UA129226C2 - Pharmaceutical composition of pancreatin - Google Patents

Abstract

The invention relates to a solid oral pharmaceutical composition of pancreatin and a method of its production.

Description

INDUSTRY TO WHICH THE INVENTION BELONGS

This invention relates to a solid oral pharmaceutical composition of Pancreatin and a method for its production.

BACKGROUND OF THE INVENTION

Pancreatin is an extract from the pancreas of pigs. It contains digestive enzymes such as lipase, protease, and amylase. It is used to treat exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis, chronic pancreatitis, pancreatectomy, and other conditions.

Pancreatin exhibits optimal activity in a nearly neutral to slightly alkaline environment. It is inactivated in the stomach, resulting in loss of biological activity. Due to the incompatibility of pancreatin with the acidic environment present in the human stomach, pancreatin formulations are typically coated with an enteric coating polymer to protect the enzymes as they pass through the stomach and reach the initial parts of the intestine, such as the duodenum.

Mo's patent EP1931317B discloses a process for producing pancreatin micropellet cores. According to the examples given in the specification, the process uses 20 to 95 m/m or more of binder relative to the weight of the core.

Patent Me EP1T93131681 discloses an enteric coating comprising at least one film-forming agent and a plasticizer, which is a mixture of cetyl alcohol and triethyl citrate, the total amount of which is more than 3 95 by weight relative to the at least one film-forming agent, where the weight ratio of cetyl alcohol to triethyl citrate is from 0.05:1 to 1:1. Preparations C, O, E, E and I, which contain only triethyl citrate as plasticizer, do not have the desired technical properties and are therefore not preferred preparations.

There is a need to provide patients with Pancreatin formulations that not only comply with government health agency recommendations to restrict the use of certain excipients, such as mineral oil (e.g., U.S. Code of Federal Regulations, 21 SEC 5201.302) and monomeric phthalic acid ester plasticizers, such as dibutyl phthalate (e.g., Directive 2003/36/EC of the European Parliament and of the Council of 26 May 2003 amending for the 25th time Directive

Council Directive 76/769/EEC), but also, in addition to economic benefits, will prevent the consumption of large quantities of additives.

The applicants have successfully developed a solid oral pharmaceutical composition containing Pancreatin that avoids the consumption of excessive amounts of supplements. The solid oral pharmaceutical composition of this invention is produced by a process that is not only simple and reliable, but also commercially viable. In addition, the solid oral pharmaceutical composition produced by the claimed process meets the recommendations of government health institutions and is also stable when tested under stressful conditions, for example at a temperature of 30 "C and a relative humidity ("RH") of 75-95 for at least three months.

BRIEF DESCRIPTION OF THE INVENTION

The main object of the present invention is the production of a solid oral pharmaceutical composition

Pancreatin.

A further object of the present invention is the production of a solid oral pharmaceutical composition.

Pancreatin, which is a core and at least one layer of enteric coating applied to the core.

Another object of the present invention is to provide a cost-effective process for manufacturing a solid oral pharmaceutical composition of Pancreatin that exhibits gastric acid resistance, dissolution and storage stability that are superior to or comparable to registered products through the selection of excipients and manufacturing process.

The following embodiments further describe the objects of the present invention, however, the disclosed invention is not limited to the specific embodiments described below and extends to modifications obvious to those skilled in the art.

In a preferred embodiment, the solid oral pharmaceutical composition comprises: a) a core which is a therapeutically effective amount of Pancreatin and at least one pharmaceutically acceptable excipient, wherein the core comprises at least one pharmaceutically acceptable binder in an amount of less than 95% by weight relative to the total weight of the core; p) an enteric coating layer applied to the core comprising at least one enteric coating agent, a plasticizer and optionally at least one anti-sticking agent.

In another preferred embodiment, the solid oral pharmaceutical composition comprises: a) a core which is a therapeutically effective amount of Pancreatin and at least one pharmaceutically acceptable excipient, wherein the core comprises at least one pharmaceutically acceptable binder in an amount of less than 10 95 by weight relative to the total weight of the core; B) an enteric coating layer applied to the core comprising at least one enteric coating agent, a plasticizer not present in the form of a mixture, and optionally at least one anti-sticking agent.

