Division of Biopharmaceutics and Pharmacokinetics
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`Faculty of Pharmacy
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`University of Helsinki
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`Biopharmaceutical Evaluation of Orally and Rectally
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`Administered Hard Hydroxypropyl Methylcellulose Capsules
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`Outi Honkanen
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`Academic Dissertation
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`To be presented with the permission of the Faculty of
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`Pharmacy of the University of Helsinki, for public criticism
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`in Auditorium 1041 at Viikki Biocentre (Viikinkaari 5),
`on April 24th , 2004, at 12 noon.
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`Helsinki 2004
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`Accord Exhibit 1029
`Page 1 of 73
`PGR2023-00043
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`

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`Supervisors Professor Martti Marvola
`Division of Biopharmaceutics and Pharmacokinetics
`Faculty of Pharmacy
`University of Helsinki
`Finland
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`Docent Sari Eerikäinen
`Faculty of Pharmacy
`University of Helsinki
`Finland
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`Ph.D. Mia Säkkinen
`Division of Biopharmaceutics and Pharmacokinetics
`Faculty of Pharmacy
`University of Helsinki
`Finland
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`Reviewers Professor Jarkko Ketolainen
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`Department of Pharmaceutics
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`Faculty of Pharmacy
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`University of Kuopio
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`Finland
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`Opponent
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`Professor Jouni Hirvonen
`Division of Pharmaceutical Technology
`Faculty of Pharmacy
`University of Helsinki
`Finland
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` 
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` Outi Honkanen 2004
`ISBN 952-10-1079-7 (nid.)
`ISBN 952-10-1080-0 (pdf, http://ethesis.helsinki.fi)
`ISSN 1239-9469
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`Yliopistopaino
`Helsinki 2004
`Finland
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`Accord Exhibit 1029
`Page 2 of 73
`PGR2023-00043
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`Contents
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`Table of contents
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`Abstract
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`List of original publications
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`1. Introduction
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`2. Review of literature
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`2.1. Hydroxypropyl methylcellulose capsules
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`2.1.1. Manufacture
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`i
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` 1
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` 3
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`2.1.2. Physicochemical properties compared with hard gelatine capsules 3
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`2.1.3. In vitro drug release
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`2.1.4. Biopharmaceutical properties
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`2.2. Hydroxypropyl methylcellulose
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`2.21. Manufacture
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`2.2.2. Physicochemical properties
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`2.2.3. Applications in pharmaceutical formulation and technology 9
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`2.2.3.1.Hydroxypropyl methylcellulose in controlled-release formulations 9
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`2.2.3.2. Factors affecting drug release from hydroxypropyl methylcellulose
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`type 2208 matrices
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`2.3. Rectal administration of hard capsules
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` 15
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`2.3.1. General considerations
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`2.3.2. Hard capsules
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`3. Aims of the study
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`4. Materials and methods
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`4.1. Model drugs
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`4.1.1. Ibuprofen
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`4.1.2. Metoclopramide hydrochloride
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`4.2. Additives
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`4.2.1. Hydroxypropyl methylcellulose
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`4.2.2. Other additives
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`4.3. Capsule preparation and composition
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`4.4. In vitro studies
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`4.4.1. Drug release from capsules (I-III)
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`4.4.2. Adherence to isolated oesophageal preparation (II)
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`4.5. In vivo studies
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`4.5.1. Bioavailability studies (I-III)
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`4.5.1.1. Procedure
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`4.5.1.2. Assay methods
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`4.5.1.3. Data analysis
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`4.5.2. Gamma scintigraphic studies (IV)
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`4.5.2.1. Procedure
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`4.5.2.2. Data analysis
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`5. Results and discussion
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`5.1. Biopharmaceutical properties of capsules diluted with lactose (I, III) 30
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`5.1.1. In vitro drug release
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`5.1.2. Oral bioavailability
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`5.1.3. Rectal bioavailability
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`5.2. Biopharmaceutical properties of capsules diluted with
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`HPMC powder (II, III)
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`5.2.1. In vitro drug release
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`5.2.2. Oral bioavailability
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`5.2.2.1. Effect of capsule shell material
