A Review - Capsule Shell Material From Gelatin to Non Animal Origin

Review Article Bhavisha Rabadiya, IJPRBS, 013; Volue 2!3"# *2$+1

ISS# 22++$-+13 IJPRBS

A REVIEW: CAPSULE SH LL MAT MATERI ERIAL AL FRO FROM M GELA GELATIN TIN TO NO NO ANIMAL ORIGIN MATERIAL

BHAVISHA RABADIYA, PARESH RABADIYA

IJPRBS$%R &'()

Accepted Date:

PAP)R$%R &'()

Abstract

20/02/2013

Capsule is most preferable dosae form. !ill no" elatin is

Publish Date:

"idely "ide ly used as as capsule capsule shell shell material material for th th preparation of the

27/06/2013

Hard Ha rd el elat atin in cap capsu sule le and and sof softt ela elati tin n caps capsule , but due to its

Keywords

anima an imall ori oriin in an and d cro cross ss lin lin#i #in n pr prop oper erty ty ot er suitable capsule

Gelatin,

material that meets the dietary and cultural needs of

Hydroxy propyl methyl

vee ve eta taria rian n patie patient ntss and and also also co comp mply ly "ith the reulatory

cellulose,

re$uirement of elatin need to be invented. Hence various non

Starch,

animal oriin materials are synthesis such as hydroxyl propyl

Pullulan,

methyl cellulose, starch, polyvinyl alcohol opolymer, pullulan

Polyvinyl alcohol

etc. and evaluate evaluate as a capsule shell material material.

copolymer

Corresponding Author Mrs. Bhavisha Rabadiya

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INTRODUCTION

and hence, easy to s"allo" "ith a drauht

!he "ord %Capsule& derived from the 'atin "orld&capsula&, "hich means a small box or container. !he "ord occurs in many scientific disciplines, ranin from anatomy, as an enclosin membrane, and in botany, as

a


descriptive

"ord

for

fruit,

to

astrophysics, as a space vehicle.

of "ater, fe"er aduncts are re$uired and economical. !hey are easy to handle and carry. !he shells can be opacified )"ith titanium dioxide* or colored, to ive protection from liht.

D-'"!"#$"%&' () C"*'+&': !he drus "hich are hyroscopic absorb

(n pharmacy, capsule "ord has been used

"ater from the capsule shell ma#in it

to describe a lass ampule and also as a

fraile and hence are inappropriate for

name of protective cap over the stopper of

fillin into capsules. !he concentrated

a bottle of medicine. (n more recent times,

solutions "hich re$uire previous dilution

capsule has been used primarily to describe

are unsuitable for capsules because if

solid dosae forms, "hich consist of a

administered as such lead to irritation of

container, filled "ith medicinal substance.

the stomach.

!hey

can

be

divided

in

main

t"o

C"*'+& ."#+)"$+-#% '$&*':

cateories,& hard capsule& )t"o piece* and %soft capsule&)one piece* accordin to the presence of lycerol or another plastici+er

R" M"$&-"' )( C"*'+&' !he ra" materials used in the manufacture



"hich ma#e it soft and elastic .

of both hard and soft elatin capsules are similar.

A!"#$"%&' () C"*'+&':

Both

contain

%&"$-#,

"$&,

(("#$' and optional materials such as Capsules mas# the taste and odor of unpleasant

drus

administered.

and

!hey

can

are

be

attracted

in

appearance and shells are physioloically inert

and

$uic#ly

diested

in

*(&'' "-' "# *&'&!"$-!&'

easily

the

astrointestinal tract. -s compared to

A

GELATIN CAPSULE

Material used for the elatin production are Bones, bovine hides and s#in )/iure *. -s 3

noted in 0SP12/

tablets, capsules are slippery "hen moist

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elatin is a product



obtained by the partial hydrolysis of

lysine 8=, serine 8=, leucine @=, valine 3=,

collaen derived from the s#in, "hite

phenylalanine 3=, threonine 3=, (soleucine

connective tissue, and bones of animals.

=, hydroxylysine =, methionine and

!he hydrolysis may be cataly+ed by the

histidine A= and tyrosine A<.9=. !hese

addition of stron acid or base. Gelatin

values

derived from acid4cataly+ed hydrolysis are

constituents, dependin on the source of

referred to as !ype -, and elatin derived

the ra" material and processin techni$ue .

from the base4cataly+ed hydrolysis are referred to as !ype B. !he main difference bet"een elatins derived from these t"o processes is that the elatin derived from the acid4cataly+ed process typically exhibits an isoelectric point )p(* of about 546.

vary,

especially

the

minor

@

Bloom strenth is a measure of the ability of a iven "eiht of elatin to set up in "ater under controlled conditions and is a function of the molecular "eiht of the elatin molecules, the concentration of the elatin in the el, and the pH of the el. (t is

7hereas the p( of elatin obtained from the

a measure of the resultant el&s resistance

base4cataly+ed process is typically 8.519.8.

to compression and is reported in bloom4

!he lo"er p( resultin from the treatment

rams or simply rams. Bloom strenth

"ith base is due to the hydrolysis of the

increases "hen the elatin concentration in

amide roups of Glutamine and asparaine,

the el increases, "hen the averae

creatin lutamic acid and aspartic acid.

molecular "eiht of the elatin increases,

Because of the manufacturin process used,

and "hen the pH of the el approaches

elatin

sini:cant

neutrality )from either direction*. Bloom

polydispersity; !he molecular "eiht of

strenth also can have an effect on the

individual molecules typically ranes from

clarity and color of the li$uid4:lled li $uid4:lled capsules.

