J Pharm Pharmaceut Sci (www.cspsCanada.org) 13(3) 428 - 442, 2010
`
`
`
`HPMC Capsules: Current Status and Future Prospects
`
`Moawia M. Al-Tabakha
`
`College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, U.A.E.
`
`Received, July 13, 2010; Revised, September 20, 2010; Accepted, October 11, 2010; October 13, 2010
`
`ABSTRACT Hydroxypropyl methylcellulose (HPMC) is employed for a wide variety of pharmaceutical and
`food preparations. Its applications as viscolizing agent (thickening agent), coating polymer, bioadhesive, in solid
`dispersion to enhance solubility, binder in the process of granulation and in modified release formulations have
`been well documented. One other notable use is in the production of capsule shells, replacing the animal derived
`gelatin in conventional two-piece capsules. The aim of this review is to systemically survey published literature
`on the HPMC use in capsule shells and resolve questions regarding their suitability as a replacement for hard
`gelatin capsules. Future refinements in the production and filling of HPMC capsule shells and improvement in
`their in vivo/in vitro dissolution would ensure their superiority over hard gelatin capsules.
`__________________________________________________________________________________________
`
`INTRODUCTION
`
`(HPMC), now
`Hydroxypropyl methylcellulose
`commonly known as hypromellose, is produced by
`synthetic modification of the naturally occurring
`polymer cellulose and is considered safe for normal
`consumption in humans (1). The material have been
`used and experimented as viscolizing agent i.e.
`thickening agent (2,3), in controlled release systems
`(4) and as a coating polymer (5), as a bioadhesive
`(6), in solid dispersion to enhance drug solubility
`(7) and as a binder (8). In the USP30-NF25 (9), the
`excipient is listed under coating agent, suspending
`and/or viscosity-increasing agent and tablet binder.
`The material is described as a white to slightly off-
`white powder or granules, hygroscopic after drying,
`practically insoluble in hot water, in acetone, in
`dehydrated ethanol and in chloroform, but dissolves
`in cold water giving a colloidal solution owing to
`the reversible thermal gelation property. HPMC is
`available in different substitution type with limits
`on methoxy and hydroxypropoxy groups. These
`groups influence many of the HPMC properties
`such as gelation temperature, viscosity, flexibility
`and hydration (10).
`In addition to the listed excipient categories,
`HPMC polymer is now used as shell material for
`capsules (11). The origin of the word capsule comes
`from the Latin capsula, which means a small box
`(12). Pharmaceutically, capsules are either hard
`(two-piece) or soft (one-piece) and are used to
`encapsulate pharmaceutical formulations (13). The
`two-piece capsule is made of a cap-piece that slips
`
`over one side open body-piece forming closed
`cylindrical object (14). Capsules may offer better
`solid dosage form to tablets for drugs with low
`compressibility, slow dissolution and bitter tasting.
`They are also used in clinical studies for blinding
`purpose. The administration of the capsules is
`usually orally, but capsules for inhalation (15) such
`as Spiriva HandiHaler
`(Boehringer
`Ingelheim
`International GmbH), vaginal (16) such as Gyno-
`Daktarin (Janssen-Cilag) and rectal administrations
`(17) are all possible.
`Despite the fact that most of pharmaceutical
`capsules available in market are made of gelatin,
`several HPMC capsules for powdered herbs and
`dietary supplements have been available in recent
`years. Many investigational new drugs with HPMC
`encapsulation are in clinical trials (18). HPMC
`capsules may offer attractive alternative to gelatin
`capsules because of its vegetable source. The cross-
`linking of gelatin and drug incompatibilities and the
`strict regulations regarding the use of animal
`derived gelatin requiring the absence of bovine
`spongiform encephalopathy (BSE)/ transmissible
`spongiform encephalopathy (TSE) have encouraged
`the search for gelatin replacement. Religious,
`cultural and personal issues may affect patients’
`preference towards the medications presented in
`capsule dosage forms.
