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
  • A61K9/48—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
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the field of the invention is that of pharmaceutical, particularly pediatric or geriatric, formulations intended for the oral administration of antibiotics (for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) for the treatment of bacterial conditions, especially those caused by antibiotic-resistant germs, such as Streptococcus pneumoniae.
• antibiotics for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• multimicrocapsular pharmaceutical formulations, in particular pediatric or geriatric formulations.
• Amoxicillin is a known antibiotic belonging to the ⁇ -lactam family.
• Clavulanic acid and its salts, in particular potassium clavulanate, are known ⁇ -lactamase inhibitors.
• Clavulanate is known to improve the effectiveness of amoxicillin against resistant microorganisms, including Streptococcus pneumoniae, which is the most commonly implicated organ in respiratory tract and ear infections in pediatric patients. sinusitis for patients of all ages as well as pneumonia and acute bronchitis in adults.
• amoxicillin and clavulanate exists as aqueous solutions or suspensions (eg flavored syrup or powder for suspension reconstitution), but also in tablet form.
• a bacteriological cure rate of 85 to 100% is reached when the serum concentrations exceed the MIC for a time greater than about 40% of the administration interval (CRAIG and ANDES, Ped Inf Dis J , 1996, 15, 255, 259), or for a 12 hour administration interval, T cm i ⁇ 4.8 hours.
• this cover time does not stop the increase in resistance of germs
• the consequence is a steady increase in the minimum inhibitory concentration (MIC), and a steady increase in doses prescribed. This phenomenon poses a major public health problem since, over time, the proposed treatments will become less and less effective.
• WO-A-97/09042 proposes a bi-daily administration of high-dose amox to increase the X m i and the Cmax of amoxicillin.
• This document teaches the use of amoxicillin and clavulanate in a nominal weight ratio of 14: 1 for the production of a medicament for oral administration in pediatric patients in the form of a powder or a product granular for reconstitution in the form of suspension or solution for twice-daily administration, at high doses of 75 to 115 mg / kg of amoxicillin per day and from 5 to 7.5 mg / kg of clavulanate per day. day, for the treatment of infections of the respiratory tract.
• the strategy of the invention according to WO-A-97/09042 is therefore to increase the dose in order to increase the protection time
• the intermediate resistance corresponds to a MIC between 0.12 and 1.0 ⁇ g / ml, and the resistance to penicillin is defined by a MIC> 2 ⁇ g / ml.
• the teaching of WO-A-97/09042 confirms what the scientific community also agrees is that the problem of increasing bacterial resistance to antibiotics is all the more serious. that the process of increasing MICs of antibiotics, and therefore doses, is inexorable. This results in a corresponding decrease in the therapeutic coverage time. Thus, if nothing is done, it could lead in a few years to a dramatic inefficiency of all known antibiotics.
• the high dosage according to WO-A-97/09042 is also likely to cause a number of undesirable side effects including sneezing, vomiting, contact dermatitis, fever, diarrhea, erythema, among others.
• Another technical solution for increasing the T cm i is described in the
• WO-A-00/61116 which relates to a laminated tablet comprising an immediate release layer of amoxicillin and potassium clavulanate and a slow-release layer of amoxicillin, the tablet being coated with a film of hydroxypropyl methylcellulose.
• This tablet comprises, for example, 1000 mg of amoxicillin and 62.5 mg of potassium clavulanate.
• the recommended dosage is 2 x 2 tablets per day.
• This "compressed" form makes it possible to increase the amoxicillin T cm i and Cmax, by acting on the prolonged release of amoxicillin and on the increase in gastric residence time provided by a large monolithic tablet. These huge tablets can never be given to children.
• WO-A-03/084517 discloses liquid, orally administrable, modified-release amoxicillin pharmaceutical formulations. These formulations are constituted by suspensions of coated amoxicillin particles (microcapsules), the coating composition of said microcapsules is designed so that the microcapsules have amoxicillin modified release properties, undisturbed by the aqueous liquid phase of the suspension, which liquid phase is also saturated with amoxicillin.
• the coating of these microcapsules of amoxicillin eg 70% ethyl cellulose, 23% polyvinylpyrrolidone and 7% castor oil for example. Any magnesium stearate surfactant / lubricant may be incorporated in this coating.
• the invention according to WO-A-03/084517 relates to a problem of stability in aqueous suspension of amoxicillin microcapsules. There is no mention in this document of a use of said microcapsules to stop the increase in antimicrobial resistance, which appears to be a major public health problem.