9,<<< to 39<,<<<.

Gelatin "ith bloom strenths ranin from

molecules

exhibit

!he approximate amino acid composition of elatin)/iure3* is lycine 3=, Proline 3=, hydroxyproline 3=, lutamic acid <=, alanine 6=, arinine >=, aspartic acid ?=,

9< to @<< is available most elatins used in the manufacture of li$uid4:lled capsules have bloom strenth of approximately 9<1 3<< for soft els and 33<13>< for hard els. Gelatin manufacturers commonly blend

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different sublots of elatin to meet bloom

•

3

re$uirements .


Gel

strenth;

3<<1@<<

Bloom,

dependin on the elatin type

- schematic presentation of the elatin

•

Discosity )?
manufacturin process appears in the

884?< mPa, dependin on the elatin

fiure. 8.

type

1 H" %&"$-# "*'+&:

•

PH 8.9 4?.9

!he maority of capsule products is made of

•

-erobic Plate CountA<<
hard elatin capsules. Hard elatin capsules

11 M&$( () *(+$-(# () &.*$4 "

are made of t"o shells; the capsule body

%&"$-# '&':

and a shorter cap. !he cap fits tihtly over the open end of the capsule body. !he basic

Some of the maor suppliers of empty

hard elatin capsule shells are made from

elatin capsules are; li 'illy and Company,

mixtures of elatin, suar, and "ater. !hey

7arner 'ambert&s Capsuel )formerly Par#

are

avis* and R. P. Scherer Corporation. !he

clear,

colorless,

and

essentially

metal moulds at room temperature are

tasteless.

dipped into a hot elatin solution, "hich !"o4piece capsules have been used for almost a century in the pharmaceutical field, and the elatin has been adopted as the main material of these capsules due to its excellent characteristic as a elatini+er.

els to form a film. !his is dried, cut to lenth, removed from the mouldsand the t"o parts are oined toether, these processes are carried out as a continuous process in lare machines)/iure9*.

Ho"ever, elatin is one of the proteins derived from animals therefore, it is

12

unstable from a chemical vie"point and has

%&"$-# "*'+&

a ris# of !S.

S-5& "# '*&-)-"$-(#

() "

/or human use, empty capsules ranin in

- perfect hard elatin capsule should have

si+e from <<< the larest to 9 the smallest.

the follo"in specifications;

Generally, hard elatin capsule is used to

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encapsulate bet"een ?9 m to  ram

body "hich is slihtly tapered )/iure 5*.

)/iure?*.

!he slihtly tapered body facilitates oinin

2ote; refer to the ?I reference in the text.

on hih speed machines and prevents the problem of telescopin. !elescopin is

13 S"*& () C"*'+&'

slidin of a capsule body )or a capsule cap*

!o prepare capsules easily differentiated from those of other manufacturers, the shape of the capsule end )"hich is usually round* can be altered. Capsules from li 'illy )PulvulesJ* have the body shell "ith a tapered end and the round shaped cap. Capsules from GlaxoSmithKline have both

over another capsule body )or a capsule cap*. !he tapered rim ma#es it more difficult to slide a capsule body over another o"in to the smaller diameter. !he BcapsJ capsule is different from the Coni4 SnapJ capsule in that the upper capsule part )cap* covers most of the lo"er part )body* so that only the rounded ede of the

ends hihly tapered.

body is visible. !he decrease in rippin !o ensure reliable closin of the filled

surface ma#es it impossible to Hard Gelatin

capsules,

loc#in

Capsules hold the body and open "ithout

been

crushin it. !hus, the BcapsJ capsule

prepared .xamples are Posilo#J )Lualicaps,

provides increased security of the contents

a division of Shionoi  Co., 'td.*, Coni4

and the interity of the capsule. /iure >

SnapJ )Capsuel, a division of Pfi+er, (nc.*,

illustrates the differences bet"een ordinary

and 0ni4'oc#J )Cardi4nal Health*. !he t"o

capsules, Coni4SnapJ capsules, and BcapsJ

rooves fit into each other for tiht closin

capsules)/iure>*.

rooves

capsule )or

shells

indentations*

"ith have

and prevent accidental separation )or splittin* of the capsules. Capsules from Capsuel are sold as Snap4/itJ, Coni4SnapJ, and BcapsJ. Snap4/itJ has the concentric loc#in rins on the body and cap "hich prevent reopenin after fillin. !he Coni4 SnapJ capsule, "hich is the improved form of Snap4/itJ, has the rim of the capsule

