Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-12-01
2003-01-14
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C514S843000
Reexamination Certificate
active
06506742
ABSTRACT:
FIELD OF THE INVENTION
This invention provides a process for preparing a pharmaceutically useful oral contraceptive liquid formulation. More particularly, this invention provides a convenient process for preparing a oral contraceptive liquid formulation using certain ingredients having improved solubility, bioavailability and stability and pharmaceutically useful as a reference standard for comparing the bioavailability of another oral contraceptive formulation.
BACKGROUND OF THE INVENTION
Pharmaceutical manufacturers are required to compare the bioavailability of dosage forms after formulation changes have been made. For example, the bioavailability of an approved formulation of a tablet batch produced at commercial scale is compared with that of a formulation for which approval is sought, hereinafter referred to as a “biobatch.” A comparative bioavailability study must then be conducted wherein tablets from the approved and biobatch formulation are each administered to volunteers. Plasma samples are then drawn and the amount of active agent present is analyzed. For an agent that is metabolized quickly after absorption, though, relative bioavialability must be measured instead. The parent compound remains in such a low quantities for quickly metabolized agents that the plasma concentration cannot be measured due to analytical equipment limits of detection. Therefore, the amount of metabolite present serves as a measure of relative bioavailability.
Relative bioavailability of a biobatch formulation is determined by using a reference standard that delivers a known and measurable quantity of the active agent. Such a reference standard may be in the dosage form of an IV solution, an oral solution or a tablet. Many steroid contraceptive drugs, however, are either poorly soluble or completely insoluble in water. Therefore, formulating an IV reference standard for such drugs is subject to many problems associated with low aqueous solubility properties. While an IV reference standard will provide a higher dose of active agent, a suitable IV formulation is limited by the poor solubility of the active agent in water and is not as convenient to administer as a tablet.
Although a contraceptive reference standard in a tablet dosage form is convenient to administer, tablets can have the undesirable characteristic of slow dissolution and corresponding poor bioavailability. Moreover, tablet reference standards for low dose contraceptive formulations must also provide enough active agent to enable accurate measurement of the relative bioavailability for each formulation compared. Since a very small amount of active agent is present in such tablet formulations, an accurate quantitation of the agent in a low dose tablet used as a reference standard is accordingly very difficult to achieve.
While an oral solution as a reference standard is also convenient to administer, conventional excipients and processes for preparing an oral solution of contraceptive steroids result in both poor solubility and stability. Accordingly, there exists a need for a convenient process for preparing an orally administered contraceptive reference standard that overcomes the problems of poor solubility, bioavailability and stability associated with known methods of preparing such reference standards.
Norgestimate (NGM), ethinyl estradiol (EE) and 17-&bgr; estradiol (E
2
) are contraceptive progestin and estrogen steroids known as active agents in oral contraceptive tablet combination formulations. NGM in combination with EE is marketed under the trademark Tricyclen® in a triphasic package containing tablets having 180, 215 and 250 &mgr;g NGM dosage strengths in combination with 35 &mgr;g EE. In addition, a monophasic package containing tablets having 250 &mgr;g NGM in combination with 35 &mgr;g EE is marketed under the trademark Cyclen®. Also, a hormone replacement therapy formulation approved for marketing under the trademark Prefest® contains tablets having 90 &mgr;g NGM in combination with 1 mg E
2
. It is known that the poor solubility of NGM limits the rate of absorption. Also, after absorption, NGM is quickly metabolized to 17-deacetyl norgestimate (17-dNGM), wherein this metabolite is used as the measure of relative bioavailability. To accurately compare the bioavailabilities of contraceptive formulations, therefore, and in particular those described herein, the need remains for a convenient process for preparing an oral contraceptive liquid formulation that is soluble, bioavailable and stable and pharmaceutically useful as a reference standard.
Many attempts to increase the solubility of active drugs have been heretofore made by pharmaceutical manufacturers. For example, U.S. Pat. No. 5,681,822, herein incorporated by reference, discloses a 2-chloro-2′-deoxyadenosine intravenous formulation that was made more soluble and stable by the addition of selected solubilizing agents. This reference describes, however, a non-analogous formulation and process compared to the present invention. Further, WO 98/20340, discloses a process for determining the dissolution rate of tablet formulations of norgestimate in combination with ethinyl estradiol tablets. This reference also only describes an analytical procedure that is distinguished from that of the present invention. EP 0012523B2 discloses a dry solid form of a poorly soluble or water insoluble drug in a composition described as yielding a higher dissolution rate and increased bioavailability. This reference also describes a formulation and process that is unlike that of the present invention. State of the art technology and the indicated references have not, however, met the need for a conveniently prepared oral contraceptive liquid formulation that is soluble, bioavailable and stable and pharmaceutically useful as a reference standard.
It is an object of the present invention to provide a convenient process for preparing an oral contraceptive liquid formulation. It is another object of this invention to provide a oral contraceptive liquid formulation having improved solubility, bioavailability and stability that is pharmaceutically useful as a liquid reference standard.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing an oral contraceptive liquid formulation that is surprisingly soluble, bioavailable and stable for use in bioavailability studies, thus overcoming the problems associated with poorly soluble or water insoluble contraceptive drugs. The process for preparing the present invention is convenient; in addition to weighing and measuring out the ingredients to be mixed, the entire process takes from 1 to 3 minutes to complete.
Accordingly, this invention provides a convenient process for preparing an oral contraceptive liquid formulation comprising:
(a) adding from about 15 &mgr;g to about 4.0 mg of a contraceptive to from about 1 mL to about 5 mL ethyl alcohol;
(b) adding to the solution of step (a) up to about 2 mL polyethylene glycol, wherein the average molecular weight of the polyethylene glycol is from about 200 to about 800, and;
(c) adding to the solution of step (b) up to about 3 mL water to afford the oral contraceptive liquid formulation.
In another embodiment of the invention, the instant formulation is a 5 mL dose of an oral contraceptive liquid formulation, wherein the dosage strength is from about 3 &mgr;g/mL to about 0.8 mg/mL.
REFERENCES:
patent: 92101531.3 (1993-09-01), None
patent: 19539860 (1996-05-01), None
Anongguo Yiyao Gongye Szzhi (Chinese Journal of Pharmaceuticals), vol. 23(3)(1992), pp. 108-110 Research on Solubilization of Paracetamol Solutions.
Uang Herling
Wei Shifeng
Wong George
Ortho-McNeil Pharmaceutical , Inc.
Peselev Elli
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