Field of the Invention
The present invention relates to multiple unit tablet composition comprising a
pharmaceutically active ingredient and a process for preparing them.
Background and Prior Art of the Invention
Multiple unit dosage forms are multiparticulate drug delivery systems consisting of
plurality of pellets, granules, spherules, micro spheres, mini tablets and other drug
substance containing agglomerations or particles that can be loaded into either a
capsule or tablet. Single unit dosage forms are traditional tablets and powder-filled
capsules.
Multiple unit dosage forms offer numerous significant therapeutic advantages over
traditional single unit dosage forms, that these generally disperse freely in the
gastrointestinal tract and behave like liquids, leaving the stomach within a short
period of time, which results in:
- improved biopharmaceutical characteristics, such as improved bioavailability,
reduced the effect of the food on plasma profiles and in such way reduced intra- and
inter-subject variability of plasma profiles,
- reduced peak plasma fluctuations and in such way minimized potential side effects, -
minimized local irritation in gastrointestinal tract.
When formulated as modified release dosage forms, multiple units perform improved
safety and efficacy, since they are less susceptible to dose dumping than single unit
formulations with modified release. Multiple unit dosage forms are commonly filled
into hard capsules. The alternative method of formulating multiple units is
compacting into multiple unit tablets. This approach becomes increasingly important
in pharmaceutical industry because of combining the advantages of multiple unit
dosage forms and tablets in one final dosage form.
Two main challenges of formulating of multiple units into multiple unit tablets are:
- Tableting of multiple units into multiple unit tablets is mechanically stressful

process for multiple units that are likely to be mechanically damaged during
compression step of tableting. The damage of the multiple units during compression
step of tableting can result in altered drug release. This is especially critical when
multiple units coated with functional coating that assures modified release are tableted
into multiple unit tablets, because compression step of tableting often results in
rupture of functional coating.
During the compression step of tableting of pellets with tableting excipients the
particle segregation tends to occur, because of different size and shape of multiple
units and particles of excipients. The particle segregation results in inappropriate
content and mass uniformity of multiple unit tablets.
Therefore, two main requirements that must be met when formulating multiple unit
tablets are that drug release from multiple unit tablets is not altered compared to the
drug release from multiple units prior to tableting, and that the content and mass
uniformity of multiple unit tablets complies with pharmacopoeia prescriptions.
Additionally, multiple unit tablets must be coherent and have appropriate hardness
and friability, so that they could be further handled, such as coated and packed.
There are two approaches in multiple units tableting:
- tableting of multiple units without other excipients for tableting, and
- tableting of multiple units together with pharmaceutically acceptable excipients.
The approach of compacting of only multiple units without other excipients for
tableting does not include the problem of particle segregation, but includes very
difficult formulation of multiple units and the coating of multiple units. Multiple unit
cores must be deformable enough so that they form coherent tablets, and the coatings
of multiple units must be able to withstand compacting without damages, which can
be ensured by formulating the coating of multiple units in such way that the coating
posses improved elasticity.

The approach of compacting of multiple units together with pharmaceutically
acceptable tableting excipients moderates requirements for the multiple units coating
elastic properties, since plastically deformable or soft tableting excipients are able to
partly absorb compaction forces and protect multiple units from mechanical damages.
This approach enables also easier obtaining of coherent multiple unit tablets that have
appropriate hardness and friability, because tableting excipients have larger surface
area than subunits and better bonding inside multiple unit tablets.
However, tableting of multiple units together with pharmaceutically acceptable
tableting excipients includes problem of particle segregation. Particle segregation in
the tableting mixture results in tableting problems, such as weight variation and poor
content uniformity.
US 5,753,265 relates to an oral pharmaceutical composition in the form of a multiple
unit tablet comprising: a tablet excipient; a multiple of a core unit comprising as an
active ingredient an acid-labile H+ K+-ATPase inhibitor compound in a neutral form
or a salt form, a single enantiorner or an alkaline salt of a single enantiomcr;
the core unit being covered with at least one enteric coating layer having mechanical
properties so as not to significantly affect the acid resistance of the enteric coating
layered unit by compression during tableting.
WO 2008/047320 relates to multiple unit tablet compositions of benzimidazole
compounds and process of preparation thereof. The compositions are useful against
various gastrointestinal disorders. The multiple unit tablet composition comprises: a)
tablet excipients, and b) multiple enteric coated core units containing a benzimidazole
compound, wherein each core unit is covered with an enteric coating layer comprising
a plasticizer in an amount of less than 15% by weight of the enteric coating layer
polymer.
WO 2008/006534 discloses multiple unit tablets comprising multiple units compacted
together with at least two tablet filler-binders and optionally other pharmaceutically
acceptable excipients, wherein at least one of said tablet filler-binder is a tablet filler-
binder having mean particle size-to-mean multiple unit size ratio from 10% to 40%,