Some capsules )KapsealJ from Pfi+er, (nc., and LualicapsJ from Shionoi  Co., 'td.* are made tamper4proof and lea# proof. !he oint bet"een the t"o capsule parts are sealed "ith a elatin or polymer band. -nother approach has been developed to ma#e capsules tamper resistant or tamper




evident. !he contact areas of the cap and

Soft elatin )also called softel or soft

body are "etted "ith a mixture of "ater

elastic*

and ethanol and then thermally bonded at

hermetically sealed soft shells. Soft elatin

8<189 EC. -ny attempt to separate a sealed

capsules

5

capsule "ill destroy the capsule .

capsules

are

consist

prepared

of

by

one4piece

addin

a

plastici+er, such as lycerin or polyhydric

1 T4*&' () ."$&-"' )( )--#% -#$( "

alcohol )e.g., sorbitol*, to elatin. !he plastici+er ma#es elatin elastic. Soft elatin

%&"$-# "*'+&':

capsules come in various shapes such as ry solids )Po"ders, pellets, ranules or

spherical, elliptical, oblon, and special tube

tablets*, Semisolids )Suspensions or pastes*,

shapes "ith and "ithout t"ist off )/iure

'i$uids )2on4a$ueous li$uids*.

*. !hey can contain non4a$ueous li$uids,

1 E))&$

()

R&"$-!&

+.--$4

"#

suspensions,

pasty

materials,

or

dry

po"ders. !hey are especially important to

.(-'$+& (#$&#$ (# '& *(*&$4:

contain volatile dru substances or dru Gelatin is a hyroscopic material, and the

materials susceptible to deterioration in the

relationships

presence of air.

amon

relative

humidity,

elatin moisture content, and hard elatin

A!"#$"%&' () '()$ %& "*'+&':

>

capsule properties are sho"n in /iure 6 . >

6

Bond and 'ees , Kontny and Muls#i also have studied the relationship bet"een relative humidity and brittleness of hard elatin capsules. Because certain solvents are

#no"n

particularly mechanical

hydrophilic important properties

aents,

to of

monitor

it

is the

li$uid4filled

capsules stored under various conditions of temperature and relative humidity.

2 S()$ %&"$-# "*'+&:

ase of use 4 easy to s"allo", no taste, unit dose delivery, temper proof, versatile and accommodates

a

"ide

variety

of

compounds filled as a semisolid, li$uid, el or paste. -vailable in "ide variety of colors, shapes and si+es. (mmediate or delayed dru delivery4can be used to improve bioavailability by deliverin dru in solution or other absorption enhancin media.

D-'"!"#$"%&' () '()$ %& "*'+&':




Re$uires special manufacturin e$uipment,

choice of the elatin type and rade is

stability concerns "ith hihly "ater soluble

related to technoloical issues, consumer

compounds, and compounds susceptible to

preference and pricin. /or pharmaceutical

hydrolysis

or health and nutrition products, medium

- perfect soft capsule elatin should have

bloom limed bone )'B* elatins, or blends of limed bone and pis#in )'BFPS* or limed

<

the follo"in specifications ;

bone, pis#in and limed hide elatin •

Gel

strenth;

9<13<<

Bloom,

dependin on the elatin type •

)'BF'HFPS* are commonly used, "ith a certain preference for 'B elatin in the

Discosity )?18.9 mPa s, dependin on the elatin

0nited States and for blended elatins in urope. 'o"4viscosity, hih4bloom elatins such as a 3<< Bloom pis#in )PS* or acid

type

bone )-B* •

7ell4controlled

deree

of

viscosity Gelatin is often used for the encapsulation

brea#do"n

of hyroscopic formulations andFor "ater4 •

•

7ell4defined particle si+e to allo" fast

sensitive drus, "here standard elatin

dissolution

the

formulations have to be modified to contain

molten mass, even at hih elatin

less "ater and dry faster, thus improvin

concentrations

the

and

deaeration

of

- broad molecular "eiht distribution to provide a fast settin and the fusion temperature bein "ell belo" the meltin temperature of the plastici+ed

product

stability

durin

capsule

manufacturin. Mixtures of lo" )A<< Bloom* and medium Bloom )N9< Bloom* elatins have been proposed for the formulation of che"able soft capsules )Overholt, 3<<* to achieve the desired

"et film.

mouthfeel and solubility of the shells, a lo" !he main elatin types and rades used for

stic#iness for improved machinability and

the manufacture of soft capsules are listed

sufficient

in

encapsulation.

!able3

toether

"ith

their

interity

physicochemical specifications. !he proper


(n

for addition

stable to

fill the


pharmacopoeia rade elatin types listed in

revolvin dies and an eection "ede



3

!able 3 .

)/iure<* .

2ote;Refer to

21


<

reference in the text.