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`5.2.2.2. Effect of diluent
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`5.2.3. Rectal bioavailability
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`5.2.3.1. Effect of capsule shell material
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`5.2.3.2. Effect of diluent and route of administration
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`5.3. In vitro oesophageal sticking tendency of the capsule shells (II) 45
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`5.4. Gamma scintigraphic evaluation (IV)
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`6. Conclusions
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`Acknowledgements
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`References
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`Original publications
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`Accord Exhibit 1029
`Page 5 of 73
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`Abstract
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`Hydroxypropyl methylcellulose (HPMC) capsules are a new type of hard two-
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`piece capsules developed as an alternative to classic hard two-piece gelatine
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`capsules. HPMC capsules have several technical advantages over gelatine
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`capsules, e.g. lower moisture content, chemical inertness and an ability to
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`maintain mechanical integrity under very low moisture conditions. In addition,
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`HPMC capsules are made of plant-derived material, whereas the gelatine capsules
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`are of animal origin (swine and bovine). This eliminates the problems relating to
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`religious and vegetarian dietary restrictions.
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` There is not enough information available about the bioavailability of drugs
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`from HPMC capsules to be regarded as interchangeable with gelatine capsules.
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`Therefore, the main objective of the present thesis was to evaluate the
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`biopharmaceutical properties of HPMC capsules made by Shionogi Qualicaps
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`S.A. in comparison with hard gelatine capsules. Both in vitro drug release and in
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`vivo oral and rectal bioavailability of the model drugs, ibuprofen and
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`metoclopramide hydrochloride, were investigated. The capsules were diluted with
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`either lactose or HPMC powders of different viscosities.
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`The overall conclusion of the studies reported here was that the HPMC and
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`gelatine capsule shells could be regarded as interchangeable for both oral and
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`rectal administration regardless of the model drug or the diluent used. However,
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`after
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`the rectal administration of
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`the capsules,
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`the
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`time
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`lapse
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`to
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`the
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`commencement of drug absorption was always greater for the HPMC capsules
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`than for the corresponding gelatine capsules. Therefore, the rectally administered
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`HPMC capsules could be regarded as an alternative to gelatine capsules if rapid
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`onset of action is not needed. In addition, the tendency of the HPMC capsules to
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`stick to the oesophagus turned out to be high, making further investigation of this
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`phenomenon necessary.
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`The orally and rectally administered HPMC and gelatine capsules diluted with
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`HPMC powders fulfilled
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`the basic requirements of a prolonged-release
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`formulation. The release of the model drugs could be controlled also by changing
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`the viscosity grade of the HPMC polymer when the capsules were administered
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`orally, but not when the rectal route was used. The hard capsules proved to be of
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`value as a rectal dosage form, although attention should be paid to the technique
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`of insertion and to the time lapse to the onset of drug absorption, which was about
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`30 min for the gelatine capsules and about 60 min for the HPMC capsules.
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`List of original publications
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`This dissertation is based on the following publications, which are referred to in
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`the text by the Roman numerals I-IV.
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`I
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`II
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`III
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`IV
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`Honkanen O., Seppä H., Eerikäinen S., Tuominen R. and Marvola
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`M., 2001. Bioavailability of ibuprofen from orally and rectally
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`administered hydroxypropyl methyl cellulose capsules compared to
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`corresponding gelatine capsules. S.T.P. Pharma Sci. 11, 181-185.
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`Honkanen O., Laaksonen P., Marvola J., Eerikäinen S., Tuominen
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`R. and Marvola M., 2002. Bioavailability and in vitro oesophageal
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`sticking
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`tendency of hydroxypropyl mehtylcellulose capsule
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`formulations and corresponding gelatine capsule formulations. Eur.
