Note: Descriptions are shown in the official language in which they were submitted.
CA 02211778 1997-08-14
Preparation of pregelatinized high amylose starch an~ debranched starch
useful as an excipient for controlled release of active agents
5 FIELD O~ THI~ INVENTION
The present invention relates to a process for the manufacture of tablet
excipients for use in the pharmaceutical industry.
More particularly, it relates to an economical process for the industrial
manufacture in an aqueous medium of sustained release excipients comprising an
10 enzymatically debranched starch or a pregelatinized high amylose starch.
The debranched starch and the pregelatinized high amylose starch prepared
according to the invention are suitable in the preparation of tablets, pellets, pills and
granules. Therefore, the invention further relates to the use of these excipients for the
preparation of tablets or other dosage administration forms for sustained release of
15 active agents.
BACKGROUND OF TFIE INVENTION
One of the most pressing problems facing the pharmaceutical industry today
is that in the past few years, only a very limited number of new drug products have
20 been approved for marketing by the l~ood and drug administration (FDA). Tlle lack
of FDA-approved drugs, the high cost of new drug development, and the expirationof patents for existing dmgs means that many pharmaceutical companies will be
faced with a decreasing number of patent-protected drugs from which they may
generate revenue. Development of novel methods of delivering these drugs may not25 only expend the patent life of tlle existing dmgs but also minimize the scope and
expenditure of testing required for }~DA approval [Controlled-Release Drug
Administration: Logic, by Y.W.Chien in Novel Drug Delivery Systems, vol. l 4,
chap. l, Marcel Dekker, New York, l 982~.
In this context, many efforts were devoted to the development of new
30 excipients for the controlled release of drugs by various routes of administration. In
the recent years, particular emphasis l1as been placed on tl1e oral administration of
drugs and, among the multitude of forms in which the drug may be so-dispensed, the
CA 02211778 1997-08-14
compressed tablet form is the one that has been the most frequently employed.
In addition to the active ingredient(s), tablets usually contains several inert
substances, referred to as excipients, in sufficient amount to accomplish the desired
effect. Excipients are generally classified by their functions and the major types used
5 are fillers or diluents, binders, disintegrants, binder-disintegrants, lubricants and
glidants [see for example "Compressed tablets" by B. B. Sheth et al in
Pharmaceutical dosage forms, vol. l, chap. 3, p 109- 185,11. A. Lieberman and L.Lachman, Marcel Dekker, New York 1980]. Other specific excipients that are
commonly used include colorants, sweeteners, navors and the like.
1 0 Further specific excipients tbat are commonly used in this field consist of
"slow release" excipients that are usually made of polymers selected to prolong and
sustain the release of actives ingredients [see for example U.S. pat no. 3,087,860;
U.S. pat. no. 2,987,445]. Use of polymers in the area of controlled delivery really
began in the 1960's. Colin [Colin D. M., ~ydrophilic matrix sustained release
1 5 systems based on polysacchal ide Carriers, Critical Reviews in Therapeutic Drug
Carrier Systems, 8 (4), l991, 395-421.] have reported that hydrophilic matrices
prepared with polysaccharides and their derivatives are polymers of choice as tl1e rate
controlling carriers for these systems.
Among the polysaccharidic material, starch is one of the most interesting
20 polymer used in the field. Starch is a natural carbohydrate and is considered to be
tl1e most important source of energy in plants. It is composed of two distinct
fractions, namely (l ) amylose whicl1 is a non-ramirled rraction containil1g about
4,000 glucose units joint by c~-1,4 links, and (2) amylopectin whicll is a branched
fraction composed of about l 00,000 glucose units. Starch is a natural occurring25 diluent but it can also be used as a tahlet disintegral1t agent. Starch Call be modiried
through physical, chen1ical or enzymatic processes.
Pregelatini%ed commol1 starch contail1s usually 20 to 30 % w/w oramylo.se. It
is produced by gelatinization directly followed by a thermal dehydration process like
drum-drying, spray drying or extrusion. It is commonly used in the place of starcl1,
30 as a filler and binder-disintegratillg agent. However, Nakano et al. [Nakano M.,
Naka~ollo N. and Inotsume N., Preparation and evaluation orsustained release
tablets prepared with a-starch, Chem. Pharm. Bull. 35 (l 987) 4346-43501 has already
CA 02211778 1997-08-14
reported that pregelatinized starch may also be used as sustained release hydrogels.
Herman et al. [Herman J. and Remon J. P., Modified starches as hydrophilic
matrices for controlled oral delivery. TI. In vitro drug release evaluation of thermally
modified starches, Internatiollal Jourllal of Pl1arlIlaceutics, 56 (1989) 65-70] have
5 investigated the effect of many parameters on the sustained release properties of
pregelatinized starch. They have concluded that the ratio amylose/amylopectin is the
most important factor influencing swelling characteristics and iM l~ilro drug release
rate. Tablets made wilh common pregelatinized starch and tested in vilro
(25 % of amylose w/w) are reported to splits into two parts resulting in a burst of
10 drug release because of an increase in free surface area. In their article, Herman et al.
have also concluded that pregelatillized higll amylose starch (70% of amylose) do not
form a coherent gel layer and do nOt sustain release. Pregelatinized waxy corn starch
(100 % of amylopectin w/w and amylose free) is reported to form a gel layer during
hydration and to decrease the drug release rate. However, the swollen gel layer of
15 the amylose free starches (amylopectin) are reported to be very weak and the in vivo
tablet erosion may considerably accelerate the drug release.
Visavarungroj et al. [Visavarullgro; N., Herman J. and Remon J. r.,
Cross-linked starch as sustained release agent, Drug Development and Industrial
Pharmacy, 16, (7), 1091-1108, 1990] have also disclosed that cross-linked waxy
20 starches (amylose free starches) could be used as filler and disintegrant but are not
recommended to use as a hydrophilic matrix in a sustained release formulation.
