Patent Application
20170128358
The present invention is directed to disintegratable films and methods for delivering pharmaceutically active or cosmetic agents. More particularly, the present invention provides in one embodiment a water soluble mucoadhesive film composition containing an active pharmaceutical or cosmetic ingredient for administration to the oral cavity in unit dosage form. Upon administration, the composition rapidly disintegrates to release the active ingredient.
Disintegratable films can provide a convenient and effective delivery vehicle for delivering active ingredients, such as pharmaceutical compounds and breath freshening or other cosmetic agents, to the mucosa of humans and animals. Upon placement onto the mucosa of, for example, the oral cavity, the film disintegrates and releases the active ingredient. However, the film should have adequate strength for processing and use as a unit dosage form, and also ensure appropriate release of the active ingredient while eliminating or minimizing any undue discomfort to mucosal surfaces.
U.S. Pat. Nos. 4,029,757; 4,029,758; and 4,031,200 refer to pharmaceutical dosage units formed from a multiplicity of edible webs that are sealed. One layer is fabricated by “fan folding” and compressing a continuous web structure, and subsequently sealing the composite into a geometric shape. The films rely on a complex process of fan folding and sealing to maintain the pharmaceutical compound internally within the multilayered dosage form.
U.S. Re 33,093 refers to controlled-release medicament-containing single or multi-layer thin films for intra-oral drug delivery. The thin film includes a polymeric matrix layer of 20-93% by weight of a hydroxypropyl cellulose having a molecular weight above 100,000; 5-60% of a homopolymer of ethylene oxide having a molecular weight from 3,000,000-5,000,000; 0-10% of a water insoluble polymer selected from the group consisting of ethyl cellulose, propyl cellulose, polyethylene and polypropylene; 2-10% of a plasticizer; and a pharmaceutically effective amount of medicament. The controlled-release films of U.S. Re. 33,093 are relatively slow to dissolve/disintegrate in the mouth.
U.S. Pat. No. 5,984,430 (Reexamination Certificate issued Mar. 4, 2003); U.S. Pat. Nos. 6,177,096; and 6,284,264 refer to oral films for the delivery of pharmaceutical and cosmetic compounds. The compositions referred to in these patents contain a water-soluble polymer, a polyalcohol, a surfactant, and a pharmaceutically or cosmetically active ingredient. According to these patents, inclusion of the surfactant component imparts “instant wettability” followed by rapid disintegration of the film when placed into an aqueous environment such as the oral cavity.
U.S. Pat. No. 4,136,145 refers to a pharmaceutical unit dosage composition in which the pharmaceutically active medicament is uniformly dissolved or suspended in a flexible, water-soluble film carrier. The compositions include various drug compounds, water-soluble polymers, surfactants, release agents, parting compounds, and fillers.
Each film delivery system can be characterized by its film strength and its disintegration profile (the speed at which the film will disintegrate in an aqueous media such as saliva). Surfactants have been used to affect the disintegration speed and decrease the time required for complete film disintegration and thus release of the active ingredient. The present invention provides disintegratable film compositions that rapidly disintegrate upon application to mucosal surfaces and which, at the same time, have sufficient film strength without requiring the use of any surfactant. While a surfactant is optional in certain embodiments of the present invention, as described below, other embodiments are surfactant-free or substantially free of surfactants.
The present invention provides disintegratable film compositions prepared with a combination of ingredients that yield films of sufficient film strength and rapid disintegration profiles. Films prepared pursuant to this invention yield similar or improved disintegration speeds as compared to prior art films, including the prior art surfactant-containing films.
The films according to the present invention contain a mixture of high molecular weight and low molecular weight water soluble components; and a pharmaceutically or cosmetically active ingredient. Optionally, the films further contain a starch component, a glucose component, a plasticizer and/or a humectant. Also optionally, the films can include a filler, which is a dispersed phase or particle within the film and which, in certain embodiments, can cause faster disintegration of the films.
The films are preferably in the form of a monolayer having a thickness sufficient to rapidly disintegrate in the oral environment and release the active ingredient without undue discomfort to the oral mucosa. The monolayer can be cut to any desired size or shape to provide conveniently useable unit dosage forms for administration to oral or other mucosal surfaces for human pharmaceutical, cosmetic, or veterinary applications. The films are preferably mucoadhesive, in that upon contact with a mucosal surface the films adhere to the membrane until disintegration.