• One of the essential objectives of the present invention is therefore to provide an oral pharmaceutical formulation, in particular pediatric, which is based on at least one active principle chosen from antibiotics (for example amoxicillin optionally combined with clavulanic and / or at least one of its salts) and that remedies this deficiency.
• antibiotics for example amoxicillin optionally combined with clavulanic and / or at least one of its salts
• Another essential objective of the present invention is to provide a pharmaceutical, in particular pediatric, modified-release, orally administrable, formulation which is based on at least one active ingredient chosen from antibiotics (for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) and which allows the X m i to be as high as possible, at a given dose of antibiotic active, regardless of the number of doses.
• antibiotics for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• Another essential objective of the present invention is to provide a pharmaceutical, in particular pediatric, modified-release, orally administrable, formulation which is based on at least one active ingredient chosen from antibiotics (for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) and which is not monolithic (tablet).
• antibiotics for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• Another essential objective of the present invention is to provide a pediatric, modified-release antibiotic formulation which is administrable once or twice a day, (for example based on amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) and which provides sufficient therapeutic coverage to eradicate the germs responsible for the infection, while limiting or even stopping the increase in the resistance of said germs to antibiotics.
• Another essential objective of the present invention is to provide a pharmaceutical formulation, in particular pediatric, modified-release, orally administrable, which is based on at least one active ingredient chosen from antibiotics (for example, arnoxicillin optionally combined with clavulanic acid and / or at least one of its salts) and which allows, for a given type of microcapsules, to release the antibiotic continuously and leading to a mono-modal plasma concentration profile.
• antibiotics for example, arnoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• Another essential objective of the present invention is to provide a pharmaceutical formulation, in particular pediatric modified-release, orally administrable, which is based on at least one active principle selected from antibiotics (for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) and which is very effective in the fight against bacterial infections with resistant S. pneumoniae-type germs, and without prohibitive increase in doses likely to cause unwanted side effects.
• antibiotics for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• Another essential objective of the present invention is to provide a pharmaceutical formulation of amoxicillin (with or without clavulanate or the like), the amoxicillin T cm i at 4 ⁇ g / ml represents at least 40% of a range of administration of twelve hours, preferably at least 60% and more preferably still at least 80%, and for doses of amoxicillin of between 70 and 130 mg / kg / day.
• Another essential objective of the present invention is to provide an oral, in particular pediatric, modified-release amoxicillin and clavulanate pharmaceutical formulation making it possible to obtain a pharmacokinetic parameter X m i greater than or equal to 40% of an interval of administration of twelve hours, for a MIC of amoxicillin at 4 ⁇ g / ml, and for doses less than 90 mg / kg / day, preferably between 50 and 80 mg / kg / day.
• Another essential objective of the present invention is to propose the use of at least one active ingredient chosen from antibiotics (eg amoxicillin optionally combined with clavulanic acid and / or at least one of its salts) for the preparation of a pharmaceutical formulation as defined in the above objectives.
• antibiotics eg amoxicillin optionally combined with clavulanic acid and / or at least one of its salts
• Another essential objective of the present invention is to provide a method of treating bacterial infections with resistant germs (for example of the S. pneumoniae type) said method of administering orally and in one or two doses per day a pharmaceutical formulation, in particular pediatric, modified release based on at least one active principle chosen from antibiotics (for example amoxicillin optionally combined with clavulanic acid and / or at least one of its salts).
• modified release microcapsules which comprise a core containing at least one PAl active ingredient formed by at least one antibiotic and a coating of said core governing the modified release of this active ingredient, to make an antibiotic pharmaceutical formulation drinkable or orodispersible, allowing to limit the increase of antimicrobial resistance of target germs.
• This formulation is advantageously administrable in one or two doses (preferably two) daily.
• the formulation can also be designed to be administrable in at least three doses per day. Indeed whatever the number of catches, it is desirable to increase the X m i, as permitted by the therapeutic indication according to the invention.
• this formulation is definable as follows, with respect to an immediate-release oral formulation (FLI *) comprising at least one active ingredient PA1 and for the same dose D in PA1 as FLI *: preferably
• T cmi 1, l. T * cmi of FLI * and even more preferentially: 3. T * cmi of FLI *> T cmi > 1,1. T * cmi of FLI * where Xmi is the time during which the plasma concentration is greater than or equal to the minimum inhibitory concentration for a given antibiotic and where T * cm i is the X m i of an immediate-release oral formulation (FLI) *).
