EP1868577A1 - Particules de lacidipine - Google Patents

Particules de lacidipine

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Publication number
EP1868577A1
EP1868577A1 EP06749977A EP06749977A EP1868577A1 EP 1868577 A1 EP1868577 A1 EP 1868577A1 EP 06749977 A EP06749977 A EP 06749977A EP 06749977 A EP06749977 A EP 06749977A EP 1868577 A1 EP1868577 A1 EP 1868577A1
Authority
EP
European Patent Office
Prior art keywords
lacidipine
particles
solution
particle size
less
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06749977A
Other languages
German (de)
English (en)
Other versions
EP1868577A4 (fr
Inventor
Venkataraman Sundaram
Manoj Ramesh Kharkar
Sharat Pandurang Narsapur
Surya Narayana Devarkonda
Suhas Lalitadas Jawlekar
Ravi Kumar Komareddy
Adolf Ceaser Coldwyn
Aniruddha Bhalachandra Pandit
Mamta Mishra
Arunava Ghosh
Gurvinder Singh
Vijay Dinanathji Nasare
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories 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 Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1868577A1 publication Critical patent/EP1868577A1/fr
Publication of EP1868577A4 publication Critical patent/EP1868577A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

  • the present invention relates to agglomerate free particles of lacidipine, processes to prepare the same, the pharmaceutical compositions comprising such agglomerate free particles and their use in the therapy of hypertension.
  • Lacidipine chemically named (E)-4-[2-[3-(1 ,1-dimethylethoxy)-3- oxopropenyl]phenyl]-1 ,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, is represented structurally by Formula I.
  • Lacidipine is a dihydropyridine calcium antagonist, which is useful in the treatment of hypertension and is commercially available as MOTENS tablets (2, 4, and 6 mg). Lacidipine is a white to pale yellow crystalline powder, practically insoluble in water.
  • PCT International Application Publication No. WO 2004/009057 describes a process to prepare dispersions of nano-crystalline particles in an aqueous medium.
  • Preparations of small particles of water insoluble drugs can also be suitable for oral, pulmonary, topical, ophthalmic, nasal, buccal, rectal, vaginal, transdermal, or other routes of administration.
  • the small size of the particles improves the dissolution rate of the drug, hence may improve its bioavailability and potentially its toxicity profiles.
  • the present invention relates to agglomerate free particles of lacidipine, processes to prepare the same, the pharmaceutical compositions comprising such agglomerate free particles and their use in the therapy of hypertension.
  • An embodiment of a process for preparing fine, uniform and agglomerate- free particles of crystalline lacidipine includes; (a) dissolving lacidipine in an organic solvent or mixture of solvents to form a first solution;
  • the invention provides a premix composition having finely divided lacidipine, prepared by depositing a lacidipine solution onto a substrate material that is a pharmaceutical excipient or a mixture of pharmaceutical excipients, then removing at least a portion of the solvent.
  • An aspect of the invention comprises lacidipine particles having a particle size distribution with a span less than about 5. Another aspect of the invention comprises lacidipine particles having a particle size distribution with a span less than about 3.
  • the invention comprises a pharmaceutical composition comprising lacidipine particles having a span less than about 5, or less than about 3, and at least one pharmaceutically acceptable excipient.
  • Fig. 1 shows an ultrasound flow cell that is useful in an aspect of the invention.
  • the present invention relates to agglomerate free particles of lacidipine, processes to prepare the same, pharmaceutical compositions comprising such agglomerate free particles and their use in the therapy of hypertension.
  • An embodiment of a process for preparing fine, uniform and agglomerate free particles of crystalline lacidipine includes;
  • the organic solvents that can be used for the preparation of the first solution include various classes of solvents in which the lacidipine is soluble. Examples include but are not limited to alcohols, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, or mixtures thereof. Lower alkanols are useful and can be any alcohol such as for example one or more of the primary, secondary or tertiary alcohols having from one to about six carbon atoms.
  • the lower alkanol can be for example one or more of methanol, ethanol, denatured spirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like.
  • the ketones can be any solvent from this class such as for example one or more of acetone, propanone, 2-butanone and the like.
  • the halogenated solvent can be any solvent from this class such as for example one or more of chloroform, dichloromethane, 1 ,2-dichloroethane, carbon tetrachloride and the like.
  • the ester can be any solvent from this class such as for example one or more of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and the like.