Another embodiment of the present invention provides a process for preparing a solid oral pharmaceutical composition of Pancreatin, comprising the steps of mixing Pancreatin with at least one pharmaceutically acceptable binder, wet granulation, grinding of the granules, extrusion of the wet mass followed by spheronization of the resulting extrudates, drying the pellets, coating the pellets with an enteric polymer solution. In the solid oral pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient includes binders, enteric coating agents, plasticizers and anti-caking agents.

DETAILED DESCRIPTION OF THE INVENTION

Although this description concludes with claims that specifically point out and clearly state what is considered to be the invention, it is expected that the invention will be more readily understood by reading the following detailed description of the invention and studying the included examples.

The term "composition" as used herein in the context of a pharmaceutical composition encompasses a drug product comprising Pancreatin and other inert ingredient(s). Such pharmaceutical compositions are synonymous with "preparation" and "dosage form". Pharmaceutical compositions according to the invention include, but are not limited to, extrudates, pellets, micropellets, microspheres, microtablets, granules, granulates, tablets, modified release tablets, mini-tablets, pellets encapsulated, and the like. The term pharmaceutical composition primarily refers to enteric coated granules encapsulated.

The term "Pancreatin" as used herein is synonymous with the terms "Pancreatic enzyme", "Pancreatic acid" and "Pancrelipase".

The term "immediate release (IR)" as used herein refers to pharmaceutical compositions containing Pancreatin that do not contain release rate regulators. As a result, the release of the active ingredient from the composition results in the release of the ip-migo within a short period of time, i.e. (less than an hour).

The term "controlled release (CR)" as used herein refers to pharmaceutical compositions comprising Pancreatin and one or more pharmaceutically acceptable excipients that comprise at least one release rate regulator.

The term "sustained release (SR)" as used herein refers to pharmaceutical compositions comprising Pancreatin, at least one pH-dependent release rate regulator and one or more pharmaceutically acceptable excipients. For the purposes of the present invention, enteric-coated compositions are sustained release dosage forms.

The term "approximately" as used herein refers to any value that is within a range defined by a deviation of up to 10 95 from 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) are about 5 mm or less.

The term "gastric acid resistance" as used herein refers to the ability of enteric-coated Pancreatin pellets to prevent drug release when the pellets are exposed to 800 ml of artificial gastric juice (20 g sodium chloride and 70 ml concentrated hydrochloric acid in 10 liters of water) in a rotating basket apparatus at 370.5 "C and 100 rpm for 60 minutes, and which are rapidly dissolved when the pellets are exposed to a phosphate buffer with a pH of 6.0 (20 g sodium chloride and 92 g potassium dihydrogen phosphate in 10 liters of water and adjusted to pH 6.0-0.5 with 4 M sodium hydroxide solution).

Unless otherwise stated, the weight percentages given herein are based on the final weight of the composition, preparation, or dosage form.

This 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 95 by weight of Pancreatin; ii. less than 10 95 by weight of at least one pharmaceutically acceptable binder; ii. optionally at least one organic solvent, where the percentages are expressed relative to the total weight of the core

B) an enteric coating layer applied to the core, comprising: i. at least one enteric coating agent; i. a plasticizer; i. optionally at least one anti-sticking agent;

The authors of the present invention have discovered that a solid oral pharmaceutical composition containing

Pancreatin and having less than 10 95 by weight of at least one pharmaceutically acceptable binder in the core and which is coated with a layer of enteric coating exhibits excellent storage stability.

The term "storage stability" as used herein refers to the stability of a solid oral pharmaceutical composition containing Pancreatin at a temperature of 30°C and a relative humidity ("RH") of 75-95% relative humidity for 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, sustained 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, extrudates, pellets, micropellets, microspheres, microtablets, granules, granulates, modified release tablets, mini-tablets, pellets enclosed in a capsule, and the like. In a preferred embodiment, the solid oral pharmaceutical composition is in the form of pellets enclosed in a capsule.

According to another embodiment of the above aspect, the coating is applied to achieve a mass gain in the range of about 5 95 to about 35 95. In a preferred embodiment of the above aspect, the coating is applied to achieve a mass gain in the range of about 10 95 to about 30 95. In an even more preferred embodiment of the above aspect, the coating is applied to achieve a mass gain in the range of about 20 95 to about 30 95. In a most preferred embodiment, the coating is applied to achieve a mass gain in the range of about 26 95 to about 30 95.

