FIELD OF THE INVENTION
The present invention relates to a solid oral pharmaceutical composition of Pancreatin and a
process of preparing the same.
BACKGROUND OF THE INVENTION
Pancreatin is an extract derived from porcine pancreatic glands. It contains different digestive
enzymes such as lipases, proteases, and amylases. It is used in treatment of pancreatic exocrine
insufficiency (PEI) due to cystic fibrosis, chronic pancreatitis, pancreatectomy and other
conditions.
Pancreatin exhibits optimal activity under near neutral and slightly alkaline conditions. Under
gastric conditions, it gets inactivated with a resulting loss in biological activity. Owing to the
incompatibility of Pancreatin with the acidic environment present in human stomach, Pancreatin
compositions are generally coated with an enteric coating polymer so that the enzymes remain
intact during their transit through the stomach till they reach the upper part of intestine such as
the duodenum.
Patent No. EP1931317B discloses a process for the manufacture of pancreatin micropellet cores.
As per the examples given in the specification, the process uses 20% w/w or more of binder with
respect to the weight of the core.
Patent No. EP1931316B1 discloses an enteric coating comprising at least one film-forming agent
and a plasticizer which is a mixture of cetyl alcohol and triethyl citrate, which are collectively
present in an amount of greater than 3% by weight relative to the at least one film forming agent
and wherein the weight to weight ratio of cetyl alcohol to triethyl citrate is from 0.05:1 to 1:1.
Formulation C, D, E, F and 1 containing only triethyl citrate as the plasticizer are exemplified to
lack desired technical attributes and hence, are not the preferred compositions.
There exists a need to provide patients with compositions of Pancreatin which are not only in
compliance to the recommendations of governmental health authorities limiting the use of certain
excipients such as mineral oil (e.g. US Code of Federal Regulations, 21 CFR §201.302) and
monomeric phthalic acid ester plasticizers like dibutyl phthalate (e.g. directive 2003/36/EC of the
European Parliament and the Council of 26 May 2003 amending for the 25th time Council
2
Directive 76/769/EEC) but also prevent the intake of high amount of additives besides being cost
effective.
The Applicants have successfully developed a solid oral pharmaceutical composition comprising
Pancreatin which avoids the ingestion of undue amount of additives. The solid oral
pharmaceutical composition of the present invention is prepared by a process which is not only
simple, robust, but is also commercially viable. Further, the solid oral pharmaceutical
composition prepared by the process of the invention is in compliance to recommendations of the
governmental health authorities and is also stable when subjected to testing under stressed
conditions e.g. at a temperature of 30°C. and relative humidity ("RH") of 75% relative humidity
for a period of at least three months.
SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a solid oral pharmaceutical
composition of Pancreatin.
Further object of the present invention is to provide a solid oral pharmaceutical composition of
Pancreatin, wherein said composition comprises a core and at least one enteric coat layer over
the core.
Another object of the present invention is to provide a cost effective process for preparing a solid
oral pharmaceutical composition of Pancreatin, wherein said composition exhibits gastric acid
resistance, dissolution and storage stability which is either superior or comparable to the
marketed products by virtue of selection of excipients and manufacturing process.
The following embodiments further describe the objects of the present invention, however, the
disclosed invention is not restricted to the particular embodiments hereinafter described and
extends to cover the modifications obvious to one of ordinary skill in the art.
In a preferred embodiment, the solid oral pharmaceutical composition comprises: a) a core
comprising a therapeutically effective amount of Pancreatin with at least one pharmaceutically
acceptable excipient, wherein the core comprises at least one pharmaceutically acceptable
binding agent in an amount less than 10% by weight with respect to total weight of the core; b)
3
an enteric coat layer over the core comprising at least one enteric coating agent, a plasticizer and
optionally at least one anti-sticking agent.
In an another preferred embodiment, the solid oral pharmaceutical composition comprises: a) a
core comprising a therapeutically effective amount of Pancreatin with at least one
pharmaceutically acceptable excipient, wherein the core comprises at least one pharmaceutically
acceptable binding agent in an amount less than 10% by weight with respect to total weight of
the core; b) an enteric coat layer over the core comprising at least one enteric coating agent, a
plasticizer which is not present as a mixture and optionally at least one anti-sticking agent.
Another embodiment of the present invention provides a process for the preparation of a solid
oral pharmaceutical composition of Pancreatin, comprising the step of blending Pancreatin with
at least one pharmaceutically acceptable binding agent, wet granulating the blend, milling the
granules, extrusion of the wet mass followed by spheronisation of the extrudes obtained, drying
of the pellets, coating of the pellets with a solution of enteric polymer.
