WO1994001093A1 - Pompe osmotique pour la liberation d'enalapril a porosite regulee - Google Patents

Pompe osmotique pour la liberation d'enalapril a porosite regulee Download PDF

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Publication number
WO1994001093A1
WO1994001093A1 PCT/US1993/006271 US9306271W WO9401093A1 WO 1994001093 A1 WO1994001093 A1 WO 1994001093A1 US 9306271 W US9306271 W US 9306271W WO 9401093 A1 WO9401093 A1 WO 9401093A1
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WO
WIPO (PCT)
Prior art keywords
osmotic pump
pump according
enalapril
wall
core
Prior art date
Application number
PCT/US1993/006271
Other languages
English (en)
Inventor
Gerald S. Rork
John L. Haslam
Original Assignee
Merck & Co., Inc.
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 Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU46609/93A priority Critical patent/AU4660993A/en
Publication of WO1994001093A1 publication Critical patent/WO1994001093A1/fr

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Classifications

    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • Hf x Op where ⁇ is less than 1, usually 0 to 0.8.
  • any polymer film by itself permeable to water but impermeable to solutes as previously defined may be used. However, the film may be covered initially by a rapidly dissolving coat used for aesthetic purposes or containing the same or a different drug substance.
  • cellulose acetate having a degree of substitution meaning the average number of hydroxyl groups on the anhydroglucose unit of the polymer replaced by a substituting group, up to 1 and acetyl content up to 21%
  • cellulose triacetate having a D.S.
  • cellulose propionate having an acetyl content of 1.5 to 7% and a propionyl content of 2.5 to 3% and an average combined propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%
  • cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15%, and a butyryl content of 34 to 39%
  • cellulose acetate having an acetyl content of 2 to 99.5%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%
  • cellulose triacylates having a D.S.
  • esters prepared from acyl anhydrides or acyl acids in an esterification reaction to yield esters containing different acyl groups attached to the same cellulose polymer such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate palmitate and cellulose acetate heptanoate.
  • Additional polymers that can be used for the purpose of the invention include cellulose acetate acetoacetate, cellulose acetate chloroacetate, cellulose acetate furoate, dimethoxyethyl cellulose acetate, cellulose acetate carboxymethoxypropionate, cellulose acetate benzoate, cellulose butyrate naphthylate, cellulose acetate benzoate, methyl- cellulose acetate methylcyanoethyl cellulose, cellulose acetate methoxyacetate, cellulose acetate ethoxyacetate, cellulose acetate dimethyl sulfamate, ethylcellulose, ethylcellulose dimethyl sulfamate, cellulose acetate p-toluene sulfonate, cellulose acetate methylsulfonate, cellulose acetate dipropylsulfamate, cellulose acetate butylsulfonate, cellulose acetate laurate, cellulose ste
  • the microporous wall may be formed in situ, by a pore-former being removed by dissolving or leaching it to form the microporous wall during the operation of the system.
  • the pores may also be formed in the wall prior to operation of the system by gas formation within curing polymer solutions which result in voids and pores in the final form of the wall.
  • the pore-former can be a solid or a liquid.
  • the pore-formers include organic compounds such as saccharides.
  • the saccharides include the sugars sucrose, glucose, fructose, mannose, galactose, aldohexose, altrose, talose, lactose, monosaccharides, disaccharides, and water soluble polysaccharides.
  • solvents suitable for manufacturing the wall of the osmotic device include inert inorganic and organic solvents that do not adversely harm the core, wall, and the materials forming the final wall.
  • the solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatics, heterocyclic solvents and mixtures thereof.
  • plasticizers suitable for the present purpose include plasticizers that lower the temperature of the second-order phase transition of the wall or the elastic modulus thereof; and also increase the workability of the wall, its flexibility and its permeability to fluid.
  • Plasticizers operable for the present purpose include both cyclic plasticizers and acyclic plasticizers.
