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WO2007106960A9 - Formes galéniques flottantes à libération contrôlée - Google Patents

Formes galéniques flottantes à libération contrôlée

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Publication number
WO2007106960A9
WO2007106960A9 PCT/BE2007/000028 BE2007000028W WO2007106960A9 WO 2007106960 A9 WO2007106960 A9 WO 2007106960A9 BE 2007000028 W BE2007000028 W BE 2007000028W WO 2007106960 A9 WO2007106960 A9 WO 2007106960A9
Authority
WO
WIPO (PCT)
Prior art keywords
mini
composition
tablets
coating
advantageously
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.)
Ceased
Application number
PCT/BE2007/000028
Other languages
English (en)
Other versions
WO2007106960A1 (fr
Inventor
Francis Vanderbist
Phillippe Baudier
Arthur Deboeck
Karim Amighi
Jonathan Goole
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.)
LABORATOIRES SMB SA
Smb S A Lab
Original Assignee
LABORATOIRES SMB SA
Smb S A Lab
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 LABORATOIRES SMB SA, Smb S A Lab filed Critical LABORATOIRES SMB SA
Publication of WO2007106960A1 publication Critical patent/WO2007106960A1/fr
Publication of WO2007106960A9 publication Critical patent/WO2007106960A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to oral controlled release floating dosage form or composition, especially- multiple units controlled release floating systems or granulated systems.
  • the floating dosage form or composition comprises one or more mini-tablets able to float on the surface of aqueous fluids, including gastric juice, over an extended period of time.
  • the oral dosage form or composition of the invention enables a sustained release of one or more active agents for 12 hours or more.
  • the present invention also relates to a method of manufacturing of said controlled release floating dosage forms or compositions, such as granulated multiple units systems which is very simple and based on a melt (thermoplastic) granulation step following by compression into mini-tablets and coating said mini- tablets.
  • the coated mini-tablets can be filled into capsules. Melt granulation is a low cost, rapid and solvent-free manufacturing process.
  • said floating dosage mini-tablets which contain at least one drug, at least one fusible (low melting point) binder, at least one gas generating agent and appropriated excipients in order to control efficiently both the release of the drug and the floating properties of the composition.
  • a coating layer is added on the mini-tablets.
  • the amount of dry coating is equal or superior to 20% (w/w) of the mini-tablets weight.
  • the coating comprises also a pharmaceutically acceptable plasticizer.
  • An orally administrated drug delivery system is exposed to a wide range of highly variable conditions as pH, agitation, intensity and gastric emptying times.
  • the convenience of administering a single dose of medication which releases an active medicament over an extended period of time as opposed to the administration of a number of singles doses at regular intervals has long been recognized in pharmaceutical field.
  • the advantages to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized [reference 3] .
  • a prolongation of gastric residence time (GRT) of a rate-controlled oral drug delivery system reduces the inter-subject variability, reduces the so called “peak and valley” effect and leads to a more predictable and a bioavailability increase of the dosage form, especially for molecules with a narrow absorption window. Moreover, the total gastrointestinal transit time is prolonged and thus, the number of dosage regimen can be reduced.
  • GRT gastric residence time
  • sustained-release dosage forms capable of staying in the stomach over an extended period of time may be particularly useful for drugs that may act locally in the stomach (e.g. antacids, antibiotics for bacterially-origin ulcers), drugs that are absorbed primarily in the stomach (e.g. albuterol) , drugs that are poorly soluble in intestinal pHs (weak bases such as dipyridamole) , drugs that have a narrow absorption window and absorbed (mainly) from the upper small intestine (e.g. levodopa, riboflavin), drugs that absorbed rapidly from the GI tract (e.g. amoxicillin) , drugs having a low bioavailability and drugs that degrade in the colon (e.g. metoprolol) [references 2 to 6]
  • drugs that may act locally in the stomach e.g. antacids, antibiotics for bacterially-origin ulcers
  • drugs that are absorbed primarily in the stomach e.g. albuterol
  • Bioadhesive drug delivery systems can be formulated to adhere on the gastric mucous membrane. According to in vivo studies and despite that the principle of bioadhesion has found very interesting applications for other routes of administration, it does not seem that mucoadhesive polymers are able to prolong significantly the GRT of oral drug delivery systems [reference 8] .
  • the use of solid dosage forms with high density (heavy pellets and tablets) which might remain positioned in the lower part of the antrum during a prolonged period of time, has been also proposed. The success of such systems is limited since the bioavailability depends on a lot of physical and physiological factors [reference 8].
  • Magnetic systems and superporous biodegradable hydrogel systems are also described [reference 9] .