In the solid oral pharmaceutical composition of the present invention, the pharmaceutically
acceptable excipient comprises binding agents, enteric coating agents, plasticizers, and antisticking agents.
DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming
that, which is regarded as the invention, it is anticipated that the invention can be more readily
understood through reading the following detailed description of the invention and study of the
included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to
encompass a drug product comprising Pancreatin and other inert ingredient(s). Such
pharmaceutical compositions are synonymous with “formulation” and “dosage form”.
Pharmaceutical compositions of the invention include, but are not limited to, extrudes, pellets,
micropellets, microspheres, microtablets, granules, granulates, tablets, modified release tablets,
mini-tablets, pellets filled in capsule and the like. Preferably, the pharmaceutical composition
refers to enteric coated pellets filled in capsule.
4
The term “Pancreatin” as used herein, is synonymous to “Pancreatic enzyme", "Pancreatic acid"
and "Pancrelipase.
The term “immediate release (IR)” as used herein, refers to pharmaceutical compositions
comprising Pancreatin, which do not contain any drug release rate controlling agent. As a result,
release of the active ingredient from the composition results in an in-vitro release over a short
period of time, i.e., (less than one hour).
The term “controlled release (CR)” as used herein, refers to pharmaceutical compositions
comprising Pancreatin and one or more pharmaceutically acceptable excipients, which contain at
least one drug release rate controlling agent.
The term “delayed release (DR)” as used herein, refers to pharmaceutical compositions
comprising Pancreatin, at least one pH dependent drug release rate controlling agent, and one or
more pharmaceutically acceptable excipients. For the purpose of this invention enteric-coated
compositions are delayed release dosage forms.
The term "about" as used herein, refers to any value which lies within the range defined by a
variation of up to ±10% of the value.
The term "micro" as used herein, refers to an oral pharmaceutical composition if the diameter of
the oral dosage form or all of its dimensions (length, height, width) is equal to or below about 5
mm.
The term "gastric acid resistance" as used herein, refers to the ability of the enteric coated pellets
of Pancreatin to prevent release of the drug when the pellets are exposed to 800 mL of Simulated
gastric fluid (20 g of sodium chloride + 70 ml of concentrated hydrochloric acid in 10 litres of
water), using a basket apparatus at a temperature of 37±0.5°C and a rotation speed of 100
revolutions per minute for 60 minutes and exhibit rapid dissolution when the pellets are exposed
to pH 6.0 phosphate buffer (20 g of sodium chloride and 92 g of potassium dihydrogen
phosphate in 10 litres of water and adjust the pH to 6.0 ± 0.5 with 4 M sodium hydroxide
solution).
Unless otherwise stated the weight percentages expressed herein are based on the final weight of
the composition or formulation or dosage form.
5
The present invention relates to a cost effective solid oral pharmaceutical composition of
Pancreatin or its pharmaceutically acceptable salts.
A first aspect of the present invention provides a solid oral pharmaceutical composition
comprising Pancreatin, wherein the composition comprises:
a) a core comprising:
i. more than 85% by weight Pancreatin;
ii. less than 10% by weight of at least one pharmaceutically acceptable binding agent;
iii. optionally at least one organic solvent
wherein, the percentages are expressed with respect to the total weight of the core
b) an enteric coat layer over the core comprising:
i. at least one enteric coating agent;
ii. a plasticizer;
iii. optionally at least one anti-sticking agent;
It was found by inventors of the present invention that a solid oral pharmaceutical composition
comprising Pancreatin having less than 10% by weight of at least one pharmaceutically
acceptable binding agent in the core and surrounded by an enteric coat layer exhibited excellent
storage stability.
The term “storage stability” as used herein, refers to the stability of the solid oral pharmaceutical
composition comprising Pancreatin at a temperature of 30°C. and relative humidity ("RH") of
75% relative humidity for a period of at least three months.
According to one embodiment of the above aspect, the solid oral pharmaceutical composition is
an immediate release composition or a controlled release composition. The term controlled
release composition is used interchangeably with modified release composition and includes
delayed release composition, extended release composition or sustained release composition. In a
preferred embodiment, the solid oral pharmaceutical composition is a delayed release
composition.
According to another embodiment of the above aspect, the solid oral pharmaceutical composition
is in the form of powder, extrudes, pellets, micropellets, microspheres, microtablets, granules,
6
granulates, tablets, modified release tablets, mini-tablets, pellets filled in capsule and the like. In
a preferred embodiment, the solid oral pharmaceutical composition is in the form of pellets filled
in capsule.