•

2orton Capsule Machine; !his machine produces

F( (..&-" M"#+)"$+& ()

capsule

completely

automatically by leadin t"o films of

S()$ G&"$-# C"*'+&

elatin bet"een a set of vertical dies. •

P"$&8P(&''

-

"arm

sheet

of

!hese dies as they close, open, and

prepared elatin is laid over the lo"er

close, are in effect a continual vertical

plate and the li$uid is poured on it. -

plate formin ro"s after ro" of poc#ets

second sheet of elatin is carefully put

across the elatin film. !hese are filled

in place and this is follo"ed by the top

"ith medicament and as they proress

plate of the mold. !he set is placed

throuh the dies, are sealed, shaped,

under the press "here pressure is

and cut out of the film as capsules

applied to form the capsule "hich is

"hich drop into a cooled solvent bath .

3

"ashed off "ith a volatile solvent to remove any trace of oil from the

•

-ccoel Capsule Machine. Or Stern machine; uses a system of rotary dies

3

exterior .

but is •

uni$ue in that it is the only

R($"4 D-& P(&'' !he rotary die

machine that can successfully fill dry

machine is a self4contained unit capable

po"der in a soft elatin capsule .

of

continuously



3

automatically

22 S"*& 9 '-5& () "*'+&

producin finished capsules from a supply of elatin mass and fillin

Soft elatin capsule is available in various

material "hich may be any li$uid, semi4

shapes, si+e and color )/iure* e;

li$uid, or paste that "ill not dissolve •

Spherical 1 <.<9 49 ml

•

Ovoid 1 <.<9 4 5 ml

•

Cylindrical 1 <.94 39 ml

•

!ubes 1 <.9 4 < ml

elatin. !"o continuous elatin ribbons, "hich the machine forms, are brouht into converence bet"een a pair of


Review Article Bhavisha Rabadiya, IJPRBS, 2013; Volue 2!3"# *2$+1 •

Pear shaped 1 <.@ 4 9ml

23

T4*&' () ."$&-"' )( )--#% -#$(

'()$ %&"$-# "*'+&'13: •

•

solubility, and also improve stability by inhibitin dru crystalli+ation*. •

S+'*&#'-(# F-': -ctive dispersed in a carrier.

N&"$ S+'$"#&, &'*&-"4 (-4 -;+-'; e. Cod liver oil capsules


Suspensions can accommodate about @<= solids before viscosity and fillin become a

S(+$-(# F-':

problem. Suspensions can be heated up to

a. -ctive dissolved in a carrier; Oils such as soybean oil and Milyol >3 )neutral oil, trilycerides of medium chain

@9C to decrease viscosity durin the fillin process. Suspended solids must be smaller than >< mesh 44 mill or homoeni+e before fillin to prevent needles from cloin

fatty acids*

durin fillin. Polyethylene Glycols; especially PG 8<< 4

3

?<<

S*&-" $4*&' () " %&"$-# "#

'()$ %&"$-# "*'+&' Other solvents; -ny other solvent, "hich does not derade or solubili+e the elatin

31

A$&& R&&"'&:

shell, i.e., dimethyl isosorbide, surfactants,

!he rate of release of capsule contents can

diethylene lycol monoethly ether.

be varied accordin to the nature of the

b. Optional (nredients for solution fills;

dru and the capsule excipients. (f the dru is "ater4soluble and a fast release is

7ater or alcohol; up to <= "F" )if needed

desired,

for solubility*.

hydrophilic and neutral. (f a slo" release of

Glycerin;  to 8= "F" )to retard the miration of the lycerin out of the shell

the

excipients

should

be

"ater4soluble dru is desired, hydrophobic excipients "ill reduce the rate of dru dissolution. (f the dru is insoluble in "ater,

into the fill*.

hydrophilic excipients "ill provide a faster Polyvinylpyrrolidone; 0p to <= "F" used

release hydrophobic and neutral excipients

in combination "ith PG )can increase dru

"ill slo" its release. - very rapid release of




the capsule contents can be obtained by

alter release rates to this extent should be

piercin holes in the capsule to allo" faster

avoided .

penetration by fluids in the astrointestinal

@

32

C("$-#% "*'+&':

tract, or by addin a small $uantity of sodium bicarbonate and citric acid to assist

Coatins

have

been

applied

in openin the capsule by the evolution of

extemporaneously to enhance appearance

carbon dioxide.

and conceal taste, as "ell as to prevent release of the medication in the stomach

-bout <. to = of sodium lauryl sulfate may be added to enhance the penetration of "ater into the capsule and speed dissolution. (f slo"er release of the active dru is desired, it can be mixed "ith various excipients, such as cellulose polymers )methylcellulose* or sodium alinate. (n eneral, the rate of release is delayed as the proportion

of polymer

or

increased

relative

"ater

to

alinate

is

soluble

inredients, such as lactose. (t should be mentioned that it is difficult to predict the exact release profile for a dru and to obtain consistent results from batch to batch. /urther, reliable, consistent blood levels and duration of action can only be proved

