US20040018327A1

US20040018327A1 - Delayed release dosage forms

Info

Publication number: US20040018327A1
Application number: US10/393,765
Authority: US
Inventors: David Wynn; Narendra Parikh
Original assignee: Individual
Current assignee: Kenvue Brands LLC
Priority date: 2001-09-28
Filing date: 2003-03-21
Publication date: 2004-01-29
Also published as: BR0213589A; WO2003026629A3; US20040241208A1; US7968120B2; ES2311073T3; ES2444549T3; DE60237294D1; US8545887B2; KR20040045034A; HK1072902A1; DE60239945D1; HUP0401686A2; BR0213593A; KR20040045032A; US20030235616A1; KR20040045026A; US20040241236A1; US20040213849A1; CA2461870A1; US7635490B2

Abstract

A dosage form comprises:

(a) a core having an outer surface, wherein the core comprises at least one active ingredient and at least one disintegrant; and

(b) a shell comprising at least a first shell portion which resides upon at least a portion of the core outer surface, wherein the shell comprises (i) at least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, and the weight ratio of film forming polymer to lipid is in the range of about 40:60 to about 60:40. A method of providing a delayed burst release of an active ingredient from a dosage form comprises contacting the dosage form of this invention with a liquid medium such as gastrointestinal fluid.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of PCT Application Nos. PCT/US02/31129, filed Sep. 28, 2002; PCT/US02/31117, filed Sep. 28, 2002; PCT/US02/31062, filed Sep. 28, 2002; PCT/US02/31024, filed Sep.28, 2002; and PCT/US02/31163, filed Sep. 28, 2002, which are each continuations-in-part of U.S. Ser. No. 09/966,939, filed Sept. 28, 2001; U.S. Ser. No. 09/966,509, filed Sep. 28, 2001; U.S. Ser. No. 09/966,497, filed Sep. 28, 2001; U.S. Ser. No. 09/967,414, filed Sep. 28, 2001; and U.S. Ser. No. 09/966,450, filed September 28, the disclosures of all of the above being incorporated herein by reference in their entirety.[0001]

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to delayed release or pulsatile release dosage forms such as delayed release or pulsatile release pharmaceutical compositions, and methods of providing predetermined active ingredient concentrations in a delayed or pulsatile release manner using such dosage forms. More particularly, this invention relates to dosage forms for delivering one or more active ingredients in a delayed or pulsatile release manner upon contacting of the dosage form with a liquid medium such as gastrointestinal (GI) fluid. In a preferred embodiment, the dosage form provides a delayed or pulsatile release profile for one or more active ingredients contained therein, i.e. contact of the dosage form with a liquid medium is followed by a programmed time delay, followed by a prompt release of one or more doses (portions) of one or more active ingredients. The dosage form comprises a core containing at least one active ingredient and a disintegrant, and a shell comprising at least a first shell portion which resides upon at least a portion of the core. The shell or first shell portion comprises at least one water insoluble film forming polymer and at least one water insoluble lipid in a weight ratio of about 40:60 to 60:40.

2. Background Information

Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. In some instances, it is particularly desirable for a dosage form to deliver more than one dose of one or more drugs at different rates or predetermined times. Because the onset and duration of the therapeutic efficacy of drugs vary widely, as do their absorption, distribution, metabolism, and elimination, it is often desirable to modify the release of different drugs in different ways, or to have a first dose of active ingredient (e.g. drug) immediately released from the dosage form, while a second dose of the same or a different drug is released in a modified (e.g. delayed, pulsatile, repeat action, controlled, sustained, prolonged, extended, or retarded) manner.

An important objective of modified release dosage forms is to provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for each drug. Fundamentally, the PK profile for a drug is governed by the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood. To be absorbed into the blood (circulatory system), the drug must first be dissolved in the GI fluids. For those relatively rapidly absorbed drugs whose dissolution in GI fluids is the rate limiting step in drug absorption, controlling the rate of dissolution (i.e. drug release from the dosage form) allows the formulator to control the rate of drug absorption into the circulatory system of a patient. The type of PK profile desired depends, among other factors, on the particular active ingredient or ingredients, and physiological condition being treated.

One particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of one or more doses of drug from the dosage form is delayed for a pre-determined time after contact of the dosage form by a liquid medium, such as for example, after ingestion by the patient. The delay period (“lag time”) can be followed either by prompt release of the active ingredient (“delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”). U.S. Pat. No. 5,464,633, for example, discloses delayed-release dosage forms in which an external coating layer was applied by a compression coating process. The coating level ranged from 105 percent to 140 percent of the weight of the core in order to yield product with the desired time delayed profile.

One particularly desirable type of delayed release PK profile is a “pulsatile” profile, in which for example, a first dose of a first drug is delivered, followed by a delay period during which there is substantially no release of the first drug from the dosage form, followed by either prompt or sustained release of a subsequent dose of the same drug. In one particularly desirable type of pulsatile drug delivery system, the first dose is released essentially immediately upon contacting of the dosage form with a liquid medium. In another particularly desirable type of pulsatile drug delivery system, the delay period corresponds approximately to the time during which a therapeutic concentration of the first dose is maintained in the blood. Pulsatile delivery systems are particularly useful for applications where a continuous release of drug is not ideal. Examples of this are drugs exhibiting first pass metabolism by the liver, drugs that induce biological tolerance (i.e. the therapeutic effect decreases with continuous presence of the drug at the site of action), and drugs whose efficacy is influenced by circadian rhythms of body functions or diseases. One typical pulsatile dosage form design contains the first dose of drug in an exterior coating, or shell, while subsequent doses of drug are contained in underlying layers of subcoatings, or a central core. PCT publication No. WO99/62496, for example, discloses a dosage form comprising an immediate-release dose of drug contained within an overcoat applied onto the surface of the semipermeable membrane of an osmotic dosage form. U.S. Pat. Nos. 4,857,330 and 4,801,461 disclose dosage forms comprising an exterior drug coat that surrounds a semipermeable wall, which in turn surrounds an internal compartment containing a second dose of drug, and comprises exit means for connecting the interior of the dosage form with the exterior environment of use. These dosage forms are designed to release drug immediately from the exterior coating, followed by a relatively short delay period, followed by a sustained release of drug from the internal compartment.

Another design for a pulsatile delivery system is exemplified in U.S. Pat. No. 4,865,849, which describes a tablet able to release active substances at successive times, comprising a first layer containing a portion of the active substance, a water soluble or water gellable barrier layer which is interposed between the first layer and a third layer containing the remaining portion of active substance, and the barrier layer and third layer are housed in an insoluble, impermeable casing. The casing can be applied by various methods such as spraying, compression, or immersion, or the tablet parts can be inserted into a pre-formed casing. Multilayer compressed tablets in stacked layer configurations necessarily require an impermeable partial coating (casing) to provide a pulsatile release profile. These systems suffer from the complexity and high cost of assembling multiple, separate compartments comprising multiple, different compositions.

Well known mechanisms by which a dosage form (or drug delivery system) can deliver drug at a controlled rate (e.g. sustained, prolonged, extended or retarded release) include diffusion, erosion, and osmosis. It is often practical to design dosage forms which use a combination of the above mechanisms to achieve a particularly desirable release profile for a particular active ingredient. It will be readily recognized by those skilled in the art that a dosage form construct which offers multiple compartments, such as for example multiple core portions and/or multiple shell portions, is particularly advantageous for its flexibility in providing a number of different mechanisms for controlling the release of one or more active ingredients.

