Note: Descriptions are shown in the official language in which they were submitted.
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Description
MULTIPARTICULATE ORAL DOSAGE FORMS
Technical Field
The present invention relates to a convenient oral dosage form. In
s particular, the invention relates to a convenient oral dosage form
containing a drug that is loaded onto an ion-exchange resin and
subsequently coated.
Background Art
Oral administration represents the preferred route of administration for a
to wide range of pharmaceutical agents. Particular advantages associated
with oral administration include ease of administration and convenience
for the patient, both of which can lead to improved patient compliance.
However, some drugs have an inherently bitter or unpalatable taste
associated with them. This is a distinct problem if it is desirable to
~s formulate these drugs in an oral dosage form. Various methods have
been developed for masking the taste of such drugs so as to facilitate
their formulation for oral administration.
US 5,032,393 (Glaxo Group Ltd.) teaches that the bitter taste of
ranitidine may be masked by forming an adsorbate with a synthetic
ao cation exchange resin. The adsorbate may then be incorporated into
compositions for oral administration. Specifically, the synthetic cation
exchange resin is selected from copolymers of styrene and
divinylbenzene which are sulphonated, and copolymers of methacrylic
acid and divinylbenzene. US 5,188,825 (Iles et al.) discloses a freeze-
2s dried dosage form comprising a water-soluble active agent which is
bonded to an ion-exchange resin to form a substantially water insoluble
complex. The dosage form is prepared by mixing the water insoluble
complex with a compatible carrier and freeze-drying the mixture. It is
taught that these freeze-dried dosage forms reduce the undesirable odour
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and / or taste of active agents. Chlorpheniramine maleate and
phenylephrine hydrochloride compositions are given as examples.
However, it is apparent that in the case of particularly bitter or
unpleasant tasting drugs the use of such drug / resin complexes or
s adsorbates, as described above is not sufficient to eliminate the
undesirable taste. Additionally, some ion-exchange resin materials
themselves have unpleasant taste characteristics which add to, rather
than reduce, the problems of formulating organoleptically acceptable
oral dosage forms.
to Therefore, a need exists for a taste-masked composition which masks
the taste of particularly bitter of unpleasant tasting drugs. It is an object
of the present invention to address this need.
Further, an ion-exchange resin can be used as a vehicle onto which a
drug compound may be adsorbed for release in a controlled or sustained
is fashion. There are a number of factors which affect the performance of
such drug / resin formulations. These include choosing a suitable resin,
optimising the drug load within the resin particles and ensuring that the
structural integrity of the particles is maintained. The last point is of
considerable importance in sustained release formulations since the drug
Zo loaded particles tend to swell in a liquid environment which can rupture
any coating on the particles with the result that the drug load is dumped
in an uncontrolled manner. US 4,221,778 (Pennwalt Corporation)
teaches the use of an impregnating / solvating agent, which is added to
the drug / resin particles prior to application of a diffusion barrier
Zs coating to retard swelling. Alternatively, US 5,186,930 (Schering
Corporation) teaches the use of an inner wax coating, applied prior to
enteric coating, to prevent swelling.
It has been disclosed (US 4,996,047 Richardson-Vicks Inc.) that
diffusion barrier coated drug-resin particles having a critical drug load
30 (the active ingredient making up greater than 38 % by weight of the
drug-resin particles) maintain their integrity and avoid cracking. US
5,4 i 3,782 (Rhone Poulenc Rorer Pharmaceuticals) discloses a method
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of achieving greater than 40 % (by weight) loading of resin particles by
carrying out the loading process in the absence of carbon dioxide or
bicarbonates.
Rhee et al., Yakhak Hoeji, 38(3):250-264 (1994) discloses an
s omeprazole-ion exchange resin complex. The particles of the complex
were granulated into larger sized granules prior to coating with an
enteric coating.
The documents mentioned above in relation to drug / resin formulations
are based on the premise that the drug is to be delivered in a sustained or
~o prolonged manner. The mode of action of many drugs involves
reversible binding of a target molecule or receptor establishing an
equilibrium between the bound state and the free target molecule or
receptor and free drug. In these cases it is advantageous to have a
sustained release of the active ingredient in order to ensure that the
~s equilibrium favours the bound, and therefore therapeutically active,
state. Thus, the reversible nature of the drug / target interaction in these
instances dictates the use of a sustained release formulation.