`
`_________________________________________
`
`Corresponding Author: Dr. Moawia Al-Tabakha, College of
`Pharmacy, Al Ain University of Science and Technology, Al-
`Ain, U.A.E, Email: sphmaa@hotmail.com
`
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`Vegetarians for example are becoming increasingly
`aware of the capsule shell materials which also
`encouraged the companies to search for alternatives.
`As a result, the first vegetable capsules with the
`trademark Vegicaps made of HPMC were produced
`in 1989 by G S Technologies Inc. (now R.P.
`Scherer Technologies ownership).
`The first patent registered for gelatin capsule
`alternative was in 1950 by H W Murphy of Eli Lilly
`and Company for methyl cellulose which did not
`in vivo
`last
`long
`in
`the market because of
`disintegration delay. Several attempts were made
`later to improve disintegration notably by Dow
`Chemical Company and included the use of HPMC.
`The production of HPMC capsules are by thermal
`gelation and a gelling system used to lower thermal
`gelation temperature of HPMC (19). The production
`technique remains similar to that of hard gelatin
`capsules and involves the use of pins dipping into
`HPMC solution, although the machinery may
`require some modifications such as the use of
`heated pins. The HPMC capsules patented are not
`all the same and differ mainly in whether a gelling
`system is used and in the type of gelling system.
`Therefore, there are different types of HPMC
`capsules which may have different in vitro and in
`vivo performances among
`themselves and
`in
`comparison to hard gelatin capsules.
`Since the introduction of HPMC capsules of
`different kinds is recent and because these shells in
`pharmaceutical preparations have not acquired full
`potential, it is necessary to systemically analyze the
`published literature in terms of their manufacture, in
`vitro and in vivo performances and to compare them
`with the hard gelatin capsules. This will help
`
`
`
`pharmaceutical companies to decide on whether to
`adventure into using HPMC capsules for their new
`formulations or use conventional capsules that have
`enjoyed long successful history.
`Searching in the published literature were by
`using Google
`(web, scholar and books) at
`www.google.com, United States Patent
`and
`Trademark Office website (www.uspto.gov) and the
`European Patent Office (www.epo.org). The main
`search was
`conducted
`using Pubmed
`at
`http://www.ncbi.nlm.nih.gov/pubmed which utilizes
`Medline. The later comprises the major component
`of Pubmed. Searching were made using the terms
`“HPMC capsule”, “hydroxypropyl methylcellulose
`capsule’,
`“hypromellose
`capsule”,
`“cellulose
`capsule”,
`“vegetable
`capsule”,
`“non-animal
`capsule” and “hard gelatin capsule”. The vast
`results were filtered by title to include relevant
`information for the purpose of this review with
`focus on publications over the last 10 years.
`
`Hard Capsules Production Issues
`
`HPMC Capsules Manufacture and Types
`Information regarding the empty HPMC capsules
`and their manufacturer are listed in table 1. The
`results from
`the search were filtered
`to use
`information regarding the two-piece capsules (hard
`capsules) only, since there are the soft capsules such
`as Vegicaps Soft (Catalent Pharma Solutions),
`HPMC based soft capsules, which are available as
`alternative to soft gelatin capsules.
`are
`capsules
`Hard gelatin
`and HPMC
`manufactured using similar equipments developed
`by Eli Lilly (20).
`
`Table 1. Information on the empty HPMC capsules and their manufacturers.
`Capsule Shell Brand Name
`Manufacturer
`Registered Year in USA
`Quali-V
`Shionogi Qualicaps
`July, 2002
`Vcaps Plus
`Capsugel (A division of Pfizer)
`-
`Vcaps
`Capsugel (A division of Pfizer)
`April, 2003
`VegiCaps
`G S Technologies Inc. (now R.P.
`May, 1989
`Scherer Technologies ownership)
`Suheung Capsule Co., Ltd
`Baotou Capstech Co., Ltd
`
`Embo Caps -Vg
`Capstech’s HPMC Capsule
`
`-
`-
`
`Gelling Aid
`Carrageenan
`None
`Gellan gum
`None
`
`Pectin and glycerin
`None
`
`Natural Plant Capsule
`
`Zhejiang LinFeng Capsules Co. Ltd.