To date, erosion has been the primary mechanism for delaying release of active from a portion of a dosage form for a period of time.

A commonly used erosion-controlled release system comprises a “matrix” throughout which one or more drugs are distributed. The matrix typically comprises a material which swells at the surface, and slowly dissolves away layer by layer, liberating drug as it dissolves. The rate of drug release (dM/dt) in these systems depends on the rate of erosion (dx/dt) of the matrix, the concentration profile in the matrix, and the surface area (A) of the system according to the following equation:

dM/dt=A {dx/dt} {f(C)}

Again, variation in one or more terms, such as surface area, typically lead to a non-constant release rate of drug. In general, the rate of drug release from erosion-controlled release systems typically follows first order kinetics.

Another type of erosion controlled delivery system employs materials which swell and dissolve slowly by surface erosion to provide a delayed release of pharmaceutical active ingredient. Delayed release is useful, for example in pulsatile or repeat action delivery systems, in which an immediate release dose is delivered, followed by a pre-determined lag time before a subsequent dose is delivered from the system. In these systems, the lag time (T ₁) depends on the thickness (h) of the erodible layer, and the rate of erosion (dx/dt) of the matrix, which in turn depends on the swelling rate and solubility of the matrix components according to the following equation:

T ₁ =h(dx/dt)

The cumulative amount of drug (M) released from these systems at a given time generally follows the equation:

M=(dM/dt) (t−T ₁)

where dM/dt is generally described by either the diffusion-controlled or erosion-controlled equations above, and T ₁is the lag time.

Delayed release dosage forms are known in the art. For example, U.S. Pat. No. 6,143,327 discloses a delayed release coated tablet. The coated tablet comprises: a core having glyceryl behenate and the antidepressant drug bupropion hydrochloride contained therein; a first coating containing a water insoluble, water permeable film forming polymer, a plasticizer and a water soluble polymer; and a second coating containing a methacrylic polymer and a plasticizer. WO98/30208 discloses a delayed release coated tablet comprising: a core having bupropion hydrochloride contained therein; a first barrier layer which coats a first face of the core; and an optional second barrier layer which coats the opposite face of the core. The barrier layer or layers contain a polymeric material which shows a high degree of swelling and gelling in an aqueous medium, or non-swellable wax or polymeric material which is aqueous media. The composition of the present invention advantageously accomplishes its function in a single coating layer.

The delayed or pulsatile release dosage forms of this invention employ a core containing at least one active ingredient and a shell which surrounds the core. The shell comprises at least a first shell portion which comprises a novel composition which enables the shell to provide a delay in release of one or more active ingredients contained in the underlying core or core portion. The time period of the delay in release is independent of the pH of the surrounding liquid medium (e.g. GI fluid). The delay period may be followed by a burst or immediate release of active ingredient, or alternatively, the delay period may be followed by a controlled release of active ingredient.

In contrast, current core-shell systems are limited by the available methods for manufacturing them, as well as the materials that are suitable for use with the current methods. A shell, or coating, which confers delayed release properties is typically applied via conventional methods, such as for example by compression, to produce either multiple stacked layers, or core and shell configurations. In one such system, the outer compressed coating layer may function via an erosion mechanism to delay release of an active ingredient contained in the core. U.S. Pat. No. 5,464,633, for example, discloses delayed-release dosage forms in which an external coating layer was applied by a compression coating process. The coating level ranged from 105 percent to 140 percent of the weight of the core in order to yield product with the desired time delayed profile. Additional modified release dosage forms prepared via compression are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO99/51209. It is possible, via compression-coating, to produce a 2-portion shell, which may function as a barrier, or release delaying coating, however compression-coated systems are limited by the shell thickness and shell composition. Gunsel et al., “Compression-coated and layer tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A. Lieberman, L. Lachlnan, J. B. Schwartz (2 nd ed., rev. and expanded. Marcel Dekker, Inc.) pp. 247-284, for example, discloses the thickness of compression coated shells is typically between 800 and 1200 microns. U.S. Pat. No. 5,738,874, discloses a 3-layer pharmaceutical compressed tablet capable of liberating one or more drugs at different release rates, in which an immediate release dose of active may be contained in a compressed coating layer, and the compressed coating layer has a weight which is 230% to 250% of the weight of the core, and a sustained release dose of active ingredient is contained in the core. Spraying methods have not traditionally been found to be optimal for applying a delayed-release coating, due to the preference of formulators for using water-swellable materials to achieve an erosion mechanism for dissolution of the release-delaying coating. Water swellable materials typically swell irreversibly in the coating dispersion, accordingly losing their swellability in the finished dosage form. The present invention advantageously provides a sprayable formulation for forming a release-delaying coating, optionally without the use of water-swellable materials, and which retains its release delaying properties when formed into a coating on a substrate, whether by spraying or by molding.

It is one object of this invention to provide a dosage form in which at least one active ingredient contained therein exhibits a delayed or pulsatile release profile upon contacting of the dosage form with a liquid medium. It is one feature of the dosage form of this invention that the core contains at least one active ingredient and at least one disintegrant. It is another feature of the dosage form of this invention that the shell comprises at least a first shell portion which contains at least one water insoluble film forming polymer and at least one water insoluble lipid. It is another feature of the dosage form of this invention that the weight ratio of film forming polymer:lipid in the shell or first shell portion is in the range of about 40:60 to 60:40. It is another feature of the dosage form of this invention that the time period of delay prior to the release of the active ingredient or ingredients is independent of the pH of the liquid medium contacting the dosage form. It is yet another feature of the dosage form of this invention that the shell may contain an additional optional component which promotes permeation of the liquid medium through the shell into the core.

It is another object of this invention to provide a method for providing a delayed or pulsatile release of an active ingredient from the dosage form of this invention upon contacting the dosage form with a liquid medium. It is a feature of the dosage form of this invention that the delay time period prior to the release of the active ingredient or ingredients may be controlled by the shell weight as compared to the total weight of the dosage form. It is another feature of the dosage form of this invention that the time period of delay prior to the release of the active ingredient or ingredients is independent of the pH of the liquid medium contacting the dosage form. Other objects, features and advantages of this invention will be apparent to those skilled in the art from the detailed description set forth below.

SUMMARY OF THE INVENTION

The present invention provides a dosage form comprising: a) a core having an outer surface, wherein the core comprises at least one active ingredient and at least one disintegrant; and b) a shell which resides upon at least a portion of the core outer surface, wherein the shell comprises at least a first shell portion comprising (i) at least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, and the weight ratio of film forming polymer to lipid is in the range of about 40:60 to about 60:40.

