US20060275376A1 - Microcapsules with modified release of active principles with low solubility for oral delivery - Google Patents

Microcapsules with modified release of active principles with low solubility for oral delivery Download PDF

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US20060275376A1
US20060275376A1 US10/522,234 US52223403A US2006275376A1 US 20060275376 A1 US20060275376 A1 US 20060275376A1 US 52223403 A US52223403 A US 52223403A US 2006275376 A1 US2006275376 A1 US 2006275376A1
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Prior art keywords
coating
agents
weight
total mass
microcapsules
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US10/522,234
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Florence Guimberteau
Catherine Castan
Remi Meyrueix
Gerard Soula
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    • 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
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the field of the present invention is that of systems with modified release of medicinal and/or nutritional active principles (APs), intended to be administered orally.
  • APs medicinal and/or nutritional active principles
  • the present invention also relates to microcapsules intended to be administered per os and containing at least one AP with low solubility.
  • the invention also relates to the medicinal products containing these microcapsules mentioned above and to the use of the latter for producing medicinal products.
  • modified release denotes without distinction a release of the active principle(s) beginning as soon as the pharmaceutical form has been brought into contact with its dissolving medium (in vivo or in vitro) or else a release of the active principle(s) beginning only after a predetermined period of time ranging, for example, from 0.5 to several hours.
  • a prolonging of the release corresponds to a release time for 50% of the active principle(s) which is typically several hours and which can extend from 0.25 to 20 hours, for example.
  • low solubility relates to active principles the water-solubility of which is less than 10 g/l at 25° C.
  • the invention relates to pharmaceutical formulations with prolonged release of active principles with low solubility, this formulation consisting of a plurality of microcapsules consisting of a core containing the active principle of low solubility and coated with a layer of polymer which controls the release of the AP.
  • pharmaceutical systems with modified release consisting of a plurality of microcapsules of the reservoir type with an average diameter of less than 1000 microns are particularly advantageous.
  • the dose of active principle(s) to be administered is distributed among a large number of microcapsules (typically 10 000 for a dose of 500 mg and a diameter of 400 microns) and this type of system, as a result, has the following intrinsic advantages:
  • the diffusion of the active principle through the coating film surrounding each microcapsule takes place under the action of the dissolved AP concentration gradient between the inside and the outside of the microcapsule. In other words, it is the difference in osmotic pressure of the AP between the inside and the outside of the microcapsule which drives the release.
  • the internal concentration of AP is the saturation concentration.
  • the external concentration of AP is, for its part, negligible under usual conditions (termed “sink”). The driving of release is therefore directly linked to the saturation concentration of the AP, i.e. to its solubility.
  • the saturation concentration of AP is relatively low and the diffusion of the AP to the outside is therefore, a priori, very slow, even for coating films that are not very thick.
  • multimicrocapsular pharmaceutical systems those consisting of a multiplicity of particles or microcapsules each carrying active principle(s) coated with a film-coating layer based on ethylcellulose, on polyvinylpyrrolidone, on magnesium stearate and on castor oil, for example, are known.
  • a film-coating layer based on ethylcellulose, on polyvinylpyrrolidone, on magnesium stearate and on castor oil, for example.
  • Such a pharmaceutical system is disclosed in PCT application WO 96/11675.
  • These microcapsule reservoirs obtain an advantage from their multiplicity, which is a more even and reproducible gastric emptying time.
  • their size is between 50 and 1000 ⁇ m and also the characteristics of their coating make it possible to increase their transit time in the upper parts of the gastrointestinal tract and, consequently, to maintain absorption of the active principle(s) for all or part of this time spent in the small intestine.
  • the multimicrocapsular pharmaceutical system according to WO 96/11675 is perfectable as regards APs with low solubility that can be administered orally, since it does not propose any solution to the problem of the diffusion of such an AP with low solubility through a coating film of sufficiently large thickness, for example of several microns.
  • PCT patent application WO 00/18374 describes an invention of the same type as the previous one: the active principle in the form of submicronic ( ⁇ 1000 nm) particles is stabilized by a compound associated at the surface of the particles and mixed with a polymer. This mixture can then be formulated into granules or pellets and, optionally, into tablets.