`
`-
`
`Carrageenan
`
`
`
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`In hard gelatin capsule manufacturing, pins (molds
`for making the capsules) at 22°C are dipped in a dip
`pan or pot that holds a fixed quantity of gelatin at a
`constant temperature, between 45° and 55°C. The
`level of solution is maintained automatically by a
`feed from the holding hopper. Once the molds are
`dipped a film will be formed on them by gelling
`since they are at lower temperature. The slowly
`withdrawn pins from the dipping pan are rotated to
`maintain uniform film thickness, where they are
`passed through a series of drying kilns at controlled
`temperature and humidity. The dried films (shells)
`are stripped of the pins, cut to the correct length and
`the two pieces (cap and body) are joined together.
`The pins are then cleaned and lubricated to start the
`next cycle.
`The manufacture of HPMC based capsules
`necessitates some modification to the molding
`machine or to the formulation of the shell materials.
`HPMC gelling from solution occurs when the
`temperature is raised while it is converted to its
`original solution as the temperature is lowered,
`unlike gelatin solution. This means that the pins
`immersed in the dip pan containing the HPMC
`solution must be of higher temperature (70°C) in
`order for
`the film
`to be formed. To avoid
`liquefaction of the films formed on the pins, the
`temperature of the pins must be further maintained
`post-dip to facilitate gelation until the films dry out
`in the kilns (21-24).
`Because HPMC shell walls are much weaker
`than gelatin made shells, removal of the capsule
`from the pins and subsequent handling and filling
`are in jeopardy. To overcome these problems, three
`approaches were adapted. These approaches were to
`use a stripper jaw with depressions on the inner
`surface, increase the formed HPMC film thickness
`and the use of gelling agents. The following gelling
`agents were
`experimented:
`tamarind
`seed
`polysaccharide, carrageenan, pectin, curdlan, gellan
`gum and furcellaran.
`U.S. Pat. Nos. 5,264,223 and 5,431,917
`registered for Yamamoto et al. (25,26) of Japan
`Elanco Company, Ltd. (Osaka, JP) claiming that
`capsules can be produced by the use of HPMC with
`the gelatinizing agent
`such as carrageenan
`(HPMCcarr) and auxiliary for gelation is a water-
`soluble compound containing potassium ion. The
`production of such capsules were claimed to occur
`under similar temperature setting as that of gelatin
`capsules. Shionogi Qualicaps Co. (Japan) was able
`
`to produce HPMCcarr capsule using the standard
`machinery for the hard gelatin capsule by using
`HPMC gelling system containing carrageenan as a
`gelling aid (kappa- and iota- carrageenans are
`preferred) and potassium chloride as gelation
`promoter. The company has a Quali-V registered
`trademark. European patent EP0592130 claims that
`HPMC with higher whiteness, lower equilibrium
`moisture content and better film properties and
`compatibility with drugs could be produced by
`exposing the materials to ultraviolet light in the
`wavelength range of at least 200 nm (27). The claim
`indicates that at the wavelength 253.7 nm, the
`preferred conditions for ultraviolet radiation are a
`spacing of about 10 cm for about 10 hours.
`Yang (28) of Suheung Capsule Co., Ltd., a
`Korean based company, had patented cellulose
`capsules using mixed solution of pectin and
`glycerin. The steps involved in the manufacture are
`to add the mixed solution of pectin and glycerin to
`the HPMC solution followed by the addition of
`small amount of glacial acetic acid, calcium
`gluconate, and sucrose fatty acid ester.
`An invention of Warner-Lambert Company
`(now with Capsugel that later became part of
`Pfizer) (29) have documented the preparation of
`HPMC capsules with hydrocolloids such as gellan
`gum (HPMCgell) and sequestering agents (such as
`ethylenediaminetetraacetic acid, sodium citrate,
`citric acid and their combinations). Gellan gum is a
`water-soluble polysaccharide produced by
`the
`bacteria Sphingomonas elodea. 5% of the capsule
`shell materials comprised of approximately equal
`proportions of both the hydrocolloid and the
`sequestering agent. The claim shows that these
`capsules would have films that are less brittle
`(unlike those produced with carrageenans), no poor
`disintegration in vivo and the film transparency is
`retained.