The present invention also provides a method of providing a delayed burst release of an active ingredient from a dosage form, wherein the method comprises: (I) providing a dosage form comprising: a) a core having an outer surface, wherein the core comprises at least one active ingredient and at least one disintegrant, and b) a shell comprising at least a first shell portion which resides upon at least a portion of the core outer surface, wherein the shell or first shell portion comprises (i) at least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, and the weight ratio of film forming polymer to lipid is in the range of about 40:60 to about 60:40; and (II) contacting the dosage form with a liquid medium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a cross sectional side view of one embodiment of the dosage form of this invention. [0024]
FIG. 2 depicts the dissolution profile of active ingredient from the dosage form of Example 1.[0025]

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “dosage form” applies to any solid, semi-solid, or liquid composition designed to contain a specific pre-determined amount (dose) of a certain ingredient, for example an active ingredient as defined below. Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. Preferably the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components. In a particularly preferred embodiment, the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the GI tract of a human. [0026]
At least one active ingredient contained within the dosage form of this invention exhibits a delayed release profile. As used herein, a delayed release profile for a certain active ingredient means the dissolution of that active ingredient from the dosage form is delayed for a predetermined period of time (lag time). The delay period may be preceded by a period of release for a prior dose of the same or another active ingredient, or the delay period may begin upon contacting of the dosage form with a liquid medium, such as suitable in vitro dissolution media or GI fluids. [0027]
In a preferred embodiment, at least one active ingredient contained within the dosage form of this invention exhibits a delayed burst release profile. As used herein, a “burst release profile” refers to a release profile which meets immediate release criteria during a specified interval. The specified interval may optionally follow a predetermined lag time. By “delayed burst release profile” it is meant that the release of at least a portion, or dose, of that particular active ingredient from the dosage form is delayed for a pre-determined time after contact with a liquid medium, such as after ingestion by the patient, and the delay period (“lag time”) is followed by prompt (i.e. immediate) release of that dose of active ingredient. The shell or first shell portion provides for the delay period and is substantially free of the portion of active ingredient to be released in a delayed burst manner. The delayed burst active ingredient is typically contained within the corresponding underlying core portion. The core may be prepared by any method, for example compression or molding, and is formulated for immediate release, as is known in the art, so that the core is readily soluble upon contact with the dissolution medium. The core comprises a disintegrant, and optionally comprises additional excipients such as fillers or thermoplastic materials selected from water-soluble or low-melting materials, and surfactants or wetting agents. As used herein, “core” refers to a material which is at least partially enveloped or surrounded by another material. Preferably, the core is a self-contained unitary object, such as a tablet or capsule. Typically, the core comprises a solid, for example, the core may be a compressed or molded tablet, hard or soft capsule, suppository, or a confectionery form such as a lozenge, nougat, caramel, fondant, or fat based composition. In certain other embodiments, the core or a portion thereof may be in the form of a semi-solid or a liquid in the finished dosage form. For example the core may comprise a liquid filled capsule, or a semisolid fondant material. In embodiments in which the core comprises a flowable component, such as a plurality of granules or particles, or a liquid, the core preferably additionally comprises an enveloping component, such as a capsule shell, or a coating, for containing the flowable material. In certain particular embodiments in which the core comprises an enveloping component, the shell or shell portions of the present invention are in direct contact with the enveloping component of the core, which separates the shell from the flowable component of the core. [0028]
In one embodiment the core is a compressed tablet having a hardness from about 2to about 30 kp/cm[0029] ², e.g. from about 6 to about 25 kp/cm². “Hardness” is a term used in the art to describe the diametral breaking strength of either the core or the coated solid dosage form as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare values across different size tablets, the breaking strength must be normalized for the area of the break. This normalized value, expressed in kp/cm², is sometimes referred in the art as tablet tensile strength. A general discussion of tablet hardness testing is found in Leiberman et al., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2^nded., Marcel Dekker Inc., 1990, pp. 213-217, 327-329.
In embodiments wherein the dosage form provides a delayed burst profile, the dissolution of the burst release portion of active ingredient, after the delay period, meets USP specifications for immediate release tablets containing that active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus [0030] 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. (See USP 24, 2000 Version, 19-20 and 856 (1999)).
The shell or first shell portion functions to confer a delay of the release of one or more active ingredients contained in the underlying core or portion thereof, and preferably provides a delay of greater than one hour, for example at least about 3 hours, or at least about 4 hours, or at least about 6 hours, or at least about 12 hours to the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium such as water, GI fluid or the like. The delay period is typically controlled by erosion of the shell or portion thereof, diffusion through the shell or portion thereof, or a combination thereof. The delay period may also be controlled by the shell composition, e.g., for example, the relative amounts of the water insoluble film forming polymer and water insoluble lipid. The delay period is essentially independent of the pH of the dissolution media or fluid environment. For example, the average lag-time for dissolution of active ingredient in 0.1 N HCl is not substantially different (i.e. within about 30 minutes, preferably within about 15 minutes) from the average lag-time for the dissolution of active ingredient in pH 5.6 buffer system. [0031]
In addition to delaying the release of at least one active ingredient, the dosage forms of this invention may optionally further exhibit modified release of one or more active ingredients contained therein. Additionally, the dosage forms of this invention may optionally further exhibit immediate release of one or more active ingredients contained therein. The active ingredient or ingredients may be found within the core, the shell, or a portion or combination thereof. As used herein, the term “modified release” shall apply to dosage forms, coatings, shells, cores, portions thereof, or compositions that alter the release of an active ingredient in any manner. The active ingredient or ingredients that are released in a modified manner may be contained within the coating, shell, core, composition, or portion thereof providing the modification. Alternatively the modified release active ingredient may be contained in a different portion of the dosage form from the coating, shell, core, composition, or portion thereof providing the modification; for example the modified release active ingredient may be contained in a core portion, and the modification may be provided by the overlaying shell portion. Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art. Moreover, the modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or the shell or portion thereof, or a combination of two or more of these parts of the dosage form. [0032]
The dosage forms of this invention are designed to release substantially all (i.e. at least about 80%, or at least about 90%, say at least about 95%) of the active ingredient contained therein, within a specified amount of time. As used herein, the total amount of time required for substantially all of the active ingredient or ingredients to be released from the dosage form shall be referred to as the “dosing interval”. During the dosing interval, the amount of drug released is typically measured at several time points. [0033]
As used herein, the term “time interval” shall refer to periods of time during the dosing interval, over which a periodic rate of release may be measured. The time interval may be the entire dosing interval, or a portion thereof. [0034]
As used herein, the “release rate” of an active ingredient (e.g., drug) refers to the quantity of active ingredient released from a dosage form per unit time, e.g., milligrams of active ingredient released per hour (mg/hr). Active ingredient rates are calculated under in vitro dosage form dissolution testing conditions known in the art. As used herein, an active ingredient rate obtained at a specified time “following administration” refers to the in vitro active ingredient release rate obtained at the specified time following implementation of an appropriate dissolution test. [0035]
In this invention, the core comprises at least one disintegrant such as sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, effervescent compounds, effervescent mixtures, and the like, and combinations thereof. As used herein, “effervescent” is meant to include inorganic salts of carbonic acid, inorganic bicarbonate salts, acid/base pairs that react to liberate gases, and the like. In one embodiment, the disintegrant is a “superdisintegrant”, selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, and combinations thereof. [0036]
The shell or first shell portion resides upon at least a portion of the outer surface of the core. In one embodiment, the shell is a single layer in contact with the outer layer of the core. In another embodiment, the shell comprises first and second shell portions which each are in contact with the outer layer of the core. The shell or first shell portion comprises at least one water insoluble film forming polymer and at least one water insoluble lipid. The weight ratio of total water insoluble film forming polymer: total weight of water insoluble lipid must be in the range of about 40:60 to about 60:40. [0037]
In one embodiment, the water insoluble film forming polymer may be at least one of ethylcellulose, cellulose acetate, polymethacrylic acid, methyl methacrylate, cellulose acetate butyrate, cellulose acetate propionate, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, or mixtures thereof. [0038]