Milojevic et al. [Milojevic S.et al, Amylose, the new perspective in oral drug
delivery to the human large intestine, STP Pharma Sciences 5(1) 47-53 (1995)] teach
the preparation of coated pellets using a mixture of amylose and ethylcellulose as a
25 coating excipient to suppress drug release over a period of 1 2h. The
amy]ose-Ethocel(~) mixture may be used in the formulation of an a-amylase resistant
coating for the drug delivery to the human large intestine. In this article, amylose is
extracted from starch by sequential aqueo-ls leachillg in hot water and thell is isolated
as a complex with the addition of butanol- I . Tllis article also reports that amylose
30 alone is unsatisfactory as a coating material and that the butanol-treated amylose
must actually be mixed with at least 60% of ethylcellulose to be efficient.
CA 02211778 1997-08-14
Modified and/or cross-linked starches are known to be powerful
disintegrating agents witll poor bindhlg properties [see U.S. pat. No. 3,622, 677 and
U.S. pat no. 4,369,308]. Usually, starch granules are cross-linking to increase their
resistance to shear or to prevent gelatinization when heated, thereby permitting5 utili%ation of cross-linked starch granules in applications whicll would destroy
granules of unmodified starch. The preparation of modified and/or cross-linked
starch is well known in the art and such preparation is described in numerous text
books or publications [see for example "Starch derivatives: production and uses" by
M. W. Rutellberg and D. Solarek in Starch chemistry and technology, 2nd ed., chap.
10 x, p. 31 1-379, R. L. Whistler, J. N. BeMiller and E. F. Paschall, Academic Press,
1984]. Only a few investigators have reported that cross-linked pregelatinized starch
can be used as a sustained release agent. Kost et al. [Kost J. and Shefer S.,
Cllemically-modified polysaccharides for enzymatically-controlled oral drug
delivery, Biomaterials I 1 (1990) 695-698] teach the preparation and use of starch
15 ionically cross-linked starch by calcium chloride for entrapment and controlled
release of bioactive molecules. The drug release rate is reported to be greatly
affected by a-amylase activity. Van Aerde et al. [Van Aerde P. and Remon J. P."nvitr~ evaluation of modified starches as matrices for sustained release dosage form,
International Journal of rharlllace~ltics, 45, 145-152 (1988)] also reports ~hat20 increasing the degree of cross-linking of pregelatinized starch increases the tablet
drug release rate.
Mateescu et al. [see U. S. pat. No. 5,456,921 to Labopharm Inc.] teach how to
prepare cross-linked amylose useful as a sustained release excipient. The so-prepared
cross-linked amylose has a cross-linking degree from 0.1 to 10 % (based on the
25 quantity of epichlorohydrin used to cross-link 100 g of high amylose starch). It is
prepared by a water-miscible organic solvent process. In the description of the
patent, it is demonstrated that pregelatinized high amylose starch (not cross-linked) is
not suitable as a sustained release excipient. In fact, tablets made of 400 mg of
pregelatinized high amylose starch containillg 100 mg of theophylline released the
30 totality of the drug in about 1.2 hours only.
Cartilier et al. [see International laid-open patent no. WO94/21236 to
~abophann Inc.] teach that cross-linked amylose having a cross-linking degree of 6
CA 02211778 1997-08-14
to 30, can be used as a binder and/or disintegrant agent for the preparation of tablets
by direct compression. The binding properties of this product are reported to bederlnitively superior to starch. The quality of the binding and the controlled release
properties of cross-linked amylose are closely related to the cross-linking degree and
5 to the relative amount of amylose present in the starch used for the manufacture.
Mateescu et al. [see International laid-open patent no. W094/02 l 2 l to
Labopharm] also describe the association of oc-amylase in tablets made of
cross-linked amylose in view of increasing the dissolution rate of low soluble drugs.
Recently, Dumoulin et al.[see IJ. S. application serial No 08/800,5t8 to
10 Rougier Inc.] have described an economical and industrial aqueous process for the
manufacture of a tablet excipient, and in particular, to a slow release excipient
mainly composed of cross-linked amylose useful in the preparation of controlled
release dosage form by direct compression.
Wai-Chiu [see l~uropean patent EP-~\-449,648 to National Starch] teach how
15 to prepare a tablet binding-disintegrating excipient by enzymatic debranchillg of
starch. Tlle starch product obtained is. characterize by a content of at least 20 % of
short chain amylose by weight. Short chain amylose as such or modified and /or
cross-linked short chain amylose resulting from the enzymatic debranching of starch
prior to after chen1ical modification, can be used as a binder-disintegrant in tablets. It
20 is reported that tl1e bindil1g-disintegratil1g properties of SUCIl producls increase Witll
the quantity of short amylose chains produced by the hydrolysis of amylopectill . It is
reported by Wai-Chiu that pregelatini7ed higl1 amylose starch containing at least 50
% of long chain amylose is also useful as a binder/disintegrant.
Arends-Scl1olte et al. ~see International laid-open patent no. wos6/nss l 5 to
25 Cooperaieve Verkoop-Enproductiev-Erel1iging Van Aardappelmeel En Derivaten
Avebe B.A.] teach how to manufacture a tablet excipient from disintegrated starch
granules prepared by enzymatic debranching of starch and characteri7.ed by a content
of long chain amylose of at least l O % by weight based on the annount of drug. In the
description of this laid-open application, it is shown that a tablet manufactured with a
30 starch product contailling 65 % of long chain amylose and 35 % of short chainamylose which has not been dehydrated with ethanol, disintegrates and is therefore
not suitable as a sustained release excipient.
