OA21021A

OA21021A - Pharmaceutical composition of pancreatin.

Info

Publication number: OA21021A
Application number: OA1202200497
Authority: OA
Inventors: Sanjeev Gupta; Rajeev Gupta; Tg CHANDRASHEKHAR; Swati Mukherjee; Vineet Bhardwaj; Vikas BALI
Original assignee: Kusum Healthcare Pvt. Ltd
Priority date: 2020-06-10
Filing date: 2021-06-10
Publication date: 2023-08-24

Abstract

The present invention relates to a solid oral pharmaceutical composition of Pancreatin and a method of preparing the same. The solid oral pharmaceutical composition prepared by the process of the invention is also stable when subjected to stability testing at a temperature of 30°C and relative humidity ("RH") of 75% for a period of at least three months.

Description

DETAILED DESCRIPTION OF THE INVENTION

While this spécification 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.

The term “Pancreatin” as used herein, is synonymous to “Pancreatic enzyme, Pancreatic acid and Pancrelipase.

The term “immédiate release (IR)” as used herein, refers to pharmaceutical compositions comprising Pancreatin, which do not contain any drug release rate controlling agent. As a resuit, release ofthe active ingrédient 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 dépendent drug release rate controlling agent, and one or more pharmaceutically acceptable excipients. For the purpose ofthis 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 ail of its dimensions (length, height, width) is equal to or below about 5 mm.

The term gastric acid résistance as used herein, refers to the ability of the enteric coated pellets ofPancreatin to prevent release ofthe 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 température of 37±0.5°C and a rotation speed of 100 révolutions 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.

The présent invention relates to a cost effective solid oral pharmaceutical composition of Pancreatin or its pharmaceutically acceptable salts.

A first aspect of the présent 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. optionaliy 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. optionaliy at least one anti-sticking agent;

It was found by inventors of the présent 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 température 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 immédiate 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, extrades, pellets, micropellets, microspheres, microtablets, granules, granulates, tablets, modifiée! 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 présent invention is présent 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 ofthe présent 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 pharmaceuticaliy acceptable solvent can be used for processes such as wet granulation and extrusion. Préférable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, éthanol, 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 ofthe présent 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, magnésium 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 présent in an amount less than 9% by weight with respect to total weight of the core. Preferably, binding agent is présent in an amount less than 7% by weight with respect to total weight of the core. More preferably, binding agent is présent 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 ingrédient (API) in the core is less than about 0.05.

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, camaubyl 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 température 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 température of about 40°C. and relative humidity (RH) of about 75% relative humidity for a period of at least three months.

A second aspect of the present invention provides a process for the préparation 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 température;

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 préparation 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 ofthe 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 température of the solid pharmaceutical composition during coating is kept at a température between 25 °C and 45°C. Preferably, the product température of the solid pharmaceutical composition during coating is kept at a température between 25°C and 40°C.

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 préparé 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 présent invention relates to a solid oral pharmaceutical composition comprising Pancreatin, prepared by a process comprising the following steps:

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 température in a vacuum dryer;

According to one embodiment of the above aspect, the binding agent used in the préparation of a solid oral pharmaceutical composition comprising Pancreatin may be same or different.

According to another embodiment of the above aspect, binding agent is présent in an amount less than 10% by weight with respect to total weight of the core. Preferably, binding agent is présent in an amount between 0% and 9% by weight with respect to total weight of the core. More preferably, binding agent is présent in an amount between 0% and 7% by weight with respect to total weight of the core. Still more preferably, binding agent is présent in an amount between 0% and 5% by weight by weight with respect to total weight of the core.

According to one embodiment of the above aspect, ratio of binding agent to active pharmaceutical ingrédient (API) in the core is less than about 0.05.

According to yet another embodiment ofthe above aspect, coating is performed till a weight build up in the range of about 5% to about 35% is achieved. In a preferred embodiment ofthe 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 température of the solid pharmaceutical composition during coating is kept at a température between 25°C and 45°C. Preferably, the product température of the solid pharmaceutical composition during coating is kept at a température between 25°C and 40°C.