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`J. Pharm. Sci. 15, 479-488.
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`Honkanen O., Nordberg M., Eerikäinen S., Tuominen R. and
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`Marvola M., 2002. Bioavailability of metoclopramide from orally
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`and rectally administered novel hydroxypropyl methylcellulose
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`capsules containing different diluents: a comparison with
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`corresponding gelatine capsules. S.T.P. Pharma Sci. 12, 299-307.
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`Honkanen O., Marvola J., Kanerva H., Lindevall K., Lipponen M.,
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`Kekki T., Ahonen A. and Marvola M., 2004. Gamma scintigraphic
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`evaluation of the fate of hydroxypropyl methylcellulose capsules in
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`the human gastrointestinal tract. Eur. J. Pharm. Sci. (in press)
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`Accord Exhibit 1029
`Page8 of 73
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`Accord Exhibit 1029
`Page 8 of 73
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`1. Introduction
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`Hard two-piece capsules were first invented in 1846 when Parisian pharmacist
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`J.C. Lehuby was granted French Patent 4435
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`for “Mes envelopes
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`médicamenteuses” (Jones, 1987). These capsules were made of starch or tapioca.
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`Three additions to the original patent were granted in the following four years,
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`extending the range of raw materials to carragheen, various gelatines (including
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`animal gelatine) and gums. The sole use of animal gelatine for making hard two-
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`piece capsules was first described in British Patent 11,937, which was granted to
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`J. Murdoch in 1848. Nowadays, hard gelatine capsule is a widely popular oral
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`dosage form due to the relative ease of manufacture and flexibility of size to
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`accommodate a range of fill weights.
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`Hard gelatine capsules have some disadvantages owing to the raw material.
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`Gelatine capsule shells have 13-15% water content and therefore may not be
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`suitable for water-unstable drugs. They also loose their mechanical strength and
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`become brittle when the moisture content of the capsule shell is decreased, e.g.
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`when the capsule contains strongly hygroscopic material (Kontny and Mulski,
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`1989). Furthermore, some drugs react with amino groups of the gelatine protein
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`during storage under severe conditions, causing the gelatine to cross-link and
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`reducing the solubility of the capsule shell (Digenis et al., 1994). Gelatine for
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`capsules is mainly of bovine origin, which creates a theoretical risk of
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`transmitting bovine spongiform encephalopathy (BSE) via capsules (U.S.
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`Department of Health and Human Services, 1997; EMEA, 2001). In addition,
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`gelatine products from bovine and swine sources are sometimes avoided as a
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`result of religious or vegetarian dietary restrictions. To overcome these problems,
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`hard two-piece capsules made of only plant-derived materials, i.e. hydroxypropyl
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`methylcellulose (HPMC), have been developed by Shionogi Qualicaps S.A.
`(HPMC capsule), Capsugel Division of Pfizer Inc. (Vcaps), Natural Capsules
`Ltd. (Cellulose Capsule) and Associated Capsules Ltd. (Naturecaps).
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`The physicochemical properties of the HPMC capsules (Shionogi Qualicaps
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`S.A.) compared with corresponding gelatine capsules have been sufficiently
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`described in the literature by the manufacturer (Ogura et al., 1998). The
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`biopharmaceutical properties of the capsules were also described in the same
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`publication, but to a far more limited extent. No other studies on the
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`bioavailability of drugs in humans from the two different capsule shells could be
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`found
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`in
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`the
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`literature. Thus,
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`there was an evident need for further
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`biopharmaceutical studies in human volunteers before the HPMC and gelatine
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`capsule shells could be regarded as interchangeable. The main objective of the
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`present thesis, therefore, was to widen knowledge of the biopharmaceutical
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`properties of the HPMC capsules made by Shionogi Qualicaps S.A. The HPMC
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`capsules were compared with classic hard two-piece gelatine capsules of the same
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`size and both the in vitro drug release and the in vivo drug absorption following
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`oral and rectal administration were investigated. Rectal administration was
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`evaluated, because it is known that in hospitals commercial hard gelatine capsules
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`are sometimes used rectally (Storey and Trumble, 1992), although they are not –
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`contrary to some soft gelatine capsules – officially accepted for rectal use. Both
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`the HPMC and gelatine capsules contained two model drugs of different water
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`solubilities,
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`ibuprofen or metoclopramide hydrochloride, and
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`lactose or
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`hydroxypropyl methylcellulose powder of different viscosities as diluents to
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`obtain immediate-release or sustained-release formulations. In addition, gamma
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`scintigraphic method was utilised in order to gain a better understanding of the
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`fate of the HPMC capsules in the human gastrointestinal (GI) tract.