CA 02211778 1997-08-14
Te Wierik et al [Te Wierik G.H.P., Eissens A.C., Besemer A.C. and Lerk
C.T~.~ Prepalatioll, chal-acteri7.a~ion and aplllicalion oramylodextrill, melaslahle
amylodextrins and metastable amylose, Pharmaceutical Research, vol. 10, No. 9,
1993] teach how to prepare amylodextrin by enzymatic hydrolysis of waxy maize
5 starch with Pullulanase. The resulting soluble fraction of amylodextrin is freeze-
dried or dehydrated by treatment with organic solvent as ethanol. They also report
the successful application of amylodextrin as an excipient in the preparation ofcontrolled release systems. They furtller report that all amylodextrin tablets tested in
vi~ro showed fracturing on immersion in the dissolution medium. Te Wierik et al
10 [Te Wierik G.H.P., Van der Veen J., Eissens A.C. and Lerk C.F., Preparation,
characterization and application orlinear dextrins. Part VI. General applicability and
mechallism of programmed release from amylodextrin tablets, J. Control. Release, 27
(1993) 9-17]. Dissolution profile and release kinetics may be altered by the presence
of tablet fracturing and this may lead to a lack of reproducibility of the system.
Te Wierik et al [Te Wierik G.I-I.P., Eissens ~.C.,Bergsma J., ~rends-Scholte
A.W., Lerk C.F., A new generation of starcll products as excipient in pharmaceutical
tablets. II. I-Iigh surface area retrograded pregelatinized potato starcll products in
sustained-release tablets, J. Control. Release, 45 (1997) 25-331 also teach the
preparation of new linear short chain starch of high specific surface area possessing
20 sustained release properties. lhe short chain starch is prepared by gelatinization of
potato starch followed by a complete degradation of amylopectin USillg a
debranching enzyme (Pullulanase) and a controlled enzymatic hydrolysis of amylose
chain using a-amylase. The short chain starcll of high specific surface area is
obtained following a precipitation (retrogradation), filtration and dehydration by
25 freeze-drying or by substitution of water by alcohol or acetone prior to air drying. It
is reported that low surface area linear product obtahled by thermal dehydration(drying at room or elevated reference temperatures or spray drying) do not have
sustained release properties and quickly disintegrate.
Te Wierik et al. [Te Wierik G. I l. 1'., l~issens A. C., 13esemer A. C. and l,erk
30 C. F., Preparation, characterization, and pharmaceutical application of linear
dextrins. I. Preparation and characterisation of amylodextrin, metastable
amylodextrins, and metastable amylose, Pharmaceutical Research, vol 10, no 9,
CA 02211778 1997-08-14
1993] further teach the pl elJa~ ~lion of metastable amylose useful as sustained release
excipient. Metastable amylose is prepared by complexation of amylose V(~) supplied
by AVEBE, with 2-methyl-1-butanol followed by a dehydration with ethanol ~Te
Wierik G.H.P., Eissens A.C., Bergsma J., Arends-Scholte A.W., Lerk C.F., A new
5 generation of starch products as excipient in pharmaceutical tablets,, J. Colltrol.
Release, 45 (1997) 25-33]. Te Wierik et al also report and insist 011 the fact that
pregelatinized high amylose starch do not sustained release and long chain linear
amylose (amylose V(~) must be dehydrated USillg an organic solvent (ethanol) to
obtain sustained release properties. However, water front penetration into tablets
made of metastable amylose has a higher deviation from linear kinetics than intoamylodextrin tablets.
As may be appreciated, none of the starch products briefly disclosed
hereinabove display all of the desirable sustained release properties. In fact, due to
the high production cost and the complexity of the manufacturing processes, there is
a need lor a low cost starcll wllicll is suitable as s-lslairled release excipielll.
Until llOW, the literature has demonstrated that pregelatinized high amylose
starch (70 % of amylose w/w) seems not to be suitable as a llydrophilic matrix in a
sustained release formulation and tllat debranched starch must be dehydrated using
an organic solvent to obtain sustained release properties.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an economical process for the
industrial manufacture in an aqueous medium of pregelatinized higll amylose starch
possessing unpredictable sustained release properties.
Another object of the invention is to provide a process for the industrial
manufacture by aqueous processing and thermal dehydration, of an enzymatically
debranched starch having the same desired sustained release properties as presently
obtained by ethanol treatment.
Still another object of the invention is to provide tablets or similar oral
dosage forms containillg the so-prepared pregelatinized high amylose starch or
debranched starch as a suitable excipient for controlled release of the active agent(s)
contained in the tablets.
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Gelatinization
The process according to the invention for the industrial manufacture of
starch products useful as excipient for controlled release of active agents comprises a
first step of gelatinization, that is common to all kinds of starting materials.It is known that Micellar crystallites held together by hydrogen bonding
between amylopectin and amylose are responsible for the integrity of starch granules.
When aqueous suspension of starch is heated to a certain temperature
(gelatinization), the hydrogen bonding weakens and the granules swell until
collapsing.
There are numerous methods of gelatini~ation of starch that are known in lhe
art, including direct or indirect heating of an aqueous dispersion of starch, chemical
treatment USil1g a strong alkali or the combinatiol1 ora mechal1ical and heat
treatment.
Pregelatinized starch is known to be soluble in cold water. At first sight, one
15 could argue that gelatinization of starch should not be desirable to obtain a controlled
release excipient. However, it has been fo~lnd that the gelatinization of starch is
essential to achieve leaching of amylose from granules of starcl1 in view of obtaining
release properties.
20 Optional debranching
As reported in the prior art, most starch granules contain two types of
polymers: amylose (5-75% by weight based on dry substallce) and amylopectin (25-95% by weight based on dry substance). Amylose is essentially a long linear
molecule whereas amylopectin is a highly branched molecule. Amylopectin may be
25 debranched by treatment with a debranching enzyme, such as Pullulanase and
isoamylase. After such treatment the resulting starch will essentially be composed of
long amylose chains and short amylose chains in a ratio depending of the initialamylopectin content and the efficiency of the enzymatic treatment.