`the
`that most of
`It
`is worth mentioning
`companies producing HPMC capsules such as
`Capsugel of Pfizer and Shionogi Qualicaps are also
`producing the standard gelatin capsules.
`
`Marketed Products
`The HPMC capsule shells have found popularity for
`their use with nutraceuticals and over-the-counter
`(OTC) formulations. Using Google web search,
`many nutritional products were found. Only few
`examples of those with sufficient information
`obtained are given in table 2.
`
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`Table 2. Some examples of products formulated in HPMC capsules and their manufacturers.
`Product
`Nature of the Formulation
`Pure powdered herbs (Damiana turnera aphrodisiaca)
`Damiana Herb 300mg
`Thera Veda’s Ajay- Allergy
`Vegetable extracts and powders
`Support Formula
`Natren Life Start 2
`Coloclear (in VegiCap)
`Jarro-Dophilus EPS
`Culturelle HS Capsules
`
`Bacteria, vitamin C, potato powders and whole goat milk
`Flax seeds, slippery elm and other herbs
`8 probiotic species and ascorbic acid
`80 mg lactobacillus GG (L. rhamnosus GG) Vegetarian
`Formula
`Bifidobacterium infantis
`
`Manufacturing Company
`Bio-Health Ltd., UK
`Organix South, USA
`
`NATREN, Inc., USA
`Higher Nature Ltd., UK
`Jarrow Formulas, USA
`Kirkman Labs, USA
`
`Procter and Gamble, USA
`
`Sportlegs, USA
`Planetary Herbals, USA
`
`Progressive Labs, USA
`
`Align Daily Probiotic
`Supplement Capsules
`Sportlegs Supplement
`Planetary Herbals Cinnamon
`Extract
`
`Ex-Tox II
`
`
`Capsule Size Information
`HPMC capsules are available in similar physical
`dimensions of sizes and shell weights as that of hard
`gelatin capsules. Gelatin capsules are the main
`stream
`in
`the production
`for most capsule
`manufacturing companies and because
`their
`production has been standardized over long period,
`they are available in wider range of sizes. For
`example Capsugel company (division of Pfizer)
`produces Coni-Snap hard gelatin capsules in the
`standard sizes from 000 to 5 with elongated sizes
`(have capacities approximately 10% more than the
`standard ones) for capsules 00, 0, 1 and 2, while the
`same company produces Vcaps Plus HPMC
`capsules with sizes from 00 to 4 with elongated
`capsules for size 0. Quali-V capsules are available
`in sizes from size 0 to 4 with elongated size 0 only
`and the empty shells weights varied by ± 10%
`according to the Qualicaps Group company website,
`but not exceeding 8% for Vcaps Plus according to
`the Capsugel company website. If the variations in
`the capsule shell weights are large, this may result
`in several filled capsules being rejected from the
`batch during weight sorting, even though the filled
`weights are accurate.
`The cross sectional part of the capsule joints has
`been evaluated under electron microscope for three
`types of capsule shells (18). The examination
`intended to measure the maximum observed gap
`between the body and the cap. It was found that the
`largest maximum gap is for Quali-V capsules
`(132.14 μm), while Vcaps Plus capsules showed
`slightly larger gap than that of hard gelatin capsules
`
`
`
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`
`Vitamin D, calcium and magnesium
`Cinnamomum aromaticum 300 mg,
`bark extract 10:1 yielding 8% flavonoids,
`cinnamomum aromaticum bark 100 mg
`Folic acid, cilantro powder (leaf), ethylenediamine tetra-
`acetic acid, N-Acetyl L-cysteine, fulvic (humic) acid, R-
`lipoic acid (K-RALA), L-methionine
`
`Coni-Snap (88.77 and 66.86 μm respectively). The
`benefit of this decrease in gap clearance with Vcaps
`Plus compared to Quali-V meant improvement in
`the powder leakage quality attribute and decrease in
`the rejection rates. It is worth mentioning that this
`was
`reported by
`researchers
`from Capsugel
`Company (division of Pfizer), the producer of
`Vcaps Plus.