  • Typical plasticizers are those selected from the group consisting of phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, sulfonamides, and halogenated phenyls.
  • plasticizers from 0.001 to 50 parts of a plasticizer or a mixture of plasticizers are incorporated into 100 parts of wall forming material.
  • Suitable plasticizers can be selected for blending with the wall forming materials by selecting plasticizers that have a high degree of solvent power for the materials, are compatible with the materials over both the processing and use temperature range, exhibit permanence as seen by their strong tendency to remain in the plasticized wall, impart flexibility to the material and are non-toxic to animals, humans, avians, fishes and reptiles. Procedures for selecting a plasticizer having the described characteristics are disclosed in the Encyclopedia of Polymer Science and Technology. Vol. 10, pages 228 to 306, 1969, published by John Wiley & Sons, Inc.
  • plasticizer properties including solvent parameters and compatibility such as the Hildebrand solubility parameter w, the Flory- Huggins interaction parameter x, and the cohesive-energy density, CED, parameters are disclosed in Plasticization and Plasticizer Processes. Advances in Chemistry Series 48, Chapter 1, pages 1 to 26, 1965, published by the American Chemical Society.
  • the amount of plasticizer added generally is an amount sufficient to produce the desired wall and it will vary according to the plasticizer and the materials. Usually about 0.001 part up to 50 parts of plasticizer can be used for 100 parts of wall material.
  • the amount of flux regulator added to a material generally is an amount sufficient to produce the desired permeability, and it will vary according to the lamina forming material and the flux regulator used to modulate the permeability. Usually from 0.001 parts up to 50 parts, or higher of flux regulator can be used to achieve the desired results.
  • Illustrative of such an osmotic pump according to the present invention are those in which the cardiovascular agent is selected from alpha receptor blocking agents, alpha and beta receptor blocking agents, antianginal agents, antiarrhythmics, antiembolus agents, antihypertensives, beta blocking agents, calcium ion influx inhibitors, diuretics, digitalis, hemorheologic agents, inotropic agents, myocardial infarction prophylaxis, quinidine, cerebral vasodilators, coronary vasodilators, peripheral vasodilators, and vasopressors.
  • the cardiovascular agent is selected from alpha receptor blocking agents, alpha and beta receptor blocking agents, antianginal agents, antiarrhythmics, antiembolus agents, antihypertensives, beta blocking agents, calcium ion influx inhibitors, diuretics, digitalis, hemorheologic agents, inotropic agents, myocardial infarction prophylaxis, quinidine, cerebral vasodilators, coronary vaso
  • Exemplifying such an osmotic pump according to the present invention are those in which the cardiovascular agent is selected from the calcium ion influx inhibitors or diuretics.
  • the cardiovascular agent is selected from the calcium ion influx inhibitors or diuretics.
  • Such calcium ion influx inhibitors include but are not limited to diltiazem and its pharmaceutically active salts.
  • Such diuretics include but are not limited to hydrochlorothiazide.
  • a multiparticulate formulation of enalapril maleate was prepared as follows: enalapril maleate (120g) was placed in a beaker and a slurry of sodium bicarbonate (62.4g) and water (300 ml) was slowly added. This mixture was allowed to stir until the neutralization was complete (as evident by no further evolution of carbon dioxide). In a Hobart planetary mixer, 360g lactose, 150g com starch and 450g Avicel® PH-101 were mixed for 5 minutes. The above solution was then added to the solids and mixed (additional water was added until an appropriate consistency was obtained).
  • EXK(F)S-1 Xtruder using a 1.2 mm screen.
  • the extmdate was then spheronized in a Lewa Model QJ-230 Marumerizer with a bottom plate speed of 1000 RPM for 10 minutes.
  • the resultant beads were dried overnight at room temperature at 20% relative humidity, then sized using standard mesh screens.
  • the coating solution was prepared by placing 900 ml of acetone in an appropriate container and slowly adding 36g of cellulose acetate buryrate (grade CAB381-20) with vigorous stirring. Once the polymer was dissolved, 300ml of methanol, 10.8g triethyl citrate and a sucrose solution (10.8g sucrose dissolved in 150g water) were added.
