto. Representative osmotic polymers used for the purposes herein are known to those skilled in the art and are described, for example, in Scott & Roff, Handbook of Common Polymers pp. 72 to 81, 98, 281 (1971); Ratner & Hoffman, ACS Symposium Series, No. 31, pp. 1 to 36 (1976) (published by the American Chemical Society); and Schacht, Recent Advances in Drug Delivery Systems. 259 to 278 (1984). The amount of osmotic polymer combined with the core component is from about 0 to about 90%, for example from about 20 to about 50%, based on the total dry weight of the core.

In embodiments in which the core or core portion is produced by compression, anhydrous blending (ie, direct compression) or wet gelling processes may be used. In anhydrous formulations (direct compression), the active ingredient (s) and excipients are formulated in a suitable mixer and then delivered directly to a compressor for compression into tablets. In the wet granulation method, solutions or dispersions of the active ingredient (s) or suitable excipients and wet binders (eg aqueous prepared starch pastes or solutions of polyvinyl pyrrolidone) are mixed and granulated. Alternatively, anhydrous binders may be included in the excipients and the mixture may be granulated with water or other suitable solvent. Suitable tools for wet granulation are known in the art and include low shear, such as celestial mixers; High shear mixer; And a fluid bead comprising a rotary fluid bead. The resulting granulated material is dried and optionally anhydrous blended with additional ingredients such as auxiliaries and / or excipients such as lubricants, colorants and the like. The final dry blend is then suitable for compression. Methods of direct compression and wet granulation and processes are known in the art and are described, for example, in detail in Lachman, et al., The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rd ed. 1986). It is described.

Anhydrous blended or water granulated powder mixtures are typically tableted using rotary compressors known in the art, such as Fette America Inc., Rockaway, New Jersey, or It is compressed into tablets commercially available from Manesty Machines LTD, Liverpool, UK. In the rotary compactor, the volume of the metered powder is filled into the die cavity, which compresses the powder from the filling position to the discharge point between the upper and lower punches, and the resulting tablets are punched out of the die cavity by the lower punches to produce a static "departure". rotate as part of the "die tablet" to a press position guided to an ejection chute by a "take-off" bar.

In one particular embodiment, the core or core portion can be prepared by the compression method and apparatus described in US patent application 2003/0072799. Specifically, the core comprises a rotary compression module comprising a filling zone, an insertion zone, a compression zone, a discharge zone and a purging zone in a single device having a double row die structure as shown in FIG. 6 of US patent application 2003/0072799. Are prepared using. The die of the compression module is typically filled using a vacuum with a charger located in or near each die of the vacuum. The purging zone of the compression module includes any powder recovery system for recovering excess powder from the charger and returning the powder to the die.

In another aspect of the invention, the core, shell or part thereof is produced by molding. In particular, the core, shell or parts thereof are produced by solvent-based molding, or parts of the core or shell are produced by solvent-free molding. In this embodiment, the core, shell or portion thereof is made from a flowable material optionally comprising the active ingredient. The flowable material is any edible material that is flowable at a temperature of about 37 to about 250 ° C., which may be solid or semisolid, or may form a gel at a temperature of about 10 to about 35 ° C. When present in a fluid or fluid state, the flowable material includes a solvent, such as water or an organic solvent, or mixtures thereof, with respect to the dispersion, dissolution, or melt components, and the shell formulation of a portion of the shell. The solvent may be partially or substantially removed by drying. At least a part of the shell consists of the polymeric composition described above.

In one embodiment, solvent-based or solvent-free molding may be performed via thermosetting molding using the methods and apparatus described in US Patent Application 2003/0124183. In this embodiment, the core or a portion of the shell is formed by injecting a flowable material into the forming chamber. The flowable material may comprise a thermosetting material at temperatures above the melting point and below the decomposition temperature of any active ingredient contained therein. The flowable material is cooled and solidified in the shaping chamber in shaped form.

According to the thermosetting molding method, the flowable material may comprise solid particles suspended in a melt matrix, for example a polymer matrix. The flowable material may be completely melted or present in paste form. The flowable material may include the active ingredient dissolved in the molten material in the case of solvent-based molding. Alternatively, the flowable material can be prepared by dissolving the solid in a solvent and then evaporating the solvent, after the molding step, for solvent based molding. At least one part of the shell consists of the polymeric composition mentioned above.

In another embodiment, solvent based or solvent free molding is performed by thermal cycle molding using the methods and apparatus described in US Patent Application 2003 / 0086973A1. Heat cycle molding is performed by injecting a flowable material into a heated forming chamber. The flowable material may include the active ingredient and the thermoplastic at a temperature above the curing temperature of the thermoplastic and below the decomposition temperature of the active ingredient. The flowable material is cooled and solidified in the shaping chamber in a shaped form (ie, having the shape of a mold). At least one part of the shell consists of the polymeric composition mentioned above.

In the heat cycle molding method and apparatus of US patent application 2003 / 0086973A1, a heat cycle molding module having the general arrangement shown in FIG. 3 is used. The thermal cycle molding module 200 includes a rotor 202 with a plurality of mold units 204 arranged around it. The heat cycle shaping module includes a reservoir 206 for holding the flowable material to manufacture the core. In addition, the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold unit. 55 and 56 illustrate a temperature control system 600.

According to the thermal cycle molding method, the mold unit may include a central mold assembly 212, an upper mold assembly 214, and a lower mold assembly 210, as shown in FIGS. 26 to 28, for example. For example, it is made to form a mold cavity having the desired shape of the core or the shell surrounding it. As the rotor 202 rotates, the opposing center and upper mold assemblies or the opposing center and lower mold assemblies are closed. Flowable material heated in the flow state in reservoir 206 is injected into the resulting mold cavity. The temperature of the flowable material is reduced and the flowable material hardens. The mold assembly opens and releases the final product.

In one embodiment of the present invention, the shell may be applied in dosage form using a heat cycle molding apparatus of the general type shown in Figures 28A-28C of US Patent Application 2003 / 0086973A1. The apparatus consists of a rotatable central mold assembly 212, a lower mold assembly 210 and an upper mold assembly 214. The core is continuously fed into the mold assembly. Shell flowable material, which may be composed of the polymeric composition described above, is heated in a fluid state in reservoir 206 and then injected into a mold cavity created by a closed mold assembly that holds the core. The temperature of the shell flowable material is reduced and cured around the core. The mold assembly opens and releases the final dosage form. Shell coating is performed in two stages, with each half of the dosage form separately coated as shown in the schematic diagram of FIG. 28B of US Patent Application 2003/0068367 via rotation of a central mold assembly.

One method for preparing a dosage form with a shell or shell portion from a wet flowable material such as the wet polymeric composition mentioned above is

In the above-mentioned polymeric composition, or in a suitable solvent, for example, another composition consisting of membrane formers, gelling agents, optional active ingredients, optional plasticizers, optional release-controlled excipients and other shell materials. Preparing a fluid dispersion (a),

(B) injecting said flow dispersion into a mold cavity (under room temperature) comprising a core such that the flow dispersion (which can be heated in a heated feed tank) is surrounded by a first portion of the core in the mold cavity,

(C) rapidly changing the temperature of the mold cavity in order to induce thermal curing of the careful flowable dispersion in the first portion of the core, ie reduce the temperature below the gelation temperature of the flowable dispersion,

(D) opening the mold cavity and rotating the portion of the mold containing the core to expose the second portion of the core,

Closing the mold cavity (e),

(F) injecting a heated flowable dispersion into the mold cavity such that the flowable dispersion surrounds a second portion of the core in the mold cavity, which may be the same or different than the flowable material used to form the first portion,

Rapidly changing the temperature of the mold cavity to induce thermosetting of the flowable dispersion surrounding the second portion of the core, ie reducing the temperature below the gelation temperature of the flowable dispersion (g),

(H) removing the coated core from the mold cavity and

It is through a molding method based on a solvent consisting of the step (i) of drying the coated core to remove residual solvent. The mold may be heated to remove solvent and then cooled to set the shell material.