In one embodiment, the water insoluble lipid may be at least one of fatty acid esters, which include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GLYCOWAX-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glyceride;. fats such as mono-, di-, and tri-glycerides having chain lengths of about C[0039] ₁₀-C₄₀, waxes such as include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax and the like, cocoa butter, hydrogenated vegetable oils, palm kernel oil, cottonseed oil, sunflower oil, soybean oil, long chain fatty acids such as those having a fatty acid chain length of about C₁₀-C₄₀, fatty acid esters such as those having a fatty acid chain length of about C₁₀-C₄₀, or mixtures thereof.
Without wishing to be bound by any one theory, it is believed that the water insoluble film forming polymer forms a water insoluble film around the core or core portion (thereby providing for the delay of release of active ingredient), and the water insoluble lipid acts as an insoluble barrier within the shell, which gradually erodes away to weaken the film, which aids in the eventual rupture or failure of the shell or first shell portion (thereby providing the immediate release of active ingredient from the core). [0040]
The weight ratio of water insoluble film forming polymer to water insoluble lipid in the shell or first shell portion is critical to this invention. If excess film forming polymer is used, the shell or first shell portion will not rupture to release active ingredient from the core. If excess lipid is used, the shell or first shell portion will lack sufficient mechanical strength, and the shell or first shell portion will rupture too quickly to provide the desired delay prior to release of active ingredient from the core. [0041]
In one embodiment, the shell weight is about 10% to about 30% of the total weight of the dosage form. [0042]
In another embodiment, the shell or first shell portion may additionally contain up to about 20% of its weight of at least one of a water soluble polymer, a water soluble crystalline material, a water swellable material, or mixtures thereof. [0043]
In one embodiment, the water soluble polymer may be at least one of hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone (PVP) or mixtures thereof. [0044]
In one embodiment, the water-soluble crystalline material may be at least one of sugars such as mono- or di-saccharides (e.g., sucrose, glucose, fructose, lactose, mannose, or maltose), polyhedric alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, xylitol, or lactitol), water soluble inorganic salts (e.g., NaCl, KCl, Nal, KI, CaCl[0045] ₂and the like), or combinations thereof.
In one embodiment, the water swellable material may be at least one of water swellable cellulose derivatives, polyalkalene glycols, polyalkalene oxides, acrylic polymers, hydrocolloids, gelling starches, and swelling cross-linked polymers, and derivatives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC) such as those available from Dow Chemical Company under the tradenames METHOCEL K4M, METHOCEL K15M, and METHOCEL K100M, hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glycols include polyethylene glycol. Examples of suitable polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, synthetic high-molecular weight acrylic acid homopolymers and copolymers crosslinked with allyl sucrose or allyl ethers of pentaerythritol, such as those available under the tradename CARBOPOL, and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, and chitosan. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium. [0046]
Without wishing to be bound by any one theory, it is believed that the water soluble polymer, water soluble crystalline material or water swellable material acts as a pore former to promote permeation of liquid medium through the shell or first shell portion into the core. Accordingly, the additional water soluble polymer, water soluble crystalline material or water swellable material may also be employed to control the time period of delay or lag-time prior to release of active ingredient from the core. [0047]
A first embodiment of the dosage form of this invention is depicted in FIG. 1, which is a cross-sectional view of a [0048] dosage form 2 having a core 4 and a shell 6, which in this embodiment resides upon the outer surface of core 4 and completely surrounds core 4. Core 4 contains at least one active ingredient and at least one disintegrant. Shell 6 contains at least one water insoluble film forming polymer, and at least one water insoluble lipid. The weight ratio of film forming polymer to lipid in the shell is in the range of about 40:60 to about 60:40.
Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistames, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, anti fungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, oral contraceptives, diuretics, expectorants, GI agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof. [0049]
Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like. [0050]
Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like. [0051]
Examples of suitable GI agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sticraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for [0052] H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
In one embodiment of the invention, the active ingredient may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0053]
In another embodiment, the active ingredient is selected from analgesics, anti-inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g. mefenamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In one embodiment, the active ingredient is selected from propionic acid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In another embodiment of the invention, the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0054]
In another embodiment of the invention, the active ingredient may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0055]
Examples of suitable polydimethylsiloxanes, which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference. As used herein, the term “simethicone” refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone. [0056]
The active ingredient is present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dosing regimen, the age and weight of the patient, and other factors must be considered, as known in the art. Typically, the dosage form comprises at least about 1 weight percent, preferably, the dosage form comprises at least about 5 weight percent, e.g. about 20 weight percent of a combination of one or more active ingredients. [0057]
The active ingredient may be present in the dosage form in any form. For example, the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In one preferred embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns. [0058]
At least a portion of the active ingredient may be optionally coated with a release-modifying coating, as known in the art. This advantageously provides an additional tool for modifying the release profile of active ingredient from the dosage form. For example, the core may contain coated particles of one or more active ingredients, in which the particle coating confers a release modifying function, as is well known in the art. Examples of suitable release modifying coatings for particles are described in U.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240; 5,286,497; 5,912,013; 6,270,805; and 6,322,819. Commercially available modified release coated active particles may also be employed. Accordingly, all or a portion of one or more active ingredients in the core may be coated with a release-modifying material. [0059]
In embodiments in which it is desired for the active ingredient to be absorbed into the systemic circulation of an animal, the active ingredient or ingredients are preferably capable of dissolution upon contact with a fluid such as water, gastric fluid, intestinal fluid or the like. [0060]
In one embodiment, the dissolution characteristics of one or more active ingredients are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like. In a particular embodiment in which one or more active ingredients are released in a modified manner, the modified release active ingredient or ingredients are contained in the core. In one particular such embodiment, the dosage form releases one or more active ingredients contained in the core at a substantially constant rate over a specified time interval. [0061]
In another embodiment, the dissolution characteristics of at least one active ingredient contained in the dosage form meets USP specifications for immediate release tablets containing the active ingredient. In certain such embodiments, the immediately released active ingredient or ingredients are contained in a further coating, which resides upon at least a portion of the shell of the present invention. In certain other such embodiments, the dissolution characteristics of a delayed release dose, or portion, of active ingredient meet immediate release criteria following the delay period (i.e. lag time). In these embodiments, the delayed release dose, or portion of active ingredient is preferably contained within the core. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus [0062] 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP appraratus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999).
In one embodiment of the invention, the core comprises multiple portions, for example a first portion and a second portion. The portions may be prepared by the same or different methods and mated using various techniques, such as the thermal cycle molding and thermal setting molding methods described herein. For example, the first and second portions may both be made by compression, or both may be made by molding. Or one portion may be made by compression and the other by molding. The same or different active ingredient may be present in the first and second portions of the core. Alternately, one or more core portions may be substantially free of active ingredients. [0063]
In certain other embodiments, a portion of the core may optionally function as an eroding matrix from which dispersed active ingredient is liberated by the dissolution of successive layers of the matrix surface. In these embodiments, the rate of active ingredient release from the eroding matrix core portion will depend on the dissolution rate of the matrix material. Particularly useful eroding matrix materials for providing surface erosion include those which first absorb liquid, then swell and/or gel prior to dissolving. In certain such embodiments, the eroding matrix portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof. [0064]
In certain other embodiments, a portion of the core may function as a diffusional matrix. In these embodiments, the diffusional matrix core portion comprises active ingredient distributed throughout an insoluble porous matrix, which contains pores or channels through which fluids can enter the core portion, and the active ingredient must diffuse to be released from the dosage form. In these embodiments, the rate of active ingredient release from the diffusional matrix core portion will depend upon the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drug solubility (Cs) in the dissolution medium, and the drug concentration (Cp) in the dosage form. In embodiments in which a core portion functions as a diffusional matrix, the release of active ingredient from the diffusional matrix core portion may be described as controlled, prolonged, sustained, or extended. In these embodiments, the contribution to active ingredient dissolution from the diffusional matrix core portion may follow zero-order, first-order, or preferably square-root of time kinetics. In these embodiments, the diffusional matrix core portion preferably comprises a pore former. [0065]