In accordance with the invention, the starch product that is being used for the
30 preparation of the excipient, must contain at least 50% by weight of amylose.Tl1erefore, if use is made of high amylose starch (viz. a starch already containing
50% by weight or more of amylose), debranching is optional. I--lowever, if use is
CA 02211778 1997-08-14
made of"common" starch (viz. a starcl~ containing from 20 to 50% by weight of
amylose only) or of"waxy" starch, it is necessary to subject the gelatinized starch to
a debranching step, in which the amylopectin molecules are hydrolysed with a
suitable enzyme, viz. Pullulanase.
Drying
The process according to the invention further comprises a drying step whicll
must be carried out in order to dry the gelatinized higl1 amylose starch or debranched
starch that have been prepared.
Numerous methods are described in the literature for drying gelatinized
starch: such as drum-drying or spray drying techniques USil1g spray nozzle or
atomisation disc. I~owever, according to the literature, the pregelatinized highamylose starch prepared by the drying method mentioned above is supposedly not to
be suitable as a sustained release excipient.
In accordance with the present invention, it has surprisingly been found that
gelatinized higl1 amylose or debranched starch prepared in an aqueous medium andthermally dehydrated, are particularly useful and efficient as a sustained release
excipient.
Among the numerous aqueous thermal method that can be used, spray drying
is the one that is particularly preferred in accordance with the invention.
Optional therm~l tre:~tment
As is already disclosed in U.S. application No. 08/800,5 l 8 to Dumoulin et al,
if the pregelatinized starcll or the debrancl1ed starch is cooled and kept at a
temperature in the range of l to 20~C for transportation or any other reason, the
starch product must be thermally treated at a temperature higl1er than l 00~C to obtain
the sustained release properties.
Optional wet granulation
The particle size of the particles of starches powder obtained by spray drying
is smaller than 5011m. Accordingly, it may be useful to subject the so-obtained
powder to a granulation in order to enlarge the particle size and obtain uniform
CA 02211778 1997-08-14
particles that will easily flow througl1 a tablet macl1ine hopper and feed frame into
tablet dyes. Powder recovered from the spray dryer may be wet formulated in lineusing a fluid bed granulator. Alternatively, such a powder can be granulated in a fluid
bed or a V-blender.
Formulation
As aforesaid, the dried products that is so obtained can be used as an
excipient for the manufacture of controlled release tablets or similar oral dosage
forms.
In accordance with a preferred embodiment of the invention, the amylose
starch or debranched starch that is so-obtained, can be admixed with small amounts
of polymers such as Carhopol(~, Ale~hocel@~ or any similar adjuvant which becomes
viscous in the presence of water and may fill the small cracks that are formed in the
tablets during dissolution. Such permits to obtain a quasi zero order drug release
15 without profile fluctuation. This addition is particularly useFul and efrlcient ror
tablets. ~owever, it is not compulsory for other dosage forms, such as granules.The amount of drug contained in the dosage form may vary within a wide
range, depending on the solubility of the drug. It is however preferred that theamount of drug in the form be lower than 60n/o by weight of the total weight of the
20 form.
It is worth mentioning that, in addition to raw starches, chemically cross-
linked or substituted pregelatinized starches are also eligible for use as starting
materials in the process according to the inventiol1. The cross-linking or substitution
of the starch may be realized before or after hydrolysis of amylopectin molecules. If a
25 moderate chemical modification of the starch is carried out prior to the hydrolysis,
the debranching enzyme will still recognize and hydrolyse the amylopectin and
convert it into short chain amylose.
The invention and its advantages will be better understood upon reading the
following non-restrictive detailed description.
CA 02211778 1997-08-14
.
DETAILI~D DESCRIPTION OF THI~ INVENTION
1. Preparation of gelatinized lligh amylose starch
5 Step (l.a) Starch gelatillizatiol1 by thermol1lechanical lreatmel1t
High amylose starch in the form of an aqueous dispersion (l to 20% w/w
based on dry weight) is preferably gelatini%ed in a scraped-surface heat exchanger at
a temperature range of l l 0 to l 60~ C for 5 to 60 mil1utes depending on tlle amylose
content, temperature and quantity introduced.
Step (l .b) Spray drying of the gelatinized high amylose starch
The so obtained aqueous gelatinized high amylose starch, at a concentration
in the range of 0,5 to l 5% w/w, most preferably in the range of 4 to l 2% w/w, and at
a temperature in the range from 20 to 90~C, most preferably from 40 to 70~C, can be
15 spray dried using a spray nozzle or a rotating disc having an inlet temperature in the
range of l 75 to 350~C and an outlet temperature in the range of 60 to l 35~C.
2. Preparation of gelatini~ed debr7~nche(l starch
20 Step (2.a) Starch gelatinization prior to the enzymatic treatment
Like in the case of the high amylose starch, common starch or waxy starch
can be gelatinized thermomechanically as described itl step l.a. I-lowever, it must
thereafter be treated with a debranching enzyme.
25 Step (2.b) Hydrolysis of amylopectin molecules using Pullulanase
The aqueous solution of gelatinized starch (5 to 20% by weight based on dry
substance) can be treated with Promozyne 200 L (Pullulanase) in the range of 0.1 to
l 0% (v/g based on weight of the dry substance) at a pH in the r ange of 3.5 to 6 and at
temperature in the range of 35 to 65~C for l to 24 hours depending of the
30 amylopectin content and the hydrolysis parameters chosen. The p~-l of the resulting
debranched starch may be adjusted in a preferable manner between 6 and 7. The
CA 022ll778 l997-08-l4
12
debranching reaction is ended by heating the starch slurry at a temperature higl1er
than 70~C until enzyme inactivation.