One aspect of the present invention on the other hand is directed
towards the delivery of drug compounds for which sustained delivery
Zo may not be of value; for example drugs, such as proton pump inhibitors,
that interact in an irreversible manner with the target molecule or
receptor. As such, an object of the present invention is to provide a
controlled release palatable convenient dosage form for the effective
delivery of such drugs including proton-pump inhibitors (hereinafter
Zs PPIs). It is another object of the present invention to provide a
composition in which the active ingredient is released rapidly after an
initial delay period. It is a further object of the invention to provide a
stable composition for PPIs as well as other acid labile active
ingredients. It is a further object of this invention to provide a
3o preparation containing a drug / resin complex which may be used to
deliver the active ingredient to a region of specific pH.
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Disclosure of Invention
One aspect of the invention is a convenient oral dosage form that
includes a multiparticulate composition and each particle includes an
active ingredient reversibly adsorbed onto an ion exchange material to
s form an active ingredient-resin complex and each core is coated with a
polymeric coating material. The ion exchange resin can be either a
cation exchange resin or an anion exchange resin. Further, the active
ingredient can be entrapped with the ion exchange material in the core.
The active ingredient can be one with a strong and unpleasant taste or
to odour or an acid labile compound. The polymeric coating can be a pH
dependent or independent polymer and can include a combination or
two or more polymeric materials.'
In another aspect of the invention, the oral dosage form provides taste
masking for an active ingredient having a strong and unpleasant taste or
t s odour.
In a further aspect of the invention, the oral dosage form is a controlled
release dosage form such as a delayed release dosage form.
Other aspects of the invention include methods of manufacturing the
oral dosage form as well as final oral dosage forms that can be either
Zo solid or liquid oral dosage forms.
Convenient oral dosage forms such as suspensions, syrups, sprinkles,
fast melt tablets, effervescent tablets and fast dissolving tablets are
readily acceptable to patients resulting in increased patient compliance
for a given therapeutic regimen. The present invention allows for the
2s presentation of acid labile drugs and drugs of unpleasant odour or taste
into a range of different palatable convenient dosage forms. The
invention is based on loading the drug, be it acid labile or unpleasant
tasting, onto an ion exchange resin of opposite charge, coating the
discrete resin particles with either a taste masking or enteroprotective
3o coating and incorporating the resulting coated drug loaded resin
particles into the convenient oral dosage form.
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The oral dosage form of the present composition comprises a plurality of
particles, each particle having a core containing an active ingredient or a
pharmaceutically acceptable salt thereof and a coating material coated
onto the core; wherein the core further comprises an ion exchange resin
material, the active ingredient or a pharmaceutically acceptable salt
thereof being reversibly adsorbed onto the ion exchange resin material
to form an ion exchange resin drug complex.
The terms "active ingredient" or "drug", used interchangeably herein,
includes any drug compound that is either acid labile or which is
io characterised by an unpleasant odour or taste and which can be bound to
an ion exchange resin may be used in the present invention.
For drugs of unpleasant odour or taste the combination of complexing
the drug with an ion-exchange resin and coating the resultant drug-resin
complex in accordance with the invention provides good taste masking
~s and facilitates the incorporation of the drug into dosage forms for oral
administration. Complexing the drug with an ion-exchange resin
prevents leaching of drug from the formulation and thus the likelihood
of a bitter taste in the case of a formulation such as a fast melt tablet or
liquid formulation.
2o Representative drugs of unpleasant taste or odour include, but are not
limited to, H, receptor antagonists, antibiotics, analgesics,
cardiovascular agents, peptides or proteins, hormones, anti-migraine
agents, anti-coagulant agents, anti-emetic agents, anti-hypertensive
agents, narcotic antagonists, chelating agents, anti-anginal agents,
Zs chemotherapy agents, sedatives, anti-neoplastics, prostaglandins,
antidiuretic agents and the like. Typical drugs include, but are not
limited to, nizatidine, cimetidine, ranitidine, famotidine, roxatidine,
etinidine, lupitidine, nifentidine, niperitone, sulphotidine, tuvatidine,
zaltidine, erythromycin, erythromycin derivatives such as for example
3o ketolide ( 1 1,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-
(oxycarbony I ( 4-(4-(3-pyridinyl)-1 H-im idazol-1-yl)butyl )imino))
erythromycin), penicillin, ampicillin, roxithromycin, clarithromycin,
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psylium, ciprofloxacin, theophylline, nifedipine,prednisone,
prednisolone, ketoprofen, acetominophen, ibuprofen, dexibufen lysinate,
flurbiprofen, naproxen, codeine, morphine, sodium diclofenac, acetyl
salicylic acid, caffeine, pseudoephedrine, phenylpropanolamine,
s diphenyhydramine, chlorpheniramine, dextrometorphan, berberine,
loperamide, mefenamic acid, flufenamic acid, astemizole, terfenadine,
certrizine, phenytoin, guiafenesin, N-acetylprocainamide hydrochloride,
pharmaceutically acceptable salts thereof and derivatives thereof.
