Issue: Vol. 2 No. 2 March/April 2002, Posted Date: 3/27/2008

Advantages to HPMC Capsules: A New Generation's

 

INTRODUCTION

Two-piece capsules have been used for almost a century in the pharmaceutical field, and gelatin has been adopted as the main material of these capsules due to its excellent characteristic as a gelatinizer. The gelatin dissolves under high concentration into water of a high temperature and quickly gels in room temperature. The thickness of the film made by the gelatin becomes uniform. However, gelatin is one of the proteins derived from animals; therefore, it is unstable from a chemical viewpoint and has a risk of TSE.

Several materials have been examined as a substitute for the gelatin in two-piece hard capsules. Hydroxypropylmethyl cellulose (HPMC) has become a successful alternative material for two-piece capsules and is actually on the market in the world. HPMC is also being adopted as a film coating or a sustained-release tablet material in the pharmaceutical field. HPMC capsules have been developed for both pharmaceutical products and dietary supplements. QUALI-V, developed by Shionogi Qualicaps, is the first HPMC capsule developed for eventual use in pharmaceutical products. QUALI-V has been submitted to the FDA and its DMF number is 12900.

In this article, the characteristics of QUALI-V, when the oral dosage form (powders or granules) is filled into QUALI-V, will be shown. The features of QUALI-V are shown in Table 1. QUALI-V can be filled with many kinds of liquid or semi-solid dosage forms, but this information is only briefly described in this article

FUNDAMENTAL CHARACTERISTICS OF QUALI-V

Generally, the thickness of a hard two-piece capsule shell is about 0.1 mm, and the thickness of QUALI-V's is the same. The capsule shell acts as a container and/or a protective wall. The important matter for the former is a compatibility with ingredients to QUALI-V. The important matter for the latter is a permeability of vapor water and oxygen through the capsule shell.

Moisture Contents in Capsule Shell
The equilibrium moisture contents in the capsules were measured by a Micro-balance System (VTI). Capsules were cut, and almost 10 mg was placed on a dish in the Microbalance. After the piece was dried until the moisture content was zero, the change of weight was continuously measured by changing relative humidity. The moisture contents in the gelatin capsule were higher than those in QUALI-V over the whole range of humidity (Figure 1). In fact, the moisture contents of the gelatin capsules and QUALI-V measured by Karl-Fisher were 13% to 15% and 4% to 6%, respectively when stored at 20� C to 25� C and 40% to 60% RH. Because hard gelatin capsules contain 13% to 15% water, water-sensitive drugs are not considered to be suitable to them. However, QUALI-V contains only 4% to 6% of water in the shell and is able to be filled with water- sensitive drugs.

The moisture content in the capsule shell also influences the brittleness of hard capsules. When the moisture content in the gelatin capsule shell decreases to below 10%, the capsules can break easily (Figure 2). However, QUALI-V does not crack even with 1% or less in the moisture content.

Compatibility to Filled Substances
Gelatin is chemically active on the molecular level. Lysine residual is a typical example; therefore, some substances are considered not to be suitable for gelatin capsules. In particular, hard gelatin capsules may not be suitable for the accelerated stability test, 40� C and relative humidity 75%. Furthermore, it is thought that compounds that contain an aldehyde group, reduction sugars, and ascorbic acid to name a few, are not suitable for the gelatin capsule. However, QUALI-V is capable of being filled with numerous materials because HPMC is chemically inactive. Two typical examples are described. The first example is spiranomycin, which includes an aldehyde group. The hard gelatin capsules filled with spiranomycin failed to dissolve in Japanese Pharmacopoeia 1st fluid (pH1.2) after 60� C and RH 75% in 10 days. However, HPMC capsules did not change the disintegration time under the same condition.1 The second example is ascorbic acid. After the hard gelatin capsules, which were filled with ascorbic acid, were stored under the condition of 40� C and RH 75% for 2 months, the capsules that were formerly white turned brown. HPMC capsules, however, did not change color.1

Gas Permeability Through QUALI-V
Figure 3 shows the data of water vapor permeability through both gelatin and HPMC films. Calcium chloride was placed in a cup, and the cup was sealed with the films and kept under the condition of 92% RH and 25� C. The weight of calcium chloride increased linearly against time. The permeability rate of water vapor through the gelatin and the HPMC film was 446 and 263 g/m2/24hr, respectively, indicating water vapor permeated more rapidly through the gelatin film than the HPMC film.2

The structure of the HPMC film is looser than that of the gelatin film from the result of the SEM observation of those sections. Oxygen permeability relates to the looseness of film. Because of this oxygen permeability when oxygen-sensitive products are filled in the HPMC capsule, either an anti-oxidant should be formulated with the dosage or the filled capsule should be packaged as to minimize the oxygen permeation (eg, blister package with aluminum foil). The fundamental information of QUALI-V is shown in Table 2 compared with gelatin capsules.