According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 18% to 65%. Preferably, the process is carried out at a relative humidity in the range of 40% to 65%. More preferably, the process is carried out at a relative humidity in the range of 50% to 65%.

A fourth aspect of the présent invention provides a stable delayed release solid oral pharmaceutical composition comprising:

(a) a core comprising Pancreatin in an amount of more than about 85% by weight with respect to the weight of core and at least one pharmaceutically acceptable excipient;

(b) an enteric coating layer comprising about 80% to about 95% by weight of enteric polymer, anti-sticking agent in an amount of 0% to about 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.

The term substantially free of binder refers to less than about 10% by weight of at least one pharmaceutically acceptable binding agent with respect to the total weight of the core.

According to one embodiment of the above aspect, binding agent is présent in an amount less than 10% by weight with respect to total weight of the core. Preferably, binding agent is présent in an amount between 0% and 9% by weight with respect to total weight of the core. More preferably, binding agent is présent in an amount between 0% and 7% by weight with respect to total weight of the core. Still more preferably, binding agent is présent in an amount between 0% and 5% by weight by weight with respect to total weight of the core.

According to another embodiment of the above aspect, core is devoid or completely free of binding agent.

According to yet another embodiment of the above aspect, the core comprises Pancreatin in an amount of more than about 95% by weight with respect to the weight of core.

In accordance with yet another embodiment of the above aspect, the core comprising Pancreatin is in the form of powder, granules, granulates, beads, pellets, micropellets, microspheres, microtablets, minitablets or tablets.

In accordance with a preferred embodiment of the above aspect, the core comprises Pancreatin in an amount of about 95.5% by weight and at least one pharmaceutically acceptable binding agent in an amount of about 4.5% by weight with respect to the weight of the core.

In accordance with another preferred embodiment of the above aspect, the core comprises Pancreatin in an amount of about 100% by weight and at least one pharmaceutically acceptable binding agent in an amount of 0% by weight with respect to the weight of the core.

In accordance with yet another preferred embodiment of the above aspect, the enteric coating layer comprises about 85% to about 95% by weight of enteric polymer, anti-sticking agent in an amount of 0% to about 3% by weight, plasticizer in an amount of 0% to about 5% by weight with respect to the weight of the coating layer.

In accordance with yet another embodiment of the above aspect, the pharmaceutical composition is in the form of a delayed release pellets comprising:

(a) a core comprising Pancreatin in an amount of 95.5% by weight with respect to the weight of core and at least one pharmaceutically acceptable excipient;

(b) an enteric coating layer comprising about 93% by weight of enteric polymer, anti-sticking agent in an amount of about 2.00% by weight, plasticizer in an amount of about 5% by weight with respect to the weight of the coating layer;

wherein the core is core is substantially free of binder.

According to yet another embodiment, core further comprises pharmaceutically acceptable binding agent in an amount less than 5% by weight with respect to the weight of core. In a preferred embodiment of the above aspect, core comprises pharmaceutically acceptable binding agent in an amount of 4.51% by weight with respect to the weight of core.

According to yet another embodiment, core is devoid or completely free of binding agent.

According to yet another embodiment, enteric coating layer comprises 93% by weight of enteric polymer, anti-sticking agent in an amount of 2.00% by weight, plasticizer in an amount of 5% by weight with respect to the weight of the coating layer.

The solid oral pharmaceutical composition prepared by the above process can be subjected to in vitro dissolution évaluation as per the United States Pharmacopoeia (USP) to détermine the rate at which the active substance is released from the dosage form in buffer stage after exposure to the acid stage, and the content of the active substance in solution can be determined by potentiometry.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition prepared as per the invention exhibits dissolution profile which is comparable to the marketed delayed release reference product Creon® capsules by Abbvie.

In accordance with yet another embodiment of the above aspects, the solid oral pharmaceutical composition comprising Pancreatin is a coated composition. Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art such as spray coating in a conventional coating pan, fluidized bed processor, dip coating, or compression coating. The percentage of the coating build-up shall be varied depending on the required drug release profile. Suitable solvents used for forming a solution or dispersion for coating are selected from the group comprising water, éthanol, methylene chloride, isopropyl alcohol, acetone, methanol, dichloromethane and combinations thereof.