For acid labile drugs, the combination of complexing the drug with an
to ion-exchange resin and coating the resultant drug-resin complex in
accordance with the invention provides protection for the drug from the
acid environment of the stomach upon ingestion and facilitates the
incorporation of the drug into dosage forms for oral administration.
Complexing the drug with an ion-exchange resin prevents leaching of
is drug from the formulation in the stomach after ingestion and thus the
likelihood of degradation of the drug in the case of a formulation such as
a fast melt tablet or liquid formulation.
Acid labile drugs include those drug substances that are adversely
affected by exposure to acidic media. Representative acid labile drugs
Zo include, but are not limited to proton pump inhibitors in general,
including benzimidazole compounds, more particularly substituted 2-
pyridyl methyl sulfinyl benzimidazoles, either substantially in the form
of one optically pure enantiomer or, in the form of a mixture of
enantiomers or racemate where applicable, and pharmaceutically
is acceptable salts thereof. Substituted 2-pyridyl methyl sulfinyl
benzimidazoles may typically contain a chiral centre when the carbon
atom of the methyl sulfinyl bridge between the benzimidazole and
pyridyl moieties is bonded to four different substituent groups.
Preferably the active ingredient is a substituted 2-pyridyl methyl sulfinyl
3o benzimidazole compound. More preferably the active ingredient is
selected from the group consisting of omeprazole, perprazole,
lansoprazole, pantoprazole, rabeprazole and leminoprazole. Most
preferably the active ingredient is omeprazole.
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Acid labile active ingredients other than PPIs may also benefit from the
protection afforded by the adsorption of the active onto an ion exchange
material and entrapment on or within coated resin particles. An example
of such an acid labile active ingredient, which is not a PPI, is
s erythromycin which is known to loose its antibacterial activity at pH
lower than S.S.
Ion-exchange resin materials suitable for use in accordance with the
present invention include any ion-exchange resin which is capable of
binding the drug, including, for instance, anionic and cationic resin
to materials. Where the drug is a cation or is prone to protonation, the ion-
exchange resin is suitably a cation exchange resin material. That is to
say, a resin having a predominantly negative charge along the resin
backbone, or a resin having a pendant group suitable for cation
exchange, and which has an affinity for positively charged ions or
~s cationic species. Typical of such cation exchange resins include resins
having polymer backbones comprising styrene - divinyl benzene
colpolymers, methacrylic acid and divinyl benzene co-polymers, and
resins with pendant functional groups suitable for cation exchange, such
as sulphonate and carboxylate groups. Cation exchange resins suitable
Zo for use in the practice of the present invention include for example those
sold under the trade names Amberlite IRP-64, Amberlite IRP-69 and
Amberlite IRP 88 (Rohm and Haas, Frankfurt, Germany), Dowex
SOWX2-400, Dowex SOWX4-400 and Dowex SOWXB-400 (The Dow
Chemical Company, Midland, MI), Purolite C 11 SHMR and Purolite
is C 102DR (Purolite International Ltd., Hounslow, Great Britain).
Similarly, where the drug is an anion or is prone to deprotonation, the
ion exchange resin is suitably an anion exchange resin material. That is
to say, a resin having a predominantly positive charge along the resin
backbone, or a resin having a pendant group suitable for anion
3o exchange, and which has an affinity for negatively charged ions or
anionic species. Typical of such anion exchange resins include resins
having polymer backbones comprising styrene, acrylic acid or phenol
units, co-polymers thereof, styrene-divinyl benzene co-polymers and
phenolic-based polyamine condensates and resins with pendant
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functional groups suitable for anion exchange, such as ammonium or
- tetraalkyl ammonium functional groups. Anion exchange resins suitable
for use in the practice of the present invention include for example those
sold under the trade names Amberlite IRP-58, Amberlite IRA-67,
s AmberIite IRA 68 (Rohm and Haas, Frankfurt, Germany), Dowex 1X2-
400, Dowex 1 X4-400, Dowex I X8-400 and Dowex 2X8-400 (The Dow
Chemical Company, Midland, MI), Purolite A845, Purolite ASOOP and
Purolite PCA-433 (Purolite International Ltd., Hounslow, Great Britain),
Duolite AP143%1092 and Duolite A143/1093.
to Resins with various degrees of crosslinking and a range of binding
capacities may also be used in the practice of the present invention.
The oral dosage forms of the present invention can be prepared by
contacting the ion exchange resin with the active ingredient to form an
active ingredient or drug/ ion exchange resin core or complex. The
is individual cores can then be coated with the polymeric coating material.
