Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-12-28
2003-04-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S457000, C424S458000, C424S464000, C424S468000, C424S469000, C424S470000, C424S489000
Reexamination Certificate
active
06544553
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to oral dosage forms of hormones and methods for their delivery to subjects needing hormone therapy.
BACKGROUND OF THE INVENTION
Micronized progesterone formulations have been disclosed in the past Maxson et al., which discloses various progesterone oral formulations where the first major indgredient is micronized progesterone and “[t]he second major component of the present invention is an oil which serves as a vehicle for the micronized progesterone. The composition and properties of the oil employed as the vehicle have a large effect on the effectiveness of the product.” In addition, micronized progesterone has been dissolved or dispersed in a variety of oils to overcome the solubility problem. One commercially available oil-based oral formulation of micronized progesterone is available under the trademark Prometrium®. Salin-Droumn, U.S. Pat. No. 6,077,531, states in its Abstract that it provides “[a] medicament consisting of a biological medium-soluble capsule containing a micronised progesterone suspended in oil is disclosed, characterised in that the capsule also contains estradiol enclosed in microspheres, also suspended in oil, and which consist of one or more polymers that do not dissolve in oil but that dissolve in a biological medium.”
In addition to the oil based preparations, various oral progesterone formulations have been proposed:
Agnus et al., U.S. Pat. No. 6,086,916, col. 1, line 56-col. 2, line 4, discusses Gram [Novo Nordisk ]WO 95/05807 as “describ[ing] tablets containing progesterone and a polyethylene glycol, as well as an excipient chosen from the group containing starches, starch-containing components, modified starches, celluloses, modified celluloses, pectins and tragacanth. [T]he presence of polyethylene glycol and of the excipient in the tablets results in a favourable effect on the bio-availability of orally administered progesterone. * * * [T]he tablets * * * contain high percentages of excipients.” Gram's Abstract states that she provides an oral progeseterone that “may, conveniently, contain a PEG, and a further excipient selected from the group comprising a starch, a cellulose, pecting, and tragacanth.” The polyethylene glycols are referred to as “liquid or solid polymers”. Page 7, lines 20-22. Examples with progesterone and estradiol include maize starch, lactose, polyethylene glycol 6000, croscarmellose sodium, magnesium stearate and taclum powder.
Agnus '916 itself has an an object progesterone dosage forms that also include “diluents, disintegrating agents, lubricants and binding agents.” Col. 2, lines 36-37. “As examples of diluents, mention may be made of starches, polyols and celluloses * * * preferably pregelatinized maize starch, mannitol and microcrystalline cellulose.” Id., lines 38-42. Polyvinylpyrrolidone is said to be the preferred binding agent.
Agnus WO 99/45932 is stated in the English abstract to be “concern[ed with] a pharmaceutical based on natural synthesis progesterone and [ ]estradiol in tablet form, [where] its disintegration time is less than 15 minutes, preferably less than 10 minutes, and more preferably less than 5 minutes.” The progesterone used in the formulation is micronized (page 8, Tableau 1, first ingredient). The example has a 9:1 weight ratio of hydroxypropylmethylcellulose:polyethylene glycol 600, where the total quantity of this mixture is 2.0 mg per unit vis a vis 14 mg. sodium carboxymethylcellulose (3.20 mg. in two different forms).
Bair, WO 97/46242, Example 3, discloses gelatin capsules containing a powder of micronized progesterone in calcium carbonate. The micronized progesterone:calcium carbonate is in a 1:4 weight ratio that has been “placed in a grinding mill and blended to yield a homogenous powder” (id., lines 26-27); the powder is administered from a gelatin capsule administered five times per day.
Place, U.S. Pat. No. 6,117,446 and several continuing applications based thereon discloses a buccal dosage unit form for active agents, including progesterone and an estrogen; the examples use a polyethylene oxide and carbomer.
Dittgen et al., U.S. Pat. No. 6,117,450 disclose four differing compressed compositions to be jointly used in an oral dosage form. Example 1 delivers progesterone and estradiol in lactose; one of the four compressed compositions also uses hydroxypropylmethylcellulose and all use a polyvinyl propylene.
Polyethylene glycol has long been known as a polymer matrix for delivery of a wide variety of drugs. Snipes, U.S. Pat. No. 4,629,621, seeks to improve the use of polyethylene glycol by teaming it with an “erosion rate modifier [which] is an insoluble amphiphile * * * , which slows down the rate at which the matrix is eroded * * * .” Col. 3, lines 16-23. Examples given are “C12-C20 fatty acids * * * , C12-C20 alcohols * * * , amphiphilic esters of fatty acids with glycerol * * * , C12-C20 amines * * * , and amides of C12-C20 fatty acids. Col. 4, lines 1-10.”
SUMMARY OF THE INVENTION
In a first embodiment, there is provided an oral dosage form suitable to deliver a combined dosage of progesterone and which upon delivery through the gastrointestinal tract provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form comprising from about 25 mg to about 500 mg micronized progesterone in a solid polyethylene glycol carrier having an average molecular weight of from about 1000 to 10,000 and constituting at least about 30% of said first solid form; and (b) a second solid form comprising an estrogen. In one embodiment, the polyethylene glycol carrier comprises from about 45% to about 65% weight of the first solid form. In a further embodiment, the second solid form (b) contains from about 0.25 mg to about 5 mg of estradiol.
In a further embodiment, the solid polyethylene glycol carrier comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000. In a preferred embodiment there is provided an oral dosage form suitable to deliver a combined dosage of progesterone and an estrogen via the gastrointestinal tract which upon oral administration provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form containing from about 25 mg to about 500 mg micronized progesterone, said caplet having been derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000, the micronized progesterone having first been dispersed in molten cooling to a solid form, having extruded, said mixture constituting from about 45% to about 65% weight of said first solid form; and (b) a second solid form which contains from about 0.25 mg to about 5 mg of estradiol. In a preferred embodiment, the oral dosage form is provided with said first solid form as a caplet and said second solid form as a tablet.
In a second aspect of the invention, there is provided a method of providing an oral dosage of a combination therapy of progesterone and estradiol which comprises administering to a patient an oral dosage form suitable to deliver a combined dosage of progesterone and an estrogen via the gastrointestinal tract which upon oral administration provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form containing from about 25 mg to about 500 mg micronized progesterone, said caplet having been derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000, the
Ho Thomas Chun
Hsia David Chung
Tan Domingo Yap
Weihmuller Fredric B.
Foley & Lardner
Page Thurman K.
Tran S.
Watson Pharmaceuticals, Inc.
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