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`2. Review of literature
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`2.1. Hydroxypropyl methylcellulose capsules
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`2.1.1. Manufacture
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`HPMC capsules (Shionogi Qualicaps S.A., Japan) are manufactured by the same
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`dipping and forming method that is applied in the manufacture of classic hard
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`gelatine capsules (Pat.U.S. 5,756,123). Shaped pins are dipped into an aqueous
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`solution comprising 18-28% w/w HPMC 2910 having 28-30% methoxy and 7-
`12% hydroxypropoxy group and a viscosity of 2.4-5.4⋅10-6 m2/s (measured as a
`2% aqueous solution at 20(cid:176) C) as a base, 0.01-0.09% w/w carrageenan as a gelling
`agent, and 0.05-0.6% w/w potassium and/or calcium ions as a co-gelling agent.
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`Small amounts of carrageenan and potassium and/or calcium ions are added to the
`HPMC solution to enable gelling at 48-55(cid:176) C, since HPMC alone gels at
`temperatures below 60(cid:176) C. After dipping, the HPMC film is gelled, dried, trimmed
`and removed from the pins. The body and cap pieces are then joined. The finished
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`HPMC capsule shells comprise 79.6-98.7% w/w of HPMC 2910, 0.03-0.5% w/w
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`of carrageenan, 0.14-3.19% w/w of potassium and/or calcium ions and 2-5% w/w
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`of water.
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`2.1.2. Physicochemical properties compared with hard
`gelatine capsules
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`HPMC capsules are odourless and flexible (Pat.U.S. 5,756,123). Their appearance
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`corresponds to that of gelatine capsules, except that the surface of HPMC capsules
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`is matt, whereas the surface of gelatine capsules is lustrous. The physical
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`properties of HPMC capsules compared to gelatine capsules are presented in
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`Table 1 (Ogura et al., 1998). The main differences in the physicochemical
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`properties between HPMC and gelatine capsules are related to their moisture
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`content, which is 2-5% for HPMC capsules and 13-15% for gelatine capsules
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`(Table 1). The relationship between the brittleness and moisture content of HPMC
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`and gelatine capsules has been demonstrated using a hardness tester (Ogura et al.,
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`1998). The percentage of broken gelatine capsules increased to almost 100% as
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`the moisture content of the capsule shell decreased below 10%. In contrast,
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`HPMC capsules remained undamaged even at moisture levels of only 2%. This
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`difference between HPMC and gelatine capsules could be of significance in
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`practice if the drug filled in the capsule is strongly hygroscopic.
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`Table 1. Physical properties of HPMC and gelatine capsules (Ogura et al., 1998).