The invention further provides methods of administering the mucoadhesive film compositions by placing the composition into, for example, the oral cavity for a sufficient period of time, typically a matter of seconds to less than about one minute, to permit the film to disintegrate and release the active ingredient.
These and other advantages and features of the invention will be more readily understood from the following detailed description.
Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention.
The present invention provides compositions and methods for the use of film compositions which can be processed into single layer (monolayer) unit dosage forms or combined with other layers to prepare multilayer dosage forms comprising a thin film as described herein containing a pharmaceutically active or cosmetic ingredient. The thin disintegratable films according to the invention contain a mixture of high molecular weight and low molecular weight water soluble components; a pharmaceutically or cosmetically active ingredient; optionally a starch component, a glucose component, a plasticizer and/or humectant; and/or other excipients in suitable amounts as described below, or which may be determined by one of ordinary skill in the art pursuant to the guidance provided by the examples and teachings herein. The films will typically have a thickness in the range of about 10 to about 200 microns, although various other thicknesses are suitable as desired for particular applications as described in more detail below.
According to one embodiment, the disintegratable films according to the invention achieve their desirable characteristics of film strength and disintegration profile while requiring no and containing no or substantially no surfactants, release agents, or parting compounds, such as those found in U.S. Pat. Nos. 4,136,145 and 5,984,430. The term “essentially free of surfactants” refers to trace amounts or higher levels of surfactants that are sufficiently low so as not to substantially increase the disintegration rate of the film composition following contact with a mucosal surface.
According to another embodiment, the disintegratable films according to the invention contain a filler. The filler is a dispersed phase or particle that in preferred embodiments causes the films to disintegrate faster upon contact with the targeted mucosal environment than without the filler. The filler can be an optional component. Alternatively, in other embodiments, the active ingredient, when present in the film as a dispersed phase or particle, can serve the same purposes as a filler.
In one exemplary embodiment, the water soluble components of the films according to the present invention include any pharmaceutically acceptable or food grade water-soluble polymers, including but not limited to, water-soluble hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, sodium carboxy methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacantha, guar gum, acacia gum, arabic gum, carrageenan, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, and various mixtures of the above and other known water-soluble polymers, cellulose derivatives, and/or gums.
We have found that particularly beneficial properties are obtained when the water soluble polymeric component includes a combination of low molecular weight polymers (e.g., those less than about 5,000 to about 60,000 daltons) and high molecular weight polymers (e.g., those of about 60,000 to about 150,00 daltons, and to about 500,000 daltons or higher). For example, a combination of hydroxypropyl cellulose (e.g., Klucel, grade JF, Hercules Inc., Aqualon Division) and hydroxypropyl methylcellulose (e.g., Methocel, grades E5, E50, E4M, and SG A16M by Dow Chemical) is suitable. These water soluble cellulose derivative polymers have molecular weights of about 140,000; 30,000; 90,000; 400,000; and greater than about 100,000 daltons, respectively.
Additional water soluble polymers include polyvinyl pyrrolidone (PVP), such as Plasdone K-29/32 by ISP Corp., which has a molecular weight of about 58,000 daltons; and a polyvinyl alcohol-polyethylene glycol copolymer, such as Kollicoat IR by BASF Pharma, which has about 75% polyvinyl alcohol units and 25% polyethylene glycol units and has a molecular weight of about 49,000 daltons. Further, a water soluble polymer may serve the function of an additional optional component. For example, polyethylene oxide, specifically Polyox by Dow, having a molecular weight of about 200,000 daltons, can serve as a high molecular weight water soluble polymer and a plasticizer, as discussed below.
The molecular weights of the water soluble polymers can be determined as described in Keary, “Characterization of METHOCEL Cellulose Ethers by Aqueous SEC with Multiple Detectors,” Carbohydrate Polymers Vol. 45, pp 293-303 (2001), which is incorporated herein by reference.