Dissolution Profiles of QUALI-V
Figures 4 and 5 show the dissolution profiles of model drugs (acetaminophen and pyridoxine hydrochloride) from QUALI-V.3 The capsules filled with model drugs were stored under three conditions; 30� C and RH 60%, 40� C and RH 75%, and 60� C. The dissolution profiles of both drugs did not change even after the capsules were stored under any conditions. Under the same conditions, when these drugs were filled into the gelatin capsules, the dissolution profiles changed and were prolonged except for 30� C and RH 60% (Figures 6 and 7).3

However, the dissolution profiles of all HPMC capsules are not the same. This means that the different manufacturers have different dissolution profiles of HPMC capsules. Because a hard capsule cannot be manufactured from the dipping method with single HPMC, a gelling agent is added to HPMC. The solubility of gelling agents is influenced by several ions. The solubility of carrageenan, which is selected as a gelling agent for QUALI-V, is influenced by potassium and calcium ions. Therefore, the dissolution profiles of QUALI-V can be controlled minutely by adjusting the thickness of capsule shell and so on.4-6 As a result, the dissolution profiles of QUALI-V are hardly influenced by the dissolution test fluids.

Liquid and Semi-Solid Filling Into QAULI-V
QUALI-V can be filled with many liquid and semi-solid ingredients in addition to powders or granules. The stability data of both QUALI-V and the gelatin capsules are shown in Table 3 when both capsules were filled with several liquid or semi-solid excipients. In Table 3, one excipient was filled into QUALI-V or the gelatin capsule, and the cosmetic appearance and the brittleness were observed and tested after the capsules were stored at 45� C for 1 month. The gelatin capsules were easily broken after the storage. The suggested reason is as follows: the moisture content in the capsule shell decreased by the preservation condition and/or the excipients, therefore the capsules were easily broken as shown in Figure 2. The moisture content in QUALI-V also decreased but QUALI-V hardly was broken even at the low moisture content.7

Shionogi is currently investigating more data about QUALI-V filled with liquid and semi-solid excipients, and will hereafter indicate the information and data to help the dosage form design.

CONCLUSION

    The features of QUALI-V are summarized in Tables 1 and 3, indicating the following:

  • Low moisture content
  • Low water vapor permeability
  • Low static electricity
  • High tolerance to temperature
  • Chemical inactivity and solubility at room temperature.

Additionally, the capsule dosage forms, which are designed by QUALI-V, are able to be evaluated by a conventional accelerated stability test; 40� C and RH 75% for 6 months. Moreover, many liquid and/or semi-solid ingredients besides solid can be filled into QUALI-V, and it is offered from size 00 to 9 (for rats). Therefore, these advantages minimize the problem of dosage designer's scale-up and the issue of the bioequivalent studies.

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REFERENCES

  1. Ogura T, Furuya Y, Matuura S. HPMC capsules: an alternative to gelatin. Pharm Tech Europe. 1998;10(11):32-42.
  2. Nagata S. Cellulose capsules - an alternative to gelatin. In: Chiellini E, Sunamoto J, Migliaresi C, Ottenbrite RM, Cohn D, eds. Biomedical Polymers and Polymer Therapeutics. New York, New York: Kluwer Academic/Plenum Publishers; 2001;53-62.
  3. Nagata S, Tochio S, Sakuma S, Suzuki Y. Dissolution profiles of drugs filled into HPMC capsule and gelatin capsule. Abstract presented at: AAPS Annual Meeting in Denver; 2001;W4196.
  4. US Patent No. 5264223. Hard capsule for pharmaceutical drugs and method for producing the same. November 23, 1999.
  5. U.S Patent No. 543917. Hard capsule for pharmaceutical drugs and method for producing the same. July 11, 1995.
  6. US Patent No. 5756123. Capsule shell. May 26, 1998.
  7. Nagata S, Nishi N, Matsuura S. Characteristics of HPMC capsules. Abstract 161 (Scientific to Regulatory Approaches) presented at: International Symposium on Strategies for Optimizing Oral Drug Delivery in Kobe; April 19-21, 1999;161.

BIOGRAPHY

Dr. Shunji Nagata, PhD, is head of both Research & Development and Corporate Quality Assurance for Shionogi Qualicaps' Japanese division, located in Osaka, Japan. Dr. Nagata is responsible for the research and development of hard capsule products in addition to a product line of edible inks. He studied oral dosage form design and drug delivery systems while employed by the pharmaceutical parent company"”Shionogi & Co, Ltd. He has published more than 20 research articles and written chapters of several scientific books. Dr. Nagata earned his PhD from the University of Tokyo, where his thesis focused on The Activity of the Conjugation Between Anti-Cancer Drug and Antibody Against Human Hepatoma.

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