and at least one of said tablet filler-binder is a tablet filler-binder having mean particle
size-to-mean multiple unit size ratio from 1 % to 10%.
It has been surprisingly found by the inventors that robust multiple unit tablet
compositions having excellent mechanical properties of enteric coated multiple unit
cores without damaging or rupturing during the compression, further without altering
the acid resistance can be prepared by using atleast two diluents, wherein one diluent
is highly compactible microcrystalline cellulose along with enteric coated multiple
unit cores, wherein the plasticizer content of enteric coating layer is less than about
10% by weight of enteric coating polymer.
Objects of the Invention
According to one embodiment a multiple unit tablet composition comprising:
an enteric coated multiple unit cores comprising a pharmaceutically active ingredient,
wherein plasticizer content of enteric coating is less than about 10% by weight of the
enteric coating polymer,
atleast two diluents and optionally one or more pharmaceutically acceptable
excipient(s), wherein one diluent is highly compactible microcrystalline cellulose.
According to another embodiment a multiple unit tablet composition comprising:
(i) a enteric coated multiple unit cores comprising a pharmaceutically active
ingredient, wherein plasticizer content of enteric coating is less than about 10% by
weight of the enteric coating polymer,
(ii) atleast two diluents and optionally one or more pharmaceutically acceptable
excipient(s), wherein one diluent is highly compactible microcrystalline cellulose,
wherein the multiple units of the active ingredient are about 20-45% of the tablet
weight.
According to yet another embodiment a multiple unit tablet composition comprising:
(i) enteric coated multiple unit cores comprising a pharmaceutically active ingredient,
wherein plasticizer content of enteric coating is less than about 10% by weight of the
enteric coating polymer,

(ii) atleast two diluents and optionally one or more pharmaceutically acceptable
excipient(s), wherein one diluent is highly compactible microcrystalline cellulose,
wherein the multiple units of the active ingredient are about 20-45% of the tablet
weight, and the multiple unit tablet composition has mechanical properties wherein
the acid resistance is not compromised.
According to yet another embodiment a multiple unit tablet composition comprising:
(i) enteric coated multiple unit cores comprising a pharmaceutically active ingredient,
wherein plasticizer content of enteric coating is less than about 10% by weight of the
enteric coating polymer,
(ii) atleast two diluents, one or more stabilizers and optionally one or more
pharmaceutically acceptable excipient(s), wherein one diluent is highly compactible
microcrystalline cellulose, wherein the multiple units of the active ingredient are
about 20-45% of the tablet weight, and the multiple unit tablet composition has
mechanical properties wherein the acid resistance is not compromised.
According to yet another embodiment a process for the preparation of multiple unit
tablet composition comprising the steps of mixing enteric coated multiple unit cores
of active ingredient having plasticizer content of less than about 10% by weight of the
enteric coating polymer with atleast two diluents having highly compactible
microcrystalline cellulose as one diluent and one or more other pharmaceutically
acceptable excipients and compressed.
Summary of the Invention
One aspect of the present invention embodies a multiple unit tablet composition
comprising:
(i) an enteric coated multiple unit cores comprising a pharmaceutically active
ingredient, wherein plasticizer content of enteric coating is less than about
10% by weight of the enteric coating polymer;
(ii) atleast two diluents and optionally one or more other pharmaceutically
acceptable excipient, wherein one diluent is highly compactable
microcrystalline cellulose.

Yet another aspect of the invention embodies a process for the preparation of multiple
unit tablet composition comprising the steps of mixing enteric coated multiple unit
cores of active ingredient having plasticizer content of less than about 10% by weight
of the enteric coating polymer with, atleast two diluents having high compactible
microcrystalline cellulose as one diluent and one or more other pharmaceutically
acceptable excipients and compressed.
Detailed Description of the Invention
According to one embodiment a multiple unit tablet composition comprising:
an enteric coated multiple unit cores comprising a pharmaceutically active ingredient,
wherein plasticizer content of enteric coating is less than about 10% by weight of the
enteric coating polymer,
atleast two diluents and optionally one or more pharmaceutically acceptable
excipient(s), wherein one diluent is highly compactible microcrystalline cellulose
The pharmaceutically active ingredient comprised in multiple units in multiple unit
tablets according to the present invention may be selected from the group consisting
of analgesics, anticonvulsants, antiparkinsonics, anesthetics, antibiotics,
antihypertensives, antihistamines, antimalarial agents, antimigraine agents, anti-
obesity agents, serum lipid reducing agents, antipyretics, alpha-blockers, alpha-
adrenergic agonists, bactericides, bronchial dilators, beta-adrenergic stimulants, beta-
adrenergic blockers, enzymes, contraceptives, cardiovascular active substances,
calcium channel inhibitors, proton pump inhibitors, diuretics, hypnotics, hormones,
hyperglycemics, hypoglycemics, muscle relaxants and contractors,
parasympathomimetics, sedatives, sympathomimetics, tranquillizers, vitamins or their
pharmaceutically acceptable salt, polymorph, solvate(s), hydrate(s), enantiomer(s) and
any combinations thereof. Preferably, the pharmaceutically active ingredient is proton
pump inhibitor, such as omeprazole, esomeprazole, lansoprazole, rabeprazole,
pantoprazole or their pharmaceutically acceptable salt, polymorph, solvate(s),
hydrate(s), enantiomer(s) thereof.