In accordance with yet another embodiment of the above aspects, the solid oral pharmaceutical composition comprising Pancreatin or its pharmaceutically acceptable sait is filled into capsules or sachets or may be compresser! to form microtablets or tablets. Preferably, the solid oral pharmaceutical composition comprising Pancreatin is filled in hard gelatin or HPMC capsules. The capsules may be further enteric coated to achieve desired drug release profile. The capsules containing enteric coated pellets of Pancreatin are packaged in a bottle or blister pack. Preferably, the solid oral pharmaceutical composition comprising Pancreatin is filled in hard gelatin or HPMC capsules having size ‘2’, ‘1’ or ‘0’. More preferably, the solid oral pharmaceutical composition comprising Pancreatin is filled in hard gelatin capsules having size ‘1’.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from considération of the spécification. The invention is further defined by reference to the following examples describing in detail process for the préparation and testing of pharmaceutical composition comprising Pancreatin. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Following examples are set out to illustrate the invention and do not limit the scope ofthe présent invention.

Example 1 to 4

Core pellets containing 95.5 % (w/w) Pancreatin were prepared using the quantitative formula as given in Table 1:

Table 1

Ingrédient	Function	Ex. 1 (% w/w)	Ex. 2 (% w/w)	Ex. 3 (% w/w)	Ex. 4 (% w/w)
Pancreatin	Active	95.5	95.5	95.5	95.5
Macrogol 8000	Binder	0.5	0.5	0.5	0.5
Hypromellose	Binder	4.0	4.0	4.0	4.0
Isopropyl alcohol	Solvent	QS	QS	QS	QS
Dichloromethane	Solvent	QS	NA	QS	QS
Water	Solvent	NA	QS	NA	NA

ΝΑ = Not Applicable

QS = Quantity Sufficient

Core pellets prepared as per Table 1 were coated with an enteric coating using the quantitative formula as given in Table 2:

Table 2

Ingrédient	Function	Ex. 1 (% w/w)	Ex. 2 (% w/w)	Ex. 3 (% w/w)	Ex. 4 (% w/w)
Hypromellose Phthalate	Enteric coating polymer	93.0	90.5	90.5	88.0
Triethylcitrate	Plasticizer	5.0	7.5	7.5	10.0
Dimethicone	Anti-sticking agent	2.0	2.0	2.0	2.0
Acetone	Solvent	QS	QS	QS	QS

QS = Quantity Sufficient

Procedure for Ex. 1, Ex. 3 and Ex. 4:

a) Pancreatin and Macrogol 8000 were sifted through suitable sieve. The sifted blend was mixed for a suitable time.

b) The sifted material from step a) was mixed in a rapid mixer granulator.

c) Required quantity of Isopropyl alcohol was taken in stainless Steel container and Hypromellose was added to it under stirring till a homogeneous dispersion was formed.

d) Required quantity of Dichloromethane was added to above dispersion under continuous stirring to form a binder solution.

e) Material of step b) was granulated using binder solution of step d).

f) The granulated material of step e) was passed through suitable sieve.

g) The wet mass of step f) was extruded in an extruder.

h) Extrudes obtained from step g) were spheronized in a spheronizer.

i) Pellets obtained from step h) were dried to achieve the loss on drying not more than 3%.

j) Required quantity of acetone was taken in stainless Steel container and Hypromellose Phthalate was added to it under stirring till a clear solution was obtained.

k) Triethyl citrate and Dimethicone were added to the solution obtained in step j).

1) Pellets obtained from step i) were coated with the solution obtained in step k) to achieve the target weight gain of 15% to 30%.

m) Coated pellets from step 1) were dried maintaining product température between 25°C 40°C for sufficient time.

n) Pellets obtained from step m) were filled in hard gelatin capsules.

Procedure for Ex. 2:

b) The sifted material from step a) was mixed in a rapid mixer granulator.

d) Required quantity of purified water was added to above dispersion under continuous stirring to form a binder solution.

e) Material of step b) was granulated using binder solution of step d).

f) The granulated material of step e) was passed through suitable sieve.

g) The wet mass of step f) was extruded in an extruder.

h) Extrudes obtained from step g) were spheronized in a spheronizer.

m) Coated pellets from step 1) were dried maintaining product température between 25 °C 40°C for sufficient time.

n) Pellets obtained from step m) were filled in hard gelatin capsules.

