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Steroid hormone products and methods for preparing them

a technology of steroid hormone and products, applied in the field of steroid hormone products, can solve the problems of regulatory authorities objecting to the use of such solvents, environmental objectionable organic solvents are generally required, solvents often pose safety hazards, etc., and achieves the effects of improving the dissolution profile, high dissolution properties, and sufficient mechanical energy

Inactive Publication Date: 2011-02-24
SCHULTZ THOMAS +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides a steroid hormone product with improved dissolution and release rates. This is achieved by mixing the hormone with a primary excipient that stabilizes the hormone in a non-crystalline form. The resulting product has favorable dissolution properties and is useful as an oral contraceptive or HRT product. The method involves preparing a mixture of the hormone and excipient, and then imparting mechanical energy to the mixture to yield a powder blend in which the hormone is stabilized by the excipient. The ratio of hormone to excipient can vary depending on the desired concentration, and the mixture can be formed by standard wet or dry processing."

Problems solved by technology

A major disadvantage of these solvent-based processes is that environmentally objectionable organic solvents are generally required in those cases where the steroid active ingredient has poor water solubility.
Such solvents often pose safety hazards during handling, in addition to the hazards they present when they are released into the environment.
Increasingly, health regulatory authorities are objecting to the use of such solvents due to their toxicity and mutagenicity.
However, the '434 patent is silent as to release characteristics of these compositions and teaches only a mechanical interaction during the mixing operation.
As those skilled in the art recognize, known steroid hormone products present a number of disadvantages that are not addressed by either wet or dry processing techniques.
Unfortunately, known methods of dry processing do not completely eliminate the potential existence of polymorphic forms.
In addition, steroid hormone products prepared by either wet or dry processing methods may present bioavailability problems.
Low dose steroid formulations prepared by known methods of either wet or dry processing have exhibited an undesirable variability in release rate, as measured by dissolution rate techniques in an aqueous medium containing a surfactant.
Notably, upon scale up, formulations containing low dose steroids manufactured by dry processing and intended for use as oral contraceptives routinely had slower dissolution rates or at least suffered from a poorly reproducible dissolution profile.
Consequently, it is anticipated that such products may experience similar problems related to dissolution.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Amorphous Lactose / Norgestimate Dry Ground Mixture

[0041]Amorphous norgestimate was prepared by dissolving norgestimate (200 mg) in 5 ml of (DCM) dichloromethane and 0.26 ml ethanol (EtOH). The solution was filtered through a 0.2 μm filter, and solvent was evaporated under reduced pressure to afford amorphous solid.

[0042]Mixtures of norgestimate and lactose, in amorphous and crystalline forms, were milled for 20 minutes. The amorphous state of each ingredient and of the mixture was confirmed by powder x-ray pattern diffraction (PXRD). The results are described below and summarized in Table 5.

[0043]A mixture of crystalline norgestimate:crystalline lactose (1:9) was milled in a Wig-I-Bug mill. A small mill containing a ball afforded amorphous norgestimate with mostly crystalline lactose, whereas a larger mill containing a bar yielded both as crystalline materials. Milling a 1:1 mixture of crystalline norgestimate:crystalline lactose afforded partially crystalline norgestimate with mostl...

example 2

Stability Studies of Amorphous Materials

[0045]This study shows that amorphous norgestimate is stabilized by lactose in a number of norgestimate: lactose preparations. Stress studies as well as thermal analyses (Example 3) showed the stabilization of norgestimate in norgestimate: latose mixtures.

[0046]Amorphous norgestimate was prepared from DCM:EtOH solution, and its stability was studied under various humidity conditions to establish a baseline of norgestimate stability. In order to simulate drug products, non-crystalline norgestimate: lactose mixtures were obtained from one of the following four methods: co-precipitation from EtOH:H2O, or 2-BuOH:H20, spray drying onto amorphous lactose, milling of crystalline mixtures, or milling of amorphous mixtures. The physical stability of non-crystalline norgestimate to resist recrystallization was also studied in the absence of and with an equal amount of lactose.

[0047]The materials for each sample were prepared as follows:

Amorphous Norgest...

example 3

[0060]The lactose / norgestimate mixtures made as in Example 2 were subjected to thermal analysis, according to conventional Differential Scanning calorimetry (DSC).

Glass-Transition Temperature and Crystallization Exotherm Measurements

[0061]Amorphous materials exhibit glass-transition temperatures (Tg) that reflect the physical stability of the amorphous form. The stabilized mixtures, norgestimate:lactose (1:9) mixtures, were examined along with individual amorphous materials to obtain Tg values that might give insight to the stability of each mixture compared to a single-component system. Glass-transition temperature measurements generally entail trial runs on a DSC to obtain an optimal method for observing glass-transition events. Amorphous lactose exhibits a very strong Tg event at 114-115° C. However, amorphous norgestimate does not produce consistent Tg events. Some amorphous norgestimate samples produce a weak Tg event at 122-123° C., while other samples shown an exothermic even...

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Abstract

The present invention relates to steroid hormone products, such as oral contraceptive products, including at least one steroid active ingredient mixed with an excipient and having improved dissolution and release rate properties. The invention further relates to methods for making such steroid hormone products, wherein a mixture of the hormone and the excipient is subjected to sufficient mechanical energy to form a powder blend wherein the hormone is stabilized by the excipient in substantially non-crystalline form.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 022,138, filed on Dec. 13, 2001, which claims the benefit of U.S. Provisional Application No. 60 / 255,669, filed on Dec. 14, 2000, which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to steroid hormone products comprising at least one steroid active ingredient mixed with an excipient and having improved dissolution and release rate properties. More particularly, the invention provides an oral contraception product having an improved dissolution profile. The invention further relates to methods for making such steroid hormone products, either with or without the use of solvents.[0003]As used herein, the term “steroid hormone product” is a physically discrete unit suitable as a unitary dosage for a human host. The product contains a predetermined quantity of at least one steroid active ingredient effective to ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/567A61P15/00A61K9/14A61K9/16A61K31/565A61K31/569A61K31/57A61K47/26A61P5/30
CPCA61K9/145A61K9/1623A61K9/1694A61K31/565A61K31/567A61K31/575A61K31/569A61K31/57A61K2300/00A61P15/00A61P15/18A61P5/30A61K31/56
Inventor SCHULTZ, THOMASCLARK, BRADLEY A.FALZONE, ANGELA
Owner SCHULTZ THOMAS