Various other polymers can be selected by one of ordinary skill in the art given the teachings herein, so long as the polymer is water soluble, and preferably includes a sufficient amount of a high molecular weight component to impart adequate film strength, and a sufficient amount of a low molecular weight component to facilitate the desired film property of rapid disintegration profile. Various concentrations of each polymer may be utilized. Such concentrations will typically be in the range of about 2% to about 35% for each polymer based on the total weight of the dry film. In one embodiment, the concentration for the high molecular weight polymer is about 5% to 10% and the concentration of the low molecular weight polymer is about 5% to 10% of the dry film.
According to another exemplary embodiment of the invention, the water soluble low molecular weight component need not be a water soluble polymer. Instead, the low molecular weight component may be a low molecular weight monomer or a combination of various low molecular weight monomers. The low molecular weight component can also serve the function of an additional optional component. For example, the low molecular weight component can also serve as the active ingredient, a glucose component, a plasticizer, starch, flavoring, colorant, and/or sweetener, and may include any of the specific compounds listed below or other suitable compounds, which are water soluble and have a molecular weight less than about 60,000 daltons. The low molecular weight component serves to promote rapid disintegration, but is present in an amount such that film strength is adequate for processing and dispensing. Various concentrations of the low molecular weight component can be utilized. Such concentrations will typically be in the range of about 2% to about 80% or more based on the total weight of the dry film. In one embodiment, the concentration for the high molecular weight polymer is about 5% to 10% and the concentration of the low molecular weight component is about 30% to 80% of the dry film.
Any pharmaceutically or cosmetically active ingredient may be used in accordance with the principles of this invention, whether dissolved or dispersed. Examples of pharmaceutically active compounds include hormones, e.g., cyproterone acetate, progesterone, estradiol, testosterone, insulin, triiodthyronin, cortisone, etc.; prostaglandins, e.g., prostaglandin prostaglandin E2, prostaglandin Ai and prostaglandin F2α; vitamins, e.g., vitamin A, vitamin D2, vitamin D3, vitamin E, vitamin K1, vitamin K2 and derivatives of vitamin B1, e.g., thiamine tetrahydrofurfuryl disulfide or thiamine propyldisulfide; antibiotics, e.g., erythromycin and tetracycline; contraceptives, e.g., chlormadinone, chiormadinone acetate, megestrol acetate, d-norgestrel, medroxyprogesterone acetate, norethisterone, norethisterone acetate, etc.; spermicides, e.g., p-diisobutylphenoxypolyethoxyethanol, gestagens, estrogens and mixtures thereof; anxiolytics, sedatives, and hypnotics, such as bezodiazepines, e.g., diazepam and alprazolam, buspirone HCL, promethazine HCL, phenobarbital; cerebral stimulants, such as methylphenidate HCL, pemoline, caffeine; anti-diabetics; sulfonamides; proton pump inhibitors, such as omeprazole; trichomonal agents; anesthetics/analgesics, such as benzocaine, lidocaine, procaine, dyclonine HCl, phenol, aspirin, phenacetin, acetaminophen, potassium nitrate, etc.; opiate agonists, such as fentanyl citrate, meperidine HCL, morphine sulphate; anticaries agents, such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, etc.; anti-inflammatories, such as hydrocortisone acetate, triamcinolone acetonide, dipotassium, glycyrrhizinate, etc.; antihistamines, such as chlorpheniramine maleate, ephedrine HCl, diphenhydramine HCl, clemastine fumarate, loratadine, cetirizine, etc.; decongestants, such as pseudoephedrine; antibacterials, such as chlorhexidine, cetylpyridinium chloride, benzethonium chloride, dequalinium chloride, silver sulfadiazene, phenol, thymol, hexedine, hexetidine, alexidine, etc.; fungistats, such as nystatin, miconazole, ketoconazole, etc; antitussives, such as dextromethorphan, codine sulphate, menthol, etc.; anti-diarrheal agents, such as loperamide; anti-anginals, such as nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and other nitric oxide derivatives; anti-emetics, such as meclazine HCL; anti-flatulents, such as simethicone; miscellaneous autonomic and central nervous system agents, such as nicotine and sumatriptan, respectively; skeletal muscle relaxants, such as baclofen; antidepressants generally, such as olanzapine, risperidone, and specifically monoamine oxidase (MAO) inhibitors, e.g., phenelzine, selegiline, tricyclic antidepressants, e.g., amitriptyline HCL, clomipramine HCL, imipramine HCL; antipsychotics, such as phenothiazine derivatives, butyrophenone derivatives, e.g., haloperidol; smoking deterrents, such as bupropion; alcohol deterrents, such as disulfiram, naltrexone; enzymes, such as papain; cosmetic active ingredients, such as parsley seed oil; among others.