In embodiments in which one or more core portions function as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore formers. Alternately, in such embodiments in which the core portion is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. [0066]
In embodiments in which a core portion functions to modify release of an active ingredient contained therein, the release of active ingredient may be further modified by the function of the surrounding shell, as described above. In such embodiments, the release of the active ingredient from the dosage form will be governed by the sum of all the contributions acting upon it, e.g. from the relevant core and shell, and may be described as controlled, prolonged, sustained, extended, delayed, or pulsatile. In these embodiments, the dissolution of active ingredient from the dosage form may follow zero-order, first-order, or square-root of time kinetics. In another embodiment, the core portion functions to modify release of an active ingredient contained therein, and the core is surrounded by separate shell portions. [0067]
In certain other embodiments, the core comprises multiple portions, which comprise different active ingredients or have different release-modifying properties, or both; and the shell comprises a corresponding number of molded multiple portions, which each cover a specific core portion to modify or further modify the release of one or more active ingredients contained within the respective core portion. For such embodiments, it is critical to have a manufacturing process which is capable of maintaining the orientation of the core prior to and during the application of the shell or each shell portion thereon. Advantageously, the orientation of the components of the dosage forms of the present invention can be precisely controlled, when manufactured using the thermal cycle and thermal setting apparatus and described below. In one such embodiment, the dosage form comprises a core comprising a first core portion and a second core portion which are compositionally different, wherein at least one of the first or second core portions comprises an active ingredient; and a shell which surrounds the core and comprises a first shell portion and a second shell portion which are compositionally different, wherein at least the first shell portion confers a delay to the release of an active ingredient contained in the underlying first core portion, and the second shell portion may confer a modification to the release of an active ingredient contained in the underlying second core portion. [0068]
The core of the present invention may be prepared by any suitable method, including for example compression and molding, and depending on the method by which it is made, typically comprises active ingredient and a variety of excipients (inactive ingredients which may be useful for conferring desired physical properties to the core). [0069]
In embodiments in which the core, or a portion thereof, is made by compression, suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art. In embodiments in which the core is made by compression and additionally confers modified release of an active ingredient contained therein, the core preferably further comprises a release-modifying compressible excipient. [0070]
Suitable fillers for use in making the core, or a portion thereof, by compression include water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof. [0071]
Suitable binders for making the core, or a portion thereof, by compression include dry binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, starches, and the like; and derivatives and mixtures thereof. [0072]
Suitable disintegrants for making the core, or a portion thereof, by compression, include sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, effervescent compounds, effervescent mixtures, and the like, and combinations thereof. As used herein, “effervescent” is meant to include inorganic salts of carbonic acid, inorganic bicarbonate salts, acid/base pairs that react to liberate gases, and the like. Suitable lubricants for making the core, or a portion thereof, by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides and waxes. [0073]
Suitable glidants for making the core, or a portion thereof, by compression, include colloidal silicon dioxide, and the like. [0074]
Suitable release-modifying compressible excipients for making the core, or a portion thereof, by compression include swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and the like. [0075]
In certain embodiments of this invention, the core comprises a first core portion which comprises an immediate release formulation, and an optional second core portion. In these embodiments, one or more active ingredients contained in the first core portion may be released from the dosage form in a delayed burst manner upon contacting of the dosage form with a liquid medium. In embodiments wherein the second core portion functions as a modified release matrix, for example an erodible matrix, suitable release-modifying excipients for making the second core portion by compression include swellable erodible hydrophilic materials known in the art such as those disclosed in commonly assigned, copending U.S. application Ser. No. ______[MCP-321]. [0076]
Suitable pharmaceutically acceptable adjuvants for making the core, or a portion thereof, by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof. [0077]
In embodiments in which the core is prepared by compression, a dry blending (i.e. direct compression), or wet granulation process may be employed. In a dry blending (direct compression) method, the active ingredient or ingredients, together with the excipients, are blended in a suitable blender, than transferred directly to a compression machine for pressing into tablets. In a wet granulation method, the active ingredient or ingredients, appropriate excipients, and a solution or dispersion of a wet binder (e.g. an aqueous cooked starch paste, or solution of polyvinyl pyrrolidone) are mixed and granulated. Alternatively a dry binder may be included among the excipients, and the mixture may be granulated with water or other suitable solvent. Suitable equipment for wet granulation are known in the art, including low shear, e.g. planetary mixers; high shear mixers; and fluid beds, including rotary fluid beds. The resulting granulated material is dried, and optionally dry-blended with further ingredients, e.g. adjuvants and/or excipients such as for example lubricants, colorants, and the like. The final dry blend is then suitable for compression. Methods for direct compression and wet granulation processes are known in the art, and are described in detail in, for example, Lachman, et al., [0078] The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rd ed. 1986).
The dry-blended, or wet granulated, powder mixture is typically compacted into tablets using a rotary compression machine as known in the art, such as for example those commercially available from Fette America Inc. (Rockaway, N.J.), or Manesty Machines LTD (Liverpool, UK). In a rotary compression machine, a metered volume of powder is filled into a die cavity, which rotates as part of a “die table” from the filling position to a compaction position where the powder is compacted between an upper and a lower punch to an ejection position, where the resulting tablet is pushed from the die cavity by the lower punch and guided to an ejection chute by a stationary “take-off” bar. [0079]
In one particular embodiment, the core may be prepared by the compression methods and apparatus described in copending U.S. patent application Ser. No. 09/966,509, pages 16-27, the disclosure of which is incorporated herein by reference. Specifically, the core is made using a rotary compression module comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction as shown in FIG. 6 of U.S. patent application Ser. No. 09/966,509. The dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die. [0080]
In certain optional embodiments of this invention, the core, or the shell, or a portion thereof, may be prepared by molding. In such embodiments, the core, or the shell, or a portion thereof, is made from a flowable material. In embodiments in which the first shell portion of the present invention is prepared by molding, the flowable material preferably comprises least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, which may be dispersed in a suitable liquid carrier, or may be melted to form a flowable material. The water insoluble materials may be in solid particulate form, suspended in the liquid carrier, or may be dissolved in the liquid carrier. Suitable liquid carriers may comprise a solvent, such as water, alcohols, or organic solvents and mixtures thereof, or other suitable materials that are liquid at or above room temperature. The liquid carrier, or solvent, if present may optionally be partially or substantially removed by drying. [0081]
Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GLYCOWAX-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like. [0082]
Suitable solvents for optional use as components of the flowable material for making the core, or the shell or a portion thereof by molding include water; polar organic solvents such as methanol, ethanol, isopropanol, acetone, and the like; and non-polar organic solvents such as methylene chloride, and the like; and mixtures thereof. [0083]
The flowable material for making the core or the shell or a portion thereof by molding may optionally comprise adjuvants or excipients, which may comprise up to about 30% by weight of the flowable material. Examples of suitable adjuvants or excipients include plasticizers, detackifiers, humectants, surfactants, anti-foaming agents, colorants, flavorants, sweeteners, opacifiers, and the like. Suitable plasticizers for making the core, the shell, or a portion thereof, by molding include, but not be limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides; and the like and/or mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the shell or first shell portion is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers. [0084]
In one embodiment, the flowable material comprises less than 5% humectants, or alternately is substantially free of humectants, such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectants have traditionally been included in pre-formed films employed in enrobing processes, such as that disclosed in U.S. Pat. Nos. 5,146,730 and 5,459,983, assigned to Banner Gelatin Products Corp., to ensure adequate flexibility or plasticity and bondability of the film during processing. Humectants function by binding water and retaining it in the film. Pre-formed films used in enrobing processes can typically comprise up to 45% water. Disadvantageously, the presence of humectant prolongs the drying process, and can adversely affect the stability of the finished dosage form. [0085]