• the pharmaceutical formulation used in the use is an oral antibiotic pharmaceutical formulation:
• microcapsules which comprise a core containing at least one active ingredient PA1 formed by at least one antibiotic and a coating of said core governing the modified release of the active ingredient
• FLI * immediate-release oral formulation
• the pharmaceutical formulation according to the The invention opens the way to a single or multiple day oral administration regime promoting adherence, particularly for pediatric or geriatric patients.
• the antibacterial efficacy particularly with regard to resistant germs, for example of the Streptococcus pneumoniae, H. influenzae and M. catarrhalis type, is substantially increased thanks to the formulation obtained according to the invention, which also presents the advantage of being relatively well tolerated and finally offering a broad spectrum of activity.
• One of the essential advantages of the invention is to register the opposite of a logic of overdose of antibiotics to improve their effectiveness.
• the therapeutic indication according to the invention stops the dramatic increase in antimicrobial resistance, without offering drugs that are difficult to administer orally and therefore harmful to compliance, or even impossible to swallow. to children, old people or very weak people.
• the invention provides optimized pharmacokinetic profiles, especially with regard to pediatric treatments, for example for amoxicillin, optionally combined with clavulanic acid and / or at least one of its salts.
• the essential active principle PA1 quantitatively and qualitatively consists of at least one antibiotic.
• modified release is meant in the present disclosure a release of drug active principle (s) (eg amoxicillin) by a pharmaceutical formulation, this release being carried out at a lower speed than that of a FLI "Immediate Release” formulation, such as a conventional tablet or swallow capsule.
• a modified release formulation may, for example, include an immediate release phase and a slow release phase.
• Modified release formulations are well known in the art; see for example Remington: The Science and Practice of Pharmacy, 19 th Edition, Mack Publishing Co. Pennsylvania, USA.
• immediate Release the release by a FLI of most of the amount of active ingredient in a relatively short time, for example 80% in one hour, preferably in thirty minutes, after Examples of such FLIs include conventional swallowing tablets, dispersible tablets, chewable tablets, unit dose sachets and capsules.
• the formulation implemented according to the use according to the invention has a relative bioavailability with respect to FLI * greater than or equal to 70%, preferably 80%, and more preferably still between 90 and 100%.
• the formulation according to the invention makes it possible to improve the treatments, in particular in pediatrics, against bacterial infections targeting, for example, the respiratory tract, namely extra-hospital pneumonia, acute exacerbations of chronic bronchitis and acute bacterial sinusitis, among others. .
• Most outpatient respiratory infections are caused by S. pneumoniae and / or ⁇ -lactamase producing bacteria, including H. influenzae and M. catarrhalis.
• the pharmaceutical form according to the invention makes it possible to improve the treatment of these conditions.
• the antibiotic multimicrocapsular form according to the invention comprises a coating designed specifically for at least one antibiotic active ingredient PA1 and so as to allow, on the one hand, the prolonged release of the active ingredient (s) PA1, and, on the other hand, to increase the residence time of the microcapsules in the intestinal window (small intestine) in which their bioabsorption intervenes.
• the microcapsules have the particularity that a plurality of identical microcapsules continuously releases the antibiotic and leads to a mono-modal plasma concentration profile.
• the formulation additionally comprises microcapsules, at least one PAl active ingredient formed by at least one immediate-release antibiotic.
• the active ingredient PA1 immediate release can be, for example, in pure form (e.g. powder) or even in the form of granules in which said active ingredient is agglomerated with other active products and / or excipients.
• the formulation comprises at least one antibiotic PAl immediate release, in an amount less than or equal to 60% by weight, preferably less than or equal to 50% by weight and, more preferably still between 0 and 40% by weight of the total amount of the antibiotic considered.
• the formulation may comprise microcapsules all having substantially the same in vitro release profile, or comprise at least two types of microcapsules having different release profiles.
• amoxicillin is a PA1 antibiotic of choice for being present in the heart of all or some of the microcapsules of the formulation.
• the formulation comprises, in addition to the amoxicillin microcapsules, amoxicillin immediate release.
• the amoxicillin capable of forming the essential active principle of the formulation according to the invention may be amoxicillin in all its forms (eg amoxicillin trihydrate and / or at least one of its alkali metal salts, such as that amoxicillin potassium or sodium, the latter-especially in crystallized form being preferred or a mixture of different forms of amoxicillin).