According to another embodiment of the above aspect, the enteric-coated pellet is nearly 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. In a still more preferred embodiment, the enteric-coated pellet has a diameter in the range of about 0.6 mm to about 1.95 mm. In a most preferred embodiment, the enteric-coated pellet has a diameter in the range of about 0.6 mm to about 1.70 mm.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition comprises a therapeutically effective amount of Pancreatin. The Pancreatin according to the composition of the present invention is present in an amount of from about 100 mg to about 1000 mg.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition comprises Pancreatin in an amount greater than about 95% by weight relative to the total weight of the core.

According to 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-spheronization, dry granulation, dry blending, dry mixing or direct compression. Other formulation techniques are also contemplated within the scope of the present invention. Wet granulation can be performed using a high-speed mixer-granulator, a fluidized bed granulator, a planetary mixer, etc.; dry blending can be performed using an M-blender; and dry granulation can be performed using a roller compactor or compression method or any other known method. Any pharmaceutically acceptable solvent can be used for wet granulation and extrusion. Preferred 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, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), an ether such as diethyl ether, or mixtures thereof. In a preferred embodiment, the solvent used in the manufacturing process of the present invention is safe for enzymes.

The term "pharmaceutically acceptable excipients" as used herein refers to excipients commonly used in pharmaceutical compositions. Pharmaceutically acceptable excipients may include binders or components, enteric coating agents, plasticizers, anti-caking agents, and the like.

A suitable binder is selected from the group consisting of 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, polyoxyethylene-polyoxypropylene copolymers, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, carob, cottonseed oil, dextrin, dextrose, gelatin, guar gum, hydrogenated vegetable oil type 1, hydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, magnesium aluminosilicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch, pregelatinized starch, stearic acid, sucrose and zein, or mixtures thereof. In a preferred embodiment, hydroxypropylmethylcellulose or polyethylene glycol 8000 or a mixture thereof is used as the binder.

According to another embodiment of the above aspect, the binder is present in an amount of less than 995 by weight relative to the total weight of the core. In a preferred embodiment, the binder is present in an amount of less than 795 by weight relative to the total weight of the core. In a still more preferred embodiment, the binder is present in an amount of less than 5 95 by weight relative to the total weight of the core.

According to another embodiment of the above aspect, the core is free of or does not contain any binder.

According to another embodiment of the above aspect, the ratio of binder to active pharmaceutical ingredient (API) in the core is less than about 0.05.

Suitable enteric coating agents include agar, Sagroro! "m (carbomer) polymers (i.e. high molecular weight, cross-linked, acrylic acid-based polymers), carboxymethylcellulose, carboxymethylethylcellulose, carrageenan, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, chitin, corn protein extract, ethylcellulose, gum arabic, hydroxypropylcellulose, hydroxypropylmethyl acetate succinate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid-ethyl methacrylate copolymer, methylcellulose, pectin, polyvinyl acetate phthalate, polyvinyl alcohol, shellac, sodium alginate, starch acetate phthalate and/or styrene/maleic acid copolymer or mixtures of these polymers for enteric coating, in a preferred embodiment, a pharmaceutically acceptable agent for enteric coating is hydroxypropylmethylcellulose phthalate, for example NRMP NRB5, NRMPS NRB55 or NRMPS NRB0.

A suitable plasticizer is selected from the group consisting of 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, arachidonic alcohol, behenyl alcohol, carnaubico alcohol, ceryl alcohol, corianyl alcohol, melisyl alcohol, glycerol fatty acid esters, glycerol, propylene glycol and sorbitan fatty acids. In a preferred embodiment, the pharmaceutically acceptable plasticizer is triethyl citrate.

Suitable anti-sticking agents are dimethicone and castor oil.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition does not contain any plasticizer mixture.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition is stable under stress conditions, for example at a temperature of about 30°C and a relative humidity ("RH") of about 75-95% relative humidity for at least three months.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition is stable when exposed to a temperature of about 40°C and a relative humidity ("RH") of about 75-95 relative humidity for at least three months.

A second aspect of the present invention provides a process for preparing a solid oral pharmaceutical composition containing Pancreatin, the process comprising the following steps: a) mixing Pancreatin with at least one pharmaceutically acceptable binder; p) preparing a dispersion or solution of another binder in at least one organic solvent; c) granulating the mixture obtained in step a) with the dispersion or solution of the binder obtained in step B); a) optionally sieving the granulated material from step c) through a suitable sieve; e) extruding the wet mass from step a) or c) in an extruder;

C) spheronizing the extrudates obtained in step e) in a spheronizer; 9) drying the pellets obtained in step e) at a suitable temperature;

M) coating the pellets obtained in step 9) with a solution or dispersion of an enteric coating agent.