Step (2.c) Thermal dehydration of debranched starch
According to the literature, debrancl1ed starch must be dehydrated by water
substitution with ethanol or acetone in order to obtain sustained release properties.
As aforesaid, in accordance with this invelltion, it has been found that
debranched starch prepared in an aqueous medium and dehydrated by a thermal
method is also offered as sustained release excipient.
Among the numerous aqueous thermal method described in the literature,
debranched starch is preferably dehydrated (dried) by spraying drying an aqueoussolution of debranched starch at a concentration in the range of 0,5 to l 5% w/w,
most preferably in the range of 4 to l 2% wlw, at a temperature in the range from 20
to 90~C, most preferably from 40 to 70~C. Such a spray drying can be carried out15 with a spray nozzle or rotating disc having an inlet temperature in the range of 175 to
350~C and an outlet temperature in the range of 60 to l 35~C.
3. Test methods
Despite the fact that drug dosage oral forms may be prepared in a multitude
20 of form, tablets obtained by direct compression have been chosen to evaluate and
illustrate the sustained release properties of starch products according to the
invention.
The sustained release property of the tablets made of starch products were
evaluated using the following in vitro dissolution test.
rreparation of the tablets:
Tablets of 400 mg (diameter of 12 mm and thickness of 2.9 mm) containing
20% of acetamil1ophen as model drug, from 5 to 20% of Carl~opol 940(1_~ or from 10
to 20% of hydroxypropyl-metl1yl cellulose (I IPMC) Kl OOM (A~elhocel(~ and from
30 60 to 75% w/w of starch products according of the present invention were prepared
by direct compression of a mixture of powders of the drug and excipients in a die
havil1g flat-face punclles, using a hydrau]ic press at 2.4 T/cm2.
CA 022ll778 l997-08-l4
13
In vit~o tablet dissolution
Method No. 1: Dissolution in phosl~llate buffer
Tablets were placed individually in I L of phospl1ate buffer in accordance
with USP 23 p. 1791 (text <711>, 37~C at pH = 7) in a Distelc dissolution apparatus
5 equipped with paddles rotating at 50 rpm. The drug release was monitored
spectrophotometrically at 244 nm, recorded and analysed with a T-lewlett Packarddissolution system.
Method No. 2: Dissolution in a solution containing 18nO0 EU of a-amylase
Tablets were placed ;ndividually in I L of phosphate buffer containing 18000
~U of o~-amylase (one enzyme unit releases I mg of maltose into 3 minutes at 20~C
and pH G,9) in accordance with USP 23 p. 1791 (test <711>, 37~C at pl-l = 7) in a
Distek dissolution apparatus equipped with paddles rotating, at 50 rpm. Tlle drug
release was monitored spectropllotometrically at 244 nm, recorded and analysed with
15 a l-lewlett Packard dissolution system,
Example 1 Preparation of gelatinized high amylose starch containing 70% w/w of amylose~ using a thermomechanical gelatini7~tion pretreatment
followed bv a sprav drying
Gelatiniz~tion
High amylose starch containing 70 % w/w of amylose was first gelatinized.
To do so, 266 kg of an aqueous dispersion of 14 % solids w/w (based on the dry
starch) was introduced at a rate of I Kg/min in a scraped-surface heat exchanger a
25 temperature in the range of 150 to I G0~C. The gelatinized product was recovered
and maintained under agitation at 65~C until the next step.
Spray drying of the gelatinized high amylose starch
The gelatinized product recovered from the previous step was diluted to 7%
30 of solids w/w (based on the dry starch) with hot soften potable water. The product
was maintained at 50~C llnder agitation and sprayed in a Niro spray dryer model P6.3
CA 022ll778 l997-08-l4
14
havil1g a water evaporating capacity of 50 Kg/l1, equipped with a atomizer disc, with
an inlet temperature of 300 ~C and an outlet temperature of 1 20~C.
EXAMPLE 2: Formulation of tablets with pregelatinized hi~h amylose starch
(70% w/w of amylose) and Carhopol~) and with
pregelatinized hi~h amylose starch (70% w/w of amylose) and
Me~hocel(~
(a) Tablets of 400 mg (diameter of 12 mn and thickness of 2.9 Inm)
10 containing 20% w/w of acetaminophen as a model drug, 60 or 70 % w/w of
pregeletani~ed high amylose starch and respectively 20 or l 0 or 5% w/w of
Carbopol(~ 940 were prepared by direct compression of a mixture of powders of
these ingredients in a hydraulic press at 2.4 T/cm2. The in vilro dissolution method
No. l described hereinabove was used to evaluate the sustained release properties of
15 the so-prepared tablets. The results are presented in Table 1.
(b) Tablets of 400 mg diameter of 12 mm and thickl1ess of 2.9 mm containing
20 % w/w of acetaminophen as model dl ug, 60 or 70 or 75 % of pregelatinized high
amylose starch and respectively 20 or l O w/w Methocel~ (~IPMC Kl 00~1) were also
prepared by direct compression of a mixture of powders of the ingredient in a
20 hydraulic press at 2.4 T/cm2. The in vitro dissolution method No. I describedl1ereinabove was used to evaluate tl1e sustail1ed release properties of tl~e so-prellared
tablets. The results are presel1ted in Table l.
CA 02211778 1997-08-14
TABLII I
'I'ime required to
release the following
Excipients % of the initial drug Type of starchcontent of the tablet
added
(expressed In hours)
30% 50% 90%
Example 2a Pregelatinized5% 2.5 8 18
70~/O amyloseCarbopol
s~cl~ cll
Example 2a Pregelatinized10% 2.5 7 17
70% amyloseCarhopol
starch
Example 2a Pregelatinized20% 2.5 7 16
70% amyloseCarbopol
starch
Example 2h Pregelatinized10% IIPMC 3 10 24
70% amylose
starch
Example 2b Pregelatinized20% HPMC 3 10.5 26
70% amylose
starch
The dissolution te~t results presented in table I show tl1e unsuspected and the
impressive sustained release properties of pregelatinized high amylose containing
starch (containing 70 % of amylose).
