WO2021250700A1 - Composition pharmaceutique de pancréatine - Google Patents

Composition pharmaceutique de pancréatine Download PDF

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Publication number
WO2021250700A1
WO2021250700A1 PCT/IN2021/050563 IN2021050563W WO2021250700A1 WO 2021250700 A1 WO2021250700 A1 WO 2021250700A1 IN 2021050563 W IN2021050563 W IN 2021050563W WO 2021250700 A1 WO2021250700 A1 WO 2021250700A1
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WIPO (PCT)
Prior art keywords
weight
pharmaceutical composition
solid oral
pancreatin
core
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PCT/IN2021/050563
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English (en)
Inventor
Sanjeev Gupta
Rajeev Gupta
Tg CHANDRASHEKHAR
Swati Mukherjee
Vineet Bhardwaj
Vikas BALI
Original Assignee
Kusum Healthcare Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kusum Healthcare Pvt. Ltd. filed Critical Kusum Healthcare Pvt. Ltd.
Priority to MX2022014395A priority Critical patent/MX2022014395A/es
Priority to MDA20220054A priority patent/MD20220054A2/ro
Publication of WO2021250700A1 publication Critical patent/WO2021250700A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54—Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a solid oral pharmaceutical composition of Pancreatin and a process of preparing the same.
  • 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.
  • PKI pancreatic exocrine insufficiency
  • 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 tri ethyl citrate as the plasticizer are exemplified to lack desired technical attributes and hence, are not the preferred compositions.
  • 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.
  • RH relative humidity
  • 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 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 and optionally at least one anti-sticking agent.
  • 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.
  • the pharmaceutically acceptable excipient comprises binding agents, enteric coating agents, plasticizers, and anti sticking agents.
  • 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.
  • 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.
  • immediate release refers to pharmaceutical compositions comprising Pancreatin, which do not contain any drug release rate controlling agent.
  • 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).
  • controlled release refers to pharmaceutical compositions comprising Pancreatin and one or more pharmaceutically acceptable excipients, which contain at least one drug release rate controlling agent.
  • delayed release refers to pharmaceutical compositions comprising Pancreatin, at least one pH dependent drug release rate controlling agent, and one or more pharmaceutically acceptable excipients.
  • enteric-coated compositions are delayed release dosage forms.
  • micro 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.
  • gastric acid resistance 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).
  • 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
  • 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;
  • 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.
  • storage stability 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.
  • the solid oral pharmaceutical composition is an immediate release composition or a controlled release composition.
  • controlled release composition is used interchangeably with modified release composition and includes delayed release composition, extended release composition or sustained release composition.
  • the solid oral pharmaceutical composition is a delayed release composition.
  • 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 and the like.
  • the solid oral pharmaceutical composition is in the form of pellets filled in capsule.
  • the coating is applied to achieve a weight build up in the range of about 5% to about 35%.
  • coating is performed till a weight build up in the range of about 10% to about 30% is achieved.
  • coating is performed till a weight build up in the range of about 20% to about 30% is achieved.
  • coating is performed till a weight build up in the range of about 26% to about 30% is achieved.
  • the enteric coated pellet is approximately spherical and has a diameter in the range of about 0.5 mm to about 2.5 mm.
  • 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.
  • 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.
  • 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.
  • 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 V- blender 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 can be used for processes such as wet granulation and extrusion.
  • 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.
  • the solvent used in the manufacturing process of the present invention is enzyme-friendly.
  • pharmaceutically acceptable excipients 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 , hydroxy ethyl 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.
  • binding agent is present in an amount less than 9% by weight with respect to total weight of the core.
  • 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.
  • core is devoid or completely free of binding agent.
  • ratio of binding agent to active pharmaceutical ingredient (API) in the core is less than about 0.05.
  • Suitable enteric coating agents include agar, Carbopol TM (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 phthal
  • 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, gly
  • Suitable anti-sticking agents comprise dimethicone and castor oil.
  • the solid oral pharmaceutical composition is devoid of mixture of plasticizers.
  • 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.
  • 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.
  • 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
  • the binding agent used in process for the preparation of a solid oral pharmaceutical composition comprising Pancreatin may be same or different.
  • binding agent is present in an amount less than 9% by weight with respect to total weight of the core.
  • 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.
  • coating is performed till a weight build up in the range of about 20% to about 30% is achieved.
  • the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 25 °C and 45 °C.
  • the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 25°C and 40°C.
  • the process is carried out at a relative humidity in the range of 40% to 65%.
  • 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
  • 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.
  • the binding agent used in the preparation of a solid oral pharmaceutical composition comprising Pancreatin may be same or different.
  • binding agent is present in an amount less than 10% by weight with respect to total weight of the core.
  • 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.
  • core is devoid or completely free of binding agent.
  • ratio of binding agent to active pharmaceutical ingredient (API) in the core is less than about 0.05.
  • coating is performed till a weight build up in the range of about 5% to about 35% is achieved. In a 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.
  • the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 25 °C and 45 °C.
  • the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 25°C and 40°C.
  • the process is carried out at a relative humidity in the range of 18% to 65%.
  • 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 present invention provides a stable delayed release solid oral pharmaceutical composition comprising:
  • 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;
  • 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.
  • 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.
  • binding agent is present in an amount less than 10% by weight with respect to total weight of the core.
  • 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.
  • core is devoid or completely free of binding agent.
  • the core comprises Pancreatin in an amount of more than about 95% by weight with respect to the weight of core.
  • ratio of binding agent to active pharmaceutical ingredient (API) in the core is less than about 0.05.
  • the core comprising Pancreatin is in the form of powder, granules, granulates, beads, pellets, micropellets, microspheres, microtablets, minitablets or tablets.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is in the form of a delayed release pellets comprising:
  • 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;
  • 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.
  • core further comprises pharmaceutically acceptable binding agent in an amount less than 5% by weight with respect to the weight of core.
  • core comprises pharmaceutically acceptable binding agent in an amount of 4.51% by weight with respect to the weight of core.
  • core is devoid or completely free of binding agent.
  • 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 evaluation as per the United States Pharmacopoeia (USP) to determine 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.
  • USP United States Pharmacopoeia
  • 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.
  • 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, ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, dichloromethane and combinations thereof.
  • the solid oral pharmaceutical composition comprising Pancreatin or its pharmaceutically acceptable salt is filled into capsules or sachets or may be compressed to form microtablets or tablets.
  • 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.
  • the solid oral pharmaceutical composition comprising Pancreatin is filled in hard gelatin or HPMC capsules having size ‘2’, ‘G or ‘O’. More preferably, the solid oral pharmaceutical composition comprising Pancreatin is filled in hard gelatin capsules having size 1
  • step 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).
  • step i) Pellets obtained from step i) were coated with the solution obtained in step k) to achieve the target weight gain of 15% to 30%.
  • step m) Coated pellets from step 1) were dried maintaining product temperature between 25°C - 40°C for sufficient time.
  • step n) Pellets obtained from step m) were filled in hard gelatin capsules.
  • Procedure for Ex. 2 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 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.
  • step f) The wet mass of step f) was extruded in an extruder.
  • step g) 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).
  • 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 temperature between 25°C - 40°C for sufficient time.
  • n) Pellets obtained from step m) were filled in hard gelatin capsules.
  • step g) Pellets obtained from step g) were dried to achieve the loss on drying not more than 3%.
  • 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%.
  • step l) Coated pellets from step k) were dried maintaining product temperature between 25°C - 40°C for sufficient time.
  • m) Pellets obtained from step 1) were filled in hard gelatin capsules.
  • 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 temperature of 37 ⁇ 0.5°C and a rotation speed of 100 revolutions per minute for 60 minutes followed by measurement in 800 mL of Phosphate Buffer, pH 6.0 using a paddle apparatus at a temperature of 37 ⁇ 0.5°C and a rotation speed of 100 revolutions 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.
  • 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.
  • composition prepared as per the present invention is a synergistic composition whereby the composition exhibits desirable stability characteristics of at least three months by virtue of careful selection of excipients, their weight percentages and the manufacturing process employed.
  • composition prepared as per the present invention not only demonstrates desirable storage stability for at least three months but also exhibits desired 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 administered.