According to one embodiment of the above aspect, the binder used in the preparation of the solid oral pharmaceutical composition containing Pancreatin may be the same or different.

According to another embodiment of the above aspect, the binder is present in an amount of less than 9.95% by weight relative to the total weight of the core. In a preferred embodiment, the binder is present in an amount of less than 7.95% by weight relative to the total weight of the core. In a still more preferred embodiment, the binder is present in an amount of less than 5.95% by weight relative to the total weight of the core.

According to another embodiment of the above aspect, the coating is applied until a weight gain in the range of about 20% to about 30% is achieved.

According to another embodiment of the above aspect, the temperature of the solid pharmaceutical composition product during coating is maintained between 25°C and 45°C. In a preferred embodiment, the temperature of the solid pharmaceutical composition product during coating is maintained between 25°C and 40°C.

According to another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 40% to 65%. In a preferred embodiment, the process is carried out at a relative humidity in the range of 50% to 65%.

The development process enables the preparation of a solid oral pharmaceutical composition of Pancreatin, the composition being stable and the process consistent, as well as cost-effective, and therefore suitable for industrial production.

A third aspect of the present invention relates to a solid oral pharmaceutical composition comprising

Pancreatin obtained by a process comprising the following steps: a) mixing Pancreatin with at least one pharmaceutically acceptable binder; p) preparing a dispersion or solution of another binder in at least one organic solvent; c) granulating the mixture obtained in step a) with the dispersion or solution of the binder obtained in step b); a) optionally sieving the granulated material from step c) through a suitable sieve; e) extruding the wet mass from step 4) or c) in an extruder;

I) spheronization of the extrudates obtained in step e) in a spheronizer; 9) drying of the pellets obtained in step E) at a suitable temperature in a vacuum dryer;

M) coating the pellets obtained in step 9) with a solution or dispersion of an enteric coating agent.

According to one embodiment of the above aspect, the binder used in the preparation of the solid oral pharmaceutical composition containing Pancreatin may be the same or different.

According to another embodiment of the above aspect, the binder is present in an amount of less than 10 95 by weight relative to the total weight of the core. In a preferred embodiment, the binder is present in an amount between 0 95 and 9 95 by weight relative to the total weight of the core. In a more preferred embodiment, the binder is present in an amount between 0 95 and 7 96 by weight relative to the total weight of the core. In a most preferred embodiment, the binder is present in an amount between 0 95 and 5 95 by weight relative to the total weight of the core.

According to another embodiment of the above aspect, the core is free of or does not contain any binder.

According to another embodiment of the above aspect, the ratio of binder to active pharmaceutical ingredient (API) in the core is less than about 0.05.

According to another embodiment of the above aspect, the coating is applied to achieve a mass gain in the range of about 5.95 to about 3595. In a preferred embodiment of the above aspect, the coating is applied to achieve a mass gain in the range of about 20.95 to about 30.95.

According to another embodiment of the above aspect, the temperature of the solid pharmaceutical composition product during coating is maintained between 25°C and 45°C. In a preferred embodiment, the temperature of the solid pharmaceutical composition product during coating is maintained between 25°C and 40°C.

According to another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 18.95 to 65.95. In a preferred embodiment, the process is carried out at a relative humidity in the range of 40.95 to 65.95. In a still more preferred embodiment, the process is carried out at a relative humidity in the range of 50.95 to 65.95.

A fourth aspect of the present invention provides a stable solid oral sustained release pharmaceutical composition comprising: (a) a core comprising Pancreatin in an amount greater than 85% by weight relative to the weight of the core, and at least one pharmaceutically acceptable excipient; (b) an enteric coating layer comprising from about 80% to about 95% by weight of an enteric polymer, an anti-caking agent in an amount of from about 0% to about 59% by weight, and a plasticizer in an amount of from about 0% to about 10% by weight relative to the weight of the coating layer; wherein said core is substantially free of binder.

The term "substantially binder-free" refers to a weight of at least one pharmaceutically acceptable binder that is less than about 10 95% of the total weight of the core.

According to one embodiment of the above aspect, the binding agent is present in an amount of less than 10 95 by weight relative to the total weight of the core. More preferably, the binding agent is present in an amount of from 0 95 to 9 95 by weight relative to the total weight of the core. More preferably, the binding agent is present in an amount of from 0 95 to 7 96 by weight relative to the total weight of the core. However, most preferably, the binding agent is present in an amount of from 0 95 to 5 95 by weight relative to the total weight of the core.