Example 5

Core pellets containing 96.0 % (w/w) Pancreatin were prepared using the quantitative formula as given in Table 3:

Table 3

Ingrédient	Function	Ex. 5 (% w/w)
Pancreatin	Active	96.0
Hypromellose	Binder	4.0
Isopropyl alcohol	Solvent	QS
Dichloromethane	Solvent	QS

Core pellets prepared as per Table 3 were coated with an enteric coating using the quantitative formula as given in Table 4:

Table 4

Ingrédient	Function	Ex. 5 (% w/w)
Hypromellose Phthalate	Enteric coating polymer	88.0
Triethylcitrate	Plasticizer	10.0
Dimethicone	Anti-sticking agent	2.0
Acetone	Solvent	QS

Procedure:

a) Pancreatin was sifted through a suitable sieve.

b) Required quantity of Isopropyl alcohol was taken in stainless Steel container and Hypromellose was added to it under stirring till a homogeneous dispersion was formed.

c) Required quantity of Dichloromethane was added to above dispersion under continuous stirring to form a binder solution.

d) Material of step a) was granulated using binder solution of step c).

e) The granulated material of step d) was passed through suitable sieve.

f) The wet mass of step e) was extruded in an extruder.

g) Extrudes obtained from step f) were spheronized in a spheronizer.

h) Pellets obtained from step g) were dried to achieve the loss on drying not more than 3%.

i) Required quantity of acetone was taken in stainless Steel container and Hypromellose Phthalate was added to it under stirring till a clear solution was obtained.

j) Triethyl citrate and Dimethicone were added to the solution obtained in step i).

k) Pellets obtained from step h) were coated with the solution obtained in step j) to achieve the target weight gain of 15% to 30%.

1) Coated pellets from step k) were dried maintaining product température between 25°C 40°C for sufficient time.

m) Pellets obtained from step 1) were filled in hard gelatin capsules.

Example 6

Core pellets containing 100.0 % (w/w) Pancreatin were prepared using the quantitative formula as given in Table 5:

Table 5

Ingrédient	Function	Ex. 6 (% w/w)
Pancreatin	Active	100.0
Isopropyl alcohol	Solvent	QS
Water	Solvent	QS

Core pellets prepared as per Table 5 were coated with an enteric coating using the quantitative formula as given in Table 6:

Table 6

Ingrédient	Function	Ex. 6 (% w/w)
Hypromellose Phthalate	Enteric coating polymer	93.0
Triethylcitrate	Plasticizer	5.0
Dimethicone	Anti-sticking agent	2.0
Acetone	Solvent	QS

Procedure:

a) Pancreatin was sifted through suitable sieve.

b) Required quantity of Isopropyl alcohol was taken in stainless steel container and required quantity of purified water was added to it under continuous stirring to form a solution.

c) Material of step a) was granulated using solution of step b).

d) The granulated material of step c) was passed through suitable sieve.

e) The wet mass of step d) was extruded in an extruder.

f) Extrudes obtained from step e) were spheronized in a spheronizer.

g) Pellets obtained from step f) were dried to achieve the loss on drying not more than 3%.

h) Required quantity of acetone was taken in stainless steel container and Hypromellose Phthalate was added to it under stirring till a clear solution was obtained.

i) Triethyl citrate and Dimethicone were added to the solution obtained in step h).

j) Pellets obtained from step g) were coated with the solution obtained in step i) to achieve the target weight gain of 15 % to 30%.

k) Coated pellets from step j) were dried maintaining product température between 25°C 40°C for sufficient time.

1) Pellets obtained from step k) were filled in hard gelatin capsules.