  • the multiparticulates (300 ml volume, mesh size #18) were placed in an 8" pan coater (Freund® Model HCT-20 Mini Hi-Coater).
  • the following coating parameters were used: inlet temperature 75-80°C, outlet temperature 40-45°C, pan speed 30 RPM, atomizing air 1.2-1.4 kg/cm2 and a spray rate of 8-10 ml/min. Coating was applied when the outlet temperature reached 45°C. A total of approximately 4L of coating solution was applied. The coat weight of the resultant coated beads was 36% of the total weight of the finished beads.
  • USP dissolution apparatus 2 was used with a bath volume of 1000 ml of water and a stir rate of 80 RPM to determine the drug release rate profile of the coated beads. Samples (1.5ml) of the dissolution medium were withdrawn over a 20 hour period and assayed for enalapril content by HPLC. The lag time and times for 50 and 85% of drug release are given in Table I.
  • Multiparticulates were made as per Example 1 with the following coating solution modifications: 3.6g sucrose and no triethyl citrate. This batch contained fillers and actives (fillers mesh size 18, actives mesh size 14). Sufficient coat was added to obtain 85% drug released in 8-12 hours. The lag time and time for 50 and 85% drug release are given in Table I.
  • Multiparticulates were made as per Example 1 with the following coating solution modifications: 14.4g sucrose and 7.2g diethyl phthalate.
  • the coating weight was 24% of the total weight of the finished, coated beads.
  • the lag time and time for 50 and 85% drug release are given in Table I.
  • Multiparticulates were made as per Example 1 with the following coating solution modifications: 36g cellulose acetate butyrate (grade CAB 500-5) polymer, 9g sucrose and no triethyl citrate.
  • the coating weight was 25% of the total weight of the finished, coated beads.
  • the lag time and time for 50 and 85% drug release are given in Table I.
  • Multiparticulates were made as per Example 1 with the following core modifications: 60g enalapril maleate, 31.2g sodium bicarbonate, and 420g lactose.
  • the coating weight was 21 % of the total weight of the finished, coated beads.
  • the lag time and time for 50 and 85% drug release are given in Table I.
  • Enalapril maleate tablet cores were prepared with dose strengths of 5, 10 and 20 mg per tablet. The range of ingredients are given in Table II.
  • the ingredients listed above in appropriate batch sizes were mixed in a high intensity mixer except for the magnesium stearate and water.
  • the water was added at 85°C with mixing at a spray rate sufficient to add all the water in 1 to 1.5 minutes.
  • the material was then mixed for 4 minutes.
  • the material was then discharged into a fluidized bed dryer and dried at 50°C until the moisture content was less than 1%.
  • the dried material was milled using a Tomado Comminutor with knives forward, 1.98 mm screen at 2500 rpm.
  • the magnesium stearate which had been passed through a 60 mesh screen was added to the milled material in a ribbon blender and mixed for 5 minutes.
  • Core tablets prepared as described in Example 7, containing 20 mg enalapril maleate per tablet were coated in a 8" pan coater (Freund® Model HCT-20 Mini Hi-Coater) with a microporous polymer coating consisting of cellulose acetate butyrate (grade CAB 381-20) and sucrose.
  • the coating solution was prepared by placing 900 ml of acetone in an appropriate container and slowly adding 36 g of the polymer with vigorous stirring. Once the polymer had dissolved, 300 ml of methanol was added followed by 14.4 g of sucrose dissolved in 170 ml of water. The coating solution was applied to the tablets at a rate of 12 to 14 ml per minute through an atomization spray nozzle.
  • the inlet air was adjusted to give an outlet air temperature of 40 to 44°C.
  • a coating thickness of approximately 290 ⁇ was applied to the tablets.
  • the release of drug was determined by the use of USP dissolution setup number 2 with 1000 ml of water, and a paddle rotation of 50 rpm. Samples (approximately 2 to 3 ml) of the dissolution media were taken at various times over 20 hours. The samples were assayed for enalapril by HPLC. Table III gives the lag time and the times for 50 and 85% of drug release from these tablets.
  • Core tablets were prepared as described with 20 mg of drug per tablet and coated with a different polymer than described in Example 7.
