Comparative Human In-vivo Study Of An Immediate Release Tablet

Summary:

Rapid and consistent in-vivo drug dissolution is critical for drug absorption. In-vitro dissolutions tests are used to predict in-vivo disintegration and dissolution properties of drug products. The in-vitro disintegration and dissolution times of tablets and capsules can vary significantly based on their composition and processing.

Though small differences in-vitro dissolution are not expected to result in significant in-vivo performance differences, the slight in-vitro dissolution delay observed by over-encapsulation for double blind clinical trials, as well as switching from gelatin to HPMC capsules often raises concerns on the potential impact on in-vivo bioavailability. While it is accepted that the in-vitro dissolution delay of about 5 minutes caused by over-encapsulation with gelatin capsules of immediate release (IR) tablets or powder formulation does not lead to non-bioequivalence, no data on bioequivalence exist for over-encapsulation with an HPMC capsule having a dissolution-lag time of around 10 minutes.

To assess the potential impact, a comparative investigation was performed using in-vitro dissolution, PK simulation and human bioequivalence comparing an IR fixed dose combination compressed caplet containing three different rapidly-absorbed drugs over-encapsulated with gelatin capsules and the same caplet over-encapsulated with HPMC capsules made by a thermo-gelation process.

Overview:

The plant-derived polymer hydroxypropyl methyl cellulose (HPMC) has been used in pharmaceutical and nutritional products for many years as an excipient for drug product formulation and coating applications. HPMC capsules are an alternative to HGCs, and were originally manufactured by addition of a gelling system using a gelling agent (e.g. carrageenan, gellan gum) and gelling promoter (e.g. potassium acetate, potassium chloride) to form the capsule shell. HPMC capsules produced by newly-developed thermo-gelation processes without the addition of gelling systems were introduced later and have been commercially available for some time [Al- Tabakha, 2015, Cade & He 2010].

The physical and chemical properties of HPMC address some limitations of gelatin, enabling the application of capsule technology to a broader range of drug products and formulations. Specifically, HPMC allows incorporation into capsules ingredients that are chemically incompatible with gelatin, hygroscopic or sensitive to moisture.

Studies have demonstrated differing in-vitro dissolution profiles for HGCS and different types of HPMC capsules [Gabacza et al., 2014, Honkanen et al., 2001; Vardakou et al., 2011]. The dissolution profiles of HPMC capsules depend on the capsule formulation and manufacturing process. HPMC capsules using either carrageenan or gellan gum as a gelling agent show a pH and ionic strength dependent dissolution behavior which was not the case for HPMC capsules made by a thermo-gelation process [Ku et al., 2011]. It has been shown that the bioavailability is comparable between gelatin, HPMC capsules containing gelling agents and HPMC capsules made by thermo-gelation for IR products [Ku et al., 2010; Cole et al., 2004].

The study design followed the following process:

Two dosage forms were prepared: 1) Excedrin® Extra Strength (Novartis Consumer Health) caplets each containing Acetaminophen/ Acetylsalicylic acid/Caffeine 250/250/65 mg were over-encapsulated in a standard size 00 hard gelatin capsule (Capsugel, France) and 2) the same Excedrin caplets were over-encapsulated in HPMC capsules manufactured by a thermo-gelation process without secondary gelling agents (Vcaps® Plus, Capsugel, France).

The in-vitro dissolution of the over-encapsulated caplets were performed according to the USP 29 monograph for “acetaminophen, aspirin and caffeine tablets” using a USP dissolution apparatus 2 at 100 rpm and 900 ml water at 37° C ± 0.5° C. Samples were taken after 10, 20, 30, 45 and 60 minutes, and analyzed by HPLC for acetaminophen, acetylsalicylic acid and caffeine.

PK simulations of all three compounds were performed using GastroPlus software version 9.0. We report here only the results for acetaminophen as its predicted PK was the most sensitive to the input release profile.

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