Technical Field of the Invention
The present invention relates to a controlled release metaxalone compositions for oral administration, as well as methods of preparing them.
Background of the Invention
Metaxalone, 5-[(3,5-dimethyphenoxy) methyl]-2-oxazolidinone, is a skeletal muscle relaxant used to relieve the pain of muscle injuries, spasms, sprains, and strains. The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber. The drug does not directly relax tense skeletal muscles in man. Metaxalone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.
Metaxalone is marketed under the brand name SKELAXIN® (Elan Pharmaceuticals, Inc.) in 400 mg and 800 mg tablets. The general dosage for adults and children over 12 years of age is two 400 mg tablets (800 mg) or one 800 mg tablet, three to four times a day. According to American Hospital Formulary Service (AHFS) Drug Information, following oral administration of a single 800mg dosage of metaxalone, mean peak plasma concentrations are attained in 2 hours. The onset of action is within 1 hour and duration of action is about 4 to 6 hours. It has a plasma half-life of 2-3 hours, thus requiring multiple dosing. Repeated administration of a very high dosage drug effectuates patient inconvenience and is very bothersome for ambulatory patients, leading to poor patient compliance. Therefore, there is a need for oral controlled release pharmaceutical composition that provides desirable plasma levels of metaxalone for twice-a-day or once-a-day therapy.
Due to poor aqueous solubility metaxalone has poor bioavailability. Moreover it also shows food effect. US Patents No. 6,407,128 and 6,683,102 assigned to Elan Pharmaceuticals, disclose method of increasing the oral bioavailability of metaxalone by administration of an oral dosage form with food.
US Patent No. 4,722,938, describes methods of using musculoskeletal relaxants such as
metaxalone.
WO 2004/019937, filed by Sun Pharmaceuticals describes pharmaceutical composition comprising metaxalone and pharmaceutically acceptable excipients, characterized in that the pharmaceutical composition has enhanced oral bioavailability. The metaxalone that is used is a pharmaceutically acceptable solubility improved form, i.e. micronized metaxalone, salt form of metaxalone, high-energy crystalline form of metaxalone or amorphous metaxalone.
WO 04108067, also filed by Sun Pharmaceuticals discloses a programmed drug delivery system is useful for targeted drug delivery to a specific site in the gastrointestinal tract, at which site the beneficial agent may be delivered as a pulse, or in a controlled manner.
US patent application Ser. No. 20050063913 A1, describes the composition comprising metaxalone particles having an effective average particle size of less than about 2000nm and at least one surface stabilizer that is preferably adsorbed to or associated with the surface of the drug particles.
Since metaxalone is indicated for acute painful musculoskeletal conditions that require quick relief it would be desirable to have a dosage form that maintains a balance between the amount of the drug released immediately and amount of drug released over an extended period. Further it is also desired to have a dosage form that maintains the plasma level of metaxalone without any troughs and peaks. None of the patents and applications mentioned above describe such a dosage form.
When comparing the pharmacokinetic profiles of immediate release with controlled release drug formulations, there are two major differences. First, the time to achieve the Cmax in the plasma is often longer in the controlled release versus the immediate release formulation. In controlled released formulations, a long tmax is particularly disadvantageous to patients seeking urgent treatment (especially in acute painful musculoskeletal conditions) and to maintain minimum effective concentration (MEC) levels. A second difference in the pharmacokinetic profiles of controlled release in comparison to immediate release drug formulations is that the duration of sustained plasma levels is longer in the controlled release formulations. The longer duration of such sustained plasma levels facilitated by controlled release formulations are advantageous to all patients, prolonging the desired biological effect. Therefore, although the controlled release formulation facilitates a substantially longer period of time in
maintaining plasma levels of drug or active metabolite(s), it suffers from the drawback of requiring longer periods of time to achieve the Cmax, when compared to immediate release formulations.
Thus, there remains a long felt need for improved controlled release formulations for metaxalone, including dosage formulations that might have one or more desirable characteristics of both immediate release and controlled release metaxalone formulations.
Summary of the Invention
In one general aspect there is provided a controlled release pharmaceutical composition for metaxalone that will provide a therapeutically effective blood concentration level of metaxalone for a sustained period of time of up to at least twelve hours.
In accordance with the purposes of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to controlled release composition of metaxalone and methods of preparing and using the same.