The optional glucose component of thin films according to the invention can be added as a sweetener and/or to promote rapid disintegration of the film. Preferably, the glucose component comprises a water soluble polymer or mixture of polymers having D-glucose units. The dextrose equivalent (DE) of the glucose component is preferably within the range of about 10 to about 25, or about 15 to about 20, although various other DE ranges can also be used. The glucose component can be prepared, for example, by the partial hydrolysis of starch to yield D-glucose polymer mixtures. Suitable commercially available glucose components include, for example, maltodextrin, corn syrup solids, sucrose, and dextrose. Maltodextrin having a DE of about 16.5 to 19.5, such as that commercially available from Grain Processing Corp. (GPC) under the trade name “Maltrin M180,” is particularly suitable, although various other glucose containing polymers and mixtures can be utilized, including, for example, other grades of “Maltrin,” “Lycatab DH” (Roquette Freres), and “Star-Dri” (A.E. Staley). Suitable concentrations as a weight percentage of the dry film composition will typically be in the range of about 2% to 20%, or about 3% to about 15%, although other concentrations also may be used depending on the selection of other components and the desired film properties.
The optional starch component of films according to the present invention can be added to promote rapid disintegration of the film and/or to aid in film formation. Preferably, the starch component is a water soluble polysaccharide composition containing amylose and/or amylopectin. Such compositions may be prepared by, for example, modifying natural starches, such as corn, wheat, rice, potato, or tapioca starch, to provide cold water soluble instant starches. Various water soluble compositions of amylose and/or amylopectin polysaccharides can be used. Typically, these can be made by heating a natural starch with steam to modify the natural starch product so that it is cold water soluble.
The instant starch commercially available from GPC, Muscatine Iowa, as “Instant Pure Cote B792,” (IPC B792) is an exemplary starch component for purposes of the present invention. Other suitable commercially available instant starches include “Polartex Instant 12640,” available from Cargill, Inc., and various others may also be utilized. The starch component will typically have an amylose to amylopectin ratio in the range, for example, of about 0 to about 2.5. The starch can be incorporated in the wet film composition in any suitable amount, including, but not limited to, about 2% to 50%, or about 3% to about 35% by weight based on the dry film.
The disintegratable film compositions of the present invention may also optionally contain a plasticizer or humectant, for example, polyalcohols, sorbitan esters, and citric acid esters, to increase the flexibility of the films. The plasticizers can be added directly to the formulation during manufacture. Suitable compounds include polyethylene glycol (PEG), such as Lutrol E 400, by BASF Pharma; polyethylene oxide, such as Polyox by Dow; polyoxamers, such as Lutrol F by BASF Pharma; polyvinyl alcohol; polyvinyl methyl ether, such as Lutanol by BASF; or mixtures of those polymers; triacetin; glycerin; mannitol; xylitol; and various other polyalcohols and other compounds having plasticizer and/or humectant properties can be satisfactorily employed. Sorbitol and PEG 400 are particularly suitable; although compounds having a higher molecular weight (e.g., Polyox N80) than PEG 400 may be desirable for certain applications, since they are typically less volatile than sorbitol and PEG 400. The optional plasticizer and/or humectant may be present in any suitable range, including, for example about 3% to 30%, 10% to 20%, or 15% to 18% by weight of the dry film.
Additional optional components can be added to films according to the invention. For example, flavors and sweeteners can be added to the film formulations of this invention to make the film more palatable to the patient or consumer for oral delivery. Flavors and sweeteners can be added directly to the formulation during manufacture. Flavors, sweeteners, artificial and natural, are known to those skilled in the art. The choice of flavor, sweetener, and/or other optional ingredients is not important for the practice of this invention.