`The relationships between wet film dimensions,
`dip sequences, and the physicochemical properties
`of the dip solutions in the manufacture of hard-shell
`capsules were studied (30). In the dipping process
`for making hard-shell HPMC capsules, the effects
`of solution concentration is more important than pin
`temperature. It is however difficult to predict wet
`film thickness in a hot-pin, cold solution dipping
`process.
`
`Mechanical Strength
`In a test examining the effect of humidity on the
`mechanical properties of both HPMC and gelatin
`capsules, it was found that both types of capsules
`softened, especially above 60% of
`relative
`humidity, with gelatin capsules exhibiting
`in
`general higher stiffness and hardness values
`compared to the HPMC capsules (31). In another
`study (32) it was found that at ambient conditions,
`capsules made from gelatin were harder and
`stronger but less elastic compared with HPMC
`counterparts.
`The mechanical stress applied to the empty
`Vcaps Plus HPMC capsules and empty Coni-Snap
`hard gelatin capsules (n=50) were evaluated by
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`dropping 100 g weight from 8 cm height on each
`capsule following storage at different relative
`humidity of approximately 5-65 % for one week
`(18). The resistance to breakage was similar for
`both types of capsules at higher relative humidity
`but at lower humidity the Vcaps Plus capsules were
`less affected compared to Coni-Snap capsules, as
`the later exhibiting an increase in the breakage rates
`because of the loss of water responsible for the hard
`gelatin capsules elasticity. Further tests on the
`capsules to evaluate their machineability under
`different filling machines at various speeds, during
`packaging and transportation were carried out. With
`the different filling machines, the rejection was
`lowest with hard gelatin capsules (Coni-Snap)
`compared to other HPMC capsule types (Vcaps
`Plus and Quali-V) and this was attributed mainly to
`problems in the closing station. The blistering
`process and carding the blisters containing Vcaps
`Plus with placebo powder have shown no visual
`powder
`leaking. While
`the Quali-V capsules
`showed 6% leak rate around the joint of capsule
`body and cap, Vcaps Plus and Coni-Snap showed
`none in a simulated transport test.
`
`
`Effects of Ambient Conditions
`rapid
`for
`The use of capsules as means
`disintegration in the oral cavity was experimented
`(33). One approach was to cause the capsules to
`become brittle in order to brake rapidly in the oral
`cavity by subjecting them to low humidity. While
`this approach was successful for hard gelatin
`capsules, HPMC capsules remained flexible, even
`at low moisture content. Short term stability studies
`(heating at different temperature for 24 hrs) on both
`Vcaps Plus and Coni-Snap found that overall, the
`HPMC shell exhibits a significantly better short
`term stability at high temperature than hard gelatin
`capsules on visual
`test, disintegration and
`dissolution, as well as mechanical property
`assessment (18). When they were stored at different
`relative humidity
`(RH),
`the HPMC capsules
`exhibited lower moisture contents compared to
`gelatin capsules (e.g. 6% and 14% respectively at
`50% RH) that have shown to be more hygroscopic.
`Based on the previous study, the specifications for
`moisture content are 2–7% for the HPMC shell
`corresponding to RH 10–60% and 13–16% for
`gelatin capsules corresponding to storage at RH 35–
`65%. Preliminary results from
`the effect of
`irradiation (beta or gamma) on both HPMC and
`
`gelatin capsules in air indicated their suitability for
`ionizing radiation sterilization (34).
`
`IN VITRO Disintegration and Dissolution
`Because the USP only mentions the testing of
`gelatin capsules, Donauer and Löbenberg (35) have
`called in a min review the USP to specify how to
`carry out
`the disintegration
`test with HPMC
`capsules. That is because the dissolution behaviors
`of HPMC and gelatin capsules have to be different
`in dissolution media. Moreover, HPMC capsules
`are not all the same as they may or may not contain
`a gelling agent and the gelling agents used are not
`all the same.