  • the active principle is rapidly dissolved and it is the increase in bioavailability obtained by virtue of the decrease in size which makes it possible to have an effective plasma concentration over a prolonged period.
  • Patent application GB-2 202 143 describes spheroids of diameter greater than 0.5 mm, and preferably greater than 0.8 mm, containing the poorly soluble active principle dispersed in 70 to 99.5% of microcrystalline cellulose. This matricial form requires no coating controlling the release of the active principle.
  • Patent application JP-8073345 describes a controlled-release system composed of a film-coated granule.
  • the granule contains an active principle with low solubility at neutral pH and inorganic acids. This system therefore proposes a solution that is only suitable for the case of basic active principles with low solubility.
  • European patent EP-B-0 249 587 concerns a solid preparation for the slow release of an active substance with low solubility ( ⁇ 0.1% by weight).
  • This controlled-release preparation can be provided in the form of gelatin capsules comprising capsules consisting of coated granules.
  • the granules comprise the active principle with low solubility and a solubilizing agent consisting of the commercial product Cremophor® RH 40 (polyoxyethylenated hydrogenated castor oil: 40 ethylene oxide units), and also other additives such as polyvinylpyrrolidone, cellulose, starch and lactose.
  • Cremophor® RH 40 polyoxyethylenated hydrogenated castor oil: 40 ethylene oxide units
  • other additives such as polyvinylpyrrolidone, cellulose, starch and lactose.
  • the ingredients of the granules namely polyvinylpyrrolidone, cellulose, cornstarch and lactose, appear to be the elements of the hydrophilic gel system specific to the pharmaceutical form according to EP-B-0 249 587.
  • These capsules therefore comprise a single constituent (ethylcellulose) in their coating layer, which limits its capacities in terms of modification of the release of the active principle.
  • a coating layer composed only of ethylcellulose known to form impermeable films
  • one of the essential objectives of the present invention is to propose a form with modified release of AP(s) with low solubility consisting of a plurality of microcapsules, each formed by a core containing the AP and coated with a coating film.
  • Another objective of the present invention is to provide a plurality of reservoir-type microcapsules of AP of low solubility, for oral administration of the latter, the coating film of these microcapsules being sufficiently thick to ensure a controlled and industrially reproducible permeability.
  • Another essential objective of the present invention is to provide a plurality of microcapsules of AP(s) with low solubility, less than 1000 ⁇ m in size.
  • Another objective of the present invention is to propose an oral pharmaceutical form consisting of a large number (for example of the order of several thousand) of microcapsules, this multiplicity ensuring, statistically, good reproducibility of the kinetics of transit of the AP in the entire gastrointestinal tract, such that better control of the bioavailability and therefore better effectiveness result therefrom.
  • Another essential objective of the present invention is to provide a plurality of microcapsules of AP(s) with low solubility, for oral administration of the latter according to a prolonged and/or optionally delayed release profile, such that the half-release time, t 1/2 , is between 0.25 and 20 hours.
  • Another essential objective of the present invention is to provide an oral form with modified release in which the AP(s) is (are) in the form of a plurality of particles individually coated to form microcapsules, and in which it is possible to mix several active principles in multimicrocapsular form, that are released according to different respective release times.
  • the inventors have, to their credit, developed a multimicrocapsular pharmaceutical system with prolonged release of AP(s) with low solubility, by oral administration, which, besides the properties targeted in the aims above, has, cumulatively and for a wide range of APs, the following specifications, inter alia:
  • a subject of the present invention is a pharmaceutical system made up of microcapsules for the modified release of at least one AP with low water solubility, with the possible exclusion of blood glucose-lowering agents, intended to be administered orally and of the type of those:
  • the coating film represents 3 to 40% w/w on a dry basis of the total mass of the microcapsules.
  • P1 is selected from the group of products below:
  • P2 is selected from the group of products below:
  • PL is selected from the group of products below:
  • the coating film comprises component TA in a proportion of 2 and 20%, and preferably of between 4 and 15% of the total mass of the dry coating.
  • TA is selected from the group of products below:
  • the microcapsules are designed so as to be able to spend at least approximately 5 hours, preferably at least approximately 8 hours, in the upper parts of the gastrointestinal tract, and thus allow absorption of the AP for a prolonged period of time.
  • the coating film comprises from 35 to 75% of ethylcellulose P1, from 20 to 50% of polyvinylpyrrolidone P2, from 5 to 15% of PL.