According to another embodiment of the above aspect, the core is devoid of or does not contain any binding agent.

According to another embodiment of the above aspect, the core contains Pancreatin in an amount greater than 95% by weight relative to the total weight of the core.

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

According to another embodiment of the above aspect, the core containing Pancreatin may be in the form of powder, granules, granulates, beads, pellets, micropellets, microspheres, microtablets, mini-tablets or tablets.

According to a preferred embodiment of the above aspect, the core contains 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 relative to the total weight of the core.

According to another preferred embodiment of the above aspect, the core contains Pancreatin in an amount of about 100-95% by weight and at least one pharmaceutically acceptable binding agent in an amount of 0-95% by weight of the total weight of the core.

According to another preferred embodiment of the above aspect, the enteric coating layer comprises about 85.95 to about 95.95 by weight of enteric polymer, an anti-sticking agent in an amount of 0.95 to about 3.95 by weight, a plasticizer in an amount of 0.95 to about 5.956 by weight relative to the weight of the coating layer.

According to another embodiment of the above aspect, the pharmaceutical composition is in the form of a delayed release pellet comprising: (a) a core comprising Pancreatin in an amount of 95.5-956 by weight based on the weight of the core, and at least one pharmaceutically acceptable excipient. (B) an enteric coating layer comprising about 93-95 by weight of an enteric polymer, an anti-caking agent in an amount of about 2-95 by weight, and a plasticizer in an amount of about 5-95 by weight based on the weight of the coating layer. wherein said core is free or substantially free of a binder.

According to another embodiment, the core contains a pharmaceutically acceptable binding agent in an amount of less than 55905 by weight relative to the total weight of the core. According to a preferred embodiment of the above aspect, the core contains a pharmaceutically acceptable binding agent in an amount of 4.51 95 by weight relative to the total weight of the core.

According to another embodiment, the core is devoid of or does not contain any binding agent.

According to another embodiment, the enteric coating layer contains 93% by weight of enteric polymer, an anti-sticking agent in an amount of 2.00% by weight, and a plasticizer in an amount of 5% by weight relative to the total weight of the coating layer.

The solid oral pharmaceutical composition prepared by the above process can be evaluated by in vitro dissolution tests according to the United States Pharmacopeia (USP) to determine the rate at which the active ingredient is released from the dosage form in the buffer stage after exposure to the acid stage, and the active ingredient content is determined potentiometrically.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition prepared according to the present invention exhibits a dissolution profile that is comparable to the commercial reference delayed-release Creon® capsule manufactured by Arrmie.

According to one embodiment of the above aspects, the solid oral pharmaceutical composition containing Pancreatin is a coated composition. The coating can be performed by coating in the form of a solution/suspension/mixture using any known coating technique known in the art, such as spray coating in a conventional coating tank, fluidized bed coating, dip coating or pressure coating.

The percentage of coating gain will vary depending on the BID of the desired drug release profile.

Suitable solvents for preparing the coating solution or dispersion are selected from the group consisting of water, ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, dichloromethane, or combinations thereof.

According to another embodiment of the above aspects, the solid oral pharmaceutical composition containing Pancreatin or its pharmaceutically acceptable salt is filled into capsules or sachets, or can be compressed to form microtablets or tablets. Preferably, the solid oral pharmaceutical composition containing Pancreatin is filled into hard gelatin capsules or HPMC-based capsules. The capsules can be further coated with an enteric coating to achieve the desired release profile of the active ingredient. The capsules containing the enteric coated Pancreatin pellets are packaged in bottles or blister packs. Preferably, the solid oral pharmaceutical composition containing Pancreatin is filled into hard gelatin capsules or HPMC-based capsules, size 2.1 or "0. In a more preferred embodiment, the solid oral pharmaceutical composition containing Pancreatin is filled into hard gelatin capsules, size 1.

Having described the invention with reference to certain preferred embodiments thereof, other embodiments thereof will become apparent to those skilled in the art after studying the specification. The invention is further illustrated with reference to the following examples, which describe in detail the process of preparing and testing a pharmaceutical composition containing Pancreatin. It will be apparent to those skilled in the art that many modifications, both in materials and methods, can be made to the present invention without departing from the scope of the present invention.

EXAMPLES

The following examples are provided to demonstrate the invention, but they do not limit the scope of the present invention.