Another method for producing the shell portion by solvent free molding is

Melting the thermally reversible carrier and adding and mixing the release-controlled excipient and any other desired components of the shell into the thermally reversible carrier to form a flowable shell material (a),

Injecting the flowable shell material into a mold cavity comprising a core such that the flowable shell material (heated in a heated feed tank) surrounds the first portion of the core in a mold cavity (heats and flows the flowable shell material). Step (b),

(C) rapidly lowering the temperature of the mold cavity to induce thermosetting of the flowable shell portion surrounding the first portion of the core,

(D) opening the mold cavity and rotating the portion of the mold including the core to expose the second portion of the core,

Closing the mold cavity (e),

(F) injecting the heated flowable shell material into the mold cavity (also heated) such that the flowable shell material surrounds the second portion of the core in the mold cavity,

(G) rapidly lowering the temperature of the mold cavity to perform thermal curing of the flowable shell material surrounding the second portion of the core and

Provided is a method of making a shell portion by solvent-free molding, comprising step (h) of removing the coated core from the mold cavity.

The mold is optionally quickly heated or cooled to facilitate removal of the dosage form.

In one embodiment, the core is prepared using the extrusion module of US Patent Publication No. US2003 / 0072799A1. The shell can be applied to this core using a thermal cycle molding module as mentioned above or using a zero cycle molding method as described in US Patent Application No. 10 / 677,984. The conveying device described in US 2003/0070903 can be used to convey the core from the compression module to the heat cycle forming module. Such a conveying device may have a structure shown as 300 in FIG. 3 of US 2003/0068367. This includes a number of conveying units 304 attached in cantilever form to the belt 312 shown in FIGS. 68 and 69 of US 2003/0068367. The conveying device is rotated and operated at the time of combining with the heat cycle shaping module and the compression module to be coupled. The conveying unit 304 includes a retainer 330 for supporting the core as it moves around the conveying device.

In addition to certain polymeric compositions of the present invention as set forth above, other suitable materials for or in order to be present in the flowable material for the core and / or portion of the shell are generally thermoplastics; Film formers; Thickeners such as quenched polymers or aqueous colloids; Low viscosity hydrophobic materials such as fats and waxes; Materials including amorphous carbohydrates and the like. Suitable melt components of the flowable material include thermoplastics, low melting hydrophobic materials, and the like. Suitable dissolved components of the flowable material include film formers, thickeners such as gelling polymers or aqueous colloids, amorphous carbohydrates and the like. Suitable dispersed ingredients include insoluble edible materials.

Suitable thermoplastics can be shaped and shaped when heated and can include water soluble and water insoluble polymers. Examples of suitable thermoplastics include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble cellulose derivatives, thermoplastic vinyl polymers, thermoplastic starch, thermoplastic polyalkylene glycols, thermoplastic polyalkylene oxides, amorphous sugar-glass and the like, derivatives thereof, copolymers And mixtures. Examples of suitable thermoplastic water swellable cellulose derivatives include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC). Examples of suitable water insoluble cellulose derivatives include cellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate. Examples of suitable thermoplastic vinyl polymers include polyvinyl alcohol (PVA) and polyvinyl pyrrolodon (PVP). Examples of suitable thermoplastic starch are described in US Pat. No. 5,427,614. Examples of suitable thermoplastic polyalkylene glycols include polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include polyethylene oxides having a molecular weight of about 100,000 to about 900,000 daltons. Other suitable thermoplastics include sugars of this type on amorphous glass for use in making rigid canty forms.

The flowable material for producing the core, shell or part thereof by molding may also optionally include auxiliaries or excipients which may comprise up to about 30% by weight of flowable material, based on the total wet weight of the flowable material. . Examples of suitable adjuvants or excipients include plasticizers, anti-sticking agents, wetting agents, surfactants, antifoams, colorants, flavoring agents, sweeteners, opacifying agents and the like. Plasticizers suitable for producing the cores, shells or parts thereof by molding include, but are not limited to, the plasticizers mentioned above. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the processed anhydrous shell is substantially free of plasticizers, ie contains less than about 1% or less than about 0.01% plasticizer.

In another embodiment, the flowable material comprises less than about 5% humectant, based on its total wet weight, or alternatively a humectant, such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol It does not contain substantially. Wetting agents are included in preformed membranes used in coating processes, as traditionally described in US Pat. No. 5,146,730 and US Pat. No. 5,459,983, to ensure proper flexibility or plasticity and binding capacity of the membrane during processing. Wetting agents act by the binding water and remain in the membrane. The preformed membrane used in the coating process may contain up to 45% water. Disadvantageously, the presence of the humectant prolongs the anhydrous process and can adversely affect the stability of the processed dosage form.

In certain embodiments in which a portion of the core or shell is made using solvent free molding, the core portion of the core or shell may comprise the active ingredient contained in the excipient matrix. The matrix typically has at least about 30% by weight, for example at least about 45% by weight, based on its total dry weight; For example, up to about 30% by weight of various adjuvants such as plasticizers, gelling agents, enhancers, colorants, stabilizers, preservatives, etc., as known in the art; And up to about 55% by weight of one or more controlled release mobile excipients as mentioned above. In certain embodiments wherein the shell portion is prepared by solvent free molding and acts to delay the release of one or more active ingredients from the underlined core or core portion, the controlled release excipient may be selected from swellable edible hydrophilic materials. . Solvent free molding can be used to obtain semipermeable, impermeable or diffusible shell portions.

Examples of suitable thermally reversible carriers include, but are not limited to this. Suitable thermally reversible carriers are typically thermoplastics having a melting point of about 110 ° C. or less, such as about 20 to about 100 ° C. Examples of suitable thermally reversible carriers for solvent-free molding include thermoplastic polyalkylene glycols, thermoplastic polyalkylene oxides, low melting point hydrophobic materials, waxes such as edible waxes such as beeswax, thermoplastic polymers, thermoplastic starches And the like.

Thermoplastic polyalkylene glycols suitable for use as the thermally reversible carrier include polyethylene glycols having a molecular weight of about 100 to about 20,000, such as about 100 to about 8,000 Daltons. Suitable thermoplastic polyalkylene oxides include polyethylene oxides having a molecular weight of about 100,000 to about 900,000 daltons.

Low melting hydrophobic materials suitable for use as thermally reversible carriers include fats, fatty acid esters, phospholipids and waxes as solids at room temperature, fat containing mixtures such as chocolate, and the like as mentioned above.

Thermoplastic polymers suitable for use as the thermally reversible carrier include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble polymers, thermoplastic vinyl polymers, thermoplastic starches, thermoplastic resins and mixtures thereof. Suitable thermoplastic water swellable cellulose derivatives include hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), carboxymethyl cellulose (CMC), crosslinked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxybutyl cellulose ( HBC), hydroxyethylcellulose (HEC), hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose and salts, derivatives, copolymers and combinations thereof. Suitable thermoplastic water-insoluble polymers include ethylcellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers and the like and derivatives, copolymers and combinations thereof. Include. Suitable thermoplastic vinyl polymers include polyvinylacetate, polyvinyl alcohol and polyvinyl pyrrolidone (PVP).

Examples of thermoplastic starch suitable for use as a thermally reversible carrier are described, for example, in US Pat. No. 5,427,614. Examples of suitable thermoplastics for use as the thermally reversible carrier include glycerol esters of dammar, mastic, rosin, shellac, sandac and rosin. In one embodiment, the thermally reversible carrier for producing the core or part thereof by molding is selected from polyalkylene glycols, polyalkylene oxides and combinations thereof.