It is another general aspect to provide a controlled release pharmaceutical composition for metaxalone comprising:
(i) metaxalone and
(ii) at least one rate controlling polymer
wherein the composition provides a constant release profile for a sustained period of time of up to at least twelve hours.
The composition of the present invention may be a matrix-type dosage form, multiple unit dosage form or an osmotic dosage form.
In one embodiment, the composition may be a matrix type dosage form, a reservoir type dosage form or combinations of both. Matrix-type dosage forms are those in which the drug is distributed uniformly in the one or more rate controlling material and reservoir type dosage forms utilize polymeric coating over the core of the metaxalone. A combination of the reservoir and matrix type includes extended or sustained release
coatings on extended release matrices.
Embodiments of matrix type dosage forms may include one or more following features. For example, matrix may be formulated into tablets of a single monolithic matrix, bilayered matrix or a multi-layered matrix.
The monolithic matrix may have a uniform mixture of the core containing metaxalone and one or more rate controlling polymers. The monolithic matrix may have drug release profile tailored in a fashion to provide both immediate and controlled release profile. The matrix may further include one or more pharmaceutically acceptable excipients.
In another embodiments, the matrix-type dosage forms may be a bilayered type formulations comprising at least two layers:
(i) an extended release layer, and (ii) an immediate release layer.
The ratio of immediate release metaxalone layer to the extended release metaxalone layer may range from about 20:80 to about 80:20 by weight.
The extended release layer may be a core and the immediate release layer may cover at least a portion of the core. The extended release core may be a matrix and the matrix may have a uniform mixture of the metaxalone and one or more rate controlling polymers.
In another embodiments, the controlled release metaxalone composition may be formulated as a multiple unit dosage form having plurality of discrete or aggregated particles, pellets, mini tablets, beads or granules.
It is yet another aspect of the invention to provide a controlled release metaxalone composition, in multiple unit dosage form, comprising at least two types of metaxalone -containing units:
(i) one immediate release unit, and
(ii) another controlled release unit.
The ratio of first unit to the second unit may range from about 20:80 to about 80:20 by weight.
The units containing metaxalone may include other pharmaceutically acceptable excipients. The units can be filled into a capsule or compressed into a tablet dosage form. The units prepared by the present invention may be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
Yet another aspect of the invention is to provide a controlled release metaxalone composition, in an osmotic dosage form, comprising:
(i) a core comprising metaxalone and a swelling agent, and (ii) a semipermeable membrane coating surrounding the core and optionally, one or more additional layers of metaxalone below and/or above the semipermeable membrane for immediate release.
The ratio of immediate release metaxalone layer to the metaxalone core may range from about 20:80 to about 80:20 by weight.
The dosage form may further include one or more other pharmaceutically acceptable excipients.
According to one of the embodiments, metaxalone may be included in one or more forms comprising metaxalone, micronized or nanonized metaxalone, metaxalone adsorbate and metaxalone-cyclodextrin admixture.
The rate controlling polymers may include one or more of hydrophilic polymers, hydrophobic polymers, or combinations thereof. The pharmaceutical composition may also include one or more pharmaceutically acceptable excipients acting in the capacity of one or more of fillers, binders, lubricants, glidants, colorants and flavoring agents.
It is yet another aspect to provide a method of treating muscle spasm associated with painful musculoskeletal conditions in humans, by administering a controlled release
pharmaceutical composition of metaxalone that provides a constant release profile for a sustained period of time of up to at least twelve hours.
The method may further include administering other non-steroidal anti-inflammatory agents (NSAIDs), analgesics or other pharmaceutical agents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The inventors have developed a controlled release pharmaceutical composition for metaxalone that helps to achieve the constant release profile up to atleast about 12 hours time period.
The term "controlled release" as used herein includes any type of controlled release such as prolonged release, sustained release, modified release and extended release.
The term "matrix" as used herein includes a uniform mixture of metaxalone, one or more rate controlling polymers and one or more pharmaceutically acceptable excipients.
The rate controlling polymers used in the matrix type dosage form may include one or more of hydrophilic polymers, hydrophobic polymers, or combinations thereof.
Hydrophilic rate-controlling polymers may include one or more cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose or combinations thereof; polyvinylpyrrolidone, polysaccharides, polyalkylene glycols, starch and derivatives; or mixtures thereof.