The tablets containing 5 and 10 % of C'arl~0~ ) 940 that were recovered
15 after the dissolution test (25 hours), were practically unswollen. They were showing
small cracks but had excellent mechanical properties (resistant and elastic). These
cracks seemed to be filled by tlle viscous polymer added in the tablets formulation,
CA 02211778 1997-08-14
16
thereby permitting to obtain a quas; zero order drug release without profile
fluctuation. As a matter of fact, the addition of S % of Carbopol 940 in the
preparation of acetaminopl1en tablets was sufficient to fill the small cracks formed in
the tablets. However, tlle addition of more than 5 % of Carhopol(~ slightly increase
the drug release rate. In fact, tablets containing 20 % of Ca~boJ701(~) were almost
completely eroded at the end of the dissolution (after 16 hollrs or immersion).
Drug release from tablets made of pregelatinized high amylose starch and
HPMC KIOOM was even more striking. In fact, the time required to release 90 % ofthe initial acetaminophen tablet content was about 25 hours. ~s reported for tablets
10 containing CaYbopol~, tablets recovered after connpletion of the dissolution test
(almost 40 hours) were practically unswollen. They were showing small cracks buthad excellent mechanical properties (resistant and elastic). The addition of at least
10 % of HPMC was sufficient to fill the small cracks of the tablets, thereby
permitting to obtain a quasi ~ero order drug release without profile fluctuation. The
15 addition of more thall l O % of l IPMC seemed not to have an important effect on the
drug release and mechanical properties of tablets.
This example fully illustrates the sustained release properties of
pregelatinized higll amylose starch containing 70 % of amylose, as produced by the
aqueous process according to the present h1vention.
Tablets prepared without viscous agent and tested in vil~o still had drug
sustained release properties but showed fracturing after a few hours (4 to 8 hours) of
immersion in the dissol~ltion medium. Thereby, some fluctuation in the drug release
profile was observed. As demonstrated hereinbefore, the addition of a low quantity
of viscous agent improves the linearity of the drug release profile. One skilled of the
25 art will know that the beneficial effect of Ca~bopol(~ 940 or E~PMC Kl OOM on the
drug release linearity may also be obtained with many other viscous polymers. I le or
she wi]l also knows that the amount of viscous agent needed to obtain the beneficial
effect will depend on the dosa~e form (tablet, pellet, beds), 011 the nature andquantity of drug and, of course, on the viscous agent used.
CA 02211778 1997-08-14
EXAMPLI~ 3: Preparation of yelatinized high amylose starch (containin~ 50
% w/w of amylose) usin~ a thermomechanical ~elatilli7~tion
pretreatment followed by spray drying
Gelatini7~tion
T ligh amylose starch containillg 50 % w/w of amylose was Flrst gelatinized.
I o do so, 323 kg of an aqueous dispersion of 7 % solids w/w (based on the dry
starcll) was introduced at a rate of I Kg/min hl a scraped-surface heat exchanger a
temperature in the range of l 50 to 1 60~C. The gelatinized product was recovered
and maintained under agitation at 65~C until the next step.
Spray drying of the gelatinized hi~h amylose starch
The gelatinized product recovered from the previous step (7% of solids w/w
based on the dry starch) was maintailled at 55~C under agitation and spray-dried in a
Niro spray dryer model P6.3 having an inlet temperature of 300~C and an outlet
temperature of 1 00~C.
EXAMrLE 4: Formulation of tablets with pre~elatinized high amylose starch
(50 % w/w of amylose) and Carhopol@~ and with
pregelatinized hi~h amylose starch (50% w/w of amylose! and
Methocel(~J
(a) Tablets of 400 mg (diameter 12 mm and thickness of 2.9 mm) containing
80 mg of acetaminophen as model drug, 300 mg of pregelatinized high amylose
starch (containing 50 % w/w of amylose) and 20 mg of Carbol~ol(~ 940 were
prepared by direct compression of a mixture of powders of these ingredients in ahydraulic press at 2.4 T/cm2. Tlle in ~ ro dissolution method No. 1 described
hereinabove was used to evaluate the sustained release properties of the so-prepared
tablets. The results are presented in Table Tl.
(b) Tablets of 400 mg (12 mm diameter and thickness of 2.9 mm) containing
80 mg of acetaminophen as model drug, 280 mg of pregelatinized high amylose
starch (containing 50% w/w of amylose) and 40 mg of Me~hocel(~ (I IPMC Kl OOM)
CA 022ll778 l997-08-l4
18
were prepared by direct compression of a mixture of powders of these ingredients in
a hydraulic press at 2.4 T/cm2. The i)? ~ ro dissolution method No. l herein
described was used to evaluate the sustained r elease properties of the so-prepared
tablet. The results are presented in Table Il.
TABLE Il
Time required to
release the following
Excipients% of the initial drug
Type of starch content of the tablet
added(expressed in hours)
30% 60% 90%
Example 4aPregelatinized 50%5% 2 6 14
amylose starch Carbopol
Example 4bPregelatinized 50%l 0% 1 IPMC 2 7 ] 7
amylose starch
The dissolution test results presented in Table Il sho that pregelatinized high
amylose starch containing 50% amylose possess also unsuspected sustained releaseproperties. l lowever, the drug release rrom tablets made of ti1ese starch was faster
than the one obtained with pregelatinized starch containing 70% of amylose, thereby
suggesting that the higher is the amylose content, the better will be the sustained
release properties.