  • the ether can be any solvent from this class such as for example one or more of dimethyl ether, diethyl ether, methyl tertiary-butyl ether ethyl methyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like.
  • Lacidipine can be first dissolved in the organic solvent to create a first solution. Lacidipine can be present at from about 5% (w/v) to about 30% (w/v) depending on the solubility of lacidipine in the first solvent. Heating lacidipine in a solvent or solvent mixture to temperatures about 30 0 C to about 150 0 C, or from about 10 0 C to about 15 0 C below the boiling point of the solvent or solvent mixture, will help to ensure dissolution.
  • the lacidipine solution is then mixed with an antisolvent to precipitate lacidipine.
  • the anti solvent can be mixed into the lacidipine solution.
  • the antisolvents that can be used for the preparation of second solution include polar solvents such as water, or non-polar organic solvents such as n-heptane, hexane or cyclohexane or combinations thereof.
  • the solution-antisolvent mixture can be subjected to ultrasound radiation.
  • First solution can be mixed with antisolvent, or vice versa, and subjected to ultrasound, typically for about 15-20 minutes or up to about 1 hour.
  • a power of 50- 1000 watts has been found useful, but the power applied will depend upon the size and shape of the vessel that contains the mixture. The use of longer times or other ultrasonic energy levels is not detrimental. If an ultrasonic bath having a different power is employed, the energy exposure time has to be altered correspondingly.
  • Energy is continually applied to the antisolvent and lacidipine solution during mixing, both in the ultrasonic bath and the flow cell. The lacidipine particles precipitate out immediately when lacidipine solution comes in contact with antisolvent while being exposed to ultrasound.
  • the ultrasound treatment can be carried out at any temperature or room temperature, it needs to be taken into account that, without any cooling, the ultrasonic energy radiated into the mixture will itself cause a rise in temperature.
  • the treatment of the mixture with ultrasound therefore frequently will be carried out using external cooling to maintain a desired temperature.
  • the mixture can be optionally cooled to below 20 0 C or below 10 0 C for about 1 hour, or for about 40 minutes to form slurry.
  • Solids are separated, such as using vacuum, a pressure filter, or a centrifuge, and the solids are dried, such as in a vacuum oven at about 120 0 C, or at about 85 0 C, for about 1 to 15 hours, or 11 to 13 hours, or in a fluid bed dryer at about 120 0 C, or at about 60 0 C for up to about 30 to 40 minutes or about 2 hours, to afford agglomerate free particles of lacidipine.
  • Slurry or wet cake can also be dried using spin flash drying and other techniques known in art.
  • the cooling typically increases yield of solids.
  • the present process can also use agitation to ensure uniform macro mixing.
  • the obtained fine particles of lacidipine can further also be milled to get additional particle size reduction while retaining uniformity and the agglomerate free quality.
  • Fig. 1 is a cross-sectional diagram of an embodiment of an ultrasound flow cell 10.
  • the flow cell comprises an inlet 12 and an outlet 14, for establishing a flow in the direction of the arrows through the cell of a first fluid that is introduced into inlet 12.
  • the number, locations and dimensions of the inlets and outlets may vary according to the requirements of an application, and fluid flow for an embodiment can be opposite the direction shown, in which event the positions of inlet 12 and outlet 14 would be reversed.
  • On the outer surface of flow cell 10 are mounted multiple ultrasonic transducers 16 that supply ultrasonic radiation into the contents of the flow cell, the transducers being electrically connected to a suitable external power source (not shown).
  • the number and physical arrangement of the transducers around the flow cell can vary according to the process requirements.
  • a temperature sensor 18 is optionally attached to outlet 14 to observe and control the temperature of the removed product from the outlet. Similar sensors may also optionally be attached to the inlet system and at various locations in the flow cell, as desired.
  • a dip tube 20 having an inlet 22 is used to supply a second fluid containing a reactant into the flow cell. The number, diameters and materials of construction of the dip tube may vary with the process requirements. Dip tube 20 may further be perforated at a point where it is desired to introduce reactant into the flow cell interior and therefore does not necessarily have an open lower end for delivery of the reactant.
  • the flow cell optionally is provided with an outer cover 24, for protection from the environment or for provision of heating, cooling, or insulation to the cell.
  • a first fluid comprising a reactive substance is introduced into inlet 12 and flows toward outlet 14.
  • a second fluid comprising a different reactive substance is introduced into inlet 22 of dip tube 20 and exits the dip tube into the flow of first reactive substance.