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`Capsule material
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`Moisture content
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`Water vapour permeability
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`Substrate for protease
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`Maillard reaction with drug fill
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`Deformation by heat
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`HPMC
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`Gelatine
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`2-5%
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`13-15%
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`Low
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`No
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`No
`> 80(cid:176) C
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`Low
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`Yes
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`Yes
`> 60(cid:176) C
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`Water dissolution at room temperature Soluble
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`Insoluble
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`Static
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`Light degradation
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`Low
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`No
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`High
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`Possible
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`The stability of a water-unstable drug in HPMC and gelatine capsules has been
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`tested with acetylsalicylic acid (Ogura et al., 1998). HPMC and gelatine capsules
`filled with acetylsalicylic acid alone were stored at 60(cid:176) C for two weeks. The drug
`content did not decrease to less than 95% of its initial concentration when stored
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`in the HPMC capsules, whereas it decreased to 85% of its initial concentration
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`when stored in the gelatine capsules, apparently as a result of hydrolysis. Thus,
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`due to the naturally low moisture content of the HPMC capsule shells, they are
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`more suitable than gelatine capsules for use with formulations containing water-
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`unstable drugs.
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`Another notable difference between HPMC and gelatine capsule shells is that
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`HPMC capsule shells are compatible with most filling materials, since the only
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`incompatibility known for HPMC is the interaction between some oxidizing
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`agents (Harwood, 2000). Gelatine, on the other hand, has chemically reactive
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`groups. Ogura and co-workers (1998) filled HPMC and gelatine capsules with
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`ascorbic acid and packed them in polyethylene bottles without a desiccant, and
`stored at 40(cid:176) C/75% relative humidity for two months. The gelatine capsules were
`dyed brown, whereas the colour of the HPMC capsules did not change. In both
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`cases the colour of the ascorbic acid in the capsules did not change, indicating that
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`the discoloration was the result of a reaction between the ascorbic acid and the
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`gelatine shell (called Maillard reaction).
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`The dissolution of gelatine capsule shells can be incomplete and slow if the
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`capsules contain drugs having aldehyde groups or producing aldehydes on
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`decomposition, which promote cross-linking between gelatine proteins and form a
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`thin insoluble membrane called a pellicle (Carstensen and Rhodes, 1993; Digenis
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`et al., 1994). This has been demonstrated with spiramycin, a macrolide antibiotic
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`known to cause insolubilisation of gelatine capsules (Ogura et al., 1998).
`Spiramycin was filled into HPMC and gelatine capsules and stored at 60(cid:176) C/75%
`relative humidity for ten days. After storage, the disintegration properties of the
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`HPMC capsules remained unaffected, whereas the properties of the gelatine
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`capsules changed and they did not disintegrate.
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`Chiwele and co-workers (2000) studied the shell dissolution properties of
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`empty gelatine and HPMC capsules after storage under humid tropical conditions
`(37(cid:176) C/75% relative humidity) for 24 h and after storage under ambient room
`conditions. They used the method described by Jones and Cole (1971), which
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`consists of placing a steel ball bearing inside the capsule, suspending the capsule
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`body in the test solution and measuring the time for it to fall from the capsule. The
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`dissolution medium was artificial gastric or intestinal juice (BP). The temperature
`of the medium was in the range of 10(cid:176) to 55 (cid:176) C. Storage under humid tropical
`conditions did not affect the dissolution properties of the gelatine capsules
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`regardless of the dissolution medium, whereas the dissolution time of the HPMC
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`capsule shells was unaffected only in artificial gastric juice. In artificial intestinal
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`juice the shell dissolution times of the HPMC capsules were significantly reduced
`for temperatures between 10(cid:176) and 30(cid:176) C, whereas above 37(cid:176) C the shell dissolution
`times were increased. It was suggested that the HPMC capsules were hydrated
`
`during storage, which might have caused the slower water penetration through the
`
`hydrated material and, thus, slower dissolution time of the capsule shell. The
`
`reason for the different shell dissolution times of the HPMC capsules in the
`
`different dissolution media and at different temperatures was not discussed.
`
`Nevertheless, the authors pointed out that care should be taken when the HPMC
`
`capsules are exposed to hot and humid conditions.
`
`As was mentioned earlier, Ogura and co-workers (1998) did not notice any
`
`effect on the disintegration properties of the HPMC capsules filled with
`spiramycin when stored at 60(cid:176) C and 75% relative humidity for ten days.