"ith

controlled

bioe$uivalence

studies. (n addition, many medications exhibit narro" therapeutic indices as the

)enteric coated products*. Most coatins of capsules re$uire considerable formulation s#ill and $uality control e$uipment found in manufacturin facilities. !he capsules can be coated to delay the release of the active dru until it reaches a selected portion of the astrointestinal tract. Materials found suitable include stearic acid, shellac, casein, cellulose acetate phthalate and natural and synthetic "axes the basis of their use is their acid insolubility but al#aline solubility. Many of the ne"er coatin materials are time; erosion4more dependent rather than acid; base4dependent, i.e. they erode over time

on

exposure

to

astrointestinal

contents rather than over a pH radient. !here are, in addition, a number of ne"er materials "ith predictable pH solubility @

profiles .

toxic and therapeutic doses are very close. !herefore, extemporaneous attempts to

321 E#$&-8("$& "*'+&':




nteric4coated capsules resist disinteration

reducin the number of doses per day, is to

in the stomach but brea# up in the

administer a capsule containin numerous

intestine.

coated

!hey

have

larely

been

superseded by enteric4coated tablets. !ypes of

coatin

used

commercially

include

cellulose acetate phthalate and mixtures of "axes and fatty acids andFor their esters. nteric coatin may be iven to the follo"in cateories of drus 1 •

pellets

that

release

the

dru

successively over a lon period. !he finely po"dered dru is first converted into pellets, usually by attachin it to suar ranules "ith an adhesive. !he pellets are then treated "ith protective coatins that delay release of the dru, each batch

/or substances that irritate the astric

receivin a different thic#ness. !he batches

mucosa or are destroyed by the astric

are mixed thorouhly and suitable doses

uice, and for medicaments, such as

are filled into capsules. /or example, a

amoebicides and anthelmintics that are

mixture miht contain @< percent of

intended to act in the intestine.

uncoated pellets, for immediate release of dru, @< percent each of coated pellets that

•

7hich interfere "ith diestion e.. tannins, silver nitrate and other salts of heavy metals.

•

release at 8 hours and > hours, and < percent of neutral pellets, used solely to fill the capsule. ach batch may be colored

7hich are re$uired to produce delayed

differently to simplify identification and

action of the dru.

facilitate control of mixin .

@

Several coatin methods may be used are

33

L-;+- )-& " %&"$-# "*'+&'

@

Bea#er4flas# coatin ,ippin , Sprayin .

322 S+'$"-#& &&"'& "*'+&';

2C&s )2e" Chemical ntities* are poorly

!he traditional method of ta#in a dose three or four times a day leads to periods of excess

and

deficiency

in

(t is enerally accepted that many of today&s

blood

concentration of the medicament. One "ay of correctin this and, at the same time,

"ater soluble and the classical methods, such as reduction in particle si+e are no loner ade$uate to achieve satisfactory dru adsorption from a solid oral dosae form. One of the most promisin strateies




to deliver these insoluble compounds is

production especially in the rotary die

usin dissolved systems li#e usin lipids,

process. espite these reat advantaes,

li$uids or semi4solids to formulate ne"

elatin has several dra"bac#s that limit its

products. !"p piece hard shell capsules are

use for soft capsules;

one of the most loical approaches "hen •

choosin the best dosae form to deliver

!he animal source of elatin can be a problem for certain consumers such as

these ne" li$uid formulations.

veetarians or veans and reliious or

!he ne" technoloy of pac#ain li$uids in

ethnic roups )Qe"s, Muslims, Hindus,

hard elatin capsules is considered a maor

etc.* "ho observe dietary la"s that

brea#throuh. (t can ma#e a sinificant

forbid

contribution

products.

to

the

development

of

the

use

of

certain

animal

efficacious pharmaceutical products by •

providin the flexibility to rapidly develop

crosslin#in

and test in4house formulations "hen only

•

of tablettin or po"derFpellet fillin of hard

contact

"ith

!ransparent lo"4colour capsules are difficult to produce o"in to the effect

@

elatin capsules .

of the intrinsic Maillard reaction on elatin colour.

A$&#"$-!& ."$&-" )( G&"$-# "*'+&' !raditionally, elatin has been used almost

•

moisture

humid reions and re$uires

namely its oxyen impermeability and the

thermo reversible solFel formation that

and

soft elatin capsules in very hot and

properties,

combination of film formin capability and

temperature

is an issue that complicates the use of

capsules. !his is due to its leal status and physicochemical

!he

sensitivity of elatin4based soft capsules

exclusively as shell4formin material of soft

uni$ue

in

expected "ith certain fill formulations.

available. !he process can be scaled4up and

its

"hen

aldehydes, solubility problems miht be

small $uantities of dru substance is

also #ept in4house similar to the operations

Since unmodified elatin is prone to

•

Special

pac#ain

and

storae

conditions to ensure product stability.

favour its use for the industrial soft capsule



/or lo"4price health and nutrition products,

pricin

of

commercially

available elatin miht be an additional problem.

Heat, "hich can cataly+e aldehyde formation.