  • the microporous coating of this example contains cellulose acetate (grade CA 394-60S), sucrose and polyethylene glycol 400.
  • the coating solution was prepared by placing 800 ml of acetone in an appropriate container and adding 36 g of the polymer with vigorous stirring. Once the polymer had dissolved 300 ml of methanol and 7.2 g of polyethylene glycol 400 was added. A solution of 9 g of sucrose was prepared in 200 ml of water and added to the polymer solution. Tablets were coated with this solution in the pan coater by the procedure described in Example 1.
  • Sufficient coating (350 ⁇ ) was applied to the tablets to give a release of 85% of the drug in 8 to 14 hours.
  • the release of drug was determined as described in Example 7. Table in gives the lag time and the times for 50 and 85% of drug release from these tablets.
  • Core tablets were prepared as described with 20 mg of drug per tablet and coated with an ethylcellulose coating.
  • the microporous coating of this example contains ethylcellulose and sucrose.
  • the coating solution was prepared by placing 1000 ml of acetone in an appropriate container and adding 36 g of ethy cellulose (EthocelTM 100 standard) with vigorous stirring. Once the polymer had dissolved 100 ml of ethanol and 14.4 grams of sucrose dissolved in 170 ml of water was added. Tablets were coated with this solution in the pan coater by the procedure described in Example 24. Sufficient coating (270 ⁇ ) was applied to the tablets to give a release of 85% of the drug in 8 to 14 hours. The release of drug was determined as described in Example 7. Table HI gives the lag time and the times for 50 and 85% of drug release from these tablets.
  • Core tablets were prepared as described with 5 mg of drug per tablet and coated with a cellulose acetate coating.
  • the microporous coating of this example contains cellulose acetate, sucrose and polyethylene glycol 400.
  • the coating solution was prepared by placing 1000 ml of acetone in an appropriate container and adding 36 g of cellulose acetate (grade CA 398-30) with vigorous stirring. Once the polymer had dissolved 7.2 grams of polyethylene glycol 400 and 10.8 grams of sucrose dissolved in 200 ml of water was added. Tablets were coated with this solution in the pan coater by the procedure described in Example 7. Sufficient coating (525 ⁇ ) was applied to the tablets to give a release of 85% of the drug in 8 to 14 hours. The release of drug was determined as described in Example 7. Table Ifl gives the lag time and the times for 50 and 85% of drug release from these tables.
  • Core tablets were prepared as described with 10 mg of drug per tablet and coated with a cellulose acetate coating.
  • the microporous coating of this example contains cellulose acetate, sucrose and polyethylene glycol 400.
  • the coating solution was prepared by placing 675 ml of methylene chloride in an appropriate container and adding 36 g of cellulose acetate (grade CA 436-80S) with vigorous stirring. Once the polymer had dissolved 3.6 grams of polyethylene glycol 400, 450 ml of methanol and 9 grams of sucrose dissolved in 50 ml of water was added. Tablets were coated with this solution in the pan coater by the procedure described in Example 24. Sufficient coating was applied (435 ⁇ ) to the tablets to give a release of 85% of the drug in 8 to 14 hours. The release of drug was determined as described in Example 7. Table HI gives the lag time and the times for 50 and 85% of drug release from these tablets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à une pompe osmotique, pour la libération régulée d'énalapril dans un milieu. Cette pompe comprend: (A) un noyau, qui contient une quantité thérapeutiquement efficace d'énalapril, du bicarbonate de sodium et du lactose et qui est entouré par: (B) une paroi insoluble à l'eau de régulation de la vitesse de libération, ayant une perméabilité aux fluides comprise entre 6,96 x 10-18 et 6,96 x 10 -14 cm3 sec/g ainsi qu'un coefficient de réflexion inférieur à 0,5, et qui est préparée à partir: (i) d'un polymère perméable à l'eau mais imperméable au soluté, et (ii) de 0,1 à 60 % en poids, calculé sur la base du poids total de (i) et (ii), d'au moins un additif porogène insensible au pH, dispersé sur toute l'étendue de la paroi.
PCT/US1993/006271 1992-07-09 1993-07-01 Pompe osmotique pour la liberation d'enalapril a porosite regulee WO1994001093A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46609/93A AU4660993A (en) 1992-07-09 1993-07-10 Controlled porosity osmotic enalapril pump