Typically the ion-exchange resins suitable for use in the present
invention are in the form of ion-exchange resin particles. Stirring the
ion-exchange resin particles in a solution of the selected drug is usually
sufficient to achieve binding of the drug onto the resin particles.
Zo Loading of the resin is suitably carried out at a pH that facilitates
binding of the drug compound. Some ion-exchange resins may require
"activation" by rinsing with a solution of acid or base, prior to loading
with the drug. Such activation requirements will be well known to those
skilled in the art of working with ion-exchange resin materials. Specific
Zs requirements for individual ion-exchange resin materials may be
obtained from the resin manufactures. Preferably, the particles are
spherical to enable substantially complete coating of the particle.
The use of a suitably spherical ion exchange resin can substantially but
not wholly masks the taste or odour of an active ingredient and lend
~o itself readily to complete coating with the taste masking polymer which
eliminates any residual bitter taste upon ingestion. The use of a suitably
spherical ion exchange resin can help minimise the interaction of the
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acid labile drug with the acidic enteroprotective coating while also
facilitating the coating of the acid labile drug with the enteroprotective
coating. An important aspect of the current invention is the ability to
coat the drug loaded resin particles as discrete particles hence
s minimising the potential for a gritty aftertaste after ingestion of the
drug.
The term "reversibly adsorb" means that the drug binds to an ion
exchange resin of opposite charge via an ionic interaction that can be
reversed in suitable ionic conditions
The active ingredient component of the composition may be present in
~o any amount which is sufficient to elicit a therapeutic effect. Typically
the active ingredient is present at about 1 - 70 % by weight of the
uncoated resin. Preferably the active ingredient ranges from S - 60 % by
weight of the uncoated resin. More preferably the active ingredient
ranges from 10 - 50 %, most preferably 10-40%, by weight of the
is uncoated resin.
The polymer material used for coating the drug-resin complex can be a
polymer that has properties which can prevent the release of the drug
until it reaches a specific site in the gastrointestinal tract and only then
the drug is released. The specific site in the gastrointestinal ("GI") tract
?o includes any point in the GI tract including the oesophagus, the stomach
and the intestine.
The polymer coating material used in coating the drug-resin complex
may comprise a pH independent or pH dependent coating material. pH
independent coating materials suitable for use in the present invention
2s include, for example, alkyl celluloses such as methyl cellulose,
hydroxyalkyl alkyl celluloses such as hydroxy propyl methyl- cellulose,
hydroxy alkyl celluloses such as hydroxy propyl cellulose and hydroxy
ethyl cellulose, polyvinyl alcohol, maltodextrin, polymethacrylates such
as Eudragit~ RL (Rohm-Pharma, Darmstadt, Germany). pH dependent
3o coating materials suitable for use in the present invention include for
example esters of at least one cellulose derivative such as an alkyl
cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkyl cellulose or a
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cellulose ester, with at least one polybasic acid such as succinic acid,
malefic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic
acid, trimellitic acid or pyromellitic acid. Suitable enteric coating
materials include for example those selected from the group consisting
s of hydroxy propyl methyl cellulose phthalate (HPMCP), cellulose
acetate phthalate (CAP), cellulose acetate trimillitate (CAT) and
hydroxypropyl methylcellulose acetate succinate. Also considered
useful in the practice of the present invention are for example enteric
materials such as those selected from the group consisting of poly vinyl
~o acetate phthalate (PVAP), polyvinyl acetaldiethylamino acetate, and
shellac. Particularly useful in relation to the present invention are poly
acrylic and methacrylic acids and poly acrylate and methacrylate based
coatings, and mixtures thereof, such as those sold under the tradename
Eudragit~, for example Eudragit L~ and Eudragit S~ (Rohm-Pharma,
is GmbH, Darmstadt, Germany) to 50 - 250 % by weight of the drug
loaded resin particles. A further particularly useful pH dependent
coating material suitable for use in accordance with the present
invention is Eudragit~ E (Rohm-Phanma, Darmstadt, Germany).
A particularly useful pH independent polymer for use in accordance
2o with the present invention is Eudragit~ RD 100 (Rohm-Pharma,
Darmstadt, Germany). The polymeric coating may suitably comprise a
combination of two or more polymer materials.
Acid labile drugs in the composition according to the invention are
substantially protected from the enteric coated material by adsorption
2s onto the ion exchange resin material. Thus the need for a subcoating
between the active ingredient and the enteric coating is eliminated.
The coating may be applied to the drug loaded particles by any suitable
technique. Such techniques will be apparent to those skilled in the art.