The core may be of various different shapes. For example, the core may be formed as a polyhedron, such as a cube, pyramid, prism, or the like; It may take the form of a space shape with some nonfatty faces, such as cones, cones, cylinders, spheres, toruss, and the like. In certain embodiments, the core has one or more major faces. For example, in embodiments where the core is in compression stagnation, the core surface typically has two opposing major faces formed in contact with the upper and lower punch faces in the compressor. In this aspect, the core surface is typically located between two major faces and further includes a "belly-band" formed in contact with the die wall in the compressor. Exemplary core shapes that can be used include the following: [The Elizabeth Companies Tablet Design Training Manual] (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.), Which includes tablet shapes formed from compression tool shapes:

18. Shallow Crest.

19. Standard surface.

20. Deep concave.

21. Excessive Deep Surfaces.

22. Adjusted ball surface.

23. Standard concave bisector.

24. Standard concave double bisector.

25. Standard concave European bisector.

26. Standard concave partial bisection.

27. Double Radius.

28. Diagonal and concave.

29. Flat plane.

30. Flat oblique edges (F.F.B.E.).

31.F.F.B.E. bisector.

32.F.F.B.E. Double halving.

33. Won.

34. Dimples.

35. Ellipse.

36. Ellipsoid.

37. Capsules.

38. Rectangle.

39. Square.

40. Triangles.

41. Hexagons.

42. Pentagram.

43. Octagon.

44. Diamonds.

45. Arrowheads.

46. Bullets.

47. Shallow Crest.

48. Shallow Crest.

49. Deep Surfaces.

50. Excessive Deep Surfaces.

51. Adjusted ball surface.

52. Standard concave bisector.

53. Standard concave double bisector.

54. Standard essential European bisector.

55. Standard concave partial bisector.

56. Double Radius.

57. Diagonal lines and concave.

58. Flat plane.

59. Flat oblique edges (F.F.B.E.).

60. F.F.B.E. bisector.

61.F.F.B.E. Double halving.

62. Won.

63. Dimples.

64. Ellipses.

65. Ellipsoid.

66. Capsules.

67. Rectangle.

68. Square.

69. Triangles.

70. Hexagons.

71. Pentagram.

72. Octagon.

73. Diamond.

74. Arrowheads.

75. Bullets.

76. Barrels.

77. Half moon.

78. Blank.

79. Heart

80. Almonds.

81. House / Home Signage.

82. Parallel quadrilaterals.

83. An isosceles quadrilateral.

84. Cotton 8 / barbell.

85. Bow Tie.

86. Unflattened triangle.

In one aspect of the invention, the core comprises multiple parts, for example a first part and a second part. This portion can be prepared by the same or different methods, such as the thermal cycle molding method or the thermosetting molding method described herein, and are joined using various techniques. For example, the first and second portions can be produced by compression or by molding. Alternatively, one part can be made by compression and the other is made by molding. The same or different active ingredients may be present in the first and second parts of the core. Alternatively, the one or more core portions may be substantially free of active ingredient. Details of making cores and multiparts are well known in the art and are described, for example, in The Theory and Practice of Industrial Pharmacy, 303-306 (3 ^rd Ed. 1986).

In another aspect of the present invention, the core comprises first, second and third portions, each comprising the same or different active ingredients. In another embodiment, the core comprises first, second and third portions, wherein the third portion (located between the first portion and the second portion) has a high concentration of the active ingredient, and thus one from the dosage form. The above-mentioned active ingredient generates a particularly desired release profile. In this embodiment, the release of the one or more active ingredients from the dosage form can have a substantially constant release rate and can have a substantially non-constant release rate or an elevated release rate.

In another embodiment, the core comprises first, second and third portions, wherein the third portion (located between the first portion and the second portion) is substantially free of the active ingredient and is an osmotic agent Or an osmotic polymer, or may be used as a barrier to the passage of the active ingredient between the first and second core portions.

In certain embodiments of the invention, the core or portion thereof may act to impart controlled release properties to one or more active ingredients contained herein. As noted previously, in this embodiment where the core or core portion is made by molding, the core may be composed of a release-controlled mobile excipient. In embodiments in which the at least one core portion acts as a corrosive matrix in which the dispersed active ingredient is vitrified in a sustained, extended, extended or delayed manner, the core portion is selected from swellable edible hydrophilic agents, pH dependent polymers and mixtures thereof. -May consist of controlled compressible or mobile excipients.

In embodiments wherein at least one core portion functions as a diffusive matrix in which the active ingredient is vitrified in a sustained, extended, extended or delayed manner, the core portion is a controlled release excipient selected from a combination of insoluble edible materials and pore formers. Can be configured. Alternatively, in this embodiment in which the core portion is produced by molding, the thermally reversible carrier is included in the core portion and can act by forming voids or channels through which the active component can be dissolved.

As described herein, one or more portions of the shell are semipermeable to the liquid medium. The semipermeable shell or shell portion absorbs water and absorbs it into the core of the dosage form from an environment such as a dissolution medium or gastrointestinal bodily fluid. The semipermeable shell portion acts as a barrier to the path of the active ingredient from the underlined core portion and releases the active ingredient from the dosage form through different means such as holes or passageways or through the diffuse shell portion. The semipermeable shell or shell portion is inedible, which is insoluble in body fluids. According to the invention, at least one part of this shell which is semipermeable to the liquid medium consists of the above-mentioned polymeric composition.

In one aspect of the invention, the semipermeable shell or shell portion can be prepared using any of the flowable materials, including, but not limited to, the polymeric compositions of the invention mentioned above.

In one embodiment, at least about 30% of the cross-sectional area of the semipermeable shell or semipermeable shell portion used in the dosage forms of the present invention is striped. In another embodiment, at least about 50% of the cross-sectional area of the semipermeable shell or semipermeable shell portion is striped. In another embodiment, at least about 80% of the cross-sectional area of the semipermeable shell or semipermeable shell portion is striped. As used herein, “stripe free” means homogeneous with respect to appearance and with respect to the internal structure of the shell or shell portion when observed under any magnification and illumination conditions. For example, the cross section of the shell or shell portion is stripe free and uniform with respect to refractive properties when observed using a light microscope or a scanning electron microscope at about 50 to about 400 times magnification.

Expensive and lengthy prior art methods for enhancing semipermeable coatings in tablets and pharmaceutical dosage forms by spray coating techniques result in a characteristic striped pattern, which results in a dosage form or semipermeable coating as shown in FIGS. 7A and 7B. Visible in cross section This characteristic striation is a multiple of the steps consisting of spraying and applying a coating solution (a), and then forming a layer by augmenting a plurality of layers of coating material as each application of coating material drying (b). A spray-coating method consisting of repetitions is shown. Typical sprayed semipermeable coatings have a thickness of about 60 to about 150 μm. The thickness range of each layer is typically about 10 to about 13 μm.

In contrast, the shell or shell portion of the present invention may advantageously be applied directly to the core by means of a molding process, with the homogeneous and homogeneous layer being 5 minutes or less, for example 60 seconds or less, 30 seconds or less, or 10 seconds or less. And in one embodiment, 1 second or less. As such, in certain embodiments of the present invention at least about 30% of the cross-sectional area of the shell or shell portion is not stripped.

7A and 7B show prior art spray coating compositions having stripes that are distinguishable from certain embodiments of the invention. FIG. 7A is a microscopic cross section of the prior art PROCARDIA XL tablet (commercially available from Pfizer Labs) and FIG. 7B is a microscopic cross section (800 × magnification) of the same tablet. Prior art products are clearly striped. 8A and 8B, on the other hand, show the dosage forms of the present invention (120 ×× 330 × magnifications, respectively). As shown, embodiments of the present invention do not have stripes.

The shell or shell portion of the present invention has a cross sectional area, as measured by equation (1).

In Equation 1 above,

D ₁ is the diameter of the coated dosage form,

D ₂ is the core of the coated dosage form.

About 1 to 900sq.mm, ie, about 25 to 600sq.mm or about 50 to about 500sq.mm.

In one particular embodiment, the shell comprises two portions adjacent to each other, thus forming a shell that completely surrounds the core.