  • ultrasonic radiation having a desired frequency and power is being applied to flow cell 10 through transducers 16 to influence a reaction that takes place between the reactive substances.
  • flow cell 10 has a height about 45 cm, a width about 15 cm and a depth about 15 cm, giving an enclosed flow cell volume about 10 liters.
  • Flow rates into inlet 12 and through dip tube 20 can be established as required to provide a desired proportion of reactants and a desired residence time inside the flow cell.
  • Other dimensions and shapes can be used depending on specific process requirements.
  • Lacidipine of the present invention has a mean particle size less than about 50 ⁇ m, or about 30 ⁇ m, or about 10 ⁇ m. This mean is calculated as the sum of sizes of total particles divided by the number of the particles.
  • Lacidipine of the present invention has D 90 less than about 80 ⁇ m, or less than about 30 ⁇ m, or less than about 15 ⁇ m.
  • the particle size mentioned herein refers to the diameter of the particles more commonly known as D 90 when measured by conventional particle size measuring instruments such as MALVERN, SEPTECH, PARTICLE SIZING SYSTEM and such other instruments.
  • Dgo as used herein is defined as the size of particles where 90 volume percent of the particles have sizes less than the value given.
  • the terms D 50 and Dio similarly define sizes where either 50 or 10 volume percent of the particles have sizes less than the value given. Lacidipine of the present invention is fine, uniform and agglomerate-free.
  • Agglomerate free lacidipine of present invention has a "span" of less than about 5 or less than about 3.
  • the term “span” is used herein as a measure of the particle size distribution and refers to a dimensionless measure of the spread of particle sizes in the sample. The larger the value of span, the wider the range of particle sizes present in a sample. The lower the value of the span, the narrower the range of particle sizes present in a sample. A value of zero would indicate a monodisperse particle size distribution.
  • agglomerate free lacidipine is prepared as follows: a) dissolving lacidipine in isopropyl alcohol to form a first solution;
  • agglomerate free lacidipine is prepared as follows: a) dissolving lacidipine in isopropyl alcohol to form a first solution;
  • the present invention provides a pharmaceutical composition comprising lacidipine with an improved dissolution profile.
  • lacidipine which is a compound with poor aqueous solubility, this is achieved by providing the lacidipine in the composition in a finely divided form.
  • the present invention provides two approaches towards achieving a finely divided lacidipine in a pharmaceutical composition: 1. Use of agglomerate-free lacidipine of a low particle size and a high surface area obtained by the above process in a pharmaceutical composition; or
  • the input material is agglomerate free finely divided lacidipine
  • a low particle size is desirable, such as obtained by the above process.
  • Agglomerate free material obtained from the process using the ultrasound techniques may further be subjected to milling using the techniques known in the art such as micronisation, air-jet milling, pulverization and the like.
  • agglomerate free material aids in smooth handling of the material, eases in processing the material, processing the compositions, and tends to increase the dissolution and release profiles.
  • the agglomerate free material can be formulated into a suitable dosage form such as for example tablets, capsules, syrups, suspensions, soft gels and the like by procedures known to a person skilled in the art of preparation of pharmaceutical formulations.
  • suitable dosage form such as for example tablets, capsules, syrups, suspensions, soft gels and the like by procedures known to a person skilled in the art of preparation of pharmaceutical formulations.
  • Such compositions could include other excipients as are required for the preparation of the compositions including but not limited to diluents, granulating agents, solvents, lubricants, wetting agents, disintegrating agents and the like.
  • finely divided lacidipine is provided in the form of a premix of lacidipine.
  • a premix of lacidipine is prepared by the adsorption of an organic solution of lacidipine onto a base material or onto a pharmaceutical excipient, or a mixture of pharmaceutical excipients, then removing at least a portion of the solvent.
  • premix refers to a blend or granules of lacidipine with a pharmaceutically acceptable excipient or a combination of excipients (that are compatible with lacidipine) in which the lacidipine is provided in a finely divided state.
  • a premix can be formulated with common carriers, diluents or excipients, and formed into tablets, capsules, and the like.
  • the lacidipine premix as defined above may be prepared by dissolving lacidipine in a suitable solvent or mixture of solvents.