`The shell dissolution properties of ordinary
`gelatin hard capsules, gelatin/PEG capsules and
`HPMCcarr capsules were compared independent of
`their capsule content (19). Different dissolution
`media and storage conditions were used. The
`capsule shells disintegration/dissolution time was
`determined as the time for enough parts of the
`suspended capsule to dissolve, permitting steel ball
`bearing filled into the capsule to fall free. Capsules
`were placed in media of different temperature
`(between 10º and 55º C) in order to simulate taking
`the capsules with cold, warm or hot drinks. The
`dissolution media in the glass beaker at different
`temperatures were brought back to 37º C with the
`controlled temperature of the surrounding water
`bath. Gelatin
`and
`gelatin/PEG
`capsules
`disintegrated rapidly and faster than the HPMCcarr
`capsules in the different media following storage at
`different conditions when tested at temperature ≥
`37º C. This delay
`in
`the HPMC capsule
`disintegration was especially notable in mixed
`phosphate buffer of pH 6.8. The delay at pH 6.8 is
`inherent for the HPMC shells (36). In water at 37 º
`C following storage at ambient room conditions
`(19±1 °C, 35-40% relative humidity of the air)
`HPMCcarr capsules disintegrated in approximately 4
`minutes whereas gelatin and gelatin/PEG capsules
`disintegrated in approximately 1 minute. Gelatin
`capsules dissolution times are dependent upon
`temperature and generally do not dissolve at
`temperatures below 30
`°C, however,
`their
`dissolution was rapid as temperature increased from
`30° to 55°C suggesting that gelatin capsules are
`better be taken with warm water.
`The influence of the composition of test fluids
`on dissolution from HPMCcarr capsules (Quali-V) in
`comparison to the hard gelatin capsule was studied
`
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`release from HPMCcarr capsules, unlike gelatin
`capsules in which the release was immediate.
`Similar results were obtained when testing the
`dissolution of HPMCgell capsule shells that are filled
`with ibuprofen in comparison to hard gelatin
`capsules at pH 7.2 using potassium phosphate and
`TRIS buffers (42). It was found that the presence of
`K+ cations retards HPMCgell capsule opening with
`the drug dissolution approaching 60% after 60
`minutes compared to approximately 95% at 10
`minutes for hard gelatin capsules. It was also
`reported that for acetaminophen (see Figure 1), the
`release delay was lessened when sodium ions were
`present instead of potassium in phosphate buffer at
`pH 7.2 or in acetate buffer at pH 4.5 and that the
`HPMCgell capsules failed to rupture with very little
`drug release when the medium was acidic (0.1 N
`HCl, pH=1.2). The authors explained the hindrance
`of the HPMCgell capsule dissolution in potassium
`phosphate buffer as due to the monovalent cations
`binding to the surface of individual helices of
`gellan, thus lowering their charge-density and
`reducing the electrostatic barrier to aggregation and
`hence solubility is reduced. They proposed that
`sodium ions do not efficiently bind as potassium
`ions and therefore disruption will be faster.
`They also explained that unlike the sulfate
`groups in carrageenan gelling system, the carboxyl
`groups of gellan gum, have a much higher pKa
`resulting in uncharged (-COOH) form at low pH.
`This elimination of electrostatic repulsion between
`helices makes gellan less soluble at pH 1.2. HPMC
`solubility on the other hand is independent of pH
`(10).
`
`Cross-Linking of the Hard Capsules
`Several studies have shown the detrimental effect of
`cross-linking between gelatin proteins on
`the
`solubility of the gelatin made capsules (18,43-45)
`which may
`affect
`drug’s
`bioavailability.