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Abstract

La présente invention concerne une composition pharmaceutique orale solide de pancréatine et son procédé de préparation. La composition pharmaceutique orale solide préparée par le procédé de l'invention est également stable lorsqu'elle est soumise à un test de stabilité à une température de 30°C et une humidité relative ("RH") de 75% pendant une période d'au moins trois mois.
PCT/IN2021/050563 2020-06-10 2021-06-10 Composition pharmaceutique de pancréatine WO2021250700A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
MX2022014395A MX2022014395A (es) 2020-06-10 2021-06-10 Composicion farmaceutica de pancreatina.
MDA20220054A MD20220054A2 (ro) 2020-06-10 2021-06-10 Compoziţie farmaceutică de pancreatină

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Application Number Priority Date Filing Date Title
IN202011024325 2020-06-10
IN202011024325 2020-06-10

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WO2021250700A1 true WO2021250700A1 (fr) 2021-12-16

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU638784B2 (en) * 1989-11-24 1993-07-08 Sandoz Ag Pancreatin preparations
AU2006281415A1 (en) * 2005-08-15 2007-02-22 Abbott Laboratories Gmbh Pancreatin micropellet cores suitable for enteric coating

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU638784B2 (en) * 1989-11-24 1993-07-08 Sandoz Ag Pancreatin preparations
AU2006281415A1 (en) * 2005-08-15 2007-02-22 Abbott Laboratories Gmbh Pancreatin micropellet cores suitable for enteric coating

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MD20220054A2 (ro) 2023-05-31

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