Particularly useful for application of the coating is the technique of
3o spray coating, carried out for instance using a fluidised bed coating
apparatus. Suitable excipients and / or additives may be added to the
coating formulations. For example it may be desirable to add
plasticisers, glidants, anti-tacking agents, pigments and other excipients
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to the coating formulations. Suitable plasticisers include, for example,
triethyl citrate and polyethylene glycol. Suitable glidants include, for
example, talc, syloid, glycerol monostearate and magnesium stearate.
The coating material may be applied to the drug loaded particles in any
s amount which is sufficient to give the desired taste-masking
characteristics. Typically the coating material is applied in an amount
equivalent to 10 - 300 % by weight of the drug-loaded resin particles.
Preferably, the coating material is applied in an amount equivalent to 20
- 250 % by weight of the drug loaded resin particles.
to Without wishing to be limited by any particular theory it is believed that
the physico - chemical principles underlying the present invention are as
explained below. Generally speaking, acid labile benzimidazole
compounds such as omeprazole are capable of binding to an anion
exchange resin (i.e. a resin having a positively charged backbone). This
~s may involve the loss of a proton leaving the benzimidazole molecule
with a formal negative charge which can interact ionically with the
resin. The resultant drug / resin complex particles may then be coated
with an enteric coating with additional excipients if so desired. Binding
of the active ingredient to the resin particles protects the drug from
Zo degradation by the acidic enteric coating. In a highly acidic
environment, such as the stomach, the enteric coating protects the active
ingredient from acid degradation. When the particles pass through the
stomach to a region of higher pH (such as pH > 6 - 7), the enteric
coating is compromised and the drug / resin complex is exposed to the
is surrounding environment. Exchange of negative ions, such as chloride
ions, from the surrounding environment for the drug bound to the resin
releases the drug, facilitating the onset of a therapeutic effect.
Additionally, exposure of the drug to an even slightly acidic
environment will cause it to be protonated leaving the molecule
3o electrically neutral. These two processes would be expected to
considerably reduce the drug / resin interaction, or indeed cause the drug
and resin to actually repel each other. Thus the dissociation of the drug
from the resin is actively promoted. Unlike the prior art drug / resin
formulations in which the release of the active ingredient is sustained
3s over a prolonged period of time, the composition of the present
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invention is designed to provide a relatively rapid release of active after
an initial delay. By using ion exchange resin particles as a carrier for
the active ingredient, the present invention facilitates the relatively rapid
delivery of active once the drug / resin particles are exposed. The
s enteric coating protects the drug / resin particles until they have passed
through the stomach where the strongly acidic conditions would degrade
the benzimidazole active ingredient. In addition, adsorption of the
active ingredient on to the resin protects it from the potentially
detrimental effects of the enteric coating.
~o Although the drug loaded resin compositions according to the present
invention can be used as a final oral dosage form, they can also be
adapted for a range of final oral dosage forms, including controlled
release dosage forms. Suitable final dosage forms include, for example.
suspension, syrup, capsule, tablet, sprinkle, sachet, effervescent tablet,
~s fast melt tablet, fast dissolving tablet and disintegrating tablet forms.
For example, the drug loaded, coated ion-exchange resin particles may
be formulated in a suspension and freeze-dried to form a fast dissolving
or disintegrating tablet. The compositions according to the invention
may also be formulated in solid form which is reconstituted as a
2o suspension prior to administration without losing any taste masking or
entero-protective property.
Drug loaded, coated resin particles of any size suitable for incorporation
into any one of the abovementioned final dosage forms may be used in
the practice of the invention. Typically drug loaded, coated resin
2s particles making up the multiparticulate composition of the present
invention have an average diameter (defined as Dsooo) of 20 - 750 pm.
Preferably the drug loaded, coated resin particles have an average
diameter (defined as DSOoo) of 30 - 300 p.m.
Conditions treatable by administration of a PPI and hence by an oral
3o dosage form of the present include duodenal and gastric ulcers and
reflux oesophagitis. A method for treating these conditions can include
administering to a patient suffering from said conditions a
therapeutically effective amount of a proton pump inhibitor in the form
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of an oral dosage form in which the proton pump inhibitor is adsorbed
onto ion exchange resin material forming cores of an ion exchange resin
drug complex which are subsequently coated with an enteric coating.
Specifically, the method of treatment inhibits gastric acid secretion by
administering to mammals, including humans, suffering from acid
secretion related conditions a therapeutically effective amount of a
proton pump inhibitor in the form of an oral dosage form of the present
invention.
In the following examples: all percentages are by weight (w/w) unless
o stated otherwise; and the term "purified water" relates to water which
has been distilled and purified using an ion-exchange water purification
apparatus. Omeprazole concentrations were determined using HPLC.
