Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/282—Organic compounds, e.g. fats
  • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
  • A61K9/2846—Poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens

Definitions

• the present invention relates generally to conjugated estrogen formulations and methods of administering such compositions. Accordingly, this invention covers the fields of pharmaceutical sciences, medicine, cosmetics, and related sciences.
• Conjugated estrogens have been used for years as an estrogen supplement in order to treat or prevent a variety of conditions that are induced or exacerbated by estrogen hormone deficiency. Particularly, conditions experienced by peri-menopausal, menopausal, and post-menopausal women such as osteoporosis, hot flashes, vaginal atrophy, and loss of protection against heart attacks, can be ameliorated using conjugated estrogens as part of an estrogen replacement therapy routine.
• conjugated estrogens may be administered using various routes of administration, oral tablet administration has traditionally been the most common. Such formulations have not only contained conjugated estrogens, but have also included other hormones, such as progesterone in order to balance the physiological effects of estrogen supplementation.
• oral estrogen replacement tablets containing either a conjugated estrogen, or combination of conjugated estrogen and medroxyprogesterone acetate are currently marketed under the trade names PREMARIN ® , PREMPROTM, and PREMPHASE ® , by Wyeth-Ayerst Laboratories, Inc.
• PREMARIN ® PREMARIN ®
• PREMPROTM PREMPROTM
• PREMPHASE ® a variety of drawbacks include erratic drug release, degradation of the conjugated estrogen, and cracking of the tablet formulation during storage.
• a variety oral tablet formulations of both instant and sustained release for administering conjugated estrogen are currently known. For example, U.S.
• Patent 5,395,627 which is incorporated herein by reference in its entirety, discloses pharmaceutical granulates and process for making granulates to be used in oral tablet manufacture, which are very resistant to segregation, and which display an increased stability for certain steroids, such as estrogens and progestogens.
• the sugar coating composition includes sugar, a therapeutic amount of a hormonal steroid, and a hormonal steroid release-controlling amount of microcrystalline cellulose.
• the tablet core contains a medicinal agent which is conventionally co-delivered with the specific steroid in the sugar coating.
• U.S. Patent 5,720,977 which is incorporated herein by reference in its entirety, discloses an effervescent oral formulation containing a water-soluble and stable estrogen compound, such as estropipate, or estrone, a water soluble calcium salt, and a pharmaceutically acceptable excipient.
• the effervescent activity of the tablet is purported to aid the body's absorption of estrone and other estrogens due to their water insoluble nature.
• the calcium component of the effervescent causing ingredients may be used as a calcium supplement to further protect against bone loss and osteoporosis.
• Patent 5,908,638 which is incorporated herein by reference in its entirety, discloses a solid dosage unit form containing low dose conjugated estrogens that are released at regular increments (i.e. sustained release) upon oral administration.
• sustained release of estrogens and other hormones, when included, is accomplished by the inclusion of a high molecular weight hydroxypropylmethylcellulose, which may be further combined with other hydrophilic gums.
• this patent discloses that strict control of moisture content within the formulation is essential to stabilizing conjugated estrogens and achieving a uniform release thereof.
• problems such as insolubility, instability, and tablet cracking associated with oral conjugated estrogen tablets still persist. Therefore, an oral tablet formulation which overcomes, or at least ameliorates, these shortcomings continues to be sought through ongoing research and development efforts.
• the present invention provides a pharmaceutical composition in a solid oral dosage form which does not crack after storage at about 40°C and about 75% relative humidity for about 2 months.
• the compositions are stable under ambient conditions in most environments.
• the solid oral dosage form may be a tablet having a core containing a therapeutically effective amount of a conjugated estrogen, or a hormonal component thereof, at least one organic excipient, at least one inorganic excipient.
• a conjugated estrogens and specific amounts thereof may be included.
• the conjugated estrogen may be present in an amount of from about 0.1 mg to about 3 mg. In another aspect, the amount may be about 0.625 mg.
• organic excipients may be used in the core of the present oral formulation.