The shell or shell portion composed of the above-mentioned polymeric composition of the present invention also provides for the delivery of the active ingredient from the liquid medium core or core portion outside the dosage form after contacting the dosage form with the liquid medium. In one embodiment, one or more holes or passageways are present in the shell or shell portion to allow liquid medium containing the active ingredient into the dosage form, thereby passing out of the dosage form through the shell or shell portion. In another embodiment, the shell comprises a diffusive shell or shell portion and the active ingredient diffuses into the liquid medium outside of the dosage form.

In certain other embodiments, the portion of the shell acts as a diffusing membrane comprising voids through which the liquid medium containing the active ingredient in the dosage form can be released through the diffusing shell portion in a sustained, expanded, extended or delayed manner. . In this embodiment, the release rate of the active ingredient from the underlined core or core portion is determined by the total pore area within the shell or shell portion, the path length of the pores and the solubility and diffusion of the active ingredient [release from the core or core portion itself. In addition to speed]. In certain embodiments in which the shell or shell portion acts as a diffusing membrane, release of the active ingredient from the dosage form may be referred to as controlled, extended, sustained or extended. In this embodiment, the contribution to dissolving the active ingredient from the shell or shell portion is along the square root of zero rank, first rank or time kinetics. In certain such embodiments, the diffusible membrane shell or shell portion may be composed of a release-controlled excipient such as a combination of pore formers and insoluble edible materials, such as membrane forming water insoluble polymers. Alternatively, in this embodiment in which the shell or shell portion is prepared by solvent-free molding using a thermally reversible carrier, the thermally reversible carrier may act by dissolving and forming voids or channels through which the active ingredient may be liberated. .

In certain other embodiments, the active ingredient dispersed in the shell portion acts as a corrosive matrix liberated by dissolution of a continuous layer of the shell or shell portion surface. In this embodiment, the rate of release of the active ingredient depends on the rate of dissolution of the matrix material in the shell or shell portion. Particularly useful matrix materials to provide surface corrosion include those that first absorb the liquid and then swell and / or gelate prior to dissolution. In this particular embodiment, the corrosive matrix shell or shell portion may be composed of swellable corrosive hydrophilic material.

In certain other embodiments, the at least one shell portion acts as a barrier to prevent the release of the active ingredient contained in the underlined core or core portion. In this embodiment, the active component is typically released from the portion of the core that is not covered by the barrier shell portion. Typically this is accomplished by having one or more passageways in the shell or shell portion such that the active ingredient reaches a liquid medium outside of the dosage form. This embodiment advantageously allows for the control of the surface area with respect to the release of the active ingredient. In certain particular embodiments, for example, the release surface area of the active ingredient may remain substantially constant over time. In one embodiment, the release of one or more active ingredients follows substantially zero rank kinetics. In certain such embodiments, the barrier shell portion may be comprised of a water insoluble material, such as a water insoluble polymer.

In certain other embodiments, the shell or portion thereof acts as a delayed release coating to delay release of the active ingredient contained in the core or portion thereof. In such embodiments, the delay time for initiation of active ingredient release can be dictated by diffusion or corrosion of the coating through the coating or combinations thereof. In certain such embodiments, the corrosion matrix shell or shell portion may be comprised of a swellable corrosive hydrophilic material.

In embodiments in which the shell or portion thereof serves to control the release of the active ingredient contained in the core or main shell or shell portion, the thickness of the shell or shell portion is critical to the release characteristics of the dosage form. Advantageously, the dosage forms of the invention can be prepared with precise control over the shell thickness. In one embodiment in which the shell or one or more shell portions acts to control the release of the active ingredient contained in the core or main shell or shell portion, the shell or shell portion is formed by the thermal cycle or thermoset molding methods described herein. Are manufactured.

In certain other aspects of the invention, additional flexibility in designing the dosage form of the invention may be achieved through the use of an additional outer coating, or "overlapping" that overlaps the shell or one or more portions thereof. Additional outer coatings may be applied, for example, by spray coating, compression coating, or molding coating. In such embodiments, the dosage form of the invention may comprise one or more active ingredients, which may be the same or different from the active ingredients contained in the core; core; A shell or shell portion present in one or more portions of the core; And an outer coating covering at least one portion of the shell or shell portion. The outer coating may, for example, cover a portion of the first shell portion, the second shell portion, or both, or may surround the entire shell.

In one embodiment, the outer coat is selected from the USP specification for an immediate release dosage form of the active ingredient which is essentially essentially released upon ingestion of the dosage form (ie, dissolution of the active ingredient from the outer coat is used. Matches). After selecting a known method for applying a protective film to a dosage form, a person skilled in the art, for example, includes, but is not limited to, about 100 mg or less of the active ingredient and hydroxyalkylcellulose having a molecular weight of less than about 8500. It is readily apparent how to prepare a suitable protective film composition composed of a dissolving material.

In another embodiment, the dosage form is a pulsating drug delivery system that provides a delayed release of a second dose of the active ingredient contained in the underlined core portion of the one or more shell portions.

In another embodiment, the dosage forms of the present invention may be further or wholly covered with a protective film that acts to slow or delay the passage of fluids, such as water or biological fluids. After selecting a known method for applying a protective film to a dosage form, one skilled in the art will readily know how to prepare a suitable protective film composition consisting of, for example, a polymer having a molecular weight of 8,500 to 5,000,000. Examples of suitable polymers that can be used in the delayed release protective film are nonionic water soluble polymers, cellulose ether nonionic polymers with solutions not affected by cations, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, hydroxypropylcelluloses, phenyl Non-ionic cellulose ester polymer, benzhydrylcellulose, hydroxyethyloctylcellulose, diphenylmethylcellulose, hydroxyethylcellulose, tricellulose and water with a solution of cellulose, benzylcellulose, unaffected by cations, about 7.0 hours Polymer compositions with delay of up to or about 4.5 hours or less.

In one aspect of the invention wherein the shell comprises first and second shell portions, the first and second shell portions comprise different levels of the same component, such as colorants, opacifiers, film formers, and the like. can do. In one such aspect, the first and second shell portions can be visually distinguished from each other, for example, the portions that are visually distinguished can be color, hue, glossiness, reflectivity, brightness, depth, shading, saturation, Opacity may be different. For example, the shell may have a red portion and a yellow portion, or may have a flat processed portion and a glossy portion, or an opaque portion and a translucent portion. Alternatively, the first and second shell portions can be different in thickness. The first and second shell portions can have different functionalities. For example, the first and second shell portions may impart corresponding release properties to the active ingredient contained in the main shell portion or the corresponding underlined core portion. In one particular embodiment, the first shell portion can act as a diffusion membrane containing voids into which body fluids can be introduced into the dosage form, and the dissolved active ingredient can be released from the wheaty core portion; The active ingredient in which the second shell portion is dispersed in the second shell portion can act as a corrosive matrix in which the solution of the continuous layer of the shell portion surface is released.

In one aspect of the invention, the shell portion (s) of the invention are voids having a diameter of about 0.5 to about 5.0 μm, whether prepared by a solvent-free molding process or by a solvent-based molding process. It does not contain substantially. As used herein, “substantially free of pores” means that the shell or shell portion (s) have a void volume of less than about 0.02 cc / g, i.e., in the pore diameter range of about 0.5 to about 5,0 μm. For example, less than about 0.01 cc / g, or less than about 0.005 cc / g. In contrast, typically compacted materials have a diameter range of about 0.02 cc / g or more of void volume. In another aspect of the invention, the core is a molded core and the core or core portion is substantially free of voids having a diameter of about 0.5 to about 5.0 μm.

The total dry weight of the shell or shell portion (s) is about 10 to about 400%, for example about 10 to about 50%, based on the total dry weight of the core.