!o address these concerns, there has been a reat interest in the soft capsule industry

Common causes of cross4lin#in include; •

•


-ldehydes

present

pharmaceutical

in

inredients

excipients,

pac#ain

deradants

formed

active )-P(s*,

materials, in

situ

in loo#in for elatin substitutes. (ndeed,

or

durin

several

concepts

polymers

based

on

andFor

synthetic

plant4derived

hydrocolloids have been described in the patent literature. Ho"ever, only fe" have ained commercial interest. !his is due to

storae

the fact that a chane in the capsule shell •

Hih humidity

•

(ndirect

polymer material re$uires more than ust

catalysis

in

cross4lin#in

overcomin

the

aforementioned

shortcomins of elatin. (t re$uires both

reactions

leal approval and machinability, i.e. either •

ecomposition of a stabili+er in corn

to mimic most of the physicochemical

starch

elatin characteristics that are important

"hich

•

)hexamethylenetetramine*, forms

ammonia

and

formaldehyde, "hich in turn promote

some

cross4lin#in reactions

e$uipment

Rayon coilers that contain an aldehydic functional roup

Polyethylene lycols that may auto4 oxidi+e to form aldehydes

•

adustments

characteristics

for or

of the to

the ne" use

production material completely

<

redesined machinery .

8

•

for rotary die soft capsule production "ith

0D liht, especially in the presence of hih heat and humidity

9,?I

B HPMC CAPSULE !he commercial and neutraceutical mar#ets have driven the development of alternative formin materials for traditional capsule shell material elatin accordin to need. /ormulator re$uires a non4cross4lin#in



capsule

that

is

"ell


characteri+ed,

naturally occurrin polymer cellulose and is

compatible "ith current excipients and

considered safe for normal consumption in

assays, and has a elatin4li#e dissolution.

humans .

Mar#etin prefers a capsule that meets the dietary and cultural needs of patients. Manufacturin

needs

a

capsule

"ith

elatin4li#e performance that can run on existin fillin e$uipment. Reulatory "ants a capsule polymer that has a proven safety record and "ide reulatory acceptance. Clinicians need to be certain that patient compliance is assured. evelop

alternative

5

HPMC is "hite to slihtly off "hite po"der or

ranules,

practically

insoluble

in

after hot

dryin,

"ater,

in

acetone, in dehydrated ethanol and in chloroform, but dissolves in cold "ater ivin a colloidal solution o"in to the reversible thermal elation property. HPMC is available in different substitute type "ith limits on methoxy and hydroxypropoxy

should

provide

roups. !hese roups influence many of the

improvement in the shell property, physical

HPMC

strenth,

temperature,

protection

hyroscopic

from

moisture

properties

such

viscosity,

as

elation

flexibility

and

>

protection from microbial contamination

hydration . HPMC capsules may offer

protection from liht and oxyen improve

attractive alternative

compatibility of fill material "ith capsule

because

shell.

incompatibilities and the strict reulations

Several materials have been examined as a substitute for the elatin in t"o4piece hard capsules.

Hydroxypropylmethyl

cellulose

)HPMC* has become a successful alternative material for t"o4piece capsules and is actually on the mar#et in the "orld. Hydroxypropyl

methylcellulose

)HPMC*,

no" commonly #no"n as hypermellose, is produced by synthetic modification of the

of

to elatin capsules

elatin

and

dru

reardin the use of animal derived elatin re$uirin the absence of bovine sponiform encephalopathy)BS*F

transmissible

sponiform

encephalopathy)!S*

encouraed

the

search

for

have elatin

replacement. Reliious culture and personal issues

may

affect

patient

preference

to"ards the medications presented in capsule dosae form.HPMC capsule are "ell suited for moisture sensitive drus, no ris#



of

capsule

cross4lin#in,

for

capsules do"n to belo" their standard

modified release coatins, flexibility under

moisture content and subected them to a

extreme

brittleness test that involved droppin a 9<

storae

excellent


conditions

and

machinability.

 "eiht on to them from heiht of < cm.

HPMC is also bein adopted as a film coatin

or

a

sustained4release

tablet

material in the pharmaceutical field. HPMC capsules have been developed for both pharmaceutical supplements.

products L0-'(4D,

and

dietary

developed

!he results sho"ed that elatin capsules belo" about = moisture content become very brittleness even "hen dried do"n to 3

belo" = . !he first veetable capsules "ith the

by

trademar# Deicaps made of HPMC "ere

Shionoi Lualicaps, is the first HPMC

produced in 6>6 by G.S. !echnoloies

capsule developed for eventual use in

(nc.)no"

pharmaceutical products. L0-'(4D has been

o"nership*.

submitted to the /- and its M/ number

capsules is by thermal elation and a ellin

6

is 36<< .

R.P. !he

Scherer

!echnoloies

production

of

HPMC

system used to lo"er thermal elation 33

HPMC capsules have a lo"er moisture content specification compared to elatin capsules.

Shionoi

Lualicaps

Luali4D

capsules contain 84?= and Capsuel Dcaps contain

945=.