• the organic excipients may include less than about 25% w/w of a cellulose ingredient, and less than 50% w/w of a sugar ingredient.
• the inorganic excipients may include less than about 10% w/w of a calcium phosphate tribasic ingredient.
• the oral formulation of the present invention may include an outer coating.
• the coating may be substantially free of hormones.
• the coating may contain one or more sugar ingredients.
• the coating may include one or more acrylic polymers.
• FIG. 1 shows a graphical representation of the comparative drug release results achieved for various sugar coated 0.625 mg dose conjugated estrogen tablets, as compared to a Premarin ® tablet as a control.
• FIG. 2 shows a graphical representation of the comparative drug release results achieved for various acrylic coated 0.625 mg dose conjugated estrogen tablets, as compared to a Premarin ® tablet as a control.
• DETAILED DESCRIPTION Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular structures, process steps, or materials disclosed herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts.
• free of and substantially free of refer to the absence of a specific agent or compound, or if present, such agent or compound is present in an amount that does not provide its functional purpose to a measurable degree.
• a tablet coating that is "free of,” or “substantially free of a hormone may be either totally hormone free, or contain such a minute amount of hormone, so as to provide no measurable physiological effect.
• the phrase "completely free of may be used to indicate the complete and total absence of a specific agent or compound.
• administration refers to oral delivery of conjugated estrogen. This method and other methods of administration are well known to those in the pharmaceutical arts.
• cellulose refers to a polysaccharide consisting of anhydroglucose units joined by an oxygen linkage to form long molecular chains that are essentially linear.
• a number of specific cellulose inclusive compounds are known and used as excipients in the pharmaceutical arts, including without limitation, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxybutylethylcellulose, hydroxybutylmethylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, as well as other cellulose derivatives.
• sugar refers to any type of simple carbohydrate, such as a mono or disaccharide, or a combination thereof, either naturally obtained, refined from a natural source, or artificially produced.
• sugars are known and used in various pharmaceutical formulations, including without limitation, sucrose, glucose, mannose, fructose, lactose, etc.
• sucrose sucrose
• glucose mannose
• fructose fructose
• lactose etc.
• the recitation of the term “sugar” generically should be interpreted to include such specific compounds, as well as others not expressly recited.
• Concentrations, amounts, solubilities, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a concentration range of "about 1% w/w to about 10% w/w" should be interpreted to include not only the explicitly recited concentration of about 1% to about 10% w/w, but also include individual concentrations and the sub-ranges within the indicated range.
• concentrations such as 2% w/w, 5% w/w, and 8% w/w
• sub-ranges such as from 1% w/w to 3% w/w, from 2% w/w to 4% w/w, from 3% w/w to 8% w/w, from 5% w/w to 9% w/w, from 1% w/w to 7% w/w etc.
• concentrations such as 2% w/w, 5% w/w, and 8% w/w
• sub-ranges such as from 1% w/w to 3% w/w, from 2% w/w to 4% w/w, from 3% w/w to 8% w/w, from 5% w/w to 9% w/w, from 1% w/w to 7% w/w etc.
• the same principle applies to ranges reciting only one numerical value.
• an open ended range recited as "less than about 10% w/w” should be interpreted to include all of the values and ranges as elaborated above for the range of "from about 1% w/w to about 10% w/w.”
• functional limitations may exist for limits not expressly recited by an open ended range, and that such limitations are inherently included as part of the disclosure of the present application, though not expressly recited. Such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
• the present invention relates to a formulation comprising a core containing conjugated estrogens, one or more inorganic excipients, one or more organic excipients, and one or more fillers, and a coating comprising either a sugar or one or more acrylic polymers and/ or copolymers.
• the oral dosage formulation of the present invention includes in one aspect, a tablet having a core and a coating.
• the tablet may be made in accordance with a variety of techniques known to those skilled in the pharmaceutical arts.
• the core may contain a simple admixture of particulate, or beaded ingredients, as is known, or beads may be provided that have specific configurations, such as an inner center of excipient, surrounded by a conjugated estrogen.