• PAl of the formulation according to the invention include those selected from the group consisting of: aminosalicylic acid, nalidixic acid, amoxicillin, amoxicillin and potassium davulanate, ampicillin, ampicillin and sulbactam, azithromycin, bacampicillin, carbenicillin-indanyl-sodium (and other carbenicillin salts), capreomycin, cefadroxile, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrin, cefamandole, cefonicide, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, ciprofloxacin, clarithromycin, clindamycin,
• the formulation comprises: modified release microcapsules whose core contains an active ingredient PA1 formed by an antibiotic (eg amoxicillin or any other abovementioned), o and modified release microcapsules whose core contains an active ingredient PA2 formed by an antibiotic (eg amoxicillin or any other mentioned above) or by an active ingredient different from the antibiotics.
• an antibiotic eg amoxicillin or any other abovementioned
• PA2 an active ingredient formed by an antibiotic (eg amoxicillin or any other mentioned above) or by an active ingredient different from the antibiotics.
• the formulation comprises: modified release microcapsules whose core contains an active ingredient PA1 formed by an antibiotic (eg amoxicillin or any other abovementioned), o and an active ingredient PA2 formed by an antibiotic (eg amoxicillin or any other abovementioned) or by an active ingredient different from antibiotics, this PA2 being immediate release.
• an active ingredient PA1 formed by an antibiotic (eg amoxicillin or any other abovementioned)
• PA2 formed by an antibiotic (eg amoxicillin or any other abovementioned) or by an active ingredient different from antibiotics, this PA2 being immediate release.
• the formulation comprises, in addition to the essential active ingredient PAl, at least one other active ingredient PA2, preferably formed by clavulanic acid and / or or at least one of its salts (preferably potassium or sodium clavulanate) in the case where the essential active principle is amoxicillin.
• amoxicillin: clavulanate ratio is between 2: 1 and 20: 1, preferably between 8: 1 and 20: 1, and more preferably between 14: 1 and
• Clavulanic acid and / or at least one of its alkali metal salts, eg sodium or potassium clavulanate, is advantageously in crystalline form.
• the combination of this PA2 secondary active ingredient with amoxicillin PA1 optimizes the antibiotic efficacy of the formulation.
• the fact that the amoxicillin is at least partly in the form of microcapsules does not obey the bioavailability of said secondary active principle.
• AP active ingredients
• any combination of one or more forms of modified release PAA (e.g., multimicrocapsular) and / or one or more forms of PA (e.g. antibiotic) immediate release, is also possible in the context of the present invention.
• the microcapsules of antibiotic (s) PAl -for example amoxicillin- have a particle size of between 50 nm and 800 microns, preferably between 150 and 800 ⁇ m and more preferably between 200 microns and 600 microns.
• particle size is meant in the sense of the invention a proportion of at least 75% by weight of microcapsules of diameter between the limits considered sieve opening size.
• the amount of microcapsule coating material advantageously represents from 1 to 50%, preferably from 5 to 40%, of the weight of the coated microcapsules. This advantageous characteristic is all the more difficult to obtain because the microcapsules, because of their small size, have a large specific surface area, which accelerates the release of the microencapsulated active ingredient (s) PA1, for example amoxicillin.
• At least one film-forming polymer (P1) insoluble in the liquids of the tract present in a proportion of 50 to 90%, preferably 50 to 80% by weight on a dry basis relative to the total mass of the coating composition and constituted by at least one non-water-soluble derivative of the cellulose;
• At least one plasticizer present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one of the following compounds : glycerol esters, phthalates, citrates, sebacates, esters of cetyl alcohol, castor oil;
• At least one water-soluble polymer At least one water-soluble polymer
• the coating may comprise various other additional adjuvants conventionally used in the field of coating. It may be, for example, pigments or fillers.
• the coating of the microcapsules consists of a single layer.
• the antibiotic (s) PA1, eg amoxicillin, used to prepare the microcapsules according to the invention may consist of pure antibiotic (s) and / or granules of antibiotic (s) prepared during a prior granulation step.
• Such granulation refers to conventional wet granulation processes, see EP-A-281 200 Gist Brocades NV or dry compaction methods for example using rollers, or to methods by deposition on a neutral support or else by extrusion processes.
• these granules of PAl e.g. amoxicillin may constitute the non-microencapsulated immediate release part present in the formulation according to the invention.