Typical shell or shell portion thicknesses that can be used in the present invention are about 10 to about 4000 μm. In certain embodiments, the thickness of the shell or shell portion is less than 800 μm. In embodiments in which the shell portion is prepared by a solvent free molding process, the shell portion typically has a thickness of about 500 to about 4000 μm, such as about 500 to about 2000 μm, or about 500 to about 800 μm, or About 800 to about 1200 μm. In embodiments in which the shell or shell portion is prepared by a solvent-based molding process, the shell or shell portion typically has a thickness of less than about 800 μm, such as from about 50 to about 500 μm, or from about 100 to about 350 μm.

In embodiments in which solvent-free molding is used, the flowable material may comprise a thermally reversible carrier as mentioned above.

In embodiments in which the shell portion comprises the active ingredient such that it has immediate release from the dosage form, the shell portion is prepared through the solvent-free molding method mentioned above. In such embodiments, the thermally reversible carrier may be selected from polyethylene glycols having a weight average molecular weight of about 1450 to about 20000, polyethylene oxides having a weight average molecular weight of about 100,000 to about 900,000.

In embodiments in which the shell or shell portion acts to impart controlled release properties to one or more active ingredients contained in the dosage form, in the core, the shell, or both, the shell or shell portion is typically as described above. Such as one or more release modifiers.

In an aspect of the invention wherein the core or portion thereof and the shell or portion thereof each comprise a dose of the active ingredient, the dosage form can act, for example, as a multicompartment, eg, a four-compartment pulsatile release delivery system. have. In one such embodiment, each of the compartments comprises the same dosage of active ingredient to be released at the desired time or rate. In another such aspect, the corresponding first core portion and the first shell portion comprise the same dosage of the first active ingredient to be released at the desired time or rate, while the second core portion and the second shell portion are The same dosage of the second active ingredient may be included so as to be released at the desired time or rate. In this aspect, each compartment comprises an inert material that enables the desired functionality of a particular core portion or shell portion.

In this particular embodiment, the dosage form may further comprise a water impermeable barrier layer between the first and second core portions. The water impermeable barrier layer can be prepared by any method, for example by compression or molding, and includes one or more water insoluble materials selected from water insoluble polymers, insoluble edible materials, pH dependent polymers and mixtures thereof.

In certain embodiments of the invention, the one or more active ingredients contained in the dosage form exhibit an inconsistent release rate.

In another particular embodiment of the invention, the one or more active ingredients contained in the dosage form exhibit a delayed explosion release profile. "Delayed explosive release profile" means that the release of a particular active ingredient from the dosage form is delayed for a predetermined time after ingestion by the patient, and the delay period ("delay time") involves the rapid (immediate) release of the active ingredient. do. At least one shell portion of the present invention is substantially free of active ingredients released in a delayed explosive manner. In this embodiment, the delayed polval active ingredient is typically contained in the corresponding underlined core moiety. In this embodiment, the core portion can be prepared by compression or molding and is formulated for immediate release, as is known in the art, so that the core portion readily dissolves when contacted with the dissolution medium. In such experiments, the core portion may include a disintegrant and optionally include fillers or thermoplastics selected from water soluble or low melting materials and additional excipients such as surfactants or wetting agents. In this embodiment, the dissolution of the explosive release active ingredient after a delay period meets the USP specification for immediate release tablets containing the active ingredient.

In another particular embodiment of the invention, the one or more active ingredients contained in the dosage form exhibit a delayed and sustained release profile. A "delayed sustained release profile" means that a particular active ingredient from the dosage form is delayed for a predetermined time after ingestion by the patient, and the delay period ("lag time") is the duration (extension, extension or delay) of the active ingredient. Involves release. One or more shell portions of the present invention provide for a delay time and may be substantially free of active ingredients that are released in a sustained manner after the delay. In such embodiments, the sustained release active ingredient may be contained in the corresponding corresponding underlined core moiety. In this embodiment, the core portion can act as a corrosion matrix or diffusion matrix or an intrusive pump. In embodiments in which the core portion acts as a diffusive matrix in which the active ingredient is liberated in a delayed, prolonged, extended or delayed manner, the core portion may be a release-controlled excipient such as insoluble edible material and / or pore formation. It may include the agent. Alternatively, in this embodiment in which the core portion is made by molding, the thermally reversible carrier can act by forming voids or channels in which the active component can be dissolved or liberated. In embodiments in which the core portion acts as a corrosive matrix in which the dispersed active ingredient is released in a sustained, extended, extended or retarded manner, the core portion may be a release-controlled compressible or mobile excipient such as a swellable corrosive hydrophilic It may consist of a material and / or a pH dependent polymer.

In an embodiment in which the at least one core portion acts as a corrosive matrix in which the active ingredient contained is liberated in a sustained, extended, extended or delayed manner, the core portion is selected from a combination of insoluble edible materials and pore formers. It may consist of controlled release excipients. Alternatively, in this embodiment where the pore portion is produced by solvent free molding, the thermally reversible carrier can act by forming voids or channels through which the active component can be dissolved.

In embodiments in which the shell or shell portion acts by a corrosion-based mechanism to provide a delayed time for the release of the active ingredient from the underlined core portion, the release-delayed shell or shell portion may be a controlled release excipient, for example For example, swellable corrosive hydrophilic and / or insoluble edible materials.

In embodiments of the invention in which the shell or shell portion acts to delay the release of one or more active ingredients contained in the underlined core portion, the release-delayed shell or shell portion may be in a liquid medium, for example A delay of at least 1 hour, such as at least about 3 hours, at least about 4 hours, at least about 6 hours, or at least about 12 hours, may be provided with respect to the onset of dissolution of the active ingredient when contacted with water, gastrointestinal fluids, and the like. The delay period is typically controlled by the shell or shell portion thickness, composition or a combination thereof. In one embodiment, the delay period depends on the pH of the dissolution medium or fluid environment. For example, the average delay time for dissolution of the active ingredient in 0.1N HCl is substantially different from the average delay time for dissolution of the active ingredient in a buffer system of pH 5.6 (ie, within about 30 minutes or about 15 minutes). Minutes). In certain such embodiments, the release-delayed shell or shell portion may comprise release controlling excipients such as swellable corrosive hydrophilic materials and / or insoluble edible materials.

In embodiments in which the shell or portion thereof imparts sustained, prolonged or delayed release of the active ingredient contained in the underlined core or core portion, the release-modulating agent in the shell or shell portion may contain pore formers and any film formers. It may include. In another embodiment, the shell or shell portion acts as a diffusing membrane. In some such embodiments, the dissolution of the active ingredient follows the “diffusion-controlled” release kinetics as described by way of example in Example 1 of US Pat. No. 5,286,497. The shell or shell portion, which provides sustained, prolonged or delayed release and / or acts as a diffusing membrane, can be prepared by a solvent free method or a solvent based method, as mentioned above.

In embodiments in which the shell or portion thereof provides delayed release for the active ingredient contained in the underlined core or core portion, the release-controlling agent may be selected from swellable corrosive hydrophilic materials. The shell portion providing delayed release can be prepared by a solvent free method or a solvent based method, as mentioned above.

In embodiments in which the shell portion provides a barrier to inhibit release of the underlined core or the active ingredient contained in the core portion, the shell portion can be prepared via a solvent-free molding method, as mentioned above. In such embodiments, the thermally reversible carrier can be, for example, waxes such as carnauba wax, spermaceti wax, beeswax, candelia wax, shellac wax, microcrystalline wax and paraffin wax; Hydrogenated vegetable oils such as cocoa butter, hydrogenated castor oil; Other waxy substances such as glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl triacerate, glyceryl trilaurate, glyceryl myristate; Thermally reversible polymers such as polycaprolactone and polyvinyl acetate. In certain embodiments, the impermeable barrier can be formed by essentially consisting of a thermally reversible carrier. In this embodiment, no further release-modifying agent is necessary. In certain other embodiments, the release-modifying agent is a water-insoluble polymer such as cellulose acetate, acrylate, acrylic acid copolymer, cellulose acetate, cellulose acetate propionate, cellulose acetate propionate, cellulose propionate, cellulose acetate Butyrate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbonate, cellulose acetate diethyl aminoacetate, ethylcellulose, methacrylate, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, etc. And mixtures thereof. In such embodiments, the shell or shell portion may optionally further comprise a liquid carrier such as mineral oil, propylene glycol, low molecular weight polyethylene glycol, glycerin and the like.