  • FDDS floating drug delivery systems
  • FDDS floating drug delivery systems
  • Several patents and papers describe buoyant dosage forms which improve efficiently the gastric residence time. Based on the mechanism of buoyancy, two different approaches, the use of polymer- mediated non-effervescent and effervescent systems, have been proposed in the development of FDDS [reference 10] .
  • Floating dosage forms might have a density lower than gastric fluid (less than 1 g/ml) and float on it during a prolonged period of time.
  • US Patent no 4,126,672 described a Hydrodynamically Balanced capsule System based on the mixture of drugs and hydrocolloids . In contact with gastric juice the hydrocolloid begins to swell and maintains a relative integrity of shape, a bulk density of less than unity and finally, regulates the drug release [references 11 and 6] .
  • US Patent no 4,055,178 described ' a device comprising a drugs reservoir encapsulated in a microporous compartment, to which an independent flotation chamber is attached in order to provoke the flotation of the system [reference 12] .
  • Kawashima et al (1992) have developed non effervescent hollow polycarbonate microballoons by using an emulsion - solvent evaporation method.
  • Thanoo and al . (1993) have used the same method to make hollow polycarbonate microspheres but they have employed others solvents [references 14 and 15] .
  • Yuasa et al. (1996) have developed floating granules using Hydroxypropylcellulose (HPC) , ethylcellulose and calcium silicate as a floating carrier, which has a characteristically highly porous structure. The granules acquire floating ability from the air trapped in the pores of calcium silicate when they were coated with a polymer [reference 16] .
  • Whitehead et al. have developed a highly porous multiple-unit floating dosage form. Very low density spherical beads were produced by dropping a sodium alginate solution into aqueous calcium chloride and by freeze-drying the obtained gelled beads [reference 18] .
  • Ichikawa et al. (1991) have described a gas generating multiple-unit oral floating dosage system consisting of a conventional sustained-release pill coat by two layers.
  • the inner layer was an effervescent layer and the outer layer a swellable membrane layer containing mainly polyvinyl acetate and purified shellac.
  • the system When the system was immersed in a buffer solution, it sank at once in the solution and forms swollen pills, like balloons, with a density much lower than 1 g/ml [reference 17] .
  • Atyabi et al . (1996) have developed a controlled-release gastric retentive system from coated floating ion exchange resin beads.
  • the resin is loaded with bicarbonate anions and coated by a semi-permeable membrane.
  • bicarbonate anions On exposure to gastric media, exchange of bicarbonate and chloride took place releasing carbon dioxide.
  • the gas is trapped within the membrane causing the particles to float [reference 19] .
  • US Patent no 3,901,232 and US Patent no 3, 786,813 described a very sophisticated osmotically controlled floating system, consisting of two chambers in a capsule.
  • the first chamber contains a drug
  • the second one contains a volatile liquid, such as cyclopentane that vaporizes at physiological temperature, enabling drug reservoir to float [references 20 and 21] .
  • a lot of sustained-release floating tablet systems were described in literature, using effervescent or non effervescent components and which were obtained with or without a granulation step, followed by compression.
  • US Patent no 6,261,601 describes a single-unit pharmaceutical composition in the form of tablets (or capsules) comprising a drug, a gas generating component, a swelling agent, a viscolyzing agent, and (optionally) a gel forming polymer.
  • the swelling agent, the gas entrapping viscolyzing agent and optionally the gel forming polymer form a hydrated gel matrix.
  • the tablets are prepared by mixing all the compounds .
  • the mixture may be roll compacted and sieved to obtain granules, which may be filled into capsule or compressed into tablets.
  • This invention does not resolve the problem of the high inter and intra-subject variability and the problem of unpredictability of single unit dosage forms [reference 30] .
  • US 6,514,524 [reference 31] discloses an orally administrable galenic formulation allowing improved absorption in the gastrointestinal tract by using specific absorption-promoting agent.
  • the formulation in the form of tablets or capsules can comprises effervescent excipients, and can be provided with a film-coating.
  • the formulation is a quick release formulation.
  • melt (thermoplastic) granulation in which the granulation is obtained through the melting or softening of a low melting point binder, might be a very interesting alternative to the classical wet granulation as a very short one-step single-pot production process. As it is a solvent free process, the drying phase is eliminated and thus, the process becomes less consuming in terms of time and energy.
  • the use of the melt granulation process was thoroughly discussed in the literature for the preparation of immediate release and sustained release granules, pellets and tablets. Hamdani et al. have developed a melt pelletization process allowing a substantial increase of fatty binders content of formulations, up to 80% w/w, in order to obtain prolonged-release pellets for different drugs substances showing very distinct physico-chemical
  • a single-unit dosage form diameter has to be larger than 13 mm in order to be retained in the stomach for a prolonged period of time [reference 13] .