The invention is further illustrated by the following Examples but is not
limited by these Examples.
~s Modes for Carrying_Out the Invention
Examples
Example I
Ketolide ( 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo- I 2, I 1-
20 (oxycarbonyl(4-(4-(3-pyridinyl)- I H-imidazol- I -yl)butyl)imino))
erythromycin), also referred to below as "the active ingredient" or
"ketolide" composition.
In the case of the abovementioned ketolide a taste-masked powder
formulation would be attractive due to the unpleasant taste
2s characteristics of the drug. The physicochemical properties of this
compound are such that as the pH of the drug in solution is lowered the
drug is completely ionised, each of three nitrogen atoms being
protonated according to their respective pKa values. The protonated
drug may then be loaded onto a cationic exchange resin (such as a cation
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exchange resin material as listed above) to form a drug-resin complex.
However, binding of this active ingredient to the ion-exchange resin is
not sufficient to completely mask the taste of the drug as judged by a
panel of seven. In this case coating the drug-resin complex with a
s coating polymer results in a composition possessing the required taste
masked and organoleptic character. The formulation of a taste masked
ketolide composition according to the invention is given below.
Two placebo granulates were prepared, the first having a flavouring
agent added intra-granularly and the other having the flavouring agent
~o added extra-granularly. Details of the placebo granulates are given in
Table 1. The granulates were prepared as follows: the raw materials
were dry mixed; purified water was added slowly until effective
granulation was achieved and the granulate was left to tray-dry in an
oven at ca 40 °C overnight. This resulting granulate was size-reduced
is through a 0.25 mm screen using an Erweka oscillating granulator to
form a fine granulate. In the case of the intra-granular mix, the
peppermint oil was added prior to the addition of water. In the case of
the extra-granular mix, the peppermint oil was added to the fine
granulate.
25
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1S
Material "Intra-granular" "Extra-granular"
(g) (8)
Xyiisorb 300 86.74 86.98
Neosorb P60 86.74 86.98
Citric acid 5.00 5.00
Aspartame 1.04 1.04
Kollidon 30 20.00 20.00
Peppermint oil 0.48 4.67
Table 1. Composition of placebo granulate with peppermint flavour
added intra-granularly and extra-granularly.
The cation exchange resin (Dowex SOWX2-400, 2 Kg) was washed with
s purified water (S L) for 1 S min. The washed resin was recovered and
loaded with the active ingredient to a potency of 400 mg drug / g drug
loaded resin by mixing the resin in a solution of 8 % active ingredient in
1 N HC1 for 60 min. The loaded resin was recovered by filtration,
washed with purified water and oven dried at 40 °C.
io The drug-resin complex was then mixed with the placebo granulate
described above to form an uncoated drug-resin ketolide composition.
Three different ratios of drug-resin complex to granulate were prepared
using (i) the "intra-granular" and (ii) "extra-granular" placebo
respectively in the following ratios: 75 : 2S (drug-resin complex
~s granulate); SO : SO (drug-resin complex : granulate); and 2~ : 7S (drug-
resin complex : granulate).
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The uncoated drug-resin ketolide compositions thus prepared were
found to have improved taste characteristics compared to the raw drug,
but still had an unpleasant after taste. The taste of the resin material
itself may have contributed to this.
Example 2
Taste-masked ketolide ( 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-
O-methyl-alpha-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-
(oxycarbonyl(4-(4-(3-pyridinyl)-1 H-imidazol-1-yl)butyl)imino))
erythromycin), also referred to below as "the active ingredient" or
io "ketolide" composition.
The cation exchange resin (Dowex SOWX2-400, 2 Kg) was washed
with purified water (5 L) for 1 S min. The washed resin was recovered
and loaded with the active ingredient to a potency of 400 rng drug / g
drug loaded resin by mixing the resin in a solution of 8 % the active
~s ingredient in 1 N HCl for 60 min. The loaded resin was recovered by
filtration, washed with purified water and dried in a Uniglatt (Glatt Air
Techniques, ) at 40 °C.
The uncoated drug-resin ketolide compositions prepared above was then
coated in a Glatt GPCGI, with a 15 % aqueous solution of Eudragit
'o RD100 : Syloid 244 FP : Polysorbate 80 (5:1:1) to a level of 50
weight gain with Eudragit RD 100, at a spray rate of 8 g / min and
product temperature of 23-27 °C. The particle size of the 50 % coated
resin was determined by a dry powder method in a Malvern Mastersizer
S (Malvern Instruments Limited, Malvern, Worcestershire, UK) as the
~s following: D~,,o = 95.37p,m, DSO = 125.53 pm, D",9o = 167.85 Vim. The
coated drug-resin complex was found to be essentially tasteless.