`However, they used a standard pharmacopoeial disintegration test, which is fairly
`
`drastic and does not determine the shell dissolution time and the disintegration of
`
`the powder plug separately (Chiwele et al., 2000). In the method used by Chiwele
`
`and co-workers (2000), on the other hand, the filling material (steel ball bearing)
`
`did not affect the shell dissolution time.
`
`The study of Chiwele and co-workers (2000) further revealed that the HPMC
`
`capsule shells dissolved rapidly in water (pH 5.8) and 0.1 M hydrochloric acid
`
`
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`(pH 1.0) in the temperature range of 10 to 55(cid:176) C. The gelatine capsule shells, on
`the other hand, did not dissolve at temperatures below 30(cid:176) C in the same
`dissolution medium, and the dissolution time was dependent on the temperature.
`
`2.1.3. In vitro drug release
`
`Three studies (other than those included in this thesis) describing the in vitro drug
`
`release properties of HPMC capsules (Shionogi Qualicaps S.A.) compared to
`
`corresponding gelatine capsules can currently be found in the literature (Ogura et
`
`al., 1998; Podczeck and Jones, 2002; Wu et al., 2003). Ogura and co-workers
`
`(1998) studied the release of cephalexin from HPMC and gelatine capsules in
`
`solutions having pH 1.2, 4.0 or 6.8. The procedure applied was the paddle method
`
`described in the Japanese Pharmacopoeia (JP) and the speed of rotation was 100
`
`rpm. There were no differences in the dissolution profiles between the HPMC and
`
`gelatine capsules when the pH of the solution was 1.2 or 4.0. When the
`
`dissolution medium was the JP “second test fluid” with pH 6.8, the dissolution
`
`times of cephalexin were approximately 5 min longer from HPMC capsules than
`
`from gelatine capsules. This was supposed to be due to the presence of potassium
`
`in the medium, which promotes the gelation of carrageenan. Thus, the HPMC
`
`capsule shell formed a persistence gel membrane around the drug fill. When the
`
`dissolution medium was changed to potassium-free buffer pH 6.8, there were no
`
`differences between
`
`the
`
`two different capsule shells. Since
`
`the cation
`
`concentration in the gut is low, it was suggested that pharmacopoeial buffer
`
`solutions that do not contain potassium ions could be considered acceptable
`
`alternatives for determining in vitro drug dissolution rates from HPMC capsules.
`
`Podczeck and Jones (2002) investigated the release of theophylline from
`
`HPMC capsules compared with hard gelatine capsules. The capsules contained
`
`either the model drug only or the drug and lactose or microfine cellulose as a
`
`diluent, and different fill weights and tamping forces were utilized. The
`dissolution tests were carried out using distilled water at 37(cid:176) C and a paddle speed
`of 50 rpm. The amount of theophylline released after 60 min from the different
`
`HPMC capsule formulations was always greater than from the corresponding
`
`gelatine capsules. Also the release rate was generally greater from the HPMC
`
`capsules than from the gelatine capsules. This was suggested to be due to the
`
`dissolution properties of HPMC capsule shells. HPMC capsule shells dissolve
`
`evenly and simultaneously across the whole shell, whereas gelatine capsules
`
`dissolve first from the shoulders, and only later across the whole body. Thus, the
`
`whole powder plug filled in an HPMC capsule will be subjected to the dissolution
`
`
`
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`medium earlier. The authors concluded that a change from gelatine hard shell
`
`capsules to HPMC hard shell capsules should not pose problems with respect to
`
`drug absorption and bioavailability.