The tablets containing 5% of Ca~ bopol(~ and 10% of T IPMC that were
recovered after the dissolution test, were practically unswollen. They were showing
mucl1 more small cracks but still had good mechanical properties (resistant and
elastic). Thus, the addition of C'ur1~opol(f~ or l-IPMC permits to fill the tablets cracks
and to obtain a quasi zero order drug release without profile fluctuation.
Drug release from tablets made of pregelatinized starch containing 50 % of
amylose and lO ~/0 of HPMC KIOOM was longer than the one obtained from tablets
CA 02211778 1997-08-14
.
19
containil1g Carbopol(~. In fact, the time required to release 90 % of the initial
acetalllinopllen tablet contel1t was about 17 llours.
EXAMPLE 5: Preparation of gelatinized starch contailling about 20 % of
amYlose using a thermomechanical gel~tiniz~ion pretreatment
followed by a spray drying
The purpose of this example is to compare the sustained release properties of
starch produced by the process according to this invention and to demonstrate the
1 0 beneficial effect of amylose on such properties.
Gel~tini7~tion
Common starch containing about 20 % w/w of amylose was first gelatini%ed.
To do so, 109 kg of an aqueous dispersion of 8 % solids w/w (based on the dry
1 5 starch) was introduced at a rate of I Kg/min in a scraped-surface heat exchal1ger a
temperature in the range of 135 to 145~C. The gelatinized common starch was
recovered and maintail1ed under agitation at a 60~C until the next step.
Spray dryin~ of the gelatinized common starch
The gelatinized common starch recovered rrom the previous step (8 % w/w
based on the dry starch) was maintained at a temperature in the range of 50 to 60~C
under agitation and spray dried in a Niro spray dyer model P6.3 having an inlet
temperature of 280~C and an outlet temperature of 126~C.
I~XAMPLE 6: Formulation of tablets with pregelatinized common starch and
Ca1 bopol~ and with pregelatinized common starch and
Melhoce~
(a) Tablets of 400 mg (diameter of 12 mm and thickness of 2.9 mm)
containing 20 % of acetaminophen as a model drug, 75 % of pregelatinized common
starch and 5 % of Carbopol(~ 940 were prepared by direct compression of a mixture
of powders of these ingredients in a hydraulic press at 2.4 T/cm2. The jM vilro
CA 02211778 1997-08-14
dissolution method No. l desctibed hereinabove was used to evaluate the sustained
release properties of the so prepared tablets containing the pregelatinized common
starch prepared in example 5. The results are presented in Table III
(b) Tablets of 400 mg (diameter of l 2 mm and thickness of 2.9 mm)
5 contail1ing 20% w/w of acetaminopl1en as a model drug, 70% w/w of coml11on
starch and 10% w/w of Met1?ocel(~) of HPMC Kl OOM) were prepared by direct
compression of a mixture of powders of these ingredients in a hydraulic press at 2.4
T/cm2. The in vi~ro dissolution method No. I described hereinabove was used to
evaluate the sustained release properties of tl1e so-prepared tablets. The results are
10 presented in Table III.
TABLE III
Time required to
release the following
Excipients% of the initial drug
Type of starch content of the tablet
added(expressed in hours)
30% 60% 90%
Example 6aPregelatinized 20%5% 2 6 l l
amylose starch Carbopol
Example 6bPregelatinized 20%l 0% HPMC 2 7 l 5
amylose starch
As it is reported in the prior art, tablets made of gelatinized starch contail1ing
20 about 20 % of amylose and about 80 % of amylopectin are able to provide sustained
release. I lowever, as it was the case with pregelatini~ed high amylose starch
containing 50 and 70 % of amylose, tablets recovered after the dissolution test, had
some cracks. The drug release from tablets made according both formulations using
Carbopol(~) or HPMC was faster than the one from tablets made of pregelatinized
25 starch containing 50 and 70 % of amylose. Il1 fact, the time required to release 90 %
of the initial acetaminophen from tablets n1ade of pregelatinized common starch
CA 02211778 1997-08-14
containing 10 % of HPMC was about l S hours as compared to 24 hours witll tablets
made of pregelatinized starch containing 70 % of alnylose. Th;s result confirms that
the role and quantity of amylose are decisive for achieving proper sustained release
properties.
EXAMPLE 7: Preparation of debranched starch followed by spray drying
High amylose starch was used as starting material in this example. However,
use could also be made of waxy maize starch containing 95 % w/w of amylopectill or
of common starch containing from 20 to 50 % of amylose as starting materials.
Gel~tini7.:~tion
High amylose starch containing 70 % w/w of amylose was first gelatinized.
To do so, 300 kg of an aqueous dispersion of 15 % solids w/w (based on the dry
starch) was introduced at a rate of I Kg/min in a scraped-surface heat exchanger at a
temperature in tbe range of 150 to 1 60~C. The gelatinized product was recoveredand maintained under agitation at 70~C until the next step.
I-lydrolysis of amylopectin molecules using Pullulanase
l O0 kg of gelatini~ed high amylose starch recovered from the previous step
was transfer to a 200 L GO~VEC reactor tank. The temperature of the medium was
cooled to 60~C and the pl-T was adjustecl at 5. Promozyme 200 l, (Novo-Nordisk)
was added in order to obtain a Pullulanase enzyme concentration of 3 % v/w basedon the dry weight of the gelatinized higll amylose starch. The temperature was
adjusted to 55~C and the hydrolysis was carried out for about 20 hours. Then, the
reaction medium was diluted with l O0 kg of soften potable water at 60~C and the pH
was adjusted at 6.3. The debranching reaction was ended by heatillg the resulting
debranched starch at 90~C for 20 minutes.
Thermal treatment of the debranched starch
The slurry of debranched starch recovered from the previous step was
thermally treated in a scraped-surface heat exchanger at a temperature in the range of
CA 02211778 1997-08-14
150 to 160~C. The aqueous heat-treated debranched starch was maintained under
agitation at 65~C until its subsequellt dehydlatioll by spray dryillg.