  • Single-unit dosage forms show a higher inter- and intra patients variability resulting from the all-or- none emptying process from stomach.
  • divided systems have a more reproducible gastric residence time, present lower inter-subject variability in absorption and show a better dispersion through the gastrointestinal tract.
  • the present invention relates to buoyant controlled-release dosage forms or compositions which comprises one or more mini-tablets, which may be further filled into capsules.
  • the originality of this invention consists in its specific shape or forms, as well in the process of manufacturing associated with its composition.
  • floating granules are fabricated by melt (thermoplastic) granulation in a high shear mixer.
  • melt thermoplastic
  • the granulation mixtures contain at least one drug, one or several meltable binders (preferably lipidic binders) , one or more gas-generating agents and, when required, appropriated excipients.
  • Floating minitablets can contain swellable agents and are coated by a flexible membrane in order to retain the generated gas inside the dosage form.
  • Said membrane comprises a water insoluble polymer and a platicizer.
  • the floating granules compositions according to this invention are compressed into mini- tablets, whose composition and individual size characteristics permit also to modulate both the floating and the dissolution properties of the dosage form.
  • the mini-tablets obtained after compression are preferably filled into capsules in order to obtain multiple-unit sustained-release floating dosage forms .
  • Mini-tablets, in the present invention mean a tablet with a diameter comprised between 1 mm and 7mm, preferably between 1.5 mm and 5 mm.
  • the invention relates to an oral pharmaceutical controlled release floating composition or dosage form, advantageously in the form, of multiple units composition.
  • the composition of the invention comprises : •
  • mini-tablets advantageously at least two mini-tablets, said mini-tablet (s) having a maximum size comprised between lmm and 7mm, preferably between 1.5mm and 5mm, and comprising at least one active drug, one fusible binder and one gas generating agent, and - a coating layer surrounding one or more of said mini-tablets, advantageously each of said mini-tablets, said coating layer comprising a water insoluble polymer and a plasticizer, said coating layer being present in an amount superior or equal to 20% expressed as a percentage (w/w) in dry coating of the weight of the uncoated mini-tablet, and optionally one or more mini-tablets further comprise a swelling agent.
  • compositions of the present invention are able to float on the surface of aqueous fluids, including gastric juice, for an extended period of time.
  • the compositions of the invention advantageously comprise from 2 to 20, preferably from 3 to 18, most preferably from 8 to 15 coated mini-tablets .
  • the drug containing system is advantageously prepared in the absence of water, so that solid or semi-solid excipients are bound together' by the fusible binder.
  • the active agent can be in solid forms or in semi solid forms or dissolved or dispersed in one or more excipients, said active agent being bound to other excipients particles by means of the fusible binder.
  • the preparation of drug containing system in the absence of water enables to guarantee that the gas generating agent is not wetted with water and is in its optimal condition for generating gas. It enables furthermore that the drug containing system comprises gas generating agents having to react together in presence of water or an aqueous medium for generating gas.
  • the mini-tablet form comprises a core comprising at least one active drug, one fusible binder, one gas generating agent and a swelling agent.
  • the composition further comprises one or more organic acids. Said organic acid or acids are advantageously within the mini-tablet forms comprising the drug or active agent.
  • the fusible binder has a melting point or a melting range lower than 95 0 C, preferably lower than 80 0 C, preferably between 30 0 C and 75°C, more preferably between 45 0 C and 55 0 C.
  • the fusible binder can also be a mixture of fusible binders, such as one binder with a low melting temperature or range and another binder with a high melting temperature.
  • the fusible binder has advantageously a HLB value lower than 7, for example comprised between 1 and 6.
  • the weight ratio between the fusible binder and the gas generating agent in the composition of the invention, preferably in the mini- tablet form is about 0.1 to 10, preferably from 0.2 to 5, most preferably from 0.5 to 2.
  • the unit forms which are mini- tablets have a weight average length from 1.5mm to 5mm, advantageously between 2.5mm and 4mm.
  • the composition is a multiple unit form, advantageously a capsule comprising the mini tablets.
  • the composition comprises advantageously several mini tablets, for instance more than 3, preferably more than 5 and more preferably more than 8.