The core may be in a variety of different shapes. For example, the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In certain embodiments, the core has one or more major faces. For example in embodiments wherein the core is a compressed tablet, the core surface typically has two opposing major faces formed by contact with the upper and lower punch faces in the compression machine. In such embodiments the core surface typically further comprises a “belly-band” located between the two major faces, and formed by contact with the die walls in the compression machine. Exemplary core shapes which may be employed include tablet shapes formed from compression tooling shapes described by “The Elizabeth Companies Tablet Design Training Manual” (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.) (incorporated herein by reference) as follows (the tablet shape corresponds inversely to the shape of the compression tooling):



	1.	Shallow Concave.
	2.	Standard Concave.
	3.	Deep Concave.
	4.	Extra Deep Concave.
	5.	Modified Ball Concave.
	6.	Standard Concave Bisect.
	7.	Standard Concave Double Bisect.
	8.	Standard Concave European Bisect.
	9.	Standard Concave Partial Bisect.
	10.	Double Radius.
	11.	Bevel & Concave.
	12.	Flat Plain.
	13.	Flat-Faced-Beveled Edge (F.F.B.E.).
	14.	F.F.B.E. Bisect.
	15.	F.F.B.E. Double Bisect.
	16.	Ring.
	17.	Dimple.
	18.	Ellipse.
	19.	Oval.
	20.	Capsule.
	21.	Rectangle.
	22.	Square.
	23.	Triangle.
	24.	Hexagon.
	25.	Pentagon.
	26.	Octagon.
	27.	Diamond.
	28.	Arrowhead.
	29.	Bullet.
	30.	Shallow Concave.
	31.	Standard Concave.
	32.	Deep Concave.
	33.	Extra Deep Concave.
	34.	Modified Ball Concave.
	35.	Standard Concave Bisect.
	36.	Standard Concave Double Bisect.
	37.	Standard Concave European Bisect.
	38.	Standard Concave Partial Bisect.
	39.	Double Radius.
	40.	Bevel & Concave.
	41.	Flat Plain.
	42.	Flat-Faced-Beveled Edge (F.F.B.E.).
	43.	F.F.B.E. Bisect.
	44.	F.F.B.E. Double Bisect.
	45.	Ring.
	46.	Dimple.
	47.	Ellipse.
	48.	Oval.
	49.	Capsule.
	50.	Rectangle.
	51.	Square.
	52.	Triangle.
	53.	Hexagon.
	54.	Pentagon.
	55.	Octagon.
	56.	Diamond.
	57.	Arrowhead.
	58.	Bullet.
	59.	Barrel.
	60.	Half Moon.
	61.	Shield.
	62.	Heart.
	63.	Almond.
	64.	House/Home Plate.
	65.	Parallelogram.
	66.	Trapezoid.
	67.	Figure 8/Bar Bell.
	68.	Bow Tie.
	69.	Uneven Triangle.