  • This preparation according to the invention makes it possible to produce a multimicrocapsular form with modified release of APs with low solubility, it being possible for the AP half-release time to be adjusted to between 0.25 and 20 hours in a reproducible manner through the use of a coating film, that can be described as a diffusion coating film, which is sufficiently thick.
  • such a plurality of microcapsules (typically 10 000 for a dose of 500 mg and a mean diameter of 400 microns) has the following intrinsic advantages:
  • the APs with low solubility used for preparing the modified-release, preferably controlled-release, microcapsules according to the invention can be chosen from at least one of the major varieties of active substances below: antiulcer agents, antidiabetic agents, anticoagulants, antithrombics, blood lipid-lowering agents, anti-arrhythmics, vasodilators, antiangina agents, anti-hypertensives, vasoprotective agents, fertility promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungal agents, anti-viral agents, anticancer agents, anti-inflammatories, analgesics, antiepileptics, antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine agents, antidepressives, antitussives, antihistamines or antiallergic agents.
  • active substances below: antiulcer agents, antidiabetic agents, anticoagulants, antithrom
  • the AP(s) is (are) chosen from the following compounds: prazosine, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacine, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone, acetylsalicyclic acid, quinidine, morphine, amoxicillin, paracetamol, metoclopramide, verapamil and mixtures thereof.
  • the AP consists of at least one nutritional and/or dietetic supplement, preferably chosen from vitamins, amino acids, trace elements, antioxidants and mixtures thereof.
  • the AP particles of desired mean particle size necessary for preparing the microcapsules according to the invention may be crystals of pure AP and/or AP that has undergone a pretreatment by one of the conventional techniques in the field, such as for example granulation, in the presence of at least one conventional binding agent and/or of an agent for modifying the intrinsic solubility characteristics of the AP.
  • the present invention is also directed toward a medicinal product comprising the microcapsules as defined above.
  • This medicinal product may be in solid form: tablet, gelatin capsule, powder, etc, or a in liquid form, for example an aqueous suspension.
  • microcapsules for the modified release of at least one AP with low water solubility, with the possible exclusion of blood glucose-lowering agents, intended to be administered orally, these microcapsules having these following characteristics:
  • the present invention relates to a method of therapeutic treatment, in which use is made of a medicinal product as defined above as a product per se or as a product obtained by means of the method described above.
  • FIG. 1 represents the curve of the percentage dissolution (% D) of the active principle AP, as a function of the time (t) in hours (H), of the microcapsules of example 1, in the dissolving test described in the following examples.
  • FIG. 2 represents the curve of the percentage dissolution (% D) of the active principle AP, as a function of the time (t) in hours (H), of the microcapsules of example 2, in the dissolving test described in the following examples.
  • 700 g of granules obtained above are coated, in a Glatt® GPCG1 fluidized airbed device, with 50.65 g of ethylcellulose (Ethocel® 7 Premium), 50.65 g of Povidone (Plasdone® K29/32), 12.35 g of magnesium stearate and 9.88 g of castor oil dissolved in an acetone/isopropanol (60/40 m/m) mixture.
  • Microcapsule composition Production Ingredients % by mass formula (in g) Acyclovir granules 85.0 700.0 L Plasdone ® K29/32 (2.55) Acyclovir (82.45) Coating 15.0 123.5 Ethocel ® 7 Premium (6.15) Plasdone ® K29/32 (6.15) magnesium stearate (1.50) castor oil (1.20) Test:
  • the kinetics of release of the Acyclovir are determined by means of a dissolving test (type II device according to the European pharmacopoeia, 3rd edition, phosphate buffer medium, pH 6.8, volume 900 ml, temperature 37° C., 100 rpm paddle agitation, UV detection at 268 nm).
  • FIG. 1 shows the dissolution profile obtained by means of these microcapsules.
  • microcapsule composition described above makes it possible to obtain a dissolution profile characterized by 80% of Acyclovir released at 3 hours.
  • 700 g of granules obtained above are coated, in a Glatt® GPCG1 fluidized airbed device, with g of ethylcellulose (Ethocel® 7 Premium), g of Povidone (Plasdone® K29/32) and 0.96 g of castor oil dissolved in an acetone/isopropanol (60/40 m/m) mixture.
  • Glatt® GPCG1 Glatt® GPCG1 fluidized airbed device
  • Microcapsule composition Production Ingredients % by mass formula (in g) Amoxicillin granules 82.0 700.0 Plasdone ® K29/32 (0.45) Amoxicillin trihydrate (14.55) Coating 18.0 153.6 Ethocel ® 7 Premium (12.60) Plasdone ® K29/32 (4.14) Castor oil (1.20) Test:
  • the kinetics of release of the amoxicillin are determined by means of a dissolving test (type II device according to the European pharmacopoeia, 3rd edition, phosphate buffer medium, pH 6.8, volume 900 ml, temperature 37° C., 100 rpm paddle agitation, UV detection at 240 nm).
  • FIG. 2 shows the dissolution profile obtained for these microcapsules.
  • microcapsule composition described above makes it possible to obtain a dissolution profile characterized by 80% of amoxicillin released at 4 hours.