Hydrophobic polymers may be selected from one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils.
The osmotic controlled metaxalone dosage form may be prepared by blending metaxalone, at least one swelling agent, optionally an osmotic agent and one or more pharmaceutically acceptable inert excipient; and compressing the blend into a compact core; enclosing the core with a solution/dispersion of an enclosing composition comprising one or more semipermeable membrane-forming polymers and other coating additives. The immediate release metaxalone layer may be layered to cover at least a portion of the core, using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifugal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.
The swelling agents may be selected from any such pharmaceutically acceptable polymers, which swells in presence of aqueous media, i.e. cellulose derivatives, starch, gums, alginates, acrylic acid derivatives, polyethylene oxides and carbohydrate based polymers.
The osmotic agents may be one or more of water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds having high water solubility, water-soluble amino acids, urea and urea derivatives.
Semi-permeable membrane of the osmotic dosage form is permeable to the passage of an external fluid, such as water and biological fluids, but is substantially impermeable to the passage of components in the internal compartment. Materials useful for forming the wall are essentially nonerodible and are substantially insoluble in biological fluids during the life of the dosage form.
The semipermeable membrane may be one or more of semipermeable membrane-forming polymers and coating additives. The semipermeable membrane-forming polymers may be one or more of cellulose derivatives, starch, gums, alginates, acrylic acid derivatives and carbohydrate based polymers.
Flux-regulating agents can be admixed with the semi-permeable membrane to modulate the fluid permeability of the wall. For example, agents that produce a marked increase in permeability to fluid such as water are often essentially hydrophilic, while those that produce a marked permeability decrease to water are essentially hydrophobic. Example
of flux regulating agents include, but are not limited to, polyhydric alcohols, polyalkylene glycols and polyalkylenediols, polyesters of alkylene glycols.
The immediate release outer layer may further include film-forming polymers and optionally other pharmaceutically acceptable excipients.
Metaxalone used in the present invention may be in one or more forms comprising metaxalone, micronized or nanonized metaxalone, metaxalone adsorbate and metaxalone-cyclodextrin admixture.
Due to poor bioavailability of metaxalone, it can be used in a micronized or nanonized form. The particle size of micronized or nanonized metaxalone may be in the range of 50nm to 50um. Size reduction for micronization or nanonization may be carried out in any of the conventionally known methods using air jet mill, dyno mill, ball mill, colloid mill, grinding mill, roller mill, impact mill, etc.
Metaxalone adsorbate may be prepared by dissolving metaxalone and one or more of pharmaceutically acceptable surface modifiers in organic solvent and removing the solvent to co-precipitate the metaxalone adsorbate.
The pharmaceutically acceptable surface modifiers may be one or more of cellulose derivatives, starch, gums, sugars, saccharides, alcohols, alginates, surfactants, acrylic acid derivatives and carbohydrate based polymers.
Suitable examples of cellulosic polymers include, but are not limited to, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, cross-linked carboxymethylcellulose, hydroxymethylcellulose and hydroxyethylcellulose.
Suitable examples of acrylic acid derivatives include, but are not limited to, polymethacrylates such as ethyl acrylate/methyl methacrylate copolymer (Eudragit NE-30-D) and ammonio methacrylate copolymer types A and B (Eudragit RL30D and RS30D).
Suitable surfactant can be anionic, cationic, zwitterionic and nonionic surfactants. Particularly, the compositions include at least one anionic surfactant. Suitable anionic surfactants include but are not limited to alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
Suitable examples of organic solvent may include one or more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; and chlorinated hydrocarbons, such as methylene chloride.
Solvents may be removed by techniques known in the art, for example, one or more of distillation, distillation under vacuum, evaporation, and spray drying.
Metaxalone-cyclodextrin admixture may be prepared by blending metaxalone with cyclodextrin. The admixture may also include one or more other pharmaceutically acceptable excipients.
The cyclodextrin may be a naturally occurring dextrin and also the methylated derivatives of these natural products, especially of beta-cyclodextrin.
In addition to the metaxalone and rate-controlling polymers, the matrix may further include other pharmaceutically acceptable excipients that act in one or more capacities as fillers, binders, lubricants, glidants, colorants or flavoring agents.
Suitable examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, poloxamer, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
The coloring agents of the present invention may be selected from any FDA approved color for oral use.