One or more pharmaceutically acceptable excipient(s) are but not limited to binders,
diluents, disintegrants, surfactants (solubilizers/wetting), lubricants/glidants. One
excipient can perform more than one function.
The diluents may be selected from hydrogenated vegetable oil, one or more of sugars
like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose
derivatives like powdered cellulose, microcrystalline cellulose; starches like corn
starch, pregelatinized starch, maize starch and mixtures thereof. Two grades of the
same diluent can also be used.
The one of the diluent used in the present invention acts as a means of direct
compression by providing high compactibihty, the most preferable diluent used is but
not limited to Microcrystalline cellulose i.c CEOLUS™ KG. CEOLUS™ KG has
extraordinary compactibility and is a maximum-eompactibility MCC powder with
Rodform particles.
The unparalleled compactibility of CEOLUS™ KG originates in its distinctive
rodform particles. This compactibility enables, in particular:
■ Reduced MCC addition and tablet size.
■ Reduced compression force and superior tableting of pressure-sensitive
enzymes, antibiotics, and film-coated granules.
We have surprisingly found that by using CEOLUS™ KG as one of the diluents helps
in reducing the plasticizer content in the enteric layer to about less than 10% further
without compromising the mechanical properties of enteric coated multiple unit cores
i.e without damaging or rupturing during the compression, thereby not altering acid
resistance.
In addition to mechanical properties, CEOLUS™ KG also helps in making robust
tablets having appropriate hardness and friability so that they could be further coated
and packed, it has being found that the friability of the composition of the
compoisition is less than 0.15% or most preferably nil.

The binders are selected from but not limited to one or more of cellulose derivatives
like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums
like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers
like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars
like sorbitol, mannitol and mixtures thereof.
The disintegrants are selected from but not limited to one or more of croscarmellose
sodium, carmellose sodium, carmellose calcium, crospovidone, sodium starch
glycolate, low-substituted hydroxypropyl cellulose, hydroxypropyl starch,
crospovidone, cornstarch and mixtures thereof.
The lubricants/glidnts are selected from but not limited to one or more of magnesium
stearate, stearic acid, sodium stearyl fumarate, calcium stearate, zinc stearate,colloidal
silicon dioxide or mixture thereof.
The surfactant may be selected from but not limited to one or more of sodium lauryl
sulphate, polysorbate 80 ,Polaxmer, DSS (dioctyl sodium sulfosuccinate),
triethanolamine, sodium lauryl sulphate, polyoxyethylene sorbitan and poloxalkol
derivatives, quaternary ammonium salts or mixtures thereof or other pharmaceutieally
acceptable surface-active agents known to one ordinary skilled in the art. The
surfactant further helps in improving the solubility and bioavailability of the
composition.
The core may be in the form of pellets, granules, beads or inert core. The core may be
acidic, alkaline or neutral depending on the type of Composition. The core may
contain one or more pharmaceutieally acceptable excipients selected from the group
consisting of inert carriers, binders, diluents, disintegrants, lubricants/glidants,
solubilizers/wetting agents and mixtures thereof. In the inert core the inert carrier may
be coated with the proton pump inhibitor and one or more of the binders, diluents,
disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
The inert carrier may comprise starch, microcrystalline cellulose or sugar sphere such
as nonpareil sugar seeds. The inert carrier may be further hardened by preparing the
binder solution in water or alcohol or hydroalcoliolic solvents and spraying the binder