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  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmacology & Pharmacy (AREA)
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US10/522,234 2002-07-26 2003-07-28 Microcapsules with modified release of active principles with low solubility for oral delivery Abandoned US20060275376A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0209530A FR2842735B1 (fr) 2002-07-26 2002-07-26 Microcapsules a liberation modifiee de principes actifs peu solubles pour l'administration per os
FR02/09530 2002-07-26
PCT/FR2003/002384 WO2004010984A2 (fr) 2002-07-26 2003-07-28 Microcapsules a liberation modifiee de principes actifs peu solubles pour administration per os

Related Parent Applications (1)

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PCT/FR2003/002384 A-371-Of-International WO2004010984A2 (fr) 2002-07-26 2003-07-28 Microcapsules a liberation modifiee de principes actifs peu solubles pour administration per os

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US35804706A Continuation 2002-07-26 2006-02-22

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US11/583,940 Expired - Lifetime US8821935B2 (en) 2002-07-26 2006-10-20 Microcapsules with modified release of active principles with low solubility for oral delivery

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EP (2) EP1524969A2 (xx)
JP (1) JP2005535680A (xx)
KR (1) KR20050026518A (xx)
CN (1) CN1681483B (xx)
AU (1) AU2003269068B2 (xx)
BR (1) BR0312988A (xx)
CA (1) CA2493464C (xx)
FR (1) FR2842735B1 (xx)
IL (1) IL166431A0 (xx)
MX (1) MXPA05001076A (xx)
WO (1) WO2004010984A2 (xx)
ZA (1) ZA200500734B (xx)

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US10828307B2 (en) 2014-02-21 2020-11-10 Principia Biopharma Inc. Salts and solid form of a BTK inhibitor
US10946008B2 (en) 2014-12-18 2021-03-16 Principia Biopharma Inc. Treatment of pemphigus
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EP2272506A3 (fr) 2013-07-10
KR20050026518A (ko) 2005-03-15
CA2493464C (fr) 2012-07-03
AU2003269068A1 (en) 2004-02-16
FR2842735B1 (fr) 2006-01-06
EP2272506A2 (fr) 2011-01-12
US20070160678A1 (en) 2007-07-12
MXPA05001076A (es) 2005-06-06
FR2842735A1 (fr) 2004-01-30
BR0312988A (pt) 2005-06-21
AU2003269068B2 (en) 2009-01-22
CA2493464A1 (fr) 2004-02-05
EP1524969A2 (fr) 2005-04-27
US8821935B2 (en) 2014-09-02
WO2004010984A3 (fr) 2004-04-08
CN1681483A (zh) 2005-10-12
JP2005535680A (ja) 2005-11-24
ZA200500734B (en) 2006-03-29
WO2004010984A2 (fr) 2004-02-05
IL166431A0 (en) 2006-01-15

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