Example 1 of 4

Pellet cores containing 95.5 95 (w/w) Pancreatin were prepared using the quantitative formula given in Table 1:

Table 1

Active

Binder 1 substance

SHT tnnny soRUye beeeE osoye Hook

Solvent : : its alcohol required required required required required applied | required required military advice Geo olanetya nya oda Solvent : applied | required applied | applied

The pellet cores prepared according to Table 1 were coated with an enteric coating prepared using the quantitative formula indicated in Table 2:

Table 2 m/m m/m m/m m/m child daily fruit me vo enteric-coated 93.0 90.5 90.5 88.0 phthalate coating required required required required

Procedures for Ex. 1, Ex. C and Ex. 4: a) Pancreatin and Macrogol 8000 were sieved through a suitable sieve. The sieved mixture was mixed for a suitable time.

B) The screened material from step a) was mixed in a high-speed mixer-granulator. c) Hypromellose was added to a stainless steel container with the required amount of Isopropyl alcohol, stirring until a homogeneous dispersion was formed. 4) The required amount of Dichloromethane was added to the above dispersion with constant stirring until a binding solution was formed. e) The material from step B) was granulated using the binding solution from step 4).

I) The granulate from step e) was passed through a suitable sieve. 9) The wet mass from step e) was extruded in an extruder.

p) The extrudates from step 9) were spheronized in a spheronizer. j) The pellets obtained from step 1) were dried to a weight loss on drying of not more than 95%. )) Hypromellose phthalate was added to a stainless steel container with the required amount of acetone with constant stirring until a clear solution was formed.

K) Triethyl citrate and Dimethicone were added to the solution obtained from step |).

I) The pellets obtained from step i) were coated with the solution obtained from step k) until the desired weight gain of 15% to 30% was achieved. m) The coated pellets from step i) were dried for a suitable time while maintaining the product temperature in the range of 25°C to 40°C. m) Hard gelatin capsules were filled with the pellets obtained from step k).

Procedure for Example 2: a) Pancreatin and Macrogol 8000 were sieved through a suitable sieve. The sieved mixture was mixed for a suitable time.

B) The screened material from step a) was mixed in a high-speed mixer-granulator. c) Hypromellose was added to a stainless steel container with the required amount of Isopropyl alcohol, stirring until a homogeneous dispersion was formed. 4) The required amount of purified water was added to the above dispersion, stirring continuously until a binding solution was formed. e) The material from step B) was granulated using the binding solution from step 4).

I) The granulate from step e) was passed through a suitable sieve. 9) The wet mass from step e) was extruded in an extruder. p) The extrudates obtained from step 9) were spheronized in a spheronizer. j) The pellets obtained from step p) were dried to a loss in mass on drying of not more than 95%. )) Hypromellose phthalate was added to a stainless steel container with the required amount of acetone, stirring constantly until a clear solution was formed.

K) Triethyl citrate and Dimethicone were added to the solution obtained from step )).

I) The pellets obtained from step i) were coated with the solution obtained from step k) until the desired weight gain of 15.95 to 30.95 was achieved. m) The coated pellets from step ii) were dried for a suitable time while maintaining the product temperature in the range of 25270 - 4076. p) Hard gelatin capsules were filled with the pellets obtained from step m). Example 5

Pellet cores containing 96.0 95 (w/w) Pancreatin were prepared using the quantitative formula given in Table 3:

Table With m/m tet | ESHE 10

Pancreatin substance 1 substance alcohol required required

The pellet cores prepared according to Table 3 were coated with an enteric coating prepared using the quantitative formula indicated in Table 4:

Table 4 to m/m. Polymer

Hypromellose coating adhesion

How many

Acetone Solvent will be required

Procedure a) Pancreatin was sieved through a suitable sieve.

B) Hypromellose was added to a stainless steel container with the required amount of Isopropyl Alcohol, stirring until a homogeneous dispersion was formed.

c) The required amount of Dichloromethane was added to the above dispersion with constant stirring until a binding solution was formed. 4) The material from step a) was granulated using the binding solution from step c). e) The granulate from step 4) was passed through a suitable sieve.

I) The wet mass from step e) was extruded in an extruder. 9) The extrudates obtained from step e) were spheronized in a spheronizer.

I) The pellets obtained from step 9) were dried to a loss in weight on drying of not more than 95%. j) Hypromellose phthalate was added to a stainless steel container with the required amount of acetone, stirring constantly until a clear solution was formed. )) Triethyl citrate and Dimethicone were added to the solution obtained from step ii).