`
`Wu and co-workers (2003) studied the release of an investigational drug, BMS-
`
`309403, (poorly water-soluble weak acid) from size 0 gelatine and HPMC
`
`capsules. The capsules contained either 50 or 200 mg of the granulated drug and
`
`the total fill weights were 90 and 360 mg, respectively. It was estimated that a 90
`
`mg fill weight only occupied a volume of about 20% of the capsule body, whereas
`
`360 mg occupied about 80%. The dissolution tests were carried out using the USP
`
`paddle method (60 rpm). The dissolution medium was 0.5% sodium lauryl sulfate
`in 0.1 M sodium phosphate buffer, pH 6.8 (37(cid:176) C). The results showed that when
`the capsule shell was gelatine, the 50 mg capsules surprisingly dissolved at a
`
`much lower rate than the 200 mg capsules. It was observed that the shells of the
`
`50 mg gelatine capsules softened and collapsed during the first 10 min of the
`
`dissolution test, occluding the granules and retarding the drug release. This was
`
`not observed when the gelatine capsules contained 200 mg of the drug; the
`
`capsule shells burst open within the first 10 min. When the capsule shell type was
`
`changed to HPMC, the 50 mg capsules dissolved slightly faster than the 200 mg
`
`capsules and the HPMC capsule shells did not collapse onto the granulation.
`
`However, both HPMC capsule strengths dissolved more slowly during the first 10
`
`to 20 min than the corresponding gelatine capsules, which was due to the swelling
`
`and expansion of the HPMC capsule shells without leaking much granulation
`
`during the first 10 min.
`
`2.1.4. Biopharmaceutical properties
`
`Studies describing the bioavailability of drugs from HPMC capsules (Shionogi
`
`Qualicaps S.A.) compared to gelatine capsules are limited to that of Ogura and co-
`
`workers (1998) determining the oral bioavailability of cephalexin from HPMC
`
`capsules compared to gelatine capsules. The study was conducted with 6 healthy
`
`volunteers under fasting conditions. Concentrations versus time curves were
`
`similar between the HPMC and gelatine capsules and there were no significant
`
`differences in the pharmacokinetic parameters (AUC, Cmax and tmax) between these
`capsules.
`
`
`
`
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`2.2. Hydroxypropyl methylcellulose
`
`2.2.1. Manufacture
`
`The European Pharmacopoeia describes hydroxypropyl methylcellulose
`
`(hypromellose) as partly O-methylated and O-(2-hydroxypropylated) cellulose.
`
`The structural formula of HPMC is presented in Fig. 1.
`
`
`
`
`Figure 1. Structural formula of hydroxypropyl methylcellulose. The substituent R
`represents either a -H, -CH3, or a -CH2CH(CH3)OH.
`
`HPMC is an odourless, tasteless and inert hydrophilic polymer with no ionic
`
`charge. It is manufactured from purified cellulose, which is obtained from cotton
`
`linters or wood pulp (Harwood, 2000). The cellulose is first treated with sodium
`
`hydroxide solution to produce swollen alkali cellulose, which is chemically more
`
`reactive than the untreated cellulose. The alkali cellulose is then converted to
`
`methylhydroxypropyl ethers of cellulose by treating with chloromethane and
`
`propylene oxide. Finally, the fibrous reaction product is purified and ground to
`
`powder or granules.
`
`
`2.2.2. Physicochemical properties
`
`The physicochemical properties of HPMC (e.g. solubility, glass-transition
`
`temperature and viscosity) are affected by
`
`the ratio of methoxy and
`
`hydroxypropoxy groups and the molecular weight. The molecular weight of
`
`HPMC is approximately 10,000 to 1,500,000 (Harwood, 2000). There are several
`
`grades of HPMC polymers available on the market, which vary in viscosity and
`
`extent of substitution. The grades may be distinguished by a number indicative of
`the apparent viscosity, in mPa⋅s, of a 2% w/w aqueous solution at 20(cid:176) C. The
`apparent viscosity serves as a measure of the average chain length of the polymer.