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Examples 3 and 4. Omeprazole l ion exchange resin formulation using
Eudragit L~ coating.
Example 3
(i) Loading of active ingredient on to resin.
s Anion exchange resin PCA-433 (4,000 g) was added to a stainless steel
container, washed by stirring in purified water (SO I) and subsequently
activated by stirring in a solution of NaOH ( 1 M). The resin material
particles were loaded with the active ingredient by stirring the resin in a
3.0 % solution of omeprazole (supplied by Reddy Cheminoir,
~o Ridgewood, NJ) in NaOH (I M) (4 1 total volume of omeprazole
solution) to form drug loaded particle cores. The potency of the drug
solution was determined prior to and after loading on to the resin. The
loaded particle cores were washed with purified water to remove any
surface uncomplexed omeprazole, recovered and dried at 40 °C. After
is loading, the potency of the drug loaded particles cores was determined
to be 177 mg/g.
(ii) Coating of drug l resin particles.
A coating solution was prepared according to the formulation shown in
Table 2. The coating solution was applied to the omeprazole loaded
2o resin particles cores using a Vector FLM-1 S Fluid Bed (Vector Corp.,
Cranbury, NJ) coating apparatus equipped with a Wurster column. The
coating solution was applied at a spray rate of 45-50 g/min, with the
inlet and outlet temperatures set at SS and 32 °C respectively and an
atomisation pressure of 3 bar. The product temperature during the
~s process was typically about 35 °C. 167 % solids with respect to the
drug
loaded resin particle weight was applied onto the drug loaded resin
particles. Agglomeration was found to be negligible.
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Component Quantity
Eudragit~ L 12.5 * I 5,990g
Isopropanol 12,270 g
Triethylcitrate 79g g
Micronised talc 399 g
(*supplied by Rohm as a 12.5 % w/w polymer solution in isopropanol)
Table 2. Coating solution formulation for Example 3.
(iii) Acid stability and dissolution data.
The particles prepared as detailed in (i) and (ii) above, tested according
s to a modified version of the United States Pharmacopoeia method for
enteric protection (USP 23, 1995, p. 1795). The modifications were as
follows: simulated gastric fluid (O. I M HCl/NaCI) without pepsin was
used in place of 0.1 M HC1; the sample was stirred at 75 rpm (instead of
100 rpm) and filtered prior to assay. Testing for enteric protection
~o showed no acid degradation of the omeprazole active ingredient over a
period of 1 hour, indicative of good enteric protection provided by the
coating. After 2 hours about 13 % of the active ingredient was found to
have degraded.
The rate of release of the active ingredient under alkali conditions (pH
is 9.1 buffer) was determined by spectrophotometrically using an Hewlett
Packard 8452A Diode Array UV spectrometer. Table 3 shows the
dissolution data for the particles prepared according to the procedures
detailed in (i) and (ii) (USP II paddles; 900 ml buffer pH 9.1; stirred at
100 rpm). From the data it can be seen that up to about 80 % of the
Zo active ingredient loaded on to the resin is release in under 60 mins under
the test conditions.
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Time % Omeprazole released
(min.) (pH 9.1 buffer)
0 0
15 48.5
30 68.5
45 74.5
60 80.3
90 85.1
120 87.4
Table 3. Dissolution data for particles prepared according to Example 3.
Example 4
s (i) Loading of active ingredient on to resin.
Essentially the same procedure as detailed in Example 3 was used to
prepare a second batch of omeprazole loaded resin particles. Anion
exchange resin PCA-433 (4,000 g) was added to a stainless steel
column, washed by passing purified water (80 I) through the column and
io subsequently activated using a solution of NaOH ( 1 M), (801). The
resin material particles were loaded with the active ingredient by passing
a 4.0 % solution of omeprazole in NaOH ( I M) through the column (40 1
total volume of omeprazole solution). The potency of the drug solution
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was determined spectrophotometrically prior to and after loading on to
the resin. The loaded particles were washed with purified water to
remove any surface uncomplexed omeprazole, recovered from the
column and dried at 40 °C. After loading, the potency of the drug
loaded particles cores was determined to be 370 mg/g.
(ii) Coating of drug l resin particles.
The loaded particles cores were coated using a coating solution made up
in the same proportions as that detailed in Example 3 and the same
coating conditions described in relation to Example 3. 200 % solids
to with respect to the drug loaded resin particle weight was applied onto
the drug loaded resin particles. Agglomeration was found to be
negligible.
(iii) Acid stability and dissolution data.
