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Friday, 02 May 2014 13:11

Technical Report: Effect of LoxOral™ and Lactose on In Vitro Dissolution Studies of Progesterone Sustained Release Capsules

Progesterone is a hormonal steroid used as a lipophilic drug model for evaluation of the effect of two different excipients, LoxOral and lactose monohydrate, on in vitro sustained release drug from pharmaceutical compounded oral capsules.

Introduction:

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In vitro drug release and dissolution testing play an important role in pharmaceutical formulation development and quality control. Poorly soluble candidate molecules constitute a major challenge for the formulation development since the insufficient solubility causes problems for in vitro and in vivo assays, with consequent increased risk of attrition and costs (Di et al., 2012), besides low solubility and low dissolution rate often lead to poor bioavailability (Sarnes et al., 2013). The trend in the pharmaceutical industry is to produce more and more compounds that exhibit high lipophilicity and poor water solubility, categorizing into Biopharmaceutical Classification System (BCS) classes II and IV (Vogt et al., 2008).

Progesterone is a naturally occurring steroid hormone used in the treatment of endometrial hyperplasia and secondary amenorrhea in postmenopausal women as part of a hormone replacement therapy. The drug, a BCS class II compound, suffers from poor aqueous solubility due to its highly lipophilic structure (cLog P 4.0) (Miller, 2009). Its oral absorption can be significantly improved by the physical characteristics of the progesterone and the vehicle used in the dosage form. Progesterone for oral administration has been delivered in a micronized form in order to improve the dissolution rate and oral absorption (Hargrove et al., 1989).

A variety of strategies have been adopted to increase the aqueous solubility of lipophilic drugs which include the use of surfactants, lipids, permeation enhancers, micronization, salt formation, cyclodextrin, nanoparticle and solid dispersions (Saxena et al., 2013). Recent studies have approached the use of amphiphilic excipients as both drug delivery systems and solubilization agents to improve the aqueous solubility of many of these drugs (McCrary et al., 2013).

Following the trend of the need for a new generation of versatile excipients as oral drug delivery system to enable increased bioavailability of most drug candidates (Lipp, 2013), PCCA developed LoxOral. This innovative multifunctional excipient for capsule formulations allows enhanced dissolution rate of all types of active pharmaceutical ingredients (APIs), aggregating excellent physical and chemical stability. LoxOral composition, that confers amphiphilic character to the excipient, consists of: isomalt, glyceryl behenate, poloxamer and sodium stearyl fumarate.

The focus of the present research was to investigate the effect of two different excipients, LoxOral and lactose monohydrate, on the progesterone sustained release from capsules through in vitro dissolution rate studies in simulated gastro-intestinal fluids (SGIF). Progesterone was selected as a model of a lipophilic drug with poor aqueous solubility and dissolution rate, being an ideal candidate for study of solubility enhancement by using LoxOral as an excipient. Lactose monohydrate is one of the most commonly used fillers although it provides poor powder flowability and is shown to interact negatively with various drug actives (Ferreira, 2008). Methocel (hypromellose) is one of the most widely used mean of providing prolonged release of API in a solid oral dosage form due to form a hydrophilic matrix system (Novak et al., 2012).

 

Abstract:

Progesterone is a hormonal steroid used as a lipophilic drug model for evaluation of the effect of two different excipients, LoxOral and lactose monohydrate, on in vitro sustained release drug from pharmaceutical compounded oral capsules. The study was performed over time by monitoring the percentage of progesterone dissolved in simulated gastro-intestinal fluids (SGIF), employing the USP dissolution apparatus 2. In such fluid, the amount of progesterone dissolved increased rapidly up to 480 min from both oral drug delivery systems, although the dissolution rate profiles were statistically similar. The satisfactory and comparable dissolution performances of both progesterone capsule formulations confirm the interchangeability between the two excipients. Nevertheless, the versatile oral base, LoxOral, has advantages over traditional lactose since the compounding process of progesterone formulations becomes easier due to its excellent flowability, reduced static and minimum hygroscopicity.

Conclusions:

LoxOral and lactose monohydrate oral delivery systems showed similar in vitro sustained progesterone release profile from capsules. Based on the satisfactory and comparable dissolution performances of both progesterone capsule formulations, there is a great potential of interchangeability between LoxOral and lactose monohydrate as excipients of sustained release progesterone capsules. However, PCCA’s new oral base, LoxOral, confers advantages in the process of compounding progesterone formulations in comparison with the traditional lactose, since it is a base with enhanced quality attributes such as, excellent flowability, reduced static and minimum hygroscopicity.

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