  • the solvents useful in the invention can be from any class such as for example, alcohols, ethers, halogenated organic solvents, water, esters and the like. There is no limitation on which organic solvent can be used as long as the solvent has a high enough solubility for the lacidipine for the practice of this invention and is compatible with lacidipine. Further, volatile organic solvents are used to facilitate the removal of the solvents after further processing.
  • the solution of lacidipine in the solvent or mixture of solvents may be prepared by any conventional means using mixing and other aids as required for enhancing solubility such as for example, heating or sonication, are within the scope of this invention.
  • the solution of lacidipine may also contain optionally any stabilizers or solubilizers and the like.
  • the concentration of lacidipine in the solvent or mixture of solvents is typically in the range of about 15% to about 25% w/v, although higher or lower concentrations can be used.
  • Such a solution of lacidipine is then dispersed onto a substrate material, which can comprise one or more pharmaceutically acceptable excipients, aided with continuous mixing to provide uniform distribution of the active onto the substrate material.
  • substrate material is a pharmaceutically acceptable excipient, which is used as a carrier for the lacidipine in a finely divided state. Mixtures of such excipients also are considered as a substrate material.
  • the pharmaceutically acceptable excipients include any excipients, which are compatible with lacidipine, such as but not limited to: microcrystalline cellulose, micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • the wet mass thus produced is dried to remove solvent under controlled conditions to obtain an optimum loss on drying of less than 3.5% w/w.
  • the blend thus obtained having the lacidipine in a finely divided state is further processed into various pharmaceutical dosage forms.
  • the pharmaceutical compositions of the present invention may contain one or more diluents added to increase mass and, hence, make a dosage form easier for the patient and caregiver to handle.
  • Common diluents are microcrystalline cellulose, micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • Binders also can be included in the pharmaceutical compositions of the present invention to help hold a tablet together after compression.
  • Some typical binders are acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
  • carbomer e.g. carbopol
  • carboxymethylcellulose sodium dextrin
  • ethyl cellulose gelatin
  • guar gum hydrogenated vegetable oil
  • hydroxyethyl cellulose hydroxypropyl
  • the pharmaceutical compositions to be made into tablets can further include a disintegrant to accelerate disintegration of the tablet in the patient's stomach.
  • Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
  • Pharmaceutical compositions for tabletting may further include glidants, lubricants, flavoring agents, colorants and other commonly used excipients.
  • the pharmaceutical compositions of the present invention are filled into capsules (e.g., hard gelatin capsules).
  • Pharmaceutical compositions to be filled into capsules can and preferably do include pharmaceutically acceptable excipients; for example diluents such as lactose, mannitol, calcium carbonate, or magnesium carbonate; or flow aids such as stea rates.
  • Solid oral dosage forms of the present invention are formulated to provide a unit dose of lacidipine of about 0.1 to about 20 milligrams per individual dosage form.
  • the lacidipine premix thus prepared may be a part of a pharmaceutical composition such as for example tablets, capsules, sachets, suspensions and the like.
  • a pharmaceutical composition such as for example tablets, capsules, sachets, suspensions and the like.
  • Such compositions can include other excipients as are required for the preparation of the compositions including but not limited to diluents, granulating agents, solvents, lubricants, wetting agents, disintegrating agents and the like.
  • the procedures to convert such a blend into one of the compositions mentioned above are well known to a person skilled in the art of pharmaceutical formulations.
  • the resultant material yielded 262 g of particles having a size distribution of D-io ⁇ 1.26 ⁇ m, D 50 ⁇ 10.58 ⁇ m, D 90 ⁇ 56.96 ⁇ m, and a span of 5.3. Agglomeration of particles was observed by examination of the material using a microscope.
  • the resultant material yielded 3.12 g of agglomerate free particles of a size distribution of Di 0 ⁇ 0.84 ⁇ m, D 5 o ⁇ 5.28 ⁇ m, D 90 ⁇ 11.43 ⁇ m, and a span of 2.0.
  • the span value of the material prepared from this example when compared with the span value of the material prepared from comparative example, indicates that the material obtained with the present invention process results in a more uniform particle size distribution than was obtained from the conventional method of producing particles.
