MODIFIED RELEASE

CAPSULES

Presented By: HIREN PATEL

M.Pharm, Sem -II
APMCCPER, Himatnagar
09586017050
 LIST OF CONTENTS
 Introduction
 Innovation Related To Capsule Shell
• HPMC Capsule
• Starch Capsule
• PVA Capsule
• Chitosan Capsule
• Cross linked Dextran Capsule
 Innovations In Capsule Fill Material
 Innovation In Capsule System
• Pulsincap
• Hydrophilic Sandwich (Hs) Capsule
• L-Oros System
• Port System
• Targeting Lymphatic Delivery
• Fast Disintegrating Capsules
 References
 Introduction
• Capsules are dosage forms in which unit doses of
powder, semisolid, or liquid drugs are enclosed
within either a hard or a soft envelope or shell.
• Administration route of capsules: orally (whole or
mixed with food or drink after opening capsules)
• In early 19th century, Mothes developed the first
capsule dosage form from gelatin.
• Since then this technology has been continuously
improved and refined in terms of capsule shell,
formulation and system, yielding range of capsule
forms available today
 Innovation related to capsule
shell(Alternatives to gelatin)
Ideal requirements for gelatin alternatives
includes:
• Good film forming property
• Fast dissolution in biological fluid at 37º C
• Good gelation property so that a capsule film
can be cast or dipped, hence enabling
existing capsule machinery to be used
• Low toxicity
1. Hydroxy Propyl Methyl Cellulose (Hpmc)
 Cross linking:
• HPMC hard capsules avoid the issues of gelatin cross linking and product vulnerability to aldehydes
 Moisture content:
• HPMC hard capsules (Quali-V®) have low moisture content
• Hard gelatin capsule breaks easily when moisture drops below 10% where as HPMC hard capsule
does not crack even with 1% or less in moisture content.
 Water vapour permeability:
• Water vapor permeated more rapidly through gelatin film than HPMC film.
 Dissolution:
• Dissolution profile of HPMC hard capsule with model drugs did not change even after capsules
were stored under different conditions of temperature and humidity i.e. 30ºC and 60% RH (for 1
year), 40ºC and 75% RH (for 6 months) and 60ºC (for 1 week). While, under similar conditions
when the drugs were filled into gelatin capsules the dissolution profile changed and were prolonged
except for 30ºC and 60% RH
 Liquid filling:
• Nonaqueous fill material can be filled into HPMC hard capsule provided they do not soften the shell
 Advantages:
• High commercial supply
• Capability of being processed on commonly available equipment
 Disadvantages:
• High cost
 2. Starch
 Moisture content:
 Moisture content in starch capsules lies between 12% to 14% w/w, with more than 50% being
tightly bound to starch. The presence of this bound moisture indicates that starch capsules may
provide better stability properties and reduced susceptibility to changes on storage. 
 Dissolution:
 Similar to that of gelatin capsules
 Advantages:
 Ready for filling immediately following manufacturing
 Offer greater resistance to humidity and heat than gelatin and allow easy filling as they are
non-static
 Dissolution is independent of pH
 Good surface finish
 Coating of hard gelatin capsule with aqueous spray formulations can lead to softening of
gelatin shell or gelatin shell may become brittle due to water evaporation and drying,
especially at the onset of coating. On the contrary, the coating of starch capsules seems to be
less problematic because of smooth seal of the filled unit, together with the higher bulk
density of the capsules, which provide a more uniform coating bed.
 TARGIT™ technology based on the application of pH-sensitive coatings onto injection-
molded starch capsules is especially designed for site-specific delivery of drugs in the
gastrointestinal (GI) track (colon)
 3. Polyvinyl alcohol(PVA) copolymer
 Advantages of PVA capsule:
• No animal derived material
• Low water content
• Low electrostatic propensity
• Very low oxygen permeability
• Ability to tolerate macrogol 400
• PVA copolymer does not have chemically active groups such as
those in gelatin and it is more tolerable to various agents than
gelatin and HPMC
4. Chitosan:
Used for colon targeting as chitosan is biodegrable in colon
 
 
5. Crosslinked dextran:
Promising candidate for colon specific drug delivery system
 Innovations in capsule fill material
• Previously active ingredients were formulated
into capsule in form of powder or granules for
immediate or modified release. But however now
a day along with them pellets, minitablets, liquids,
semisolids, etc can be filled into capsule. This is
heavily because of innovation in filling machines.
• Formulation considerations to be taken into mind
while formulating pellets as fill material includes
dose and type of release required
 Table 1: Patented formulation of Pellet as a fill material for hard capsule