The composition may be formulated into various pharmaceutical preparations for oral administration, e.g., in the form of a tablet or capsule in accordance with any of the conventional procedures known in the field of art, for example, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, compression, coating etc. These steps may be carried out in the conventional manner.
The bilayered or multilayered tablets prepared by the present invention may optionally have coating with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
Bilayered or multilayered tablets may be prepared by multiple-compression tablets comprising an inner core and an outer coat of metaxalone, and may be prepared such that one surface of the inner core is exposed. These types of tablets are also referred to as inlay or bull's-eye tablets and these are similar to compression-coated tablets except that one surface of the coating is eliminated.
Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate,
waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof.
The coating can also be performed using any commercially available ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.
Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
The controlled release pharmaceutical composition for metaxalone of the present invention may be used for treating muscle spasm associated with painful musculoskeletal conditions in humans, by administering a controlled release pharmaceutical composition for metaxalone that provides a constant release profile for a sustained period of time up to at least twelve hours.
The method may further include administering in combination with other medicines, for example, other non-steroidal anti-inflammatory agents (NSAIDs), any analgesics or other pharmaceutically active agents, etc.
The following examples illustrate various aspects of the present inventions. These examples are for illustration only and do not limit the scope of the inventions.
Example 1:
PREPARATION OF METAXALONE ER TABLETS
(Table Removed)
(*prepared by using Air jet mill)
Process:
Granulation of Extended Release layer
1. Metaxalone, poloxamer, lactose monohydrate, microcrystalline cellulose and
hydroxypropyl methylcellulose were mixed well and granulated with polyvinyl
pyrrolidone solution.
2. The granules were dried and mixed with magnesium stearate, colloidal anhydrous
silica and talc.
Granulation of Immediate Release layer
1. Metaxalone, poloxamer, lactose monohydrate, microcrystalline cellulose and
sodium starch glycollate were mixed well and granulated with polyvinyl
pyrrolidone solution.
2. The dried granules were mixed with magnesium stearate and colloidal anhydrous
silica.
Compression
Both the layers were compressed to give bilayered or press coated tablets using appropriate tooling.
Example 2:
PREPARATION OF METAXALONE ADSORBATE
(Table Removed)
Metaxalone was dissolved in methylene chloride with constant stirring. Polyvinyl pyrrolidone and cross-linked carboxymethylcellulose were dispersed in it. Methylene chloride was removed to obtain metaxalone adsorbate for further formulation work.
Example 3:
PREPARATION OF METAXALONE ER TABLETS
(Table Removed)
Process:
Granulation of Extended Release layer
1. Metaxalone adsorbate of example 2, poloxamer, lactose monohydrate,
microcrystalline cellulose and hydroxypropyl methylcellulose were mixed well and
granulated with polyvinyl pyrrolidone solution.
2. The granules were dried and blended with magnesium stearate, colloidal
anhydrous silica and talc.
Granulation of Immediate Release layer
1. Metaxalone adsorbate of example 2, poloxamer, lactose monohydrate,
microcrystalline cellulose and sodium starch glycollate were mixed well and
granulated with polyvinyl pyrrolidone solution.
2. The dried granules were mixed with magnesium stearate and colloidal anhydrous
silica.
Compression
The two types of granules were compressed into bilayered tablets using appropriate tooling.
Example 4:
PREPARATION OF METAXALONE ER CAPSULES
(Table Removed)
(*prepared by using Air jet mill)
Process:
1. Metaxalone and hydroxypropyl methylcellulose were mixed well and layered over
the sugar spheres
2. Ethylcellulose, hydroxypropyl methylcellulose and triacetin are mixed and coated
over the metaxalone layered sugar spheres
3. The immediate release layer of metaxalone were provided by again layering
metaxalone and hydroxypropyl methylcellulose over the coated spheres of step 2.
4. The prepared spheres were blended in a desired weight ratio and filled in
appropriate size capsule.
Example 5:
PREPARATION OF METAXALONE ER CAPSULES
(Table Removed)
(*prepared by using Air jet mill)
Process:
Preparation of Extended Release pellets
1. Metaxalone and Hydroxypropyl methylcellulose were mixed well and layered over
the sugar spheres
2. Ethylcellulose, hydroxypropyl methylcellulose and triacetin were mixed and coated
over the metaxalone layered sugar spheres
Preparation of Immediate Release pellets
Metaxalone and Hydroxypropyl methylcellulose were mixed well and layered over the sugar spheres
Preparation of finished product
The two types of pellets were blended in a desired weight ratio and filled in to the capsules of suitable size.