Example 7

The dissolution profile of enteric coated pellets of Pancreatin prepared as per Example 1 - 6 was measured in 800 mL of Simulated gastric fluid without enzyme (20 g of sodium chloride + 70 ml of concentrated hydrochloric acid in 10 litres of water), using a basket apparatus at a température of 37±0.5°C and a rotation speed of 100 révolutions per minute for 60 minutes followed by measurement in 800 mL of Phosphate Buffer, pH 6.0 using a paddle apparatus at a température of 37±0.5°C and a rotation speed of 100 révolutions per minute for 30 minutes. Phosphate buffer, pH 6.0 was prepared by dissolving 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. The dissolution test was conducted on the commercially available reference formulation CREON® capsules manufactured by Abbvie in comparison to the composition prepared as per Example 1 - 6. The dissolution data as obtained after 30 minutes in the buffer stage (Phosphate Buffer, pH 6.0) is presented in Table 7.

Table 7

Stability Conditions	Dissolution Time Point	CREON®	Ex. 1 (%)	Ex. 2 (%)	Ex. 3 (%)	Ex. 4 (%)	Ex. 5 (%)	Ex. 6 (%)
Initial	30 minutes	105	120	120	102	109	121	101
12 months at 30°±2°C / 75%±5% RH	95	109	110	107	101	114	94

It can be seen from Table 7 that the enteric coated pellets of Pancreatin prepared as per Example 1 - 6 showed more than 75% of the drug release within 30 minutes in Phosphate buffer, pH 6.0 after exposure to simulated gastric fluid without enzyme and the dissolution profile was either superior or comparable to the commercially available reference formulation CREON® capsules manufactured by Abbvie. It is évident from the data in Table 7 that the enteric coated pellets of Pancreatin prepared as per Example 1-6 exhibited desired delayed release characteristics.

Example 8

Capsules containing enteric coated pellets of Pancreatin prepared as per Example 1 - 6 were subjected to stability testing as per the ICH guidelines at a temperature/relative humidity of 30°±2°C / 75%±5% RH for at least 3 months. The formulations were also tested at more stringent conditions at a temperature/relative humidity of 40°±2°C / 75%±5% RH for at least 3 months. The capsule dosage form was packaged in blister strips and lipase content (Ph. Eur Units/Capsule) of the pellets at specified time intervals (Initial and Stability) was assessed using potentiometric method. The capsule dosage forms were found to exhibit the results as mentioned in Table 8.

Table 8

Stability Conditions	CREON®	Ex. 1	Ex. 2	Ex. 3	Ex. 4	Ex. 5	Ex. 6
Initial	11867	11637	11244	11441	12422	10919	11171
06 months at 40°±2°C / 75%±5% RH	9384	9687	10605	9530	9627	9965	9726
12 months at 30°±2°C / 75%±5% RH	9534	9863	10352	9947	11321	10862	9639

From the analysis of lipase content (Ph. Eur Units/Capsule) of pellets prepared as per Example 1 - 6, it is évident that the composition prepared as per the présent invention is a synergistic composition whereby the composition exhibits désirable stability characteristics of at least three months by virtue of careful sélection of excipients, their weight percentages and the manufacturing process employed.

The composition prepared as per the présent invention not only demonstrates désirable storage stability for at least three months but also exhibits desîred delayed release of the drug from the dosage form. High drug loading capacity along with small particle size of the pellets makes them suitable to be filled into capsules having sizes which can be easily adminîstered.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the présent invention is not limited to those précisé embodiments. Rather, in view of the présent disclosure, which describes the current best mode for practicing the invention, many modifications and variations would présent themselves to those skilled in the art without departing from the scope, and spirit of this invention.

Claims

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 présent 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 température of about 30°C. and relative humidity of about 75% relative humidity for a period of at least three months.

8. The solid oral pharmaceutical composition as claimed in claim 1, wherein the composition is further stable when subjected to a température 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 préparation of a solid oral pharmaceutical composition comprising Pancreatin, wherein the process comprises the following steps:

b) preparing dispersion or solution of another binding agent in a pharmaceutically acceptable solvent;

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 température;

10. The process as claimed in claim 9, wherein binding agent is présent 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 température of the solid pharmaceutical composition during coating is kept at a température 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:

b) preparing dispersion or solution of another binding agent in a pharmaceuticaliy acceptable solvent;

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;

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 pharmaceuticaliy 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.