According to yet another embodiment of the above aspect, the coating is applied to achieve a
weight build up in the range of about 5% to about 35%. In a preferred embodiment of the above
aspect, coating is performed till a weight build up in the range of about 10% to about 30% is
achieved. In a still more preferred embodiment of the above aspect, coating is performed till a
weight build up in the range of about 20% to about 30% is achieved. Preferably, coating is
performed till a weight build up in the range of about 26% to about 30% is achieved.
According to yet another embodiment of the above aspect, the enteric coated pellet is
approximately spherical and has a diameter in the range of about 0.5 mm to about 2.5 mm. In a
preferred embodiment, the enteric coated pellet has a diameter in the range of about 0.55 mm to
about 2.0 mm. More preferably, the enteric coated pellet has a diameter in the range of about 0.6
mm to about 1.95 mm. Still more preferably, the enteric coated pellet has a diameter in the range
of about 0.6 mm to about 1.70 mm.
According to yet another embodiment of the above aspect, the solid oral pharmaceutical
composition comprises a therapeutically effective amount of Pancreatin. Pancreatin as per the
composition of the present invention is present in an amount of about 100 mg to about 1000 mg.
According to yet another embodiment of the above aspect, the solid oral pharmaceutical
composition comprises Pancreatin in an amount of more than about 95% by weight with respect
to the total weight of the core.
In accordance with still another embodiment of the above aspect, there is provided a solid oral
pharmaceutical composition comprising a therapeutically effective amount of Pancreatin
prepared by wet granulation, extrusion-spheronisation, dry granulation, dry blending, dry mixing
or direct compression process. Other formulation techniques are also contemplated within the
scope of the present invention. Wet granulation can be performed using Rapid mixer granulator,
Fluid bed granulator, Planetary mixer and the like; dry blending can be performed using Vblender or key blender; and dry granulation can be performed using roller compacter or slugging
techniques or by any other method known in the art. Any pharmaceutically acceptable solvent
7
can be used for processes such as wet granulation and extrusion. Preferable solvents include, but
are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as
methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide
(DMA), dimethyl sulfoxide (DMSO), ether such as diethyl ether, or mixtures thereof. Preferably,
the solvent used in the manufacturing process of the present invention is enzyme-friendly.
The term "pharmaceutically acceptable excipients," as used herein, refers to excipients that are
routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may
comprise binding agents or binders, enteric coating agents, plasticizers, anti-sticking agents, and
the like.
Suitable binding agent or binder is selected from the group comprising polyethylene glycol 1500,
polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene
glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl
methylcellulose (HPMC), polyoxyethylene, copolymers of polyoxyethylene-polyoxypropylene,
acacia, alginic acid, carbomer, carboxymethylcellulose sodium, ceratonia, cottonseed oil, dextrin,
dextrose, gelatin, guar gum, hydrogenated vegetable oil type 1, hydroxyethyl cellulose,
hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminium
silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, polydextrose,
polyethylene oxide, povidone, sodium alginate, starch, pregelatinised starch, stearic acid, sucrose
and zein, or mixtures thereof. In a preferred embodiment, binding agent is hydroxypropyl
methylcellulose or polyethylene glycol 8000 or mixture thereof.
According to yet another embodiment of the above aspect, binding agent is present in an amount
less than 9% by weight with respect to total weight of the core. Preferably, binding agent is
present in an amount less than 7% by weight with respect to total weight of the core. More
preferably, binding agent is present in an amount less than 5% by weight with respect to total
weight of the core.
According to yet another embodiment of the above aspect, core is devoid or completely free of
binding agent.
According to yet another embodiment of the above aspect, ratio of binding agent to active
pharmaceutical ingredient (API) in the core is less than about 0.05.
8
Suitable enteric coating agents include agar, Carbopol™ (carbomer) polymers (i.e. high molecular
weight, crosslinked, acrylic acid-based polymers), carboxymethyl cellulose, carboxymethylethyl
cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate
trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose,
hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate,
hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer,
methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate,
starch acetate phthalate and/or styrene/maleic acid copolymer or mixtures of said enteric coating
polymers. In a preferred embodiment, the pharmaceutically acceptable enteric coating agent is
hydroxypropyl methylcellulose phthalate, e.g. HPMCP HP55, HPMCP HP55S or HPMCP
HP50.