solution on the inert carrier. The hardening solution has a binder, active ingredient
and optionally one or more pharmaceutically acceptable excipient. The hardened inert
carrier further helps in providing robustness to the composition.
The core may be coated with a separating layer prior to the enteric coating layer. The
separating layer is made up of water-soluble material, which is capable of dissolving
or forming a gel in contact with water. Such material may include water-soluble
polymer and/or water-soluble substance. The water-soluble substance may be selected
from but not limited to glucose, lactose, mannitol, sorbitol, sucrose, dextrose and
mixtures thereof. The water-soluble polymers may be selected from but not limited to
hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone,
sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and
vinyl acetate.
An enteric coating layer is applied onto the core coated with the separating layer. The
enteric coating layer may include polymers such as but not limited to cellulose acetate
phthalate, hydroxypropylmelhyl cellulose phthalate, polyvinyl acetate phthalate,
carboxymethylethylcellulose, methacrylic acid copolymers, for example, compounds
known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L
100 55 or any combinations and mixtures thereof.
The enteric coating layer contains plasticizers and may also include inert excipients
such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl
mefhylcellulose and crospovidone Such plasticizers are for instance, but not limited
to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol,
polyethylene glycols, polysorbates or other plasticizers. The plasticizer is used in an
amount of less than about 10 % by weight of the enteric coating layer more preferably
the plasticizer is about 8% by weight of the enteric coating polymer. Surprisingly, we
have found that by using CEOLUS™ KG as one of the diluents the acid resistance of
the multiple unit tablets is not compromised even if we reduce the plasticizer content
to less than about 8%.
The core covered with enteric coating layer may further be covered with one or more
over-coating layers. The materials for over-coating layers are pharmaceutically

acceptable compounds such as but not limited to sugar, polyethylene glycol,
polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose,
methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and
carboxymethylcellulose sodium, used alone or in mixtures. Additives such as
plasticizers, colorants, pigments, fillers, anti-tacking and antistatic agents, such as
magnesium stearate, titanium dioxide and talc may also be included into the over-
coating layer. Said over-coating layer may further prevent potential agglomeration of
enteric coating layered core, protect the enteric coating layer towards cracking during
the compaction process and enhance the tableting process.
These coating layers comprises one or more excipients selected from the group
comprising but not limited to coating agents, opacifiers, taste-masking agents,
diluents, polishing agents, colouring agents, antitacking agents and the like.
Pharmaceutical composition of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a tluidized bed or
a pan and hot melt (extrusion) coating. Such methods are well known to those skilled
in the art.
Another embodiment is a multiple unit tablet composition comprising:
(i) a enteric coated multiple unit cores comprising a pharmaceutically active
ingredient, wherein plasticizer content of enteric coating is less than about 10% by
weight of the enteric coating polymer,
(ii) atleast two diluents and optionally one or more pharmaceutically acceptable
excipient(s), wherein one diluent is highly compactible microcrystalline cellulose,
wherein the multiple units of the active ingredient are about 20-45% of the tablet
weight.
It has been found that by using the multiple units to about 20-45% of the total tablet
weight helps in avoiding the segregation and aids in proper flow of the powder from
the hopper thereby maintaining the content uniformity in the multiple unit tablet
composition.

According to yet another embodiment a multiple unit tablet composition comprising:
(i) enteric coated multiple unit cores comprising a pharmaceutically active ingredient,
wherein plasticizer content of enteric coating is less than about 10% by weight of the
enteric coating polymer,
(ii) atleast two diluents, one or more stabilizers and optionally one or more
pharmaceutically acceptable excipient(s), wherein one diluent is highly compactible
microcrystalline cellulose, wherein the multiple units of the active ingredient are
about 20-45% of the tablet weight, and the multiple unit tablet composition has
mechanical properties wherein the acid resistance is not compromised.
Stabilizer can be chosen among, but are not limited to, substances such as meglumine;
L-cysteine hydrochloride; glycine hydrochloride; malic acid; sodium metabisulfate;
citric acid, tartaric acid and L-cysteine dehydrochloride. sodium, potassium, calcium,
magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other
suitable weak inorganic or organic acids; aluminum hydroxide/sodium bicarbonate co
precipitate; substances normally used in antacid preparations such as aluminum,
calcium and magnesium hydroxides; magnesium oxide or composite substances, such
as Al2O3 , 6MgO.CO2.12H2O, (Mg 6 Al2(OH)16 CO3 4H2 O), MgO.Al2O3 , 2SiO2.
nH2O or similar compounds; organic pH-buffering substances such as
trihydroxymethylaminomethane, basic amino acids and their salts or other similar,
pharmaceutically acceptable pH-buffering substances. The most preferred stabilizer is
alkaline agent which helps in increasing the pH of the microenvironment and further
helps in increasing the stability of the composition.
According to yet another embodiment a process for the preparation of multiple unit
tablet composition comprising the steps of mixing enteric coated multiple unit cores
of active ingredient having plasticizer content of less than about 10% by weight of the
enteric coating polymer with atleast two diluents having highly compactible
microcrystalline cellulose as one diluent and one or more other pharmaceutically
acceptable excipients and compressed.
The pharmaceutical composition of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation (aqueous, non-aqueous,