• conjugated estrogens of the present invention are those generally known and described in the art as conjugated estrogens. See United States Pharmacopia (USP 23). While conjugated estrogens are typically a mixture of estro genie components, such as estrone and equilin, the present invention may be formulated to either utilize such a mixture, or to include only selected or individual estrogenic components. These conjugated estrogens may be of synthetic or natural origin. Naturally occurring conjugated estrogens are obtained from pregnant mare urine and then are processed and may be stabilized. Examples of such processes are set forth in U.S. Patents 2,565,115 and 2,720,483, each of which are incorporated herein by reference. Many conjugated estrogen products are now commercially available.
• Conjugated estrogens are also made synthetically. Examples of synthetically produced estrogens include estropipate and ethinyl estradiol. "Conjugated estrogens" as used herein includes both natural and synthetic conjugated estrogens, such as the Pharmacopia inclusive compounds alluded to above, as well as other estrogens so considered by those skilled in the art. Further, “conjugated estrogens” refers to esters of such compounds, such as the sulfate esters, salts of such compounds, such as sodium salts, and esters of the salts of such compounds, such as sodium salts of a sulfate ester, as well as other derivatives known in the art.
• the specific conjugated estrogen dose included in the tablet of the present invention may be any dosage required to achieve a specific therapeutic effect, and may vary depending on the specific treatment indicated, and on the specific conjugated estrogen included in the tablet. However, in general, dosages of conjugated estrogens included in the tablet, can range from about 0.2 mg/tablet to about 3.0 mg/tablet.
• the present dosage forms can include other hormones such as progestins and androgens.
• progestins include without limitation: progesterone, medroxyprogesterone, and a variety of synthetic progestins and their salts, esters, and derivatives that are generally known and used in the oral contraceptive area.
• Specific androgens include without limitation, testosterone, methyltestosterone, and other known derivatives and their esters and salts, including deconoate, cypionate, propionate, etc. Any of these hormones can also be micronized.
• the inorganic excipients include calcium phosphate tribasic, and calcium carbonate.
• the calcium phosphate tribasic is present at less than about 20% of the weight of the composition. In some aspects, the calcium phosphate tribasic is present at less than about 15% by weight; in some aspects, less than about 10% by weight; in some aspects, it is less than 8% by weight; and in some aspects, it is less than 5% by weight of the composition. In another aspect, the calcium phosphate tribasic ingredient may be present in an amount of from about 0.5% by weight to about 20% by weight. In one aspect, it has been discovered that when the calcium phosphate tribasic is present at these proportions, the physical stability of the composition is greatly increased during storage, for example by reduced cracking, as compared to those compositions of U.S. Patent 5,908,638.
• the invention also comprises one or more organic excipients in the tablet core, such as a cellulose ingredient.
• the cellulose may be hydroxypropylmethylcellulose.
• Other excipients that can be used in the core of the composition include without limitation: hydroxypropyl cellulose, carboxymethylcellulose, ethyl cellulose, methyl cellulose, their derivatives and salts, as well as mixtures thereof.
• other organic excipients such as polyethylene glycol, talc, lactose, starch, sorbitol, mannitol, polyvinylpyrrolidone can also be used.
• lactose, or another sugar may be included in the core, wherein the lactose, or other sugar is present at less than about 50% by weight of the formulation.
• the lactose, or other sugar may be present in an amount of from about 1% to about 50% by weight. In some aspects, the amount may be from about 10% to about 50% by weight; in some aspects, from about 10% to about 40%; in some other aspects, from about 10% to about 30% by weight; in yet other aspects, from about 5% to about 30% by weight; in yet some other aspects, from about 5% to about 50% by weight. In one aspect, the amount may be from about 20% to about 30% by weight.
• the tablet of the present invention may include gel forming excipients, such as various celluloses and gelatins, in an amount of less than about 25% w/w of the composition.
