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Thursday, 11 September 2014 17:22

Technical Report: Effect of Particle Size on the Bioaccessibility of Progesterone from LoxOral™ in an In Vitro Dynamic Gastrointestinal System

The oral dosing of progesterone has limitations due to poor absorption (low bioavailability) and short half-life of the drug. Progesterone must be bioavailable in order to be effective for hormonal replacement therapy (HRT).

Introduction:

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Hormonal replacement therapy (HRT) has been used extensively to treat the symptoms caused by decreased estrogen production following menopause, which can include vasomotor symptoms, urogenital atrophy, and mood or sleep disturbances (Ryan & Rosner, 2001). Estrogen therapy is frequently used in HRT and its pro-proliferative effects on the endometrium are counterbalanced by the use of progesterone, which is known to modulate the growth-stimulatory effects of estrogen (Yang et al., 2011). Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial recommend that oral micronized progesterone be the first choice for estradiol opposing therapy in postmenopausal women (Miller et al., 1995; Barret-Connor et al., 1997).

Progesterone is a drug with poor aqueous solubility and therefore has a limited dissolution rate. It can have its absorption and bioavailability significantly altered depending on the physical characteristics of the drug and the vehicle used for oral administration (Hargrove et al., 1989). Several reports have demonstrated that micronization of progesterone facilitates aqueous dissolution in the small intestine (Bolaji et al., 1993), and that the absorption and serum concentration of progesterone are enhanced by micronization (Hargrove et al., 1989). Special micronized progesterone has a smaller particle size than milled (non-micronized) progesterone.

The goal of this study was to determine the bioaccessibility (estimated bioavailability) of compounded oral special micronized progesterone when compared to compounded oral milled (non-micronized) progesterone in a simulated in vitro model of the human upper GI tract.

Abstract:

The oral dosing of progesterone has limitations due to poor absorption (low bioavailability) and short half-life of the drug. Progesterone must be bioavailable in order to be effective for hormonal replacement therapy (HRT). For the first time, testing was done to study the bioaccessibility (estimated bioavailability) of oral prolonged release compounded special micronized progesterone in comparison to oral prolonged release compounded milled (non-micronized) progesterone. Testing performed utilized the dynamic in vitro TIM-1 gastrointestinal model, which simulates the gastrointestinal tract from the stomach to the small intestine. This TIM-1 system was used to examine a 100 mg capsule of special micronized progesterone compared to a 100 mg capsule of milled (non-micronized) progesterone. Both capsule formulations contained Methocel® E4M to create the prolonged release rate and LoxOral as the excipient base. The special micronized progesterone had a smaller particle size than the milled (non-micronized) progesterone. According to in vitro data that estimates bioavailability, results for the special micronized progesterone showed a significantly greater overall bioavailability and a decreased residue deposition in the TIM-1 simulated gastrointestinal model. These results suggest that compounded special micronized progesterone may have significant clinical benefits in hormone replacement therapy (HRT).

Conclusions:

This study provides the first assessment of progesterone bioaccessibility (estimated bioavailability) from a compounded formulation using the dynamic gastrointestinal TIM-1 system. Overall, the results of this study suggest that the ultrafine particle size of PCCA’s special micronized progesterone shows an enhanced bioaccessibility profile when compared to that of milled (non-micronized) progesterone in a simulated model of the upper GI tract. These results confirm that oral compounded special micronized progesterone using Methocel E4M to create the prolonged release rate and LoxOral as the excipient is a valuable option for hormone replacement therapy (HRT).

Download the complete PDF detailing the results of this study.

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