Spray drying of the aqueous suspension of debranched starch
The debranched starch recovered from the previous step (containing 7.5 % of
solids w/w based on the dry starch) was kept at 65~C under agitation and spray dried
in a Niro spray dryer model P6.3 having an inlet temperature of 300~C and an outlet
temperature of 1 00~C.
10 EXAMPLE 8: Tablets formulatiol1 with debranched starch and Me~hocel~
(a) Tablets of 400 mg (diameter of 12 mm and thickness of 2.9 mm)
containing 20% w/w of acetaminophen as a model drug, 75% w/w of debranched
starch and 5% of Carl~opol~ 940 were prepared by direct compression of a mixture15 the powders of these ingrediellt.s in a hydraulic press at 2.4 T/c1112. l~he in vitro
dissolution method No.l described hereinabove was used to evaluate the sustainedrelease properties of the tablets prepared with the debranched starch of example 7.
The results are presented in Table TV.
(b) Tablets of 400 mg (diameter of 12 mm and thickness of 2.9 mm)
20 containing 20% w/w of acetaminophen as a model drug, 70% w/w of debranched
starch and 10% w/w of A~ethocel'~J HPMC KlOOM) were prepared by direct
compression of a mixture of powders of these ingredients in a hydraulic press at 2.4
T/cm2. The in vilro dissolution method No. 1 described hereinabove was used to
evaluate the sustained release properties of the so-prepared tablets. The results are
25 presented in Table IV.
CA 02211778 1997-08-14
TAI~LE IV
Time required to
release the following
Excipients% of the initial drug
Type of starch content of the tablet
added (expressed in hours)
30% 60% 90%
Example 8aPregelatinized 5% 3 9 22
debranched starch Carbopol
Example 8bPregelatinized 10% HPMC 4 11 28
debranched starch
The dissolution test results presented in table IV sl1ow the unsllspected and
striking sustained release properties of debranched starch subjected to thermal
10 dehydration (spray drying). The tablets made of debranched starch containing 5 % of
Carbopol(~ or 10 % of HPMC recovered after the dissolution test were practicallyunswollen. They were showing small cracks but still had good mechanical properties
(resistant and elastic).
The addition of Carbopol(~) or HPMC permits to fill the tablets cracks and to
15 obtain a quasi zero order drug release without profiles fluctuation. The drug release
from tablets made of debranched starch containil1g I-lPMC Kl OOM was longer thanthe one from tablets made with Carbopol~. In fact, the time required to release 90
% of the drug from tablets containing HPMC is very impressive, as it was about 28
hours.
EXAMPLE 9: Comparison of sustained release properties of starches
prepared accordin~ to this invention in a dissolution medium
containing 18000 UE of alpha-amylase
A comparison was made of the drug dissolution profiles of 400 nng tablets
containing 80 mg of acetaminophen (20% w/w), 20 mg of Carbopol(~ (5% w/w) and
CA 02211778 1997-08-14
24
300 mg (75% w/w) of pregelatinized high amylose starch (prepared as
disclosed in example l and containing 70 % of amylose); or
300 mg (75% w/w) of pregelatinized higll amylose statch (prepared as
disclosed in exalnple 3 and containing 50 % oramylose); or
300 mg (75% w/w) of pregelatinized common starch (prepared as disclosed
irl example 7 and containing about 20 % of amylose);
or 300 mg (75% w/w) of debrancl1ed starch (prepared as disclosed in
example 5 and containing about 70 % of long cllain amylose and 30 % o~short cllain
amylose).
The tablets were prepared by direct compression of a mixture of powders of
these ingredients in a hydraulic press at 2.4 T/cm2. The in v7~ro dissolution method
No. 2 described hereinabove was used to evaluate the sustained release properties of
the so-prepared tablets. The resistance of the starch product to alpha-amylase is
presented in Table V.
TABLE V
Time required to
release the follow;ng
Excipients% of the initial drug
Type of starch content of the tablet
added(expressed in hours)
30% 60% goo/0
Prepared as Pregelatinized 20% 5% 2 4.5 7
20in Example 5 amylose starchCarbopol
Prepared as Pregelatinized 50% 5% Carbopol 2 5 l l
in Example 3 amylose starch
Prepared as Pregelatinized5% Carbopol 2 7 17
in Example 1 70% amylose
starch
25Prepared as Pregelatinized5% Carbopol 3 9 22
in Example 7 debranched starch
CA 02211778 1997-08-14
Tllis example illustrates the high enzymatic resistance of starches rich in
amylose content prepared by the aqueous process according to the invention. Tablets
5 resistance to a-amylase increased when the ratio amylose/amylopectin increased.
Tablets made of pregenatinized 20% amylose starch (common starch) were badly
affected by the enzyme and, as a result, the time requested to release 90% of the drug
dropped from l l to 7 hours. Tablets made of pregelatinized 50% amylose starch
were slightly affected by the enzyme and the time requested to release 90% of the
10 drug dropped from 14 to 1 1 hours. Tablets made of pregelatinized 70% amylosestarcll were practically not affected by the enzyme (from 18 to l 7 hours) and tablets
made of debranched starch were the most resistant and were not afFected by a-
amylase. This high tablet resistance to enzyme is believed to be related to the
property of the amylose chain to retrograde on hydration. The retrograded gel phase
15 limits the subsequent tablet swelling, the drug diffusion and the enzymatic
amylolysis. As it is reported in the art, retrograded pregelatinized starch are not
attacked by o~-amylase in the gastrointest;nal tract. Thereby, the in vivo drug release
will be independent of the fluctuation of the a-amylase in the human intestine.
Of course, numerous modifications could be made to the present invention as
disclosed and exemplified hereinabove, without departing from the scope of the
appended claims.