• gel forming excipients such as various celluloses and gelatins
• the amount of gel forming excipients may be less than about 20% w/w of the composition.
• the amount may be less than about 15% w/w of the composition.
• the amount may be from about l%-25% w/w.
• the coating for the tablet of the present invention may be made from a wide variety of materials including sugars and acrylic polymers and copolymers. Of particular note is that in one aspect, no hormones are contained in the coating. In other aspects, the coating may contain hormones in addition to a variety of other ingredients known to those skilled in the art, such as plasticizers, colorants, and solvents or other vehicles. Notably, such ingredients create a barrier that is initially soluble in gastrointestinal fluid, in order to achieve an initial drug release. By contrast, many sustained release formulations, such as the formulation disclosed in U.S. 5,908,638 require that the tablet coating provide a coating that is impervious to stomach fluid for at least the first few hours.
• the tablet of the present invention may include a coating that provides initial drug release while in the stomach of a subject.
• initial drug release may occur in less than about 2 hours after administration.
• initial drug release may occur in less than about 1 hour after administration.
• suitable sugars include without limitation, sucrose derived from a variety of sources, such as beet or cane sources, starch, saccharide or polysaccharide converted sources, and which is considered suitable for use in pharmaceutical applications.
• a number of acrylic polymers or copolymers known to those skilled in the art may also be used to form the coating of the tablet of the present invention.
• the coating may include a mixture or blend of acrylic polymers or copolymers.
• the mixture may be present at a ratio of from about 1 : 10 to about 10:1.
• the ratio may be from about 1 :5 to 5:1.
• the ratio may be from about 1 :2 to about 2: 1.
• the present invention is distinct from the previously known and/or disclosed formulations in at least the following ways: a) in the presence of lactose or similar sugar excipient in an amount of about or less than 50% by weight; or from about l%-50% by weight; or from about 5%-50% by weight, or from about 10%-40% by weight, or from about 10%-30% by weight; or from about 20%-30% by weight; b) in the presence of calcium phosphate tribasic in an amount of less than 20% by weight; or from about 0.5%-20% by weight; or from about 5%-20% by weight; or from about 5%-15% by weight; or from about 1%-15% by weight; or from about 1%-10% by weight; or from about 5%-10% by weight; c) in the absence of a substantial amount of a hormone in the outer coating layer in some embodiments; d) in the absence of a substantial amount of a microcrystalline cellulose in the outer coating layer to aid in controlling the release of the drug from the core; e) in the absence of a substantial
• ethyl cellulose as an outer coat that prevents dissolution in the gastrointestinal fluid of the stomach, and therefore prevents of minimizes drug release in the stomach; and f) in the presence of gel forming excipients in an amount of less than about 25% w/w of the composition; 20% w/w of the composition, 15% w/w, or from about 1% w/w to about 25%o w/w of the composition.
• U.S. Patent No. 5,547,948 discloses a core comprising conjugated estrogens and excipients and a sugar coat that also comprises a hormone and microcrystalline cellulose to control the release of the hormone from the coating.
• the invention in the '948 patent is directed at delivering the hormone in the sugar coating, and does not teach or suggest compositions that deliver conjugated estrogens from the core wherein such compositions comprise inorganic excipients such as calcium phosphate tribasic and yet that do not crack.
• the present invention does not comprise a sugar coating that controls the release of the hormone.
• Patent No. 5,395,627 teaches hormonal dosage forms wherein the core is made up of desogestrel, ethinylestradiol, and lactose and polyvinylpyrrolidone, among others, and a film coat comprising HPMC and PEG.
• the specification teaches diluents such as lactose from about 70% to about 95% by weight of the composition and does not teach the inclusion of conjugated estrogens.
• the excipients of the present invention comprise lactose at about or less than about 50% by weight and contain an inorganic excipient such as calcium phosphate tribasic and comprise conjugated estrogens.