The shell or first shell portion functions to slow or delay the rate of passage of a fluid, such as water or a biological fluid therethrough. The dissolved or molten components for the flowable material for forming the shell or first shell portion typically comprise the water insoluble film forming polymer and water insoluble lipid described previously. [0087]
In a preferred embodiment, the shell or first shell portion is applied to a core directly by a spraying process, comprising the steps of: a.) preparing a dispersion of the insoluble film forming polymer and water insoluble lipid, and optionally suitable adjuvants and excipients in a suitable solvent such as water, organic solvents, or combinations thereof; b.) applying the dispersion to the cores via spraying using suitable equipment as known in the art, including for example coating pans, fluidized bed coaters, and the like; c.) drying to remove the solvent. [0088]
In another embodiment, the shell or first shell portion may advantageously be applied to a core directly by a molding process, yielding a uniform and homogeneous layer in 5 minutes or less, e.g. 60 seconds or less, or 30 seconds or less, or 10 seconds or less, and in certain embodiments, say 1 second or less. [0089]
One suitable method for making the shell or shell portion of this invention comprises: (a) preparing a dispersion of the insoluble film forming polymer and water insoluble lipid, and other shell materials in a suitable solvent, e.g. acetone or water or combinations thereof; (b) injecting the dispersion (the dispersion may be heated in a heated feed tank) into a mold cavity (at room temp or below) containing the core such that the dispersion surrounds a first portion of the core within the mold cavity; (c) rapidly changing the temperature of the mold cavity to induce thermal setting of the dispersion surrounding the first portion of the core; (d) opening the mold cavity and rotating the portion of the mold containing the core to expose a second portion of the core; (e) closing the mold cavity; (f) injecting heated dispersion into the mold cavity such that the dispersion surrounds the second portion of the core within the mold cavity; (g) rapidly changing the temperature of the mold cavity to induce thermal setting of the dispersion surrounding the second portion of the core; (h) removing the coated core from the mold cavity; and (i) drying to remove residual solvent. If the solvent-based process is employed, the mold may be optionally heated to remove solvent, then cooled to set the shell materials. This optional heating step is preferred if organic solvents are used, but is not required if the solvent used is water. [0090]
In embodiments where the solvent comprises water, suitable other shell materials preferably include a gelling agent, such as gellan gum, carrageenan, agar, gelatin, locust bean gum, thermoplastic starch, and the like, and mixtures thereof. [0091]
In embodiments wherein the solvent is an organic solvent, the flowable material is preferrably injected cold and cycled to hot after injection. [0092]
One suitable method for preparing the flowable shell material is to disperse the materials in a suitable solvent, such as water, organic solvents such as alcohols or acetone, or combinations of water and organic solvents. [0093]
The shell of the present invention has a cross-sectional area in the range of about 1 to 900 sq. mm, preferably about 25 to 400 sq. mm, most preferably about 50 to about 200 sq. mm. [0094]
In certain other embodiments, a portion of the shell functions as a diffusional membrane which contains pores through which liquid medium containing active ingredient within the dosage form can be released through the diffusible shell portion in a sustained, extended, prolonged or retarded manner. In these embodiments, the rate of release of active ingredient from the underlying core will depend upon the total pore area in the shell or shell portion, the pathlength of the pores, and the solubility and diffusivity of the active ingredient (in addition to its rate of release from the core or core portion itself). In preferred embodiments in which the shell or shell portion functions as a diffusional membrane, the release of the active ingredient from the dosage form may be described as controlled, prolonged, sustained or extended. In these embodiments, the contribution to active ingredient dissolution from the shell or shell portion may follow zero-order, first-order, or square-root of time kinetics. In certain such embodiments, the diffusional membrane shell or shell portion preferably comprises a release-modifying excipient such as a combination of a pore former and an insoluble edible material such as for example a film forming water insoluble polymer. Alternately, in such embodiments in which the shell or shell portion is prepared by solvent-free molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. [0095]
In certain other embodiments, a portion of the shell functions as an eroding matrix from which active ingredient dispersed in the shell portion is liberated by the dissolution of successive layers of the shell or shell portion surface. In these embodiments, the rate of active ingredient release will depend on the dissolution rate of the matrix material in the shell or shell portion. Particularly useful matrix materials for providing surface erosion include those which first absorb liquid, then swell and/or gel prior to dissolving. In certain such embodiments, the eroding matrix shell or shell portion preferably comprises a swellable erodible hydrophilic material. [0096]
In embodiments in which a second shell portion functions to modify the release of an active ingredient which is contained in the core or the subject shell or shell portion, the thickness of the shell or shell portion is critical to the release properties of the dosage form. Advantageously the dosage forms of the invention can be made with precise control over shell thickness. In one embodiment in which a second shell portions function to modify the release of an active ingredient which is contained in the core or the second shell portion, the second shell portion is made by the thermal cycle or thermal setting injection molding methods and apparatus described below. [0097]
In certain preferred embodiments of the invention, an immediate release dose of one or more active ingredients can be achieved through the use of an additional outer coating overlaying the shell or one or more portions thereof. The additional outer coating may be applied for example by compression, or by molding. In such embodiments, the dosage form of the invention comprises at least one active ingredient; a core; a shell or shell portion which resides upon at least a portion of the core; and an outer coating which covers at least a portion of the shell or shell portion. The outer coating may for example cover a portion of the first shell portion, or the second shell portion, or both, or may surround the entire shell. In one particularly preferred embodiment, the outer coating comprises an active ingredient, which is released immediately (i.e. the dissolution of the active ingredient from the outer coating conforms to USP specifications for immediate release dosage forms of the particular active ingredient employed). In one such particularly preferred embodiment, the dosage form is a pulsatile drug delivery system, in which one or more shell portions provides for delayed release of a second dose of active ingredient, which is contained in an underlying core portion. [0098]
In one embodiment of this invention, wherein the shell or first shell portion is prepared by molding, the shell or first shell portion is substantially free of pores having a diameter of 0.5-5.0 microns. As used herein, “substantially free” means that the shell or first shell portion has a pore volume of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns. In contrast, typical compressed materials have pore volumes of more than about 0.02 cc/g in this diameter range. In another embodiment of this invention, the core is a molded core and the core or core portions are substantially free of pores having a diameter of 0.5-5.0 microns. [0099]
The pore volume, pore diameter and density of the shell may be determined using a [0100] Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as “Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual. The PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum). Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure. The corresponding pore size diameter (d) at which the intrusion takes place is calculated directly from the so-called “Washburn Equation”: d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ is the contact angle between mercury and the sample surface and P is the applied pressure.
Equipment used for pore volume measurements: [0101]
1. [0102] Quantachrome Instruments PoreMaster 60.
2. Analytical Balance capable of weighing to 0.0001 g. [0103]
3. Desiccator. [0104]
Reagents used for measurements: [0105]
1. High purity nitrogen. [0106]
2. Triply distilled mercury. [0107]
3. High pressure fluid (Dila AX, available from Shell Chemical Co.). [0108]
4. Liquid nitrogen (for Hg vapor cold trap). [0109]
5. Isopropanol or methanol for cleaning sample cells. [0110]
6. Liquid detergent for cell cleaning. [0111]
Procedure: the samples remain in sealed packages or as received in the dessicator until analysis. The vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes. The empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and “evacuation and fill only” is selected from the analysis menu, and the following settings are employed: [0112]
Fine Evacuation time: 1 min. [0113]
Fine Evacuation rate: 10 [0114]
Coarse Evacuation time: 5 min. [0115]
The cell (filled with mercury) is then removed and weighed. The cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled. The weight of the cell and sample are then recorded. The cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set: [0116]
Mode: Low pressure [0117]
Fine evacuation rate: 10 [0118]
Fine evacuation until: 200μ Hg [0119]
Coarse evacuation time: 10 min. [0120]
Fill pressure: Contact+0.1 [0121]
Maximum pressure: 50 [0122]
Direction: Intrusion And Extrusion [0123]
Repeat: 0 [0124]
Mercury contact angle: 140 [0125]
Mercury surface tension: 480 [0126]
Data acquisition is then begun. The pressure vs. cumulative volume-intruded plot is displayed on the screen. After low-pressure analysis is complete,the cell is removed from the low-pressure station and reweighed. The space above the mercury is filled with hydraulic oil, and the cell is assembled and installed in the high-pressure cavity. The following settings are used: [0127]
Mode: Fixed rate [0128]
Motor speed: 5 [0129]
Start pressure: 20 [0130]
End pressure: 60,000 [0131]
Direction: Intrusion and extrusion [0132]
Repeat: 0 [0133]
Oil fill length: 5 [0134]
Mercury contact angle: 140 [0135]
Mercury surface tension: 480 [0136]
Data acquisition is then begun and graphic plot pressure vs. intruded volume is displayed on the screen. After the high pressure run is complete, the low-and high-pressure data files of the same sample are merged. [0137]
Typical shell thicknesses which may be employed in this invention are about 20 to about 2000 microns. In certain preferred embodiments, the shell has a thickness of less than 800 microns. In embodiments wherein the shell is prepared by a solvent-based molding process, the shell typically has a thickness of less than about 800 microns, e.g. about 20 to about 600 microns, say about 40 to about 200 microns. [0138]
In embodiments in which a first shell portion comprises the release-delaying composition of the invention, the core, or a portion thereof, or a second shell portion, may optionally comprise one or more release-modifying excipients. Suitable release-modifying excipients for making the core, or a portion thereof, or a second shell portion by molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, pore formers, and insoluble edible materials. In one embodiment,suitable release-modifying excipients for making the core, or the shell,or a portion thereof, by molding include hydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylate copolymer type B, and shellac, and combinations thereof. Suitable release-modifying excipients are known in the art, and disclosed for example in commonly assigned, copending U.S. application Ser. No. ______[MCP321]. [0139]
In another particular embodiment of this invention at least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile. By “delayed then sustained release profile” it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by sustained (prolonged, extended, or retarded) release of that active ingredient. The shell or first shell portion of the present invention provides for the delay period, and is substantially free of the active ingredient to be released in a delayed then sustained manner. In such embodiments, the delayed then sustained release active ingredient is contained within the corresponding underlying core. In such embodiments the core may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump. In embodiments in which the core functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers. Alternately, in such embodiments in which the core is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. In embodiments in which the core functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof. [0140]
In embodiments in which the core functions as a diffusional matrix through which active ingredient contained therein is liberated in a sustained, extended, prolonged, or retarded manner, the core preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore formers. Alternately, in such embodiments in which the core is prepared by solvent-free molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. [0141]
In embodiments in which a second shell portion confers sustained, extended, or retarded release of an active ingredient contained in the underlying core, the release-modifying agent in the shell preferably comprises a pore-former, and optionally a film-former. In a particularly preferred embodiment, the second shell portion functions as a diffusional membrane. In some such embodiments, the dissolution of the active ingredient may follow “diffusion-controlled” release kinetics, as described for example in Example 1 of U.S. Pat. No. 5,286,497. Shell portions which confer sustained, extended, or retarded release and/or function as diffusional membranes can be prepared by a solvent-free method, or a solvent-based method, as described above. [0142]
In one embodiment of the invention, the core and/or the shell or a portion thereof is made by the thermal setting molding method and apparatus described in copending U.S. patent application Ser. No. 09/966,450, pages 57-63, the disclosure of which is incorporated herein by reference. In this embodiment, the core and/or the shell or a portion thereof is formed by injecting a starting material in flowable form into a molding chamber. The starting material preferably comprises an active ingredient and a thermal setting material at a temperature above the melting point of the thermal setting material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold). [0143]
In another embodiment of the invention, the core and/or the shell or a portion thereof is made using the thermal cycle molding method and apparatus described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51, the disclosure of which is also incorporated herein by reference. In the thermal cycle molding method and apparatus of U.S. patent application Ser. No. 09/966,497, a thermal cycle molding module having the general configuration shown in FIG. 3 therein is employed. The thermal cycle molding module [0144] 200 comprises a rotor 202 around which a plurality of mold units 204 are disposed. The thermal cycle molding module includes a reservoir 206 (see FIG. 4) for holding flowable material to make the core, the shell, a core portion, or a shell portion. In addition, the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. FIGS. 55 and 56 depict such a temperature control system 600.
This invention will be illustrated by the following examples, which are not meant to limit the invention in any way. [0145]