  • Preparation of agglomerate free lacidipine by adding water to isopropanol- lacidipine solution in an ultrasound bath. 10 g of lacidipine was dissolved in 120 ml isopropanol at 50 to 55 0 C. This solution of lacidipine in isopropanol was placed in an ultrasound bath at 50 0 C and sonication was started. Chilled water at 10 0 C was added to this solution with sonication. After complete addition, solution was cooled to 2 0 C and maintained for 30 minutes. The slurry was filtered and dried under vacuum at 75 to 80 0 C for 12 hours.
  • the resultant material yielded 2.7 g of an agglomerate free particles of size distribution Di 0 ⁇ 7.88 ⁇ m, D 50 ⁇ 19.53 ⁇ m, D 90 ⁇ 35.39 ⁇ m, and a span of 1.4.
  • the resultant material yielded 12.4 g of agglomerate-free particles of size distribution Di 0 ⁇ 5.56 ⁇ m, D 50 ⁇ 14.91 ⁇ m, Dg 0 ⁇ 34.95 ⁇ m, and a span of 1.9.
  • n-heptane 198 ml of n-heptane was taken in a beaker and placed in an ultrasound bath. This n-heptane was cooled to about 4 0 C by circulating cooling water in the bath and sonication was started. 8.5 g of lacidipine was dissolved in 99 ml of isopropanol at 50 to 55 0 C. The solution of lacidipine in isopropanol was added to n-heptane at a rate of 5 ml/minute with continuous sonication. The slurry was filtered and dried under vacuum at 75 to 80 0 C for 12 hours.
  • the resultant material yielded 6.4 g of agglomerate-free particles of size distribution D-io ⁇ 7.14 ⁇ m, D 5 o ⁇ 29.12 ⁇ m, Dgo ⁇ 60.61 ⁇ m, and a span of 1.8.
  • the resultant material yielded 3.4 g agglomerate-free particles of size distribution D-io ⁇ 10.57 ⁇ m, D 5 o ⁇ 27.85 ⁇ m, Dgo ⁇ 54.6 ⁇ m, and a span of 1.6.
  • n-heptane 60 ml of n-heptane was taken in a beaker and placed in an ultrasound bath. This n-heptane was cooled below 10 0 C by circulating cooling water in the bath and sonication was started. 5 g of lacidipine was dissolved in 30 ml of ethyl acetate at 55 to 60 0 C. The solution of lacidipine in ethyl acetate was added to the n-heptane with continuous sonication at rate of 5 ml/min. The slurry was filtered and the solid dried under vacuum at 75 to 80 0 C for 12 hours.
  • the resultant material yielded 3.1 g of agglomerate-free particles of size distribution D-io ⁇ 6.73 ⁇ m, D 5 o ⁇ 18.63 ⁇ m, Dgo ⁇ 35.05 ⁇ m and a span of 1.5.
  • the ultrasonic wattage used for examples 1 through 7 was 250 W, at 20 KHz frequency. Either wattage or frequency is variable in the ultrasound bath used.
  • Lacidipine of desired particle size was prepared using the ultrasound flow cell, by the following process:
  • the lacidipine solution in the reactor (1 ) was fed into the flow cell through the perforated dip tube at 62.5 ⁇ 2.5°C at 10.5+0.5 L/hour while the water was being simultaneously fed at 60 ⁇ 2 L/hour.
  • compositions comprising different particle size lacidipine. Preparation of pharmaceutical composition using lacidipine of large particle size:
  • Preparation of pharmaceutical composition using lacidipine of small particle size The compositions and the procedure used to prepare tablets with smaller particle size is the same as the procedure for preparation of tablets with larger particle size.
  • Particle size of lacidipine larger particles size was Dgo ⁇ 32 ⁇ m and smaller size was D 90 ⁇ 7.6 ⁇ m.
  • Dissolution conditions herein used were USP apparatus II, 50 rpm and 500 ml of dissolution medium at 37 0 C.
  • compositions comprising lacidipine premix with different particle size lacidipine.
  • composition of lacidipine through the use of a lacidipine premix prepared from large particle size lacidipine (particle size distribution of Dg 0 ⁇ 238 ⁇ m, D 50 ⁇ 120 ⁇ m, D i0 ⁇ 39 ⁇ m).
  • Lacidipine and povidone were dissolved in a mixture of ethyl acetate and isopropyl alcohol. This solution was added to granulate 40 mesh ASTM sieve sifted lactose monohydrate, dried the granules in a fluid bed drier at 60 0 C till the moisture content was less than 2.5% w/w when tested using an infrared moisture analyzer at 105 0 C. Dried "premix" granules were sifted through a 24 mesh ASTM sieve and sieve retains were milled in a comminuting mill using a 1 mm screen, knives forward and medium speed. Sifted and milled granules were blended with 40 mesh ASTM sifted croscarmellose sodium and Flowlac 100 and then blended with 60 mesh ASTM sifted magnesium stearate. Lubricated blend was compressed into tablets.
  • Dissolution conditions herein used are USP apparatus II, 50 rpm and 500 ml of dissolution medium at 37 0 C.
  • Composition comprising lacidipine having small particles.
  • Lacidipine was dissolved in a mixture of ethyl acetate and isopropyl alcohol. The solution was used to granulate 40 mesh ASTM sifted lactose and sodium starch glycolate, dried the granules in a fluid bed drier at 60 0 C till the moisture content was less than 2.5% w/w when tested using an infrared moisture analyzer at 105 0 C. Dried granules were sifted through a 24 mesh ASTM sieve and sieve retains were milled in a comminuting mill using a 1 mm screen, knives forward and medium speed. Sifted and milled granules were blended with 60 mesh ASTM sifted magnesium stearate. Lubricated blend was compressed into tablets.
  • Particle size distribution of lacidipine used was D 90 ⁇ 8 ⁇ m.
  • Dissolution data Medium: 500 ml of water + 1% polysorbate 20, USP apparatus type II, 50 rpm.