The inventors have unexpectedly discovered that the polymeric compositions of the present invention not only have excellent tensile and yield strengths, but also advantageously withstand high osmotic pressures and hydrodynamic shearing without any cleavage and distortion of minerals. As used herein, “split” means a gap or hole in the semipermeable shell portion, which leads to the destruction of the release characteristics of the dosage form. As used herein, “distortion” refers to the stretching of a semipermeable shell membrane that causes the volume of the dosage form to increase with a drop in infiltration pressure, substantially slowing the release rate deviating from the zero order release. Since the osmotic dosage form uses enhanced osmotic pressure inside the dosage form to release the active ingredient through the passage, it is advantageous for the shell portion to have such excellent tensile and yield strengths. We further found that the incorporation of a gelling agent in the semipermeable polymeric composition contributes to reducing the disruption of the osmotic dosage form prepared therefrom. In addition, the inventors further note that the gelling agents used in the present invention are suitable for use in such polymeric compositions in place of water soluble materials, which tend to contribute to the destruction of the osmotic dosage form over an extended period of time. Found.

In addition, the cost and cycle time associated with the preparation of osmotic dosage forms using the polymeric compositions of the present invention are both significantly less than those required by prior art spray coated osmotic dosage forms.

The present invention is intended to illustrate the following examples and is not intended to limit the invention in any way.

Example 1 Preparation of Polymeric Compositions

Polymeric compositions having the formulations described in Table A and suitable for use as shells for dosage forms are prepared as follows:

Table A: Formulations of Polymeric Composition

ingredient Trade name Manufacturer weight% water - - 17.17 Acetone B & J Brand R High Purity Solvent Honeywell International Inc., Muskeron, Mich., USA 40.28 Cellulose acetate Cellulose acetate NF Eastman Chemical Company, Kingsport, Tennessee, USA 22.90 Carrageenan Gelcarin GP-812, NF FMC Corporation, Newark, Delaware, USA 0.76 Triacetin Triacetin, Food Grade Eastman Chemical Company, Kingsport, Tennessee, USA 15.27 Polyethylene Glycol 400 Polyethylene Glycol 400NF, FCC Grade The Dow Chemical Company, Gourmet, USA 3.82

Weight percent of active ingredient is based on total wet weight of polymeric composition.

Cellulose acetate is added to the blocker comprising acetone, triacetin, polyethylene glycol and water and mixed using a mixer until the powder is dissolved. The mixture is heated in a 55 ° C. water bath to give a viscous solution. Carrageenan is added to the hot solution, then the resulting mixture is heated and stirred until a homogeneous texture is obtained.

Example 2: Preparation of Compressed Cores

Cores with the formulations set forth in Table B are prepared as follows:

Table B: Formulation of Core Part:

ingredient Trade name Manufacturer weight% Polyethylene oxide (MW = 300,000) Polyox ^R WSR 750 NF The Dow Chemical Company in Midland, Michigan, USA 75 Diphenylhydramine HCl, USP Congo 15 Hydroxypropyl methylcellulose Methocel E5 The Dow Chemical Company in Midland, Michigan, USA 8.5 Magnesium stearate - Malinrodrod, Inc. (Mallinkrodt, Inc.) 1.5 D & C Yellow # 10 D & C Yellow # 10 HT Colorcon Inc., West Point, Pennsylvania, USA a very small amount Isopropyl alcohol (dried as solvent) - EM Science

Diphenylhydramine HCl, hydroxypropyl methylcellulose and PEO (MW = 300,000) are first mixed in a plastic bag for 1-2 minutes. The powder mixture is added to 5qt. Of balls in a Hobart planetary mixer and alcohol is added thereto while mixing at about 60 rpm. After mixing the components for about 10 minutes, the resulting granules are removed from the bowl and dried at room temperature for 12-16 hours to remove all remaining solvent. Granulation is screened through a # 20 mesh screen and placed into a plastic bag. Magnesium stearate is added to the dry granules and then mixed for 3 minutes.

The resulting diphenylhydramine HCl granules (440 mg) are fed into a cavity of a Model M hydraulic Carver Laboratory Press equipped with a round punched compression punch and a die unit of 0.4375 "in diameter. The granulate is pressed into a solid tablet using a compressive force of 2000 lb / sq.in. The resulting tablet has an approximate density of about 1.1 g / mL.

Example 3 Method for Making a Compressed Core With Two Parts

A dosage form comprising a core having a first core portion and a second core portion in a shell is prepared as follows.

A first core portion is prepared using the following components (infiltration layer):

Table C: Formulations of Osmotic Core Portions

ingredient Trade name Manufacturer weight% Polyethylene oxide (MW = 7,000,000) Polyox ^R WSR 750 Coagulant The Dow Chemical Company in Midland, Michigan, USA 75 Sodium chloride J.T. in Phillipsburg, New Jersey, USA. Baker (J.T. Baker) 25 FD & C Red # 40 Warner Jenkinson Company a very small amount

** based on the total dry weight of the osmotic core

Polyethylene oxide, sodium chloride and dye are placed in a jar and then mixed for about 5 minutes to prepare a first core portion mixture.

A second core portion is prepared using the following ingredients (pharmaceutical layer):

Table D: Formulations of Drug-Containing Core Portions

ingredient Trade name Manufacturer weight% Pseudoephedrine HCl Crystals BASF PharmaChemikalien GmbH & Co. 24.5 Polyethylene oxide Polyox ^R WSR N-80 NF Grade The Dow Chemical Company in Midland, Michigan, USA 75 D & C Yellow # 10 D & C Yellow # 10 HT Collorcon Inc., West Point, Pennsylvania, USA a very small amount

** based on the total dry weight of the second core portion

Polyoxyethylene, pseudoephedrine HCl and dye are mixed in the jar for about 5 minutes to prepare a second core portion mixture.

As mentioned above, the core is made from the first and second core portions. The osmotic layer mixture (203 g) of the first core portion is fed into a cavity of a Model M hydraulic carver laboratory press equipped with a round punched compression punch and a die unit with a diameter of 0.4375 ", then the powder layer is slowly The pseudoephedrine HCl pharmaceutical layer mixture (425 mg) of the second core portion is fed into a mold cavity covered with an insertable core portion The resulting powder mixture is fed into a solid two part core using a compressive force of 2000 lb / sq.in. The resulting core has a density of about 1.1 g / mL.

Example 4 Preparation of a Coated Dosage Form Having a Two-Part Core

The first and second shell portions, consisting of the composition prepared according to Example 1, consisted of the composition prepared according to Example 3 via a laboratory scale heat cycle molding unit as described in US Patent Publication 2003/0232082. To the core. The molding unit included in the single mold assembly is manufactured from an upper mold assembly portion having an upper mold assembly and a lower mold assembly portion having a lower mold cavity.

After circulating the lower mold assembly portion at a high temperature step at 55.0 ° C. for 30 seconds, about 0.2 g of Example 1 composition is added to the lower mold cavity. A two-part core prepared according to Example 3 is inserted into the lower mold cavity to insert a second core portion (which contains the medicament layer blend) into the lower mold cavity, and the first core portion (which is an osmotic layer blend) It is maintained closely by concealing the upper mold assembly portion. After the lower mold assembly and the upper mold assembly are circulated in a cooling step at 2.0 ° C. for 1 minute, the concealed upper mold assembly portion is removed from the lower mold assembly portion. After circulating the upper mold assembly portion at a high temperature step at 55.0 ° C. for 30 seconds, about 0.2 g of the composition of Example 1 was inserted into the upper mold cavity to contain an uncoated first core portion (which contains a top layer blend). ) Remains in the upper mold cavity. The lower mold assembly portion maintained at 2.0 ° C. is combined with the upper mold assembly portion. The upper mold assembly portion is circulated in a cooling step at 2.0 ° C. for 2 minutes. The lower mold assembly portion is removed and the processed dosage form, a shelled two-piece core composed of the composition of Example 1, is released from the upper mold cavity.