• the present invention comprises an inorganic excipient, in some embodiments a shellac coating, and does not contain a moisture barrier coating. Rather, only a sugar coating or an acrylic coating is used. Further, it is believed, without wishing to be bound by any theory, that the particular combination of one or more of the above unique characteristics result in conjugated estrogen formulations that deliver the drug at rates comparable to the commercially successful Premarin® formulation. Further, such a formulation is stable and does not crack on extended storage, such as for one month, or two months or longer, under accelerated stability temperature and humidity conditions.
• compositions of the present invention are stable and do not crack over an extended period of time under ambient conditions of temperature and humidity as found in various environments.
• One contributing factor to the success of the present inventions may be, again without wishing to be bound by any theory, the presence of lactose in lower amounts (i.e., at about or less than 50% by weight and other amounts disclosed herein) than in the previously disclosed formulations of conjugated estrogens.
• Another contributing factor may be, again without wishing to be bound by any theory, the presence of low amounts (less than or about 20% by weight or other amounts as disclosed herein) of calcium compound such as calcium phosphate tribasic.
• Example 1 The active bulk ingredients were weighed and comminuted with hydroxypropylmethyl cellulose (Methocel K-3) under nitrogen atmosphere. The mixture was passed through a #20 mesh screen. The resulting mixture was blended with dehydrated alcohol under nitrogen atmosphere and dried with a loss on drying no greater than 2.5%.
• Example 2 Tablets prepared as in Example 1 , and having a core composition as shown in Table 1 , were placed in a 24" Accelacota Side Vented coating pan and coated with shellac. This was followed by a coating of sugar. The resulting sugar-coated tablets were cured for 24 hours in a Nary oven at 50 °C.
• the composition of the sugar-coated tablets is given in the following Table 1.
• Example 3 Tablets as prepared in Example 1, and having the core composition as in Table 2, were placed in a 24" Accelacota Side Vented coating pan and coated with methacryhc acid copolymers. Such copolymers are commercially known as Eudragit RL30D and Eudragit RS30D. The resulting acrylic-coated tablets were cured for 24 hours in a Nary oven at 50 °C. The composition for the acrylic coated tablets is given in the following Table 2.
• Example 4 Stability and drug release rates were studied for sugar-coated tablets as prepared in Example 1 and Table 1. Stability was monitored under different storage conditions. These conditions included: 50 °C, 75% relative humidity, after two weeks; 40 °C, 75 % relative humidity, after one month; 40 °C, 75% relative humidity, after two months. The samples were monitored for various active compounds and degradation products as specified in the USP. The data are shown in Table 3. These data indicate that the sugar-coated tablets of the present invention were stable under all these accelerated conditions. This is established by the fact that the various active compounds and the degradation products were within the specified limits for USP.
• Example 5 Stability and drug release rates were studied for acrylic-coated tablets made in accordance with Example 1 and Table 2. Stability was monitored under different storage conditions. These conditions included: 50 °C, 75% relative humidity, after two weeks; 40 °C, 75 % relative humidity, after one month; 40 °C, 75% relative humidity, after two months. The samples were monitored for various active compounds and degradation products as specified in the USP. The data are shown in Table 4. These data indicate that the acrylic-coated tablets of the present invention were stable under all these accelerated conditions. This is established by the fact that the various active compounds and the degradation products were within the specified limits for USP.
• Example 6 The drug release profile was obtained for the sugar-coated conjugated estrogen tablets of the present invention. Standard USP methodology was followed, which included using distilled water (900 ml), paddles at 50 rpm. The data were displayed graphically as shown in Fig. 1. A positive control of Premarin® was used to validate further the data. These data indicate that at least some sugar-coated tablets of the present invention release under some conditions the conjugated estrogens at approximately the same rate as the Premarin® product.
• Example 7 The drug release profile was obtained for the acrylic-coated conjugated estrogen tablets of the present invention. Standard USP methodology was followed, which included using distilled water (900 ml), paddles at 50 rpm. The data were displayed graphically as shown in Fig. 2.

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• 2003
  • 2003-09-22 US US10/668,104 patent/US7303763B2/en not_active Expired - Lifetime
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