`Experiments exposing HPMC capsules to similar
`conditions under which hard gelatin
`shells
`undergone cross-linking have indicated the absence
`of such reaction (44). Cross-linking occurs because
`of the chemical interactions between gelatin and
`aldehydes, such as formaldehyde and also when the
`capsules are stored under stressed conditions of
`temperature and humidity. Attempts to reduce
`cross-linking include the modification of excepients
`used with drugs.
`
`
`(37). The results were in agreement with another
`study (19) showing significant retarding effect of
`potassium and/or calcium ions in the dissolution
`medium, while the effect of pH was minimal on the
`acetaminophen (BCS class III) dissolution. Similar
`effects of dissolution media were also documented
`when studying the effects of dissolution medium,
`capsule grade and capsule size on the in vitro
`rupture time of the capsule shells (38). The results
`further indicated that the capsules used whether
`pharmaceutical HPMCcarr capsules, nutritional
`HPMCcarr capsules or gelatin capsules all rupture in
`different times in vitro with gelatin capsules being
`the fastest. Stein and Bindra (39) who used HPMC
`capsules from Shionogi for their formulations found
`that in an acidic pH (0.1 N HCl), the dissolution of
`the capsules
`formulations were
`retarded
`in
`comparison to hard gelatin capsules at earlier times
`and therefore delaying the time of complete drug
`dissolution.
`Size 0 hard HPMC (Shionogi Qualicaps) and
`gelatin (Coni-Snap, Capsugel) capsules were tested
`for ibuprofen (BCS class II) release in tribasic
`sodium phosphate buffer (pH 7.2, 900 ml at 37 °C)
`with formulation containing release modifiers
`(powdered HPMCs grades as diluents). As the
`medium contained no potassium (apparently to
`prevent its influence on the dissolution from HPMC
`capsules), both types of capsules showed similar
`dissolution profiles (40). However, it is apparent
`that such formulations influence their own release,
`irrespective of the capsule shell rupture time,
`therefore not sharp indicative of the capsule rupture
`time in the dissolution medium.
`Honkanen (41) showed that when ibuprofen
`formulation in HPMCcarr capsules tested for drug
`release in a neutral potassium phosphate buffer, it
`was incomplete and highly variable compared with
`the gelatin capsules and attributed this to the
`presence of potassium ions (K+) in the dissolution
`medium that causes the capsule shell to form a
`membrane around the filling. Because the gut
`concentration of potassium is low, she justified the
`change of dissolution medium to neutral tribasic
`sodium phosphate which resulted in complete and
`less variable drug release. In this medium 100% of
`the drug was released for both types of capsule
`within 15-20 minutes, however, there was a lag
`time of approximately 4 minutes before the drug
`
`
`
`
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`433
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`Accord Exhibit 1028
`Page 6 of 15
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`J Pharm Pharmaceut Sci (www.cspsCanada.org) 13(3) 428 - 442, 2010
`
`
`
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`% Acetaminophen Dissolved
`
`15
`
`30
`
`Time (minutes)
`
`45
`
`60
`
`Distilled Water
`0.1 N HCl. pH 1.2
`Na Acetate Buffer, pH 4.5
`Na Phosphate Buffer, pH 7.2
`K Phosphate Buffer, pH 7.2
`TRIS Buffer, pH 7.2
`
`Distilled Water
`0.1 N HCl. pH 1.2
`Na Acetate Buffer, pH 4.5
`Na Phosphate Buffer, pH 7.2
`K Phosphate Buffer, pH 7.2
`TRIS Buffer, pH 7.2
`
`
`Figure 1. The dissolution of acetaminophen from HPMC capsules (dashed lines) and gelatin capsules (continuous lines) in
`different dissolution media (n = 6). Graph generated from Cole et al. published data (42).
`
`
`For example a combination of glycine and citric
`acid in some drug formulations to prevent cross-
`linking in hard gelatin capsules has been used (46).
`PEGs used as a fill material in hard gelatin capsules
`may be responsible for cross-linking of gelatin
`following its oxidation. This has shown to be
`minimized when
`butylated
`hydroxyanisole
`(antioxidant) together with water were used in the
`formulation even when stored at 50 ºC for three
`months (44).