• the latter may also comprise pharmaceutically acceptable ingredients, such as anti-caking agents such as, for example, talc, colloidal silica, magnesium stearate or their mixtures.
• anti-caking agents such as, for example, talc, colloidal silica, magnesium stearate or their mixtures.
• the amounts used can be e.g. 0.5 to 5% by weight, preferably 1.5 to 3% by weight.
• antibiotic (s) PA1 e.g., amoxicillin
• the formulation according to the invention may be powders, tablets, granules, capsules, syrups, suspensions or aqueous solutions.
• the tablets may be chewable tablets and / or effervescent tablets and / or fast disintegrating tablets.
• the pharmaceutical formulation may be sold in the form of a powder allowing the reconstitution of a suspension by mixing with water before administration or else it may be directly in the form of an aqueous suspension comprising the appropriate additives, namely by for example those selected from surfactants, dyes, dispersing agents, preservatives, flavoring agents, flavorings, sweeteners, antioxidants, flow agents, texturizing agents and mixtures thereof.
• the appropriate additives namely by for example those selected from surfactants, dyes, dispersing agents, preservatives, flavoring agents, flavorings, sweeteners, antioxidants, flow agents, texturizing agents and mixtures thereof.
• the formulation used in the indication according to the invention is in the form of a powder (a single-dose sachet, for example), in the form of a suspension or syrup, in the form of an orodispersible tablet, under form of dispersible tablet in a liquid or in the form of effervescent tablet.
• the microcapsules may be associated with pharmaceutically acceptable excipients or carriers.
• the invention relates to novel pharmaceutical formulations as defined above for the treatment of bacterial infections in humans or animals, in particular in children.
• the present invention relates to a method of treating bacterial infections in humans or animals, and in particular in children, this method allowing at the same time to limit or even to stop the infection. increased antimicrobial resistance of target germs;
• Said method comprises the oral administration to a subject, a therapeutically effective amount of antibiotic (s) (for example amoxicillin) at least partly in the form of microcapsules each consisting of a heart containing at least one PAl antibiotic (for example amoxicillin) and by a coating of said heart governing the modified release of PAl antibiotic (eg amoxicillin).
• antibiotic for example amoxicillin
• PAl antibiotic for example amoxicillin
• the formulation is in drinkable or orodispersible form.
• the multimicrocapsular formulation thus administered orally is definable, relative to an immediate-release oral formulation (FLP) comprising at least one active principle PA1 formed by at least one antibiotic and for the same dose D in PA1 as FLP, as follows :
• FLP immediate-release oral formulation
• T 1 CIIU ⁇ - **. T ⁇ * CHU H UPC F 1 -TLJ TI * preferably T criu > 1,1. T * criu of FLI * and more preferably still 3. T * cm i of FLI *> T cm i 1.1. T * criu of FLI *
• the method according to the invention for treating bacterial infections, in particular pediatric infections, with limitation, or even stopping, of the increase of the antimicrobial resistance can also essentially consist in administering orally, an oral pharmaceutical pharmaceutical formulation, in particular pediatric, administrable per os and which: * on the one hand comprises microcapsules which comprise a heart containing at least one active ingredient PA1 formed by at least one antibiotic and a coating of said core governing the modified release of PAl, * and, on the other hand, is definable, compared to an immediate-release oral formulation (FLI *) comprising PAl and for the same X m i that FLI *, by a dose D active principle PAl such that (relative to at a dose D * of the active ingredient PA1 of FLI *):
• the formulation administered according to the above-defined methods of treatment comprises PA1 (e.g., amoxicillin) immediate release.
• PA1 e.g., amoxicillin
• the bacterial infections concerned are, for example, those affecting the respiratory tract, and in particular those involving the resistant S. pneumoniae, H. influenzae and M. catarrahalis germs. These infections are defined above.
• This formulation is advantageously administrable in one or two doses (preferably two) daily.
• the formulation can also be designed to be administrable in at least three doses per day. Indeed whatever the number of taken, it may be interesting to increase the T cm i, as permitted by the therapeutic indication according to the invention.
• Step 2 Coating 930 g of granules obtained above are coated with 53.2 g of ethylcellulose (Ethocel 7 Premium), 7.3 g of castor oil, 2.8 g of PEG 40-hydrogenated castor oil (Cremophor RH40) and 7.3 g of povidone (Plasdone K29 / 32) dissolved in acetone / isopropanol (60/40% w / w) in a Glatt GPCG1 fluidized air bed apparatus.