Suitable plasticizer is selected from the group comprising triacetin, acetylated triacetin, tributyl
citrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl
tributyl citrate, acetyl triethyl citrate, sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, ,
diethyl malonate, polyethylene glycol, lauryl alcohol, tridecyl alcohol, myristyl alcohol,
pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic
alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol,
fatty acid esters of glycerol, glycerol, propyleneglycol and sorbitan fatty acids. In a preferred
embodiment, the pharmaceutically acceptable plasticizer is triethyl citrate.
Suitable anti-sticking agents comprise dimethicone and castor oil.
According to yet another embodiment of the above aspect, the solid oral pharmaceutical
composition is devoid of mixture of plasticizers.
According to yet another embodiment of the above aspect, the solid oral pharmaceutical
composition is stable when subjected to stressed conditions e.g. at a temperature of about 30°C.
and relative humidity ("RH") of about 75% relative humidity for a period of at least three
months.
According to yet another embodiment of the above aspect, the solid oral pharmaceutical
composition is stable when subjected to a temperature of about 40°C. and relative humidity
("RH") of about 75% relative humidity for a period of at least three months.
9
A second aspect of the present invention provides a process for the preparation of a solid oral
pharmaceutical composition comprising Pancreatin, wherein the process comprises the following
steps:
a) blending Pancreatin with at least one pharmaceutically acceptable binding agent;
b) preparing dispersion or solution of another binding agent in at least one organic solvent;
c) granulating the blend obtained in step a) with dispersion or solution of binding agent
obtained in step b);
d) optionally passing the granulated material of step c) through suitable sieve;
e) extruding the wet mass of step d) or step c) in an extruder;
f) spheronizing the extrudes obtained from step e) in a spheronizer;
g) drying the pellets obtained from step f) at a suitable temperature;
h) coating the pellets obtained from step g) with a solution or dispersion of enteric coating
agent.
According to one embodiment of the above aspect, the binding agent used in process for the
preparation of a solid oral pharmaceutical composition comprising Pancreatin may be same or
different.
According to another embodiment of the above aspect, binding agent is present in an amount less
than 9% by weight with respect to total weight of the core. Preferably, binding agent is present in
an amount less than 7% by weight with respect to total weight of the core. More preferably,
binding agent is present in an amount less than 5% by weight with respect to total weight of the
core.
According to yet another embodiment of the above aspect, coating is performed till a weight
build up in the range of about 20% to about 30% is achieved.
According to yet another embodiment of the above aspect, the product temperature of the solid
pharmaceutical composition during coating is kept at a temperature between 25°C and 45°C.
Preferably, the product temperature of the solid pharmaceutical composition during coating is
kept at a temperature between 25°C and 40°C.
10
According to yet another embodiment of the above aspect, the process is carried out at a relative
humidity in the range of 40% to 65%. Preferably, the process is carried out at a relative humidity
in the range of 50% to 65%.
The process of the invention makes it possible to prepare a solid oral pharmaceutical
composition of Pancreatin, wherein the composition is stable and the process is consistent as
well as economical and therefore feasible for industrial production.
A third aspect of the present invention relates to a solid oral pharmaceutical composition
comprising Pancreatin, prepared by a process comprising the following steps:
a) blending Pancreatin with at least one pharmaceutically acceptable binding agent;
b) preparing dispersion or solution of another binding agent in at least one organic solvent;
c) granulating the blend obtained in step a) with dispersion or solution of binding agent
obtained in step b);
d) optionally passing the granulated material of step c) through suitable sieve;
e) extruding the wet mass of step d) or step c) in an extruder;
f) spheronizing the extrudes obtained from step e) in a spheronizer;
g) drying the pellets obtained from step f) at a suitable temperature in a vacuum dryer;
h) coating the pellets obtained from step g) with a solution or dispersion of enteric coating
agent.
According to one embodiment of the above aspect, the binding agent used in the preparation of a
solid oral pharmaceutical composition comprising Pancreatin may be same or different.
According to another embodiment of the above aspect, binding agent is present in an amount less
than 10% by weight with respect to total weight of the core. Preferably, binding agent is present
in an amount between 0% and 9% by weight with respect to total weight of the core. More
preferably, binding agent is present in an amount between 0% and 7% by weight with respect to
total weight of the core. Still more preferably, binding agent is present in an amount between 0%
and 5% by weight by weight with respect to total weight of the core.
According to yet another embodiment of the above aspect, core is devoid or completely free of
binding agent.

WE CLAIM:
1. A solid oral pharmaceutical composition comprising Pancreatin, wherein the composition
comprises:
a) a core comprising:
i. more than 95% by weight pancreatin;
ii. less than 5% by weight of at least one pharmaceutically acceptable binding agent;
iii. optionally at least one pharmaceutically acceptable solvent
wherein, the percentages are expressed with respect to the weight of the core
b) an enteric coat layer over the core comprising:
i. at least one enteric coating agent;
ii. a plasticizer;
iii. optionally at least one anti-sticking agent.