Drug Type of pellet Ingredients used Uses of each

capsulated ingredient
Rosiglitazone Maleate Rapid release pellet Dibasic calcium Filler
and Metformin phosphate dihydrate
Hydrochloride Polyvinyl pyrrolidone Binder
Sodium Starch Super disintegrant
Glycolate
Magnesium Stearate Lubricant
Alprazolam Sustain release Microcrystalline Filler
pellets cellulose
Polyvinyl pyrrolidone Binder
SURELEASE Sustain release
polymer
Nifedipine Controlled release Hydroxy propyl Binder
pellet methyl cellulose E-
6
30 D Control release
polymer
Calcium stearate Antifoam
suspension
Bupropion Enteric coated Talc Antiadherant
controlled release
pellet
• While formulating tablets as a fill material for
hard capsule important points to be considered
includes size of the tablet and type of the release
required.
• Size of the tablet should be such that it can be
easily filled into capsule.
• If the dose is high, then more than one minitablets
can be filled into capsule.
• The same approach can be used to deliver first
loading dose followed by maintenance dose by
minitablet.
• Different types of tablets (Immediate or modified
release) can be filled into hard capsule to get
desired release
 Table 2: Patented formulation of Minitablet as a fill material for hard capsule

Drug Type of tablet Ingredients used Uses of each

capsulated ingredient
Riboflavin Controlled release Aluminium oxide Weighting agent
minitablet Microcrystalline cellulose Filler, binder
Polyvinyl pyrrolidone Binder
Magnesium stearate Lubricant
Ethyl cellulose or Eudragit RS Controlled release
polymer
Progestrone Sustain release Sodium CMC Osmopolymer
osmotic
Sodium chloride Osmagents
minitablet
Hydroxy proply methyl Binder
cellulose in water
Ferric oxide Colorant
Magnesium stearate Lubricant
Lansoprazole Enteric coated Lactose Filler
minitablets
Hydroxy propyl methyl Binder
cellulose E- 5LV
Sodium starch glycolate Super disintegrant
Magnesium stearate Lubricant
Eudragit L30D 55 Enteric polymer
Triethyl citrate Plasticizer used in
coating solution
Purified water Coating solvent
 • It has been found that stable preparations could be made from
liquids and deliquescent materials by preparing them as a semi-
solid matrix in commercially available excipients.
• Sustained release formulations have been prepared by using
excipients that influences the hydrophilic-lipophilic balance
(HLB) of the semisolid matrices.
• A principal constraint of such formulation is the interaction of
certain excipients and/or water with gelatin.
• The choice of excipient is made in relation to capsule shell
integrity
Table 3 : Example of thixotropic gel filled into hard capsule

Formulation ingredients Uses

Propantheline bromide Active ingredient
Miglyol 829 Liquid excipients
Aerosil 200 Gel forming agent
Table 4: Patented formulation of miscellaneous material that can be filled into hard
capsule

Drug Type of material Ingredients used Uses of each

capsulated ingredient
Propranolol Beads Sugar spheres
hydrochloride Polyvinylpyrrolidone Binder
Ethyl cellulose Release rate
controlling polymer
Hydroxy Propyl Enteric polymer
Methyl Cellulose
Phthalate
Diethyl phthalate Plasticizer used in
coating solution
Acetone/water Coating solvent
Tolterodine L- Controlled release Sugar spheres
tartrate beads Surelease Release rate
controlling polymer
Hypromellose Release rate
controlling polymer
Fractionated coconut Plasticizer used in
oil coating solution
Water Coating solvent
 Innovation in capsule system

A: Pulsincap
• Used for pulsatile drug delivery
• Three main approaches have been tried for it
• In general pulsincap consist of insoluble
capsule body and a soluble capsule cap
First approach:
• Based on separation of a plug from an insoluble capsule body
• Consists of a water permeable body prepared from a water-
swellable hydrogel i.e. crosslinked Polyethylene glycol (PEG)
• In cavity of capsule body, mixture of drug and a swelling
agent is placed.
• Internal cavity is then sealed by a plug.
• Upon oral administration by patient, cap dissolves. Water
diffuses through capsule body. Swelling causes plug to move
in upward direction causing drug release.
• Water diffusion into the core through semi permeable
membrane is controlled by: Plug

– Hydrogel composition and

Water Permeable Body Drug Formulation
– Wall thickness of the capsule
(Crosslinked PEG hydrogel)
Swelling Agent
Second approach:
 Here only difference to first approach is that capsule body is made
of gelatin coated with ethyl cellulose.
 In presence of fluid the plug swelled at a controlled rate and this
swelling is independent of the nature of pH of the fluid.
 As the plug swells it attains frustroconial shape and it gets slowly
pulled out of the capsule
 Pulse time is controlled by:
• The length of the plug and
• Insertion distance of plug
into the capsule
 Third approach:
• Here in this approach in place of hydrogel
plug, simple erodible compressed tablet is
placed.
• This overcomes the need for the precise
dimensional tolerance between capsule and
plug for sliding mechanism of the plug
B: Hydrophilic Sandwich (Hs) Capsule