K) The pellets obtained from step n) were coated with the solution obtained from step )) until the desired weight gain of 15% to 30% was achieved.

I) The coated pellets from step K) were dried for a suitable time while maintaining the product temperature in the range of 2570-4076. m) Hard gelatin capsules were filled with the pellets obtained from step 1).

Example 6

Pellet cores containing 100.0 95 (w/w) Pancreatin were prepared using the quantitative formula given in Table 5:

Table 5 . . Ex. 6 (to

Active alcohol is required

The pellet cores prepared according to Table 5 were coated with an enteric coating using the quantitative formula indicated in Table 6:

Table 6. and Example 6 (95 days of the week)

Hypromellose enteric coating 93.0 phthalate tackifier

How many

Acetone Solvent will be required

Procedure: a) Pancreatin was sieved through a suitable sieve.

B) The required amount of purified water was added to a stainless steel container with the required amount of Isopropyl alcohol, stirring constantly until a solution was formed. c) The material from step a) was granulated using the solution from step b). a) The granulate from step c) was passed through a suitable sieve. e) The wet mass from step 4) was extruded in an extruder. 1) The extrudates obtained from step e) were spheronized in a spheronizer. 9) The pellets obtained from step j) were dried to a loss in mass on drying of not more than 95%.

M) Hypromellose phthalate was added to a stainless steel container with the required amount of acetone, stirring constantly until a clear solution was formed.

I) Triethyl citrate and Dimethicone were added to the solution obtained from step n). )) The pellets obtained from step 9) were coated with the solution obtained from step i) until the desired weight gain of 15 95) to 30 95) was achieved.

K) The coated pellets from step |) were dried for an appropriate time while maintaining the product temperature in the range of 2570-4076.

I) Hard gelatin capsules were filled with the pellets obtained from step K).

Example 7

The dissolution profile of the Pancreatin pellets prepared according to Examples 1-6 was measured in 800 ml of enzyme-free artificial gastric fluid (20 g sodium chloride and 70 ml concentrated hydrochloric acid dissolved in 10 l of water) using a rotating basket apparatus at 370.5 °C and a rotation speed of 100 rpm for 60 minutes, followed by measurement in 800 ml of phosphate buffer, pH 6.0, using a paddle apparatus at 370.5 °C and a rotation speed of 100 rpm for 30 minutes. The phosphate buffer, pH 6.0, was prepared by dissolving 20 g sodium chloride and 92 g potassium dihydrogen phosphate in 10 l of water and adjusting the pH to 6.0 ± 0.5 with 4 M sodium hydroxide solution.

Dissolution tests were performed on a commercially available reference preparation, Creon® capsules, manufactured by Abremie, in comparison with the compositions prepared according to Examples 1-6. The dissolution data obtained after 30 minutes in the buffer stage (phosphate buffer, pH 6.0) are given in Table 7.

Table 7. Time is) App.1 | App. 2| App. 3 App. | App. 5| App.

TZ between cotton umbrellas 5 5 | to! zi and I 12 months at 3072" / | 30 minutes

It is apparent from Table 7 that the enteric-coated Pancreatin pellets prepared according to Examples 1-6 exhibited 75-95% drug release within 30 minutes in phosphate buffer, pH 6.0, after application of artificial gastric fluid without enzyme, and their dissolution profile was better or comparable to that of the commercially available reference drug Creon® capsules, manufactured by Abremie. It is apparent from the data in Table 7 that the enteric-coated Pancreatin pellets prepared according to Examples 1-6 exhibit desirable sustained release characteristics.

Example 8

Capsules containing enteric-coated Pancreatin pellets prepared according to Examples 1-6 were studied for stability according to the CCN guidelines, at a temperature/relative humidity of 307°C/75°C/90°C/95°C for at least

From months. The capsules were packed in blisters, and the contents of the lipase pellet (European Pharmacopoeia

Units/Capsule) was evaluated at specific time intervals (Baseline and Stability) using the potentiometric method. The capsule dosage form demonstrated the results presented in Table 8.

Table 8

Two months at 407x2 70 / 12 months at 3072 70 /

From the analysis of the lipase content (European Pharmacopoeia Units/Capsule) of the pellets prepared according to Examples 1-6, it becomes apparent that the composition prepared according to the present invention is a synergistic composition that exhibits the desired stability characteristics for at least three months, due to the careful selection of excipients, their weight ratio and the manufacturing process used.