HPMC

films

have

less

permeable to "ater vapor and moisture played a different role to that in elatin films. (t oes not act as a plastici+er, "hich means that if the capsules lose their moisture

for

"hatever

reason,

e..

exposure to lo" humidities or are filled "ith hyroscopic formulations, they do not 3<

become brittle . ried elatin and HPMC

temperature of HPMC . !he production techni$ue remains similar to that of hard elatin capsules and involves the use of pins dippin into HPMC solution, althouh the machinery may re$uire some modification such as the use of heated pins. !he HPMC capsules patented are not all the same and differ mainly in "hether a ellin system is used and in the type of ellin system. (nformation reardin the empty HPMC capsules and their manufacturer is listed in table 9.

C PVA CAPSULE



(nternational Patent -pplication 7O 6 599 3@

@5 describes

the

preferable

use

of


smooth surface appearance and the seam $uality

of

conventional

soft

elatin

polyvinyl alcohol )PD-* and optional use of

capsules. (n addition, the reulatory issues

some other materials, all bein film4formin

and the formulation of hydrophilic fills are

polymers that lac# the ellin properties

problems that have to be solved. !o

that

capsule

summari+e, it may be concluded that none

production usin the conventional rotary

of the elatin4free soft capsule concepts are

die

fully developed yet. 2evertheless, soft

are

necessary

process.

!he

for

soft

invention

therefore

provides the use of preformed rolls of

capsules

nearly "ater4free plastici+ed films that may

synthetic polymers are an interestin line

be fed to a rotary die encapsulation unit for

extension to soft elatin capsules "ith the

soft capsule production. !o render the film

potential to ain a mar#et share for certain

material more flexible and to assist the

niche products.

seam formation at temperatures dependin on the film composition, the films are partially

spray

solvated

prior

to

encapsulation. PD- films accordin to this invention may be composed of 5<159= "F" PD-, <19= "F" lycerol and 91<= "F" starch, "ith a sealin temperature of 8<1>
based

on

plant4derived

or

Polyvinyl alcohol )PD-* copolymer capsules is a form of nonelatin capsule under development. PD-, acrylic acid )--* and methyl methacrylate )MM-* are used as ra" materials. -s previously reported, these capsules have advantaes, such as lo" as permeability,

and

can

be

particularly

suitable for encapsulation of hydrophilic solvents, such as polyethylene lycol )PG* 8<<, and surfactants

38,39,3?,35,3>I

0sin such

capsules facilitates the formulation of insoluble drus and is expected to enhance bioavailability.

the capsules are readily "ater soluble "ith no

cross4lin#in

tendency.

Ho"ever,

prototype capsules lac# the shiny and

PD- copolymer capsules "ere prepared by the

dippin


and

formin

method.



Carraeenan )<.<94<.9=* "as added as a

disadvantaes of PD- copolymer capsules

ellin aent and potassium chloride )<.<94

compared

<.9=* "as added as a ellin promoter. !his

copolymer capsules have similar advantaes

method re$uires no additional investment

to HPMC capsules because both have been

for

because

developed to overcome the dra"bac#s of

conventional elatin capsule manufacturin

elatin capsules. !he advantaes of PD-

machines can be used. Prototype PD-

copolymer capsules include no animal4

copolymer capsules "ere coloured, sho"ed

derived material, a lo" "ater content, no

a ood loss and "ere not different from

Maillard reaction and a lo" electrostatic

conventional capsules.

propensity. -dditionally, PD- copolymer

capsule

manufacturers

!he PD- copolymer capsules displayed the lo"est level of electrification, as "ell as a neative chare. !he attenuation of the surface potential chare of the capsules "as affected by the functional roups of the ra" materials and their polymeric structure. !he PD- copolymer capsules are not easily electrified and sho" easy attenuation of any electricity that is enerated.

capsules

"ith

these

demonstrate

capsules.

the

PD-

uni$ue

properties of havin very lo" oxyen permeability and the ability to contain 36

macrool 8<< .

D STARCH CAPSULE (t can be formulated "ith conventional plastici+ers such as lycerol, sorbitol, etc. )<1?<= "F" of dry shell* and "ater to form a molten mass that can be extruded to

(n contrast "ith elatin and HPMC capsules,

set "ithin less than 3< s producin

it has been proven that PD- copolymer

mechanically

capsules are compatible "ith PG 8<<,

temperature4 controlled castin drums.

!"een >< and '-BR-SO'

38,39,3?I

.

stron,

elastic

films

on

Sealin may be performed at temperatures bet"een 39 and >
C(.*"-'(# () "*'+& ""$&-'$-

comparable to the one observed "ith soft Comparison "ith conventional capsules.

elatin capsules. -fter dryin, mechanically

Current

stron and hihly elastic products can be

commercially

available

hard

capsules are made of elatin or HPMC. !able

?

lists

the

advantaes

achieved.

and



Prototype

capsules

"ith

lipophilic

fill

formulations

are

shiny

"ith

hih

appearance

stability

on

storae.

!he

capsule shells do not sho" crosslin#in and exhibit a reater mechanical stability than soft elatin shells "hen exposed to elevated humidity and temperature, i.e. even under hot and humid storae conditions they may not become stic#y. /ormulation approaches "ith hydrophilic fills are expected to be as challenin as for soft elatin capsules. Oxyen permeability is comparable to elatin4based

shells.