• Ethocel 7 Premium ethylcellulose
• castor oil 2.8 g of PEG 40-hydrogenated castor oil (Cremophor RH40)
• povidone Plasdone K29 / 32
• Step 2 Embedding
• Step 1 Granulated 35 g of amoxicillin, 2.5 g of PEG 40-hydrogenated castor oil (Cremophor RH 40), 12.5 g of Povidone (Plasdone K29 / 32) and 200 g of lactose are premixed dry in a laboratory granulator (Mi-PRO / Pro-C-ept) for 5 minutes. This powder mixture is then granulated with water (20 g). The granules are dried at 40 ° C. in a ventilated oven and then calibrated on a 500 ⁇ m grid. The 200-500 ⁇ m fraction is sieved.
• Step 2 Embedding
• Step 2 Embedding
• 850 g of granules obtained previously are coated with 384.9 g of ethylcellulose in aqueous dispersion (Aquacoat ECD 30 or 117 g of dry extract), 28.5 g of dibutyl sebacate and 4.5 g of povidone (Plasdone K29 / 32) in a Glatt GPCGl fluidized air bed apparatus.
• Step 1 Granulated 700 g of amoxicillin, 300 g of Povidone (Plasdone K29 / 32) and 200 g of water are mixed using a laboratory mixer (Kitchen-Aid type) for 5 minutes. This pasty mixture is extruded through a grid of 0.5 mm using an extruder 20 (Caleva). The filaments obtained are then spheronized using a spheronizer 250 (Caleva). The particles obtained are dried at 40 ° C. in a fluidized air bed. The 300-700 ⁇ m fraction is sieved.
• Step 2 Embedding
• 450 g of granules obtained above are coated with 35 g of ethylcellulose (Ethocel Premium), 5 g of dibutylsebacate and 10 g of PEG 35000 dissolved in a water / ethanol mixture (20/80% w / w), in an apparatus Aeromatic-Fielder MPI fluidised air bed.
• ethylcellulose Ethocel Premium
• dibutylsebacate 5 g
• PEG 35000 dissolved in a water / ethanol mixture (20/80% w / w
• Step 1 Granulated 590 g of amoxicillin and 10 g of magnesium stearate are mixed using a laboratory mixer (Kitchen-Aid type) for 5 minutes. This mixture is then compacted using an Alexenderwerk WP120 laboratory compactor. The product obtained is then granulated using an Erweka oscillating granulator equipped with a 500 ⁇ m grid. The 100-500 ⁇ m fraction of the product obtained is sieved.
• Step 2 Coating 450 g of granules obtained above are coated with 35 g of ethylcellulose (Ethocel Premium), 5 g of dibutylsebacate and 10 g of PEG 35000 dissolved in a water / ethanol mixture (20/80% w / w). , in an Aeromatic-Fielder MPI fluidized air bed apparatus.
• Step 2 Embedding
• 450 g of granules obtained above are coated with 60 g of Eudragit RS100, 4 g of triethyl citrate and 16 g of PEG 35000 dissolved in isopropanol in an Aeromatic-Fielder MPI fluidized bed apparatus.
• Example 8 Preparation Formulation 8 Comprising an Amoxicillin Fraction in the Form of Modified-Release (Extended) Microcapsules and an Amoxicillin Fraction in the Immediate-Release Amoxicillin Form 300 g of granules prepared during step 1 of manufacture of the microcapsules of Example 4 are mixed with 700 g of microencapsulated amoxicillin corresponding to formulation 4 of Example 4.
• the plasma concentration profile of amoxicillin after administration of modified release microcapsules according to the invention was simulated from the following elements:
• the dose administered is 43 mg / kg.
• the modified release microcapsules release 39% of the dose in one hour and 50% of the dose in 1.4 hours.
• the plasma profile resulting from an IV injection ("IV response function") is a mono-exponential half-elimination time of 1.3 hours.
• the plasma profile is calculated by convolution of the rate of release of amoxicillin by the response function IV.
• microcapsular formulations with modified amoxicillin release according to the invention are therefore more effective, in equal doses, than the FLI * immediate release amoxicillin formulations.
• FIG. 1 shows two plasma amoxicillin concentration profiles (A and B) ( ⁇ g / ml) resulting from the administration of 43 mg / kg, the A profile being that of an immediate-release oral form (FLI *) and the profile B being that of a modified-release microcapsular oral form, in accordance with that proposed for use according to the invention for producing an effective antibiotic drug.

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• 2004
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