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  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
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Abstract

L'invention concerne des particules de lacidipine de petites dimensions et à répartition granulométrique étroite.
EP06749977A 2005-04-15 2006-04-13 Particules de lacidipine Withdrawn EP1868577A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IN432CH2005 2005-04-15
IN436CH2005 2005-04-15
US68466805P 2005-05-26 2005-05-26
US68469105P 2005-05-26 2005-05-26
PCT/US2006/013783 WO2006113309A1 (fr) 2005-04-15 2006-04-13 Particules de lacidipine

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EP1868577A1 true EP1868577A1 (fr) 2007-12-26
EP1868577A4 EP1868577A4 (fr) 2009-12-09

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Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
EP2700632A4 (fr) * 2011-04-18 2014-09-03 Hefei Beini Medical Technology Company Ltd Procédé de purification de bloquants du canal calcique de type dihydropyridine et préparation de nanoparticules de ceux-ci
LT2705839T (lt) 2012-09-10 2018-06-11 Rivopharm Sa Farmacinė kompozicija, apimanti lacidipiną ir jos gavimo būdas

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801599A (en) 1984-08-22 1989-01-31 Glaxo S.P.A. 1,4-dihydropyridines
WO1996032095A1 (fr) 1995-04-13 1996-10-17 Astra Aktiebolag Procede de preparation de particules respirables
WO2000038811A1 (fr) 1998-12-24 2000-07-06 Glaxo Group Limited Appareil et procede de preparation de particules cristallines
WO2002000199A1 (fr) 2000-06-29 2002-01-03 Glaxo Group Limited Nouveau procede servant a preparer et a recueillir des particules cristallines
WO2002089942A1 (fr) 2001-05-05 2002-11-14 Accentus Plc Formation de petits cristaux
WO2003035035A1 (fr) 2001-10-25 2003-05-01 Glaxo Group Limited Nouveau procede

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Publication number Priority date Publication date Assignee Title
IT1244728B (it) * 1991-02-13 1994-08-08 Glaxo Spa Impiego medicamentoso di derivati diidropiridinici
US7931022B2 (en) * 2001-10-19 2011-04-26 Respirks, Inc. Method and apparatus for dispensing inhalator medicament
WO2003101624A1 (fr) * 2002-05-28 2003-12-11 Battelle Memorial Institute Depot electrostatique de particules issues de l'expansion rapide de solutions fluides supercritiques
GB0216700D0 (en) * 2002-07-18 2002-08-28 Astrazeneca Ab Process
US20050095267A1 (en) * 2002-12-04 2005-05-05 Todd Campbell Nanoparticle-based controlled release polymer coatings for medical implants
GB0318353D0 (en) * 2003-08-05 2003-09-10 Phoqus Pharmaceuticals Ltd Coating of surgical devices

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801599A (en) 1984-08-22 1989-01-31 Glaxo S.P.A. 1,4-dihydropyridines
WO1996032095A1 (fr) 1995-04-13 1996-10-17 Astra Aktiebolag Procede de preparation de particules respirables
WO2000038811A1 (fr) 1998-12-24 2000-07-06 Glaxo Group Limited Appareil et procede de preparation de particules cristallines
WO2002000199A1 (fr) 2000-06-29 2002-01-03 Glaxo Group Limited Nouveau procede servant a preparer et a recueillir des particules cristallines
WO2002089942A1 (fr) 2001-05-05 2002-11-14 Accentus Plc Formation de petits cristaux
WO2003035035A1 (fr) 2001-10-25 2003-05-01 Glaxo Group Limited Nouveau procede

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2006113309A1

Also Published As

Publication number Publication date
EP1868577A4 (fr) 2009-12-09
WO2006113309A1 (fr) 2006-10-26

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