Also, any color can be imparted to the film, depending upon the dye or pigment that is used. The dye or pigment is typically an FD&C colorant that is approved for oral consumption. Further, buffers, stabilizers, additives and/or other components can be added to film formulations according to the invention to provide a film having desired properties.
As noted above, according to one embodiment, the films according to the invention also contain a filler. The filler is a dispersed phase or particle that, in preferred embodiments, causes the films to disintegrate faster upon contact with the targeted mucosal surface. The active ingredient can itself act as a filler in certain embodiments. For example, a taste masked drug (e.g., encapsulated dextromethorphan or diphenhydramine) can act as a filler and promote rapid disintegration of the film. The encapsulated or taste masked drug is a dispersed particle. Methods of taste masking include encapsulation or complexation. For example, MicroMask® pseudoephedrine by Particle Dynamics is an encapsulated form of psuedoephedrine. Additionally, when the active ingredient is present in the film at a concentration above its solubility saturation point, the excess active ingredient can act as a filler. For example, when caffeine is the active ingredient, the film can be supersaturated with the caffeine such that the excess caffeine acts as a disintegration-promoting filler.
The filler can be an optional non-active component. Examples of such components include titanium oxide and microcrystalline cellulose, which is available under the name Avicel, among others. Air or other gasses can also be used as a filler according to the invention. When air is employed as the filler, a surfactant (e.g., sodium lauryl sulfate (SLS), available under the name Stepanol, Polysorbate 80, or Pluracare F87 Pril) may be included in the film formulation. The surfactant does not itself serve to significantly increase the rate of disintegration of the films upon contact with the targeted mucosal environment. Instead, the surfactant aids in the processing and formation of the film. Specifically, the surfactant stabilizes the gaseous bubbles as a dispersed phase within a solution to allow the solution to be processed, as described in more detail below, to form the film containing the gas or air as a dispersed phase filler.
The film compositions according to the invention may be prepared by several methods, including, but not limited to, adding the combination of high and low molecular weight water soluble components, the optional starch, and optional glucose polymer ingredients to a solvent that is capable of dissolving them, such as water or ethanol or a mixture of ethanol and water. Upon forming a homogeneous solution, the active ingredient and any of the other optional components, such as plasticizers, flavors, sweeteners, colorants, and/or other components may be blended into the active-containing polymer solution. Alternatively, all of the film components may be added and concurrently blended to form a solution or dispersion. Also, a dry blend can be compounded by a V-blender. The dry blend can be subsequently used to form a solution or dispersion. Additionally, the dry blend can be subsequently subjected to a melt extrusion to form a film upon cooling. It should be understood that no particular sequence of steps is required, except as needed to effectively prepare a desired film composition. For example, when a particular sequence yields an undesirable precipitate, an alternative sequence is necessary.
The active ingredient may be soluble in the solution or it may be suspended or dispersed in the solution.
The active ingredient-containing solution or dispersion may be further processed into a film by any one of many casting, drawing, or extruding techniques. For example, the solution or dispersion may be sprayed onto a support such as a release-treated belt. Alternatively, for example, the solution or dispersion may be roll coated onto a release treated paper or film substrate.
After coating of the solution or dispersion onto a support surface, the solvent may be removed by radiant energy (such as infra-red), heat, convection, vacuum, or any combination of these to yield a dry film containing an active ingredient. The resulting dry film can be wound up into a roll for storage prior to further processing into unit dose forms. Whether stored for future processing or immediately following removal of the solvent, the resulting film can be removed from the support surface and subsequently processed into unit dose form. Additional ingredients can be applied to the dried film by, for example, printing, spraying, dusting, or vapor adsorption processes, among others.
The dry film can be processed into unit dose form by any suitable technique, including, for example, by die-cutting or cutting across the width of a singular narrow roll to prepare unit dosage forms of any desired geometric size or shape. The unit dose forms may be subsequently packaged with various suitable materials known in the art to prevent degradation and protect the active ingredient from adulteration.