2. The solid oral pharmaceutical composition as claimed in claim 1, wherein the solid oral
pharmaceutical composition is in the form of powder, extrudes, pellets, micropellets,
microspheres, microtablets, granules, granulates, tablets, modified release tablets, mini-tablets,
pellets filled in capsule.
3. The solid oral pharmaceutical composition as claimed in claim 1, wherein coating is applied to
achieve a weight build up in the range of about 5% to about 35%.
4. The solid oral pharmaceutical composition as claimed in claim 1, wherein Pancreatin is
present in an amount of about 100 mg to about 1000 mg.
5. The solid oral pharmaceutical composition as claimed in claim 1, wherein ratio of binding
agent to Pancreatin in the core is less than about 0.05.
6. The solid oral pharmaceutical composition as claimed in claim 1, wherein the composition is
devoid of mixture of plasticizers.
7. The solid oral pharmaceutical composition as claimed in claim 1, wherein the composition is
stable when subjected to a temperature of about 30°C. and relative humidity of about 75%
relative humidity for a period of at least three months.
23
8. The solid oral pharmaceutical composition as claimed in claim 1, wherein the composition is
further stable when subjected to a temperature of about 40°C. and relative humidity of about
75% relative humidity for a period of at least three months.
9. A process for the preparation of a solid oral pharmaceutical composition comprising
Pancreatin, wherein the process comprises the following steps:
a) blending Pancreatin with at least one pharmaceutically acceptable binding agent;
b) preparing dispersion or solution of another binding agent in a pharmaceutically
acceptable solvent;
c) granulating the blend obtained in step a) with dispersion or solution of binding agent
obtained in step b);
d) optionally passing the granulated material of step c) through suitable sieve;
e) extruding the wet mass of step d) or step c) in an extruder;
f) spheronizing the extrudes obtained from step e) in a spheronizer;
g) drying the pellets obtained from step f) at a suitable temperature;
h) coating the pellets obtained from step g) with a solution or dispersion of enteric coating
agent.
10. The process as claimed in claim 9, wherein binding agent is present in an amount less than
9% by weight with respect to total weight of the core.
11. The process as claimed in claim 9, wherein coating is performed till a weight build up in the
range of about 20% to about 30% is achieved.
12. The process as claimed in claim 9, wherein the product temperature of the solid
pharmaceutical composition during coating is kept at a temperature between 25°C and 45°C.
13. The process as claimed in claim 9, wherein the process is carried out at a relative humidity
in the range of 40% to 65%.
14. A solid oral pharmaceutical composition comprising Pancreatin, prepared by a process
comprising the following steps:
a) blending Pancreatin with at least one pharmaceutically acceptable binding agent;
24
b) preparing dispersion or solution of another binding agent in a pharmaceutically
acceptable solvent;
c) granulating the blend obtained in step a) with dispersion or solution of binding agent
obtained in step b);
d) optionally passing the granulated material of step c) through suitable sieve;
e) extruding the wet mass of step d) or step c) in an extruder;
f) spheronizing the extrudes obtained from step e) in a spheronizer;
g) drying the pellets obtained from step f) at a suitable temperature in a vacuum dryer;
h) coating the pellets obtained from step g) with a solution or dispersion of enteric coating
agent.
15. A stable delayed release solid oral pharmaceutical composition comprising:
(a) a core comprising Pancreatin in an amount of more than 95% by weight with respect to the
weight of core and at least one pharmaceutically acceptable excipient;
(b) an enteric coating layer comprising from 80% to 95% by weight of enteric polymer, antisticking agent in an amount of 0% to 5% by weight, plasticizer in an amount of 0% to about
10% by weight with respect to the weight of coating layer;
wherein said core is substantially free of binder.
16. The stable delayed release solid oral pharmaceutical composition as claimed in claim 15,
wherein the core comprises binding agent in an amount less than 5% by weight with respect to
the weight of core.
17. The stable delayed release solid oral pharmaceutical composition as claimed in claim 15,
wherein core is completely free of binding agent.
18.The stable delayed release solid oral pharmaceutical composition as claimed in claim 15,
wherein enteric coating layer comprises 90.5% by weight of enteric polymer, anti-sticking agent
in an amount of 2.00% by weight, plasticizer in an amount of 7.5% by weight with respect to the
weight of the coating layer.