The particles prepared according to Example 4 were tested according to
~s the USP method for enteric protection modified as described above in
Example 1 and showed no acid degradation of the omeprazole active
ingredient over a period of greater than 1 hour, indicative of good
enteric protection provided by the coating. Further, no degradation of
the active ingredient was observed after 2 hours.
Zo The rate of release of the active ingredient under alkali conditions (pH
7.4 buffer) was determined by HPLC. Table 4 shows the dissolution
data for the particles prepared according to Example 4 (USP II paddles;
900 ml buffer pH 7.4; stirred at 750 rpm). From the data it can be seen
that about 93 % of the active ingredient loaded on to the resin is release
2s in 60 mins under the test conditions.
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Time % OmeprazoIe released
(min.) (pH 7.4 buffer)
0 0
30 77.8
45 85.7
60 93 .1
Table 4. Dissolution data for particles prepared according to Example 4.
Example 5
Omeprazole l ion exchange resin formulation using HPMCP coating.
s Omeprazole loaded PCA-433 resin particles were prepared substantially
according to the method described in Example 3. In this instance a 1.0
omeprazole solution (same volume) was used in loading the resin
particles and the potency of the drug / loaded particles was determined
to be 91 mg/g.
io (ii) Coating of drug l resin particles.
A coating solution was prepared according to the formulation shown in
Table 5. The coating solution was applied to the omeprazole loaded
resin particles using a Glatt CPCGS Fluid Bed (Glatt Air Techniques,
Inc., Ramsey, NJ)coating apparatus equipped with a Wurster column.
~s The coating solution was applied at a spray rate of 45-50 g/min, with the
inlet and outlet temperatures set at 65 and 45 °C respectively and an
atomisation pressure of 3 bar. The product temperature during the
process was typically about 48 °C. 55 % solids was applied onto the
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drug loaded resin particles. Some agglomeration of particles was
evident.
Component Quantity
HPMCP-HP50" 1,006 g
NH44H 161 g
Triethylcitrate 101 g
('manufactured by Eastman Chemicals (Kingsport, TN))
s Table S. Coating solution formulation for Example 5.
Example 6
Preparation of fast melt tablets from Eudragit~ coated omeprazole l ion
exchange resin particles - 5lend.
~o (i) Manufacture ofgranulate.
A granulate comprising the components shown in Table 6, below, was
prepared by spraying an aqueous PEG 6000 solution onto the remaining
components listed in Table 6 in a Niro Aeromatic, Strea 1 granulator
(Niro Aeromatic AG, Bubendorf, Switzerland) at a temperature of 27 °C
~ s and a spray rate of 10 ml/min. After spraying the material was dried for
one hour in the fluidising chamber of the granulator.
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Component Quantity (g)
Sorbitol 220.4
Xylitol 220.4
Citric Acid I2.5
Aspartame 2.$
PEG 6000 25.0
Purified Water 50.0
Table 6. Granulate formulation for Example 6.
(ii) Manufacture offast melt tablets.
s The granulate prepared in (i) above was blended with omeprazole
loaded enterically coated resins beads (31.25 g) prepared according to
Example 3 above together with orange flavour (7.50 g) for 1 S min.
Magnesium stearate ( 1.67 g) was added and the mixture was blended for
a further 5 min. Tablets were pressed using a Ronche CT 20 single
io station tablet press (Ronche, Milan, Italy) with a 16 mm round punch.
Tablet hardness was determined using a Schleunger 6D hardness teste
(Dr. Schleunger Pharmatron AG, Solothurn, Switzerland). The average
tablet weight was 1249 mg with an average hardness of 8.1 kPa.
is
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Example 7
Preparation of fast melt tablets from Eudragit~ coated omeprazole l ion
exchange resin particles - granulate.
s Whereas the omeprazole containing resin particles were blended with a
performed granulate in Example 6 above, a second batch of fast melt
tablets was prepared in which the omeprazole containing resin particles
were added prior to granulation. Mint flavour (7.5 g) and magnesium
stearate (1.67 g) were added and the granulate, details of which are
to shown in Table 7, was pressed into tablets as described in the previous
Example. The average tablet weight was 1190 mg with an average
hardness of 5.42 kPa.
Component Quantity (g)
Omeprazole resin particles 62.5
Sorbitol 189.6
Xylitol 189.6
Citric acid 12.5
Aspartame 2.5
PEG 6000 2.5
Table 7. Composition and weight & hardness data for fast melt tablets
is prepared according to Example 7.
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The present invention is not to be limited in scope by the specific
embodiments described herein. Indeed, various modifications of the
invention in addition to those described herein will become apparent to
those skilled in the art from the foregoing description. Such
modifications are intended to fall within the scope of the appended
claims. All patents and references described above are herein
incorporated by reference.