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91154192A 1992-07-09 1992-07-09
US911,541 1992-07-09

Publications (1)

Publication Number Publication Date
WO1994001093A1 true WO1994001093A1 (fr) 1994-01-20

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005881A1 (fr) * 1995-08-04 1997-02-20 Bernard Charles Sherman Formulation solide stable de sel d'enalapril et procede de preparation correspondant
WO2002003970A2 (fr) * 2000-07-12 2002-01-17 Hexal Ag Systeme transdermique a regulation matricielle pour derives stables des inhibiteurs de l'eca
KR20020035536A (ko) * 2002-04-15 2002-05-11 (주)베스트메탈라인 도어핸들
WO2005007130A1 (fr) * 2003-07-11 2005-01-27 Sandoz Ag Compositions pharmaceutiques stables contenant un inhibiteur d'ace
WO2005097064A2 (fr) * 2004-04-12 2005-10-20 Pfizer Products Inc. Medicaments au gout masque lors de la rupture des matieres particulaires multiples
US8084437B2 (en) 2006-11-27 2011-12-27 Isis Pharmaceuticals, Inc. Methods for treating hypercholesterolemia
WO2018192000A1 (fr) * 2017-04-20 2018-10-25 上药东英（江苏）药业有限公司 Comprimé de type pompe osmotique de périndopril et de sel correspondant et son procédé de préparation
US10357462B2 (en) 2006-11-30 2019-07-23 Ben Research, Inc. Multiparticulates of spray-coated drug and polymer on a meltable core
US11116728B2 (en) 2006-11-30 2021-09-14 Bend Research, Inc. Multiparticulates of spray-coated drug and polymer on a meltable core

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4578075A (en) * 1982-12-20 1986-03-25 Alza Corporation Delivery system housing a plurality of delivery devices
US4880631A (en) * 1987-09-24 1989-11-14 Merck & Co., Inc. Controlled porosity osmotic pump
US4886668A (en) * 1987-09-24 1989-12-12 Merck & Co., Inc. Multiparticulate controlled porosity osmotic pump

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4578075A (en) * 1982-12-20 1986-03-25 Alza Corporation Delivery system housing a plurality of delivery devices
US4880631A (en) * 1987-09-24 1989-11-14 Merck & Co., Inc. Controlled porosity osmotic pump
US4886668A (en) * 1987-09-24 1989-12-12 Merck & Co., Inc. Multiparticulate controlled porosity osmotic pump

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1637142A2 (fr) * 1995-08-04 2006-03-22 Apotex Europe Limited Composition stabilisée solide d'un sel d'enalapril et procédé de préparation
EP1442746A1 (fr) * 1995-08-04 2004-08-04 Apotex Europe Limited Composition stabilisée solide d'un sel d'enalapril et procédé de préparation
WO1997005881A1 (fr) * 1995-08-04 1997-02-20 Bernard Charles Sherman Formulation solide stable de sel d'enalapril et procede de preparation correspondant
EP1637142A3 (fr) * 1995-08-04 2008-04-02 Apotex Europe Limited Composition stabilisée solide d'un sel d'enalapril et procédé de préparation
EP1527780A1 (fr) * 1995-08-04 2005-05-04 Apotex Europe Limited Composition stabilisée solide d'un sel d'enalapril et procédé de préparation
WO2002003970A3 (fr) * 2000-07-12 2002-05-23 Hexal Ag Systeme transdermique a regulation matricielle pour derives stables des inhibiteurs de l'eca
WO2002003970A2 (fr) * 2000-07-12 2002-01-17 Hexal Ag Systeme transdermique a regulation matricielle pour derives stables des inhibiteurs de l'eca
EP1792611A1 (fr) * 2000-07-12 2007-06-06 Hexal Ag Système transdermique à régulation matricielle contenant des derivés stables des inhibiteurs de l'ECA
KR20020035536A (ko) * 2002-04-15 2002-05-11 (주)베스트메탈라인 도어핸들
WO2005007130A1 (fr) * 2003-07-11 2005-01-27 Sandoz Ag Compositions pharmaceutiques stables contenant un inhibiteur d'ace
WO2005097064A2 (fr) * 2004-04-12 2005-10-20 Pfizer Products Inc. Medicaments au gout masque lors de la rupture des matieres particulaires multiples
WO2005097064A3 (fr) * 2004-04-12 2006-08-03 Pfizer Prod Inc Medicaments au gout masque lors de la rupture des matieres particulaires multiples
US8236349B2 (en) 2004-04-12 2012-08-07 Bend Research Inc. Taste-masked drugs in rupturing multiparticulates
US8084437B2 (en) 2006-11-27 2011-12-27 Isis Pharmaceuticals, Inc. Methods for treating hypercholesterolemia
US10357462B2 (en) 2006-11-30 2019-07-23 Ben Research, Inc. Multiparticulates of spray-coated drug and polymer on a meltable core
US11116728B2 (en) 2006-11-30 2021-09-14 Bend Research, Inc. Multiparticulates of spray-coated drug and polymer on a meltable core
WO2018192000A1 (fr) * 2017-04-20 2018-10-25 上药东英（江苏）药业有限公司 Comprimé de type pompe osmotique de périndopril et de sel correspondant et son procédé de préparation

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