The preferred films according to the teachings of the present invention are mucoadhesive monolayers having a thickness in the range of about 20 microns (μ) to about 1200μ, more preferably, less than about 250μ, or equal to or less than about 200μ. In another thin film embodiment, the films have a thickness of less than about 175μ, or less than about 75μ. When placed in the mouth, the films rapidly disintegrate to release the active ingredient without causing any undue discomfort to the oral cavity. By “rapid” disintegration, we mean that the active ingredient, or the taste masked, encapsulated, or complexed form of the active ingredient, is released from the film matrix in a matter of a few seconds to less than a minute. Disintegration times can be determined using the test provided by (USP) 24, Disintegration <701>. See United States Pharmacopoeia, 24th ed., Ch. 701, p. 1941 (2000), which is incorporated herein by reference.
Preferably, the composition has already disintegrated in the oral cavity after less than about 20 to about 30 seconds from initially placing the composition in the mouth. At the same time, the films have adequate strength for processing, packaging, and administration without physical failure (e.g., breakage, fracture, or otherwise) during processing and normal handling prior to administration to the intended mucosal surface. The film strength, specifically, film resilience, springiness and burst strength, can be determined using the TA.XT2i Texture Analyzer by Texture Technologies Corp. and the ASTM D3763 “High-Speed Puncture Properties of Plastics Using Load and Displacement Sensors” test method. These properties of film strength and rapid disintegration are the result of the unique combination of the components described herein.
The film compositions may be administered to the oral mucosa or other mucous membranes where they are rapidly disintegrated by saliva and/or other aqueous materials on the mucosal surface. Upon disintegration, the films release one or more pharmaceutical or cosmetic compounds to the mucous membranes. The film compositions may be administered in such a manner so as to deliver an effective amount of the active ingredient, which may be present in pharmaceutically effective trace amounts up to about 60% or more of the dry film.
The following illustrative examples provide a number of specific formulations within the scope of the present invention. These examples are by way of illustration only and are not intended to be limiting in any way. Various alternative components, concentrations, and optional excipients (plasticizers, humectants, fillers, preservatives, etc.) may be utilized given the teachings herein to yield thin monolayer films of suitable film strength and disintegration profile.
The specific embodiments of examples 1-29 below contain no surfactants. Surprisingly beneficial film quality can thus be achieved without any surfactants. The embodiments of examples 11-31 each contain a dispersed phase filler. In examples 11-24, the active ingredient also serves as a filler; whereas, in examples 25-31 an additional component serves as a filler. The embodiments of examples 30 and 31 include air as the filler. Accordingly, examples 30 and 31 also include a surfactant for stabilizing the air bubbles during processing. The exemplary formulations below are described in the following manner: 1) the concentrations of the excipients are expressed in parts in the dry film and/or the wet solution or dispersion; 2) the weight percent of the excipients in the dry film and/or the wet solution or dispersion; and/or 3) the amount of a stock solution (stock soln.) of the excipients expressed in grams, and the total weight of the wet solution or dispersion, and the total weight of the dry film expressed in grams.
Examples 21 and 22 showed disintegration times of about 0 seconds to about 12 seconds for samples of about 35 grams to about 160 grams and for film thicknesses within the range of about 20μ to about 200μ. Disintegration times were determined using the test provided by (LISP) 24, Disintegration <701>.
The formulation of example 31 was aerated prior to casting and drying. A liquid flavor was applied to the dry film such that the flavor concentration was approximately 15% w/w of the total mass of the flavored film.
The above description is only illustrative of preferred embodiments which achieve the objects, features and advantages of the present invention. It is not intended that the present invention be limited to the illustrated embodiments. Any modification of the present invention which comes with the spirit and scope of the following claims is considered part of the present invention.
This patent application claims the benefit of U.S. provisional patent application Ser. No. 60/513,547, filed Oct. 24, 2003, and titled RAPIDLY DISSOLVING FILMS FOR DELIVERY OF PHARMACEUTICAL OR COSMETIC AGENTS. U.S. provisional patent application Ser. No. 60/513,547 is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60513547 | Oct 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13709775 | Dec 2012 | US |
| Child | 15414046 | US | |
| Parent | 10970391 | Oct 2004 | US |
| Child | 13709775 | US |