Example 1 [0146]
Dosage forms of this invention were prepared as follows. A coating solution was prepared containing 13.24 g of glyceryl behenate ([0147] COMPRITOL 888, available from Gattefosse Inc.) and 13.24 g of ethylcellulose. The solution had a concentration of 10% solids in ethanol. The solution was applied to cores (i.e. MOTRIN 100 mg caplets, available from McNeil-PPC, Inc.) using a bottom spray fluid bed available from Glatt. A 150 g charge of solution was provided at a spray rate of 7 g/minute. A coating of 15% by weight was applied to the cores to obtain dosage forms having shells residing upon the cores.
The dosage forms were dissolved in pH 0.1 N HCl for 2 hours, then switched to pH 5.6 acetate buffer solution for an additional 2 hours using USP Method I with baskets at 100 RPM. The resulting dissolution profile is depicted in FIG. 2. The dosage forms exhibited a burst release of active ingredient after 4 hours. [0148]
Although this invention has been illustrated by reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made which clearly fall within the scope of the invention. [0149]

Claims

The invention claimed is:

1. A dosage form comprising:

(b) a shell which resides upon at least a portion of the core outer surface, wherein the shell comprises at least a first shell portion comprising (i) at least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, and the weight ratio of film forming polymer to lipid is in the range of about 40:60 to about 60:40.

2. The dosage form of claim 1, in which the disintegrant is selected from the group consisting of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and the like and mixtures thereof.

3. The dosage form of claim 1, in which the shell or first shell portion weight is about 10% to about 30% of the total weight of the dosage form.

4. The dosage form of claim 1, in which the film forming polymer is selected from the group consisting of ethylcellulose, cellulose acetate, polymethacrylic acid, methyl methacrylate, cellulose acetate butyrate, cellulose acetate propionate, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, and mixtures thereof.

5. The dosage form of claim 1, in which at least a portion of at least one active ingredient is released from the dosage form in a delayed manner upon contacting of the dosage form with a liquid medium.

6. The dosage form of claim 1, in which the lipid is selected from the group consisting of glyceryl behenate, fats, waxes, cocoa butter, hydrogenated vegetable oils, palm kernel oil, cottonseed oil, sunflower oil, soybean oil, long chain fatty acids having a chain length of about C₁₀-C₄₀, fatty acid esters having a fatty acid chain length of about C₁₀-C₄₀, and mixtures thereof.

7. The dosage form of claim 1, in which the shell or first shell portion is a single layer in contact with the core outer surface.

8. The dosage form of claim 1, in which the release profile of at least one active ingredient upon contacting of the dosage form with a liquid medium is a delayed burst release.

9. The dosage form of claim 1, in which the release profile of at least one active ingredient upon contacting of the dosage form with a liquid medium is a delayed then sustained release.

10. The dosage form of claim 8 or 9 in which the delay time prior to the release of at least one active ingredient is independent of the pH of the liquid medium.

11. The dosage form of claim 8 or 9, in which a first dose of at least one active ingredient is released essentially immediately upon contacting of the dosage form with a liquid medium.

12. The dosage form of claim 1, in which the shell or first shell portion additionally comprises up to about 20% by weight of the shell or shell portion of at least one additional component selected from the group consisting of a water soluble polymer, a water soluble crystalline material, a water swellable material, and mixtures thereof.

13. The dosage form of claim 12, in which the additional component is a water soluble polymer selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone and mixtures thereof.

14. The dosage form of claim 13, in which the additional component is a crystalline material selected from the group consisting of sugars, water soluble inorganic salts, polyhedric alcohols, and mixtures thereof.

15. The dosage form of claim 14, in which the additional component is a water swellable material selected from the group consisting of water swellable cellulose derivatives, polyalkalene glycols, polyalkalene oxides, acrylic polymers, hydrocolloids, gelling starches, swelling cross-linked polymers, and derivatives, copolymers, and combinations thereof.

16. The dosage form of claim 15, in which the additional component is a pore former.

17. A method of providing a delayed burst release of an active ingredient from a dosage form, wherein the method comprises:

(I) providing a dosage form comprising:

(a) a core having an outer surface, wherein the core comprises at least one active ingredient and at least one disintegrant, and

(b) a shell comprising at least a first shell portion which resides upon at least a portion of the core outer surface, wherein the shell or first shell portion comprises (i) at least one water insoluble film forming polymer, and (ii) at least one water insoluble lipid, and the weight ratio of film forming polymer to lipid is in the range of about 40:60 to about 60:40; and

(II) contacting the dosage form with a liquid medium.

18. The method of claim 17, in which at least a portion of at least one active ingredient is released from the dosage form in a delayed manner upon contacting of the dosage form with a liquid medium.

19. The dosage form of claim 1 wherein the shell comprises first and second shell portions that are compositionally different and in contact with each other at an interface.

20. The dosage form of claim 19, wherein the shell substantially surrounds the core.