  • the fusible binder is selected from the group consisting of fats, waxes, fatty alcohols, cetyl alcohol, stearyl alcohol cetostearyl alcohol or fatty alcohols with more than 18 carbon atoms) , fatty acids (preferably palmitic acid, or fatty acids with more carbon atoms such as stearic acid, behenic acid, etc. ) , glycerol esters
  • ethers of fatty alcohols e.g. mono-, di-, and tri-glycerides, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate
  • ethers of fatty alcohols esters of fatty acids, hydrogenated oils, polyethylene glycols (PEGs) , polyoxyethylenated derivatives, phospholipids and any derivatives thereof, as well as mixtures thereof.
  • PEGs polyethylene glycols
  • polyoxyethylenated derivatives phospholipids and any derivatives thereof, as well as mixtures thereof.
  • the use of a mix of fusible binders is advantageous so as to have a better control of the melting temperature or melting range temperature.
  • the gas generating agent is advantageously selected from the group consisting of sodium and potassium hydrogen carbonate, calcium carbonate, sodium glycine carbonate, sulphur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, and combinations thereof.
  • the composition advantageously further comprises a second gas generating agent.
  • the organic acid is advantageously tartaric acid, citric acid, ascorbic acid or a mix thereof.
  • the composition of the invention is provided with a coating, in which the water insoluble coating polymer is advantageously selected from the group consisting of water insoluble acrylic polymers, water insoluble cellulosic polymers, waxes and combinations thereof. Possibly, the composition of the invention can be provided with more than one coating layer.
  • the swelling agent is advantageously selected from the group consisting of gum arabic, Carrageenan, Guar gum, Gum tragacanth, Agar, Sodium Carboxymethyl cellulose, Hydroxyethyl cellulose, Hydroxypropylmethyl cellulose, Sodium alginate, Chitosan, Xanthan gum, Sodium croscarmellose, pectin and combinations thereof.
  • the composition of the invention is advantageously formulated in a form suitable for a once-a-day or twice-a-day administration in humans.
  • several mini- tablets are filled into a pharmaceutically acceptable capsule, preferably hard gelatin capsule or hypromellose capsule.
  • the mini-tablets can then have a same composition, but can also have different compositions.
  • some unit forms comprise a first gas generating agent, while other unit forms comprise a second gas generating agent different from the first gas generating agent.
  • the first and second generating agents are selected so as to react therebetween in presence of an aqueous medium.
  • one or more mini-tablets comprise a first active agent, while one or more other mini-tablets comprise another active agent .
  • the capsule comprises one or more mini-tablets having a first controlled release profile, while one or more other mini-tablets have a second controlled release profile different from the first release profile.
  • the composition further comprises an immediate release form of the same active drug or of another active agent.
  • the composition comprises a combination of two or more active drugs. For example, one drug presents a first controlled release profile (such as an sustained or extended release profile) , while the other drug presents a release profile different from the first controlled release profile, advantageously an immediate release profile.
  • composition advantageously further contains one or more classical pharmaceutical excipients like fillers, disintegrants, lubricants, pigments, anti-taching, and combinations thereof.
  • the invention relates also to mini-tablets as disclosed here above, suitable for the preparation of a composition according to the invention.
  • the mini-tablets comprise at least one active agent,
  • the coating layer is characterized by a dry weight ratio plasticizer/water insoluble polymer greater than 1:10, advantageously greater than 1.5:10, preferably comprised between 1.5:10 and 5:10.
  • the coating layer advantageously at least one anti foaming agent, and preferably also at least one detackifying agent.
  • at least 50% by weight, advantageously at least 60% by weight, preferably from 70% to 90% by weight of the coating layer consists of water insoluble polymer and plasticizer.
  • the unit form of the invention further comprises one or more organic acids.
  • the fusible binder has a melting point or a melting range lower than 95 0 C, preferably lower than 80 0 C, preferably between 30 0 C and 75°C, more preferably between 45 0 C and 55 0 C.
  • the fusible binder can also be a mixture of fusible binders, such as one binder with a low melting temperature or range and another binder with a high melting temperature.
  • the fusible binder has advantageously a HLB value lower than 7, for example comprised between 1 and 6.
  • the weight ratio between the fusible binder and the gas generating agent in the composition of the invention, preferably in the mini- tablet, is about 0.1 to 10, preferably from 0.2 to 5, most preferably from 0.5 to 2.
  • the mini-tablets have a weight average size from 1.5 mm to 5mm, preferably between 2.5mm and 4.5mm, most preferably between 2.8mm and 3.5mm.
  • the mini-tablets have advantageously a hardness of less than 8 kg/cm 2 , preferably less than 6 kg/cm 2 , most preferably less than 4 kg/cm 2 .