The weight increase due to the shell portion, ie, the difference between the weight of the processed wet coated dosage form prepared according to the example and the weight of the uncoated anhydrous core prepared according to Example 3 is about 30 greater than the weight of the anhydrous core. To about 35% greater. The processed dosage form is dried at 50 ° C. for 24 hours to remove all residual solvent. Holes of 0.55 mm are mutually driven to the surface of the pseudopendrin HCl drug layer of the dosage form using pins having a diameter of 0.55 mm.

The resulting dosage form is cut into open cross sections and then mounted on a Philips XL 30 ESEM scanning electron microscope. FIG. 7A is a micrograph cross-sectional view of a conventional PROCARDIA XL tablet (commercially available from Pfizer Labs), and FIG. 7B is a micrograph cross-sectional view (800 × magnification) of the same tablet. As shown in Figures 7A and 7B, the conventional product clearly has streaks as well as laminated textures. 8A and 8B, on the other hand, show the dosage forms of the invention (120 and 300 times magnification, respectively) prepared according to the examples.

This example shows that the dosage form of the present invention is substantially uniform in texture and without streaks.

Example 5: Dissolution Testing of Dosage Forms

The coated dosage forms prepared according to Example 4 are analyzed for dissolution using a USP Type II dissolution apparatus (paddle, 50 RPM) containing a phosphate buffer medium at pH 6.8 at 37 ° C. Samples are separated into the following time intervals (hours): 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. These dissolution samples from the dosage form of Example 4 were pseudoephedrine HCl using a Kary 50 UV-Vis spectrophotometer at a wavelength of 254 nm compared to the pseudoephedrine solution standard prepared at theoretical concentrations for 100% pseudoephedrine emission. The content is analyzed spectrophotometrically. The results are shown in FIG.

The examples show that dosage forms containing the coating compositions of the present invention provide near zero order release of pseudoephedrine.

Example 6: Tensile Testing of Polymeric Compositions

Two polymeric compositions, each suitable for use as a shell for the dosage form and having the formulations set forth in Tables E and F, are prepared as follows:

Table E: Cellulose Acetate, Gelcarin, Triacetin, PEG 400

ingredient Trade name Manufacturer weight% Cellulose acetate Cellulose acetate NF Eastman Chemical Company, Kingsport, Tennessee, USA 14.74 Triacetin Triacetin, Food Grade Eastman Chemical Company, Kingsport, Tennessee, USA 9.83 Polyethylene Glycol 400 Polyethylene Glycol NF, FCC Grade The Dow Chemical Company in Midland, Michigan, USA 1.23 Carrageenan Gelcarin GP812 NF FM Corporation in Newark, Delaware, USA 0.49 Acetone B & J Brand Al High Purity Solvent Honeywell International Inc., Muskeron, Michigan, USA 51.60 water - - 22.11

* Weight percent of active ingredient is based on total wet weight of polymeric composition.

The composition described in Table E is prepared according to the procedure described in Example 1, but uses the components in the amounts described in Table E.

Table F: cellulose acetate, POLYOX (comparative composition)

ingredient Trade name Manufacturer weight% Cellulose acetate CA NF 398-10 Eastman Chemical Company, Kingsport, Tennessee, USA 80.0 Polyethylene oxide (MW = 200,000) Polyox ^R WSR N-80 Union Carbide Corporation, Danbury, Connecticut, USA 20.0 Acetone (dried as solvent)

* Weight percent of active ingredient is based on total dry weight of polymeric composition.

Cellulose acetate is added to an acetone containing beaker with mixing until all the powder is dissolved to prepare the composition shown in Table F under ambient conditions. Polyoxyethylene oxide is added to the cellulose acetate solution and then mixed until all the PEO powder is visually dispersed.

The composition of Table E is cast into a membrane. A small amount of hot melt mixture consisting of the components of Table E is placed on top of the stainless steel sheet. Another stainless steel plate precooled to about 5 ° C. is pressed quickly and firmly on top of the mixture for 20 seconds. The solidified film is removed from the stainless steel sheet and dried at 50 ° C. for 12 hours. Each of these steps is repeated, but the composition of Table F is used.

Membranes formed from the compositions of Table E and Table F, respectively, using a "Punch-Press NAEF" device commercially available from MS Instrument Company, Inc., Sutton Creek, New Jersey Tensile test strips are prepared from membranes formed from the composition. The length of each strip of membrane is 22 +/- 0.25 mm and the width of each strip of membrane is 5 +/- 0.25 mm.

The dry and wet tensile strength of each membrane strip was determined by TA-xT2i-Texture Analyzer (TA-), available from Texture Technologies Corp., Chicago, CA, to test wet tensile strength. Analyze using an xT2i-texture analyzer, and each membrane strip is first immersed in deionized water at room temperature for 2 hours for the membrane consisting of the composition of Table E and for 1.5 minutes for the membrane consisting of the composition of Table F. . The strips are individually attached to a group of texture analyzers, preset at a distance of 10 mm, and then the grips are moved to 1 mm / sec during the tensile test. This texture analysis test is repeated for each independent wet strip. As used herein, “hydration tensile test” means that a tensile test is performed on a wet membrane that is immersed in water for 2 hours as stated in the examples.

To test the dry tensile strength, additional dry strips are attached to a group of texture analyzers, which are preset at a distance of 10 mm, and then the grips are moved to 1 mm / sec during the tensile test. The initial thickness of the dry film is 0.013 in. For the membrane consisting of the composition of Table E, and 0.013 in. For the membrane consisting of the composition of Table F.

Tensile test results performed on membranes formed from the compositions set forth in Tables E and F are shown in FIGS. 10 and 11, respectively.

The examples are superior to the coatings of the present invention as demonstrated in the films formed from the compositions of E, compared to those obtained by the coatings formed without organic and gelling agents formed through organic dispersions as demonstrated in the films formed from the compositions of Table F. It is shown to have wet tensile strength.

This example further indicates that the tensile strength of the membrane in wet form was changed as a function of wet time. More specifically, the wet membranes formed from the compositions of Table F become significantly weaker over time compared to the same dry membranes. Surprisingly, however, the tensile strength of the wet membranes formed from the compositions of Table E indicates that the tensile strength increases over time compared to the tensile strength of the same dry membrane.

Example 7: Tensile Testing of Polymeric Compositions

Two polymeric compositions, each having the formulations described in Tables G and H and suitable for use as shells for dosage forms, are prepared as follows:

Table G: cellulose acetate, triacetin (high level) prepared from acetone / water

ingredient Trade name Manufacturer weight% Cellulose acetate Cellulose Acetate, NF Eastman Chemical Company, Kingsport, Tennessee, USA 18.83 Triacetin Triacetin, Food Grade Eastman Chemical Company, Kingsport, Tennessee, USA 22.60 Carrageenan Gelcarin GP812 NF FM Corporation in Newark, Delaware, USA 2.07 Acetone (dried as solvent) B & J Brand Al High Purity Solvent Honeywell International Inc., Muskeron, Michigan, USA 39.55 Water (dry as solvent) - - 16.95

Weight percent of active ingredient is based on total wet weight of polymeric composition.

Table H: Cellulose acetate prepared from acetone / water, triacetin (low level)

ingredient Trade name Manufacturer weight% Cellulose acetate Cellulose Acetate, NF Eastman Chemical Company, Kingsport, Tennessee, USA 21.37 Triacetin Triacetin, Food Grade Eastman Chemical Company, Kingsport, Tennessee, USA 12.82 Carrageenan Gelcarin GP812 NF FM Corporation in Newark, Delaware, USA 1.71 Acetone (dried as solvent) B & J Brand Al High Purity Solvent Honeywell International Inc., Muskeron, Michigan, USA 44.87 Water (dry as solvent) - - 19.23

Weight percent of active ingredient is based on total wet weight of polymeric composition.