!he

dissolution

mechanism is completely different to the one of a soft elatin capsule. On contact "ith an en+yme4free a$ueous medium at @5EC, the capsule shell only s"ells, at a rate and to an extent dependin on the type and concentration of electrolytes present. !he capsule content may be released "hen the shell bursts at its point of lo"est resistance,


conventional plastici+er such as lycerol )3= "F"*, a lidant and a disinterant. Soft capsule production may be performed "ith a rotary die machine "ith nearly "ater4free formulations that are processed by hot melt extrusion. - narro" production "indo" and the use of a hih molecular "eiht

amorphous

amylopectin

starch

content

)9<=

"ith "F"*

hih are

necessary for the formation of acceptable capsules. /rom the reulatory point of vie", starch4based soft capsules are a lo"4price alternative

to

soft

elatin

capsules,

appropriate for pharmaceutical and health and nutrition products. Moisture sensitivity and fill compatibility of the capsule shells are comparable to soft elatin capsules, "ith the exception that cross4lin#in is not a problem. Oxyen permeability is expected to be a little hiher compared to soft elatin @

capsules .

i.e. at the seams. 0nder in vivo conditions, capsule shell dissolution may be induced by

Shell

en+ymatic deradation. (nternational Patent

deradation by amylases on contact "ith

@<

dissolution

re$uires

en+ymatic

-pplication 7O < @5 >5 describes the

amylase4free a$ueous media at @5EC, the

formation of soft capsules from a potato

capsules release their content only by

starch )891><= "F"*, "ith a specific

s"ellin

molecular

"eiht

distribution

addition of calcium carbonate is one option

amylopectin

content,

toether

and

"ith

a

induced

disinteration.

!he

to enhance capsule disinteration further.




!he visual appearance, the seam $uality,

diseases. !he technoloy is based on the

and the lon4term stability of the finished

application of pH4sensitive coatins onto

product of the prototype starch capsules

inection4moulded starch capsules .

cannot compete "ith soft elatin capsules.

@3

1

P++"# C"*'+&

!his is due to the structural rearranements "ithin the capsule shells associated "ith

Pullulan is a natural "ater4soluble hih

the tendency of starch to retrorade on

molecular polysaccharide produced from

storae, in some instances leadin to a

starch

@

subse$uent plastici+er syneresis .

or

saccharide

by

microbial

fermentation. (t has numerous uses as additives in the food, pharmaceutical and

Manufactured by the process of inection mouldin, starch capsules have been sho"n to be a very useful alternative delivery system for orally administered compounds. Made from potato starch and represent a

consumer oods industries. (t is also the source Pullulan veetable

of capsule capsule.

dissolvable is

another !he

fiber. #ind

of

advantaes

of

pullulan capsule are as follo"s;

direct alternative to hard elatin capsules. (t Offers advantaes li#e; pH independent

•

'o" oxyen transmission, is about one

dissolution, suitable for enteric coatin,

eihth of the elatin capsules and one

tamper evident, produced from non4animal

three hundred of the HPMC capsules. So

derived inredients. ifferent si+e capsules

pullulan capsules provide enhanced

are manufactured )number <, , 3, @,

protection of capsule inredients and

8*.Officially reconi+ed in 0SP 3@ and 2/ >

extend shelf life.

!-RG(! technoloy )7est Pharmaceutical Services*

is

desined

for

•

the animal oriin capsule.

site4specific

delivery of drus in the astrointestinal )G(* •

tract and, in particular, tareted release

(t has the crystal4clear transparency as

2o animal protein and fat, no microbial breedin stable in $uality.

into the colonic reion. - #ey area of application is the delivery of therapeutic aents for local treatment of lo"er G(




/ree from animal produc s, no potential

fermentation proce s. Because pullulan

ha+ard of mad co" disease, mouth and

capsules are hihly i permeable to oxyen

foot disease etc.

transmission,

2Pc ps

capsules

are

recommended for encapsulatin oxidation4 •

2atural veetable oriin, suitable for all people "ith different reliions and veetarians

2

sensitive inredients to provide enhanced protection.Pullulan is hihly stable and "ell4 characteri+ed, and has achieved broad

NP"*' P++"# C"*' &'

reulatory acceptance around the "orld @@

2PcapsJ a non4animal caps les are made

"ith its proven safety record .

from pullulan, a veetable4derived, "ater4 soluble polysaccharide produced throuh a

F-%+& 1: F( "$ )( C"*' & ."#+)"$+-#% '$&*'

F-%+& 2: A.-#( "- (.*('-$-(# () %&"$-#<=



F-%+& 3: M"$&-" +'& -# %&"$-# *(+$-(# <=

F-%+& : M"#+)"$+-#% *( &'' () %&"$-#





F-%+& : M"#+)"$+-#% *( &'' () " %&"$-# "*'+&<=

F-%+& 6: S-5& () "*'+&

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