• Capsule within capsule

• Between 2 capsules there is layer of HPMC
(hydrophilic polymer) creating hydrophilic
sandwich between 2 gelatin capsules.
• Upon oral administration, outer capsule dissolves
into the fluid. This exposes HPMC which forms
gel (barrier layer). This barrier layer provides
desired lag time for fluid to enter into second
capsule and causing 2 lot of drug release.
• Molecular weight and concentration of polymer
(HPMC) decides lag time
C: L-OROS system
• Developed by ALZA corporation for liquid drug formulation,
especially for drug’s with low solubility leading to low
bioavailability
• 3 types are available
1. L-OROS Hard cap
2. L-OROS Soft cap
3. Delayed liquid bolus delivery system 
• Basically L-OROS system consists of liquid drug, an osmotic engine
or push layer and a semi permeable membrane coating.
• Water passes through the semi permeable membrane, expands the
osmotic engine which is turn pushes the drug layer releasing the
drug through a delivery orifice into the GI tract.
• The duration and rate of drug release are controlled by the
composition of the membrane.
1. L-OROS Hard cap:
• The drug layer and the osmotic engine are encased in hard capsule which
is surrounded by the rate controlling semi permeable membrane.
• A barrier layer composed of an inert substance separates the drug layer
from the osmotic engine
• A delivery orifice is laser drilled at the opposite end of the osmotic
engine providing an outlet for the drug
L-OROS
HARDCAP System

Before Ingestion During Release

Semi permeable membrane

Push layer
Barrier layer
Liquid drug formulation
 2. L-OROS soft cap:
• The liquid drug formulation is encased in soft capsule. It is
in turn surrounded by a barrier layer, osmotic engine, and a
semi permeable membrane in order
• A delivery orifice in drilled through semi permeable
membrane, osmotic engine, and barrier layer
• When the osmotic engine expands it compresses the soft
capsule and the drug formulation is pushed out through the
delivery orifice

L-OROS SOFTCAP
System Rate controlling membrane
Osmotic layer
Barrier layer
Soft gelatin capsule
Liquid drug formulation
Before Ingestion During Release
Delivery orifice
3. Delayed liquid bolus delivery system:
• Delivers the pulse of the liquid drug.
• The system consists of placebo delay layer, a liquid drug layer, an
osmotic engine all encased by a sub coat and then surrounded by semi
permeable membrane.
• The delivery orifice is drilled on the placebo layer of the system
• When the osmotic engine expands, the placebo is released first delaying
the drug release
• Delay in drug release can be from 1-10 hours depending on the
permeability of the rate controlling membrane and the size of the placebo
layer.

Semi permeable membrane

Sub coat
Delay layer
Liquid drug formulation
Osmotic layer
Delivery orifice

Delayed Liquid Bolus System

D: Port system
• Here capsule body made up of HPMC or gelatin is
divided into two compartments by non swelling
slidable separator.
• The entire capsule body is encased by semi permeable
membrane.
• One or both compartment contain drug and the lower
compartment below the separator contains water
soluble excipients
• When the water diffuses through semi permeable
membrane, the water soluble excipients contained in
the capsule body are solubilized, creating the osmotic
pressure gradient PORT
SYSTEM
• Under the influence of osmotic pressure gradient, the
slidable separator start moving outside the capsule and
starts releasing the initial dose
• At predesigned time, the separator completely slides
out of the capsule body and the delayed dose is then
released.
E: Targeting Lymphatic delivery

• Developed by Encap Drug Delivery Ltd

• Aim behind the development of capsule targeting
the lymphatic system is to improve the absorption
of low-solubility/lipophilic compounds through
lymphatic absorption
• Capsule contains micro emulsion or self
emulsifying system for improving solubility.
F: Fast disintegrating capsules

• Novel capsule which disintegrates within 30-45

second (in vitro) and 9-13 seconds in vivo
• Disintegrates fast (twice) than regular hard gelatin
capsule
• For fast disintegrating capsule low bloom strength
gelatin is used as shell material
• The disintegration time of films can be decreased
further by the addition of sugars or PEGs
 REFERENCES
• Podczeck F. and Jones B.; Pharmaceutical Capsules; Second edition; Chapter 3- Gelatin alternatives
and additives: 61 - 63.
• Encyclopedia Of Pharmaceutical Technology.
• http://www.in-pharmatechnologist.com/news-by-product/news.asp?id=62545&k=stanelco-develops-
alternative
• http://www.samedanltd.com/members/archives/PMPS/Summer2002/WilliamBowtle.htm
• http://www.qualicaps.com/
• http://www.capsugel.com/
• http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=30
• http://www.ffnmag.com/NH/ASP/strArticleID/579/strSite/FFNSite/articleDisplay.asp
• http://www.lsbu.ac.uk/water/hysta.html
• http://www.ashley-pub.com/doi/abs/10.1517/17425247.2.1.159
• U.S patent number 4,609,675 : Stable, high dose, high bulk density ibuprofen granulations for tablet
and capsule manufacturing
• U.S patent number 6,258,816 : Anti-allergy anti-inflammatory composition
• U.S patent number 20050136127 : Gastrointestinal compositions
• U.S patent number 6,767,555 : Pharmaceutical compositions
• U.S patent number 5,948,436 : Pharmaceutical composition
• U.S patent number 6,110,493 : Terazosin capsules