`
`
`
`
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`The USP presents four different types of HPMC polymers. They are classified
`
`according to their relative methoxy-group and hydroxypropoxy-group contents:
`
`HPMC 1828, HPMC 2208, HPMC 2906 and HPMC 2910. The first two numbers
`
`indicate the percentage of methoxy groups, the last two numbers the percentage of
`hydroxypropoxy groups, determined after drying at 105(cid:176) C for two hours. The
`exact limits for the degree of substitution defining the respective HPMC types are
`
`given in Table 2.
`
`Table 2. USP specifications for different types of HPMC, classified according to their
`degree of methoxy and hydroxypropoxy substitution.
`
`Substitution type
`
`Methoxy (%)
`
` Hydroxypropoxy (%)
`
`
`
`1828
`
`2208
`
`2906
`
`2910
`
`Min.
`
`Max.
`
`16.5
`
`19.0
`
`27.0
`
`28.0
`
`20.0
`
`24.0
`
`30.0
`
`30.0
`
`
`
`
`
`
`
`
`
`
`
`Min.
`
`23.0
`
`4.0
`
`4.0
`
`7.0
`
`Max.
`
`32.0
`
`12.0
`
`7.5
`
`12.0
`
`2.2.3. Applications in pharmaceutical formulation and
`technology
`
`HPMC is an extremely versatile material, which is widely used in pharmaceutical
`
`products. HPMC is primarily used as a binder, film coating and as a controlled-
`
`release matrix in solid dosage forms (Rowe, 1980; Banker et al., 1981; Krycer et
`
`al., 1983a, b; Alderman, 1984; Harwood, 2000). Concentrations of 2-5% w/w may
`
`be used as a binder in either wet or dry granulation processes (Harwood, 2000). In
`
`film coating, concentrations of 2-20% are used, depending on the viscosity grade
`
`of the HPMC. In controlled-release matrix formulations, concentrations of 10-
`
`80% may be used. In liquid dosage forms HPMC is used as a suspending and
`
`thickening agent and as an emulsifier.
`
`2. 2. 3. 1. H ydroxypropyl m ethylcellulose in controlled-release
`form ulations
`
`Controlled-release
`
`formulations have several benefits over conventional
`
`immediate-release formulations: controlled administration of a therapeutic dose at
`
`a desired delivery rate, constant blood levels of drugs, reduction of side effects,
`
`maintenance of therapeutic concentration also during the night, minimization of
`
`dosing frequency and enhancement of patient compliance (Ritschel, 1989). On the
`
`
`
`
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`other hand, controlled-release formulations also have some disadvantages, e.g.
`
`loss of efficacy when one or two doses are skipped and poor dosage form for
`
`drugs with inactivation by first-pass metabolism, extremely short or long
`
`elimination half-life and instability in the gastrointestinal environment.
`
`Hydrophilic matrix formulations are the most widely used of the numerous
`
`controlled-release dosage forms currently available and they have been employed
`
`in the pharmaceutical industry for over 40 years (Wichterle and Lim, 1960;
`
`Alderman, 1984; Ranga Rao and Padmalatha Devi, 1988; Ferrero Rodriguez et
`
`al., 2000). Of hydrophilic polymers, hydroxypropyl methylcellulose is the most
`
`popular material for the preparation of controlled-release dosage forms and it has
`
`been employed since the 1960s (Pat.U.S. 3,065,143; Lapidus and Lordi, 1966,
`
`1968; Huber et al., 1966; Huber and Christenson, 1968; Colombo, 1993; Hogan,
`
`1989; Ferrero Rodriguez et al., 2000). One of its most important characteristics is
`
`high swellability, which has a significant effect on the release kinetics of an
`
`incorporated drug. Also its ease of compression, non-toxic nature, ability to
`
`accommodate a large percentage of drugs, and the minimum influence of
`
`processing variables on the release of drugs from matrices are some of the reasons
`
`for its popularity (Vázquez et al., 1992).
`
`When the HPMC-based matrix formulation comes into contact with a
`
`thermodynamically compatible aqueous solvent, the solvent penetrates into the
`
`free spaces on the surface between the macromolecular chains. When the solvent
`
`h