Example 6:
PREPARATION OF BILAYERED TABLETS
(Table Removed)
Process:
Granulation of Extended Release layer
1. Metaxalone, Lactose, sodium lauryl sulphate, and Hydroxypropyl methylcellulose were blended well and granulated with Polyvinylpyrrolidone solution.
2. The granules were dried and mixed with magnesium stearate and colloidal anhydrous silica.
Granulation of Immediate Release layer
1. Metaxalone, microcrystalline cellulose, sodium lauryl sulphate, and sodium starch
glycollate were blended well and granulated with Polyvinylpyrrolidone solution.
2. The granules were dried and mixed with magnesium stearate and colloidal
anhydrous silica.
Compression
Both the granules were compressed using appropriate tooling.
Example 7-10:
PREPARATION OF MONOLITHIC MATRIX TABLETS
(Table Removed)
Process:
1. Metaxalone, Lactose, sodium lauryl sulphate (in case of Example 7 & 8), and
Hydroxypropyl methylcellulose were mixed well and granulated with
Polyvinylpyrrolidone solution.
2. The granules were dried and mixed with magnesium stearate and colloidal
anhydrous silica.
3. Lubricated granules were compressed into tablets.
Example 11:
PREPARATION OF MONOLITHIC MATRIX TABLETS
(Table Removed)
Process:
1. Metaxalone adsorbate of example 2, Lactose, sodium lauryl sulphate, and
Hydroxypropyl methylcellulose were mixed well and granulated with
Polyvinylpyrrolidone solution.
2. The granules were dried and mixed with magnesium stearate and colloidal
anhydrous silica.
3. The granules of step 2 were then compressed into tablets.
In-vitro Dissolution for Example 6
The tablets prepared in the example 6 were subjected to in-vitro dissolution under the following conditions:
Media: Phosphate buffer pH 6.8 and
0.5% Sodium lauryl sulphate (SLS) - 900 ml
Apparatus: USP-2/100rpm
The results are shown in Table 1.
Table 1:
(Table Removed)
In-vitro Dissolution for Example 7-10
The tablets prepared in the example 7-10 were subjected to in-vitro dissolution under the following conditions:
Media: Phosphate buffer pH 6.8 and
0.5% Sodium lauryl sulphate (SLS) - 900 ml
Apparatus: USP-2/100rpm The results are shown in Table 2.
Table 2:
(Table Removed)
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions.

WE CLAIM:
1. A controlled release pharmaceutical composition for metaxalone comprising:
(i) metaxalone and
(ii) at least one rate controlling polymer,
wherein the composition provides a constant release profile for a sustained period of time of up to at least twelve hours.
2. The composition according to claim 1 wherein the composition comprises matrix
type dosage forms, multiple unit dosage forms and osmotic dosage forms.
3. The composition according to claim 2 wherein the matrix type dosage form
comprises single monolithic matrix, bilayered matrix and multi-layered matrix.
4. The composition according to any of the preceding claims wherein the metaxalone
is in one or more forms comprising metaxalone, micronized or nanonized
metaxalone, metaxalone adsorbate and metaxalone-cyclodextrin admixture.
5. The composition according to claim 1 wherein the composition comprises one or
more rate controlling polymers.
6. The composition according to claim 5 wherein the rate controlling polymer
comprises one or more rate controlling polymers of hydrophilic polymers,
hydrophobic polymers and combinations of both.
7. The composition according to any of the preceding claims wherein the
composition further comprises pharmaceutically acceptable excipients of one or
more of fillers, binders, lubricants, glidants, colorants and flavoring agents.
8. The composition according to claim 1 wherein the composition comprises one or
more tablets, capsules, aggregated particles, pellets, mini tablets, beads and
granules.
9. The composition according to claim 8 wherein the composition optionally comprise
one or more layers of film forming agents.
10. A controlled release pharmaceutical composition for metaxalone comprising (i)
metaxalone and (ii) at least one rate controlling polymer, substantially as
described and illustrated herein.