The compositions set forth in Table G and Table H, respectively, were prepared according to the procedures described in Example 1, except for the amounts of the compounds set forth in Table G and Table H and PEG 400, respectively.

The composition of Table G and the composition of Table H were independently cast into a membrane according to the procedure described in Example 6. Tensile test strips are prepared from membranes formed from the compositions of Table G and membranes formed from Composition H, respectively, according to the procedures set forth in Example 6. The dry and wet tensile strength of each membrane strip was analyzed through the procedure described in Example 6, immersing the test strip in deionized water for 3 minutes (a), setting the grip to 22 mm (b) And step (c) of moving the grip at a speed of 0.1 mm / sec.

For membranes composed of the compositions of Tables G and H, the initial thickness of the dry membrane was 0.005 in., And the thickness of the wet membranes of the compositions of Table G and Table H was 0.006 in., Respectively, after wetting for 3 minutes.

Tensile test results performed on membranes formed from the compositions set forth in Table G and Table H are shown in FIGS. 12 and 13, respectively.

This example shows that for both wet and dry membranes, the addition of excess plasticizer can increase the membrane's flexibility, but decreases the tensile strength of the membrane.

Example 8 Preparation of a Coated Dosage Form Having Two Partial Cores

The shell portion of the dosage form consists of the composition set forth in Example 1, and the core consists of the composition set forth in Example 3.

A molding unit similar to Example 4 includes the following single mold assembly: an upper mold assembly portion (a) having an upper mold cavity and a lower mold assembly portion (b) having a lower mold cavity. However, this unit also has an injection port into each cavity of each upper and lower mold assembly. The two-part core described in Example 3 is inserted into the lower mold cavity of the molding unit and maintained at 5 ° C. to insert the second core portion (which includes the pharmaceutical layer blend) into the lower mold cavity and the first The core portion (which includes the osmotic layer blend) is kept tight by concealing the upper mold assembly portion. About 0.2 g of the composition of Example 1 is injected into the lower mold cavity through an injection port. The concealed lower mold assembly portion is removed from the lower mold assembly portion. The upper mold assembly portion maintained at 5 ° C. is combined with the lower mold assembly portion. About 0.2 g of the composition of Example 1 is injected into the upper mold cavity through the injection port. The lower mold assembly portion is removed and a two part core coated with a processed dosage form, ie a shell composed of the composition of Example 1, is released from the upper mold cavity.

Claims (21)

At least one active ingredient (a), Core (b) having an outer surface and A dosage form comprising a shell (c) present in at least one portion of a core outer surface, wherein At least one portion of the shell is semipermeable and consists of about 40 to about 99% of a water insoluble film forming polymer and about 1 to about 30% of a gelling agent based on the total dry weight of the shell, wherein the shell is liquid And a means for providing the active ingredient to the liquid medium outside the shell after contact with the medium. The method of claim 1 wherein the water insoluble film forming polymer is in cellulose ester, cellulose ether, cellulose ester ether, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, polyacrylate, polymethacrylate or derivatives or copolymers thereof. Dosage forms consisting of one or more. The dosage form of claim 1 wherein the water insoluble film forming polymer is cellulose acetate and / or ethyl cellulose. The dosage form according to claim 3, wherein the gelling agent consists of at least one of aqueous colloids, gel starches, and derivatives or copolymers thereof. The dosage form of claim 4 wherein the gelling agent is an aqueous colloid selected from the group consisting of carrageenan, gellan gum, soybean gum, agar, alginate, pectin and mixtures thereof. The dosage form of claim 1, wherein the shell has one or more passageways extending from its surface through the shell to one or more surfaces of the core. The dosage form of claim 1, wherein the shell and core have a continuous cavity defining an inner surface, wherein the shell does not substantially extend from the inner surface. The dosage form of claim 1, wherein the core comprises a first core portion, a second core portion, and a third core portion located between the first core portion and the second core portion and comprising an osmopolymer. . The method of claim 1, wherein the core is based on its total weight: sodium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrate And about 0.01 to about 40% of an osmotic agent selected from the group consisting of: and mixtures thereof. The pore former of claim 1 wherein at least one portion of the shell is selected from the group consisting of polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose and copolymers and mixtures thereof, based on their total dry weight. And from about 0.5 to about 5%. The dosage form of claim 1, wherein the at least one portion of the shell is further comprised of about 1 to about 30% plasticizer, based on its total dry weight. 12. The composition of claim 11 wherein the plasticizer is polyethylene glycol; Propylene glycol; glycerin; Sorbitol; Triethyl citrate; Tributyl citrate; Dibutyl sebecate; vegetable oil; Polysorbate; Sodium lauryl sulfate; Dioctyl-sodium sulfosuccinate; Monoacetate of glycerol; Diacetate of glycerol; Triacetate of glycerol; Natural gums; Triacetin; Acetyltributyl citrate; Diethyl oxalate; Diethyl maleate; Diethyl fumarate; Diethyl malonate; Dioctyl phthalate; Dibutyl succinate; Glycerol tributyrate; Hydrogenated castor oil; fatty acid; Dosage forms selected from the group consisting of glycerides and mixtures thereof. Based on the total wet weight of the composition, Water-insoluble film-forming polymer (a) about 5 to about 50%, Gelling agent (b) about 0.05 to about 15% and A composition comprising about 40% to about 95% of a multisolvent system (c), And wherein the multisolvent system consists of about 10 to about 50% water and about 50 to about 90% water miscible organic solvent, based on its total weight. At least one active ingredient (a), Core (b) having an outer surface and A dosage form comprising a shell (c) present in at least one portion of a core outer surface, wherein The shell and the first shell portion are semipermeable to the liquid medium and consist of about 40 to about 99% of the water-insoluble film forming polymer and about 1 to about 30% of the gelling agent, based on its total dry weight. A second shell portion, the composition being different from the shell portion, wherein the first shell portion and the second shell portion are in substantial contact with the core outer surface, respectively, and the shell contacts the dosage form with the liquid medium, A dosage form comprising means for providing the active ingredient to an external liquid medium. The dosage form of claim 14, wherein at least one of the first shell portion or the second shell portion has one or more passageways extending from the surface of the shell portion to the one or more surfaces of the core through the shell. The dosage form of claim 14, wherein the core comprises a first core portion, a second core portion, and a third core portion located between the first core portion and the second core portion and comprising an osmotic polymer. The dosage form of claim 14, wherein the shell and the core have continuous cavities that define the inner surface, and neither of the first shell portion nor the second shell portion extends substantially at the inner surface. 15. The core of claim 14, wherein the core is based on its total weight: sodium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates. And about 0.01 to about 40% of an osmotic agent selected from the group consisting of: and mixtures thereof. 15. The pore former of claim 14 wherein at least one portion of the shell is selected from the group consisting of polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose and copolymers and mixtures thereof, based on their total dry weight. And from about 0.5 to about 5%. The dosage form of claim 14, wherein the at least one portion of the shell is further comprised of about 1 to about 30% plasticizer, based on its total dry weight. 21. The method of claim 20, wherein the plasticizer is polyethylene glycol; Propylene glycol; glycerin; Sorbitol; Triethyl citrate; Tributyl citrate; Dibutyl sebecate; vegetable oil; Polysorbate; Sodium lauryl sulfate; Dioctyl-sodium sulfosuccinate; Monoacetate of glycerol; Diacetate of glycerol; Triacetate of glycerol; Natural gums; Triacetin; Acetyltributyl citrate; Diethyl oxalate; Diethyl maleate; Diethyl fumarate; Diethyl malonate; Dioctyl phthalate; Dibutyl succinate; Glycerol tributyrate; Hydrogenated castor oil; fatty acid; Dosage forms selected from the group consisting of glycerides and mixtures thereof.