The composition prepared according to the present invention not only exhibits the desired results of stability during storage for at least 3 months, but also exhibits the desired delayed release of the drug from the dosage form. The high drug saturation together with the small particle size of the pellets makes them suitable for filling into capsules, which are of a convenient size for use.

Although this invention has been described in detail with reference to certain preferred embodiments thereof, it should be understood that it is not limited to these embodiments. Rather, in view of this application describing the current best mode of carrying out the invention in practice, many modifications and variations thereof will be presented to those skilled in the art without departing from the scope and spirit of the present invention.

TVe rgezepi ipuepnop geiiIagev (0 a zone oga! rragtaseshisa! sotro5shShop oi Rapsgeani apa a tefoy

Oh, the house is empty. That's it! The house is empty

Pshptidisu ("KN") oi 75 90 Tog a region oi a: Ivavi (pgee tops.

Claims (1)

1. A solid oral pharmaceutical composition with delayed release containing pancreatin, wherein the composition comprises the following: a) a core comprising: 1) from 95.5 to 99.5% by weight of pancreatin; 11) from 0.5 to 4.5% by weight of at least one pharmaceutically acceptable binder; 11) at least one pharmaceutically acceptable diluent, where the percentages are expressed relative to the total weight of the core; b) an enteric coating applied to the core comprising: i) at least one enteric coating agent; i) a plasticizer; i) at least one anti-sticking agent. 2. The solid oral pharmaceutical composition according to claim 1, wherein the solid oral pharmaceutical composition is in the form of powder, extrudates, pellets, micropellets, microspheres, microtablets, granules, granulates, tablets, modified release tablets, minitablets, pellets filled into capsules. 3. The solid oral pharmaceutical composition according to claim 1, wherein the coating is applied to achieve a weight gain in the range of 5 to 35,905. 4. The solid oral pharmaceutical composition of claim 1, wherein the pancreatin is present in an amount of from 100 to 1000 mg. 5. The solid oral pharmaceutical composition according to claim 1, wherein the ratio of binding agent 1 to pancreatin in the core is less than 0.05. b. The solid oral pharmaceutical composition according to claim 1, wherein the composition is stable at a temperature of 30°C and a relative humidity of 75°C for at least three months. 8. The solid oral pharmaceutical composition of claim 1, wherein the composition remains stable at a temperature of 40°C and a relative humidity of 75% for at least three months. 8. A process for preparing a solid oral pharmaceutical composition containing pancreatin, the process comprising the following steps: a) mixing pancreatin with at least one pharmaceutically acceptable binding agent; b) preparing a dispersion or solution of another binding agent in a pharmaceutically acceptable solvent; c) granulating the mixture obtained in step a) with the dispersion or solution of the binding agent obtained in step b); 4) passing the granulate from step c) through a suitable sieve; e) extruding the wet mass from step 4) in an extruder; I) spheronizing the extrudates obtained in step e) in a spheronizer; 8) drying the pellets obtained in step j) at a suitable temperature, B) coating the pellets obtained in step 6) with a solution or dispersion of an enteric-soluble agent, where the binding agent is present in an amount of from 0.5 to 4.5 wt. % relative to the total weight of the core. 9. The process of claim 8, wherein the coating is applied until a weight gain of between 20 and 30% is achieved. 10. The process of claim 8, wherein the product temperature of the solid pharmaceutical composition during the coating process is between 25 and 45 "C. 11. The process of claim 8, wherein the process is carried out at a relative humidity in the range of 40 to 65,995. 12. A stable solid oral sustained-release pharmaceutical composition comprising: (a) a core comprising pancreatin in an amount of from 95.5 to 99.5% by weight based on the total weight of the core, and at least one pharmaceutically acceptable binder and at least one pharmaceutically acceptable diluent; (b) an enteric coating layer comprising from 80 to 95% by weight of an enteric polymer as an enteric coating agent, an anti-sticking agent in an amount of from 1 to 5% by weight, and a plasticizer in an amount of from 1 to 10% by weight based on the weight of the coating layer; wherein the core comprises said binder in an amount of from 0.5 to 4.5% by weight based on the weight of the core. 13. A stable solid oral sustained release pharmaceutical composition according to claim 12, wherein the enteric coating layer comprises: 90.5% by weight of enteric polymer, an anti-sticking agent in an amount of 2% by weight, and a plasticizer in an amount of 7.5% by weight based on the weight of the coating layer.