`
`Capsules of Dry Powders for Inhalation
`Capsules were first used for dry powder inhalers 40
`years ago with the introduction of Spinhlaer of
`Fison (now with Sanofi-Aventis) which uses two
`pins to puncture the capsules and deliver cromolyn
`sodium (sodium cromoglycate). HPMC capsules
`were recommended for use in unit-dose inhaler in
`comparison to the hard gelatin capsules, especially
`for hygroscopic materials (47). This is because the
`gelatin capsules have relatively high moisture
`
`content (13-16%) in comparison to 4-6% for HPMC
`capsules; therefore an interaction of the powdered
`materials with the gelatin capsule would retain
`much of the powder adhering to the inner surfaces
`of capsules resulting in much of the dose failing to
`leave the device (48). In fact one of promoting
`strategies for HPMC capsules is their suitability for
`hygroscopic materials.
`Devices such as Spinhlaer, the first marketed
`dry powder inhaler, and Foradil inhaler (Novartis)
`rely on piercing the loaded capsule and withdrawing
`the powdered aerosol by inhalation. The holes
`created by piercing of the capsule were found to be
`different for HPMC and gelatin capsules and
`dependant on the relative humidity (49). In low
`humidity (below 10%) the gelatin capsule shell
`becomes brittle and this could cause the pierced
`parts of the capsule to detach, which may be inhaled
`causing irritation to the throat and lungs.
`
`
`
`
`
`434
`
`Accord Exhibit 1028
`Page 7 of 15
`PGR2023-00043
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`J Pharm Pharmaceut Sci (www.cspsCanada.org) 13(3) 428 - 442, 2010
`
`
`
`Capsule Coating
`Enteric and colonic delivery of HPMC capsules
`were claimed (50) by using coating materials of
`different pH solubility (at 5.5 and above and at 7
`and above
`for enteric and colonic delivery
`respectively). The US patent describes how aqueous
`dispersions of materials such as cellulose acetate
`trimellitiate,
`hydroxypropylmethyl
`cellulose
`phthalate, polyvinyl acetate phthalate, shellac,
`copolymer
`of
`methacrylic
`acid
`and
`methylmethacrylate,
`azopolymers,
`disulphide
`polymers and amylase are sprayed on the filled
`HPMC capsules when placed in Accela-Cota 10 in
`order to achieve targeted delivery.
`To avoid the lengthy and expensive sealing step
`required using the conventional capsule coating
`procedure and to prepare enteric-coated capsules for
`the use in retail or hospital pharmacy or R&D
`sections of pharmaceutical industry, the caps and
`bodies of HPMCgell capsules size 00 (Vcaps,
`Capsugel) were coated separately prior to filling in
`a fluid bed apparatus (GPCG-1, Glatt) with
`Eudragit L30D-55 or Eudragit FS 30 D (Röhm),
`Aqoat AS-HF (Shin-Etsu) and Sureteric (Colorcon),
`using an optimised coating process (51). This has
`resulted in effective protection of drug release from
`the capsules in 0.1 HCl after 2hr.
`The comparison between the coating of gelatin
`capsules and HPMC capsules showed that the later
`coating was straight forward, while gelatin capsules
`were not suitable for direct coating when Eudragit L
`and S 12.5 (acrylic polymers) was used because of
`insufficient film adhesion to the smooth capsule
`surface and the brittleness of formed films (52).
`Because HPMC capsule shell surface is rougher
`compared to gelatin capsules as examined by
`scanning electron microscope, this may provide
`good adhesion to the coating (53).
`
`IN VIVO Evaluation of the Hard Capsules
`
`Oesophageal Sticking Tendency
`Perkins and colleagues (54) have compared the
`oesophageal transit of radiolabelled enteric coated
`tablets with similar sized and shaped gelatin
`capsules when administered with 50 ml of water
`while sitting on two separate occasions, using a
`population of elderly healthy volunteers (n = 23).
`The capsules showed tendency for longer holdups
`in the oesophagus (20.9 s) compared to enteric
`coated tablets (4.3 s).