hydroalcoholic), melt granulation, direct compression, dry granulation, double
compression, extrusion spheronization, layering and the like.
The solvent(s) used in wet granulation in the present invention include all the solvents
well known in the art or their mixtures thereof.
The most preferable process used for preparation of multiple unit tablet composition
is non-aqueous and thus avoids the laborious process of drying the granules obtained
in each step which further helps in avoiding the loss of active and thus improving the
content uniformity.
The following examples are illustrative of the present invention, and the examples
should not be considered as limiting the scope of this invention in any way, as these
examples and other equivalents thereof will become apparent to those versed in the
art, in the light of the present disclosure, and the accompanying claims
Examples:
Preparation of over coated pellets
Example 1:

Process of preparation of over coated pellets:
1. Dissolved PVP, Tween 80 and API in Methanol
2. Spray the solution of Step 2 on Sugar Spheres to get the drug-loaded pellets.
3. Dissolve PEG and HPMC in IPA and DCM mixture
4. Spray the solution of Step 3 on Step 2 drug loaded pellets to get barrier-coated
pellets.
5. Dissolve Eudragit and TEC in IPA-DCM mixture and disperse Talc and
Tween 80 in the same
6. Spray the solution of Step 5 on Step 4 barrier coated pellets to get the enteric-
coated pellets.
7. Dissolve HPMC in IPA-DCM mixture and disperse talc in the same.
8. Spray the solution of Step 7 on Step 6 enteric coated pellets to get the over-
coated pellets.
Preparation of multiple unit tablets using overcoated pellets of example 2
Example 3:

Process for preparation of multiple unit tablets:
1. Mix the weighed quantity of over coated pellets, SMCC, Hydrogenated
vegetable oil, MCC 500, Crospovidone, magnesium carbonate, Avicel PH
101 & MCC (Ceolus KG -802) in a cone blender for 20 min.
2. Compress the above blend into tablet and film coat the tablets with
Opadry.
Acid Resistance
Dissolution of the multiple unit tablets was carried out in 0.1NHC1 at 100RPM Type
II apparatus for 2 hours. The results are as follows:


We Claim
1. A multiple unit tablet composition comprising:
(iii) an enteric coated multiple unit cores comprising a pharmaceutically active
ingredient, wherein plasticizer content of enteric coating is less than about
10% by weight of the enteric coating polymer;
(iv) atleast two diluents and optionally one or more other pharmaceutically
acceptable excipient, wherein one diluent is highly compactable
microcrystalline cellulose.
2. A multiple unit tablet composition according to claim 1 wherein the
pharmaceutically active ingredient is a benzimidazole derivative.
3. A multiple unit tablet composition according to claim 2 wherein the
benzimidazole derivative is a proton pump inhibitor.
4. A multiple unit tablet composition according to claim 1 wherein said multiple
units have separating layer between the core and the enteric coating layer.
5. A multiple unit tablet composition according to claim 1 wherein one diluent is
selected from confectioner's sugar, compressible sugar, dextrates, dextrin,
dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol,
talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic
or tribasic, calcium sulphate, or combinations thereof.
6. A multiple unit tablet composition according to claim 1 wherein one or more
pharmaceutically acceptable excipient is selected from the binders, diluents,
lubricants, surfactants or glidants.
7. A multiple unit tablet composition according to claim 1 wherein the multiple
units containing the active ingredient consitute about 20-45% of the total
tablet weight.
8. A multiple unit tablet composition according to claim 1, wherein the acid
resistance of the individually enteric coated multiple units is in compliance
with the requirements of enteric coated articles defined in US Pharmacopoeia

9. A process for the preparation of multiple unit tablet composition comprising
the steps of mixing enteric coated multiple unit cores of active ingredient
having plasticizer content of less than about 10% by weight of the enteric
coating polymer with, atleast two diluents having high compactible
microcrystalline cellulose as one diluent and one or more other
pharmaceutically acceptable excipients and compressed.

A multiple unit tablet composition comprising an enteric coated multiple unit cores
comprising a pharmaceutically active ingredient, wherein plasticizer content of enteric
coating is less than about 10% by weight of the enteric coating polymer; atleast two
diluents and optionally one or more other pharmaceutically acceptable excipient,
wherein one diluent is highly compactable microcrystalline cellulose and process for
preparing the same.