  • the hardness is advantageously greater than about 0.7kg/cm 2 , and thus most preferably comprised between 0.7 kg/cm 2 and 3 kg/cm 2 .
  • the hardness of the mini-tablets measured according to the method described in the European Pharmacopeia, chapter 2.9.8 - resistance to crushing of tablets is advantageously comprised between about 5N and 4ON, preferably between 5N and 15N.
  • the dry weight ratio plasticizer/water insoluble polymer in the coating layer or in at least one coating layer is greater that 1:10, advantageously greater than 1.5:10, preferably comprised between 1.5:10 and 5:10.
  • the coating layer comprises at least one anti-foaming agent.
  • the coating layer comprises at least one detackifying agent.
  • At least 50% by weight, preferably at least 60% by weight, most preferably from 70% to 90% by weight of the coating layer consists of water insoluble polymer and plasticizer .
  • the invention relates also to a process for manufacturing a composition of the invention or mini- tablets of the invention.
  • the process comprises at least the step of mixing and melt granulating the drug, the fusible binder, advantageously a swelling agent and the gas generating agent together, tabletting the granules into mini-tablets, and coating the mini- tablets with a water-insoluble polymer and a plasticizer.
  • the process for manufacturing composition of the invention or mini-tablets of the invention comprises at least
  • the mini tablets with at least a water insoluble polymer, a plasticizer and advantageously an anti foaming agent.
  • the present invention also relates to the manufacturing process of said granulated systems which is very simple and based on a melt (thermoplastic) granulation step followed by compression into mini- tablets.
  • pellets can be produced after or during melt granulation. Said pellets can thereafter be compressed into mini-tablets.
  • the present invention further relates to the unique composition of the said floating granulated system which is based on the mixture of at least one therapeutically active ingredient or drug, at least one fusible (meltable) binder, at least one gas generating agent, and appropriated excipients in- order to control efficiently both the release and the floating properties of the composition.
  • a polymer coating is applied on mini-tablets whereby further improve floating and/or release properties.
  • gel forming polymers may optionally be added.
  • the pharmaceutical composition of the granulates of the invention used for the preparation of the mini tablets of the invention is given in Table 1 and the composition of the coating solution is given in table 2.
  • the pharmaceutical composition of the granulates is given in Table 1 and 2
  • the pharmaceutical compositions of the core and the formulation used in the coating are shown in Table
  • Figure 4 shows the influence of the pharmaceutical composition of the core, in the case of coated mini-tablets, on the resultant weight profile
  • the pharmaceutical composition of the core and the formulation used in the coating are given in Table 6.
  • the pharmaceutical composition of the core and the formulation used in the coating are given in Table 6.
  • the pharmaceutical composition of the core and the formulations used in the, coating are shown in Table 8.
  • the pharmaceutical compositions are given in Table 10 (uncoated mini-tablets) .
  • the object of the present invention is to provide advantageously multiple units solid dosage forms able to float on the surface of aqueous fluids and to deliver one or more therapeutic agents incorporated therein over an extended period of time.
  • the present invention provides preferably coated floating controlled-release (CR) mini-tablets that can be filled into capsules.
  • the present invention provides also new compositions of the said floating CR mini-tablets based on the use of very simple compositions comprising at least one drug, one fusible (low melting point) binder, one gas generating agent and other pharmaceutically acceptable excipients.
  • the composition has to be designed to obtain an optimal floating properties and dissolution rate of the drug.
  • the composition of the said floating mini- tablets further comprises one or more inert (insoluble) polymer (s) and optionally a swellable agent gel forming hydrocolloid (s) in order to improve the floating capabilities of the solid dosage form by entrapping carbon dioxide generated by the effervescent component ( s ) .
  • the swellable agent and/or the coating layer further participate to the control of the drug release in addition to the sustained-release provided by the fusible binder, which is preferably lipophilic, and the polymer coating.
  • the swellable agents and the coating can also preserve the cohesion of the system.
  • a method of preparation of the floating CR mini-tablets according to the invention comprises advantageously the process of melt granulation in a high shear mixer, of compressing the granulates into mini-tablets, and of coating the mini-tablets with a coating composition comprising a water insoluble polymer and a plasticizer.
  • the fusible binder which has a low melting point or melting range is a lipophilic or optionally a hydrophilic compound selected from the group consisting of fats, waxes, fatty alcohols (preferably cetyl alcohol, stearyl alcohol cetostearyl alcohol or fatty alcohols with more than 18 carbon atoms) , fatty acids (preferably palmitic acid, or fatty acids with more carbon atoms such as stearic acid, behenic acid, etc.), glycerol esters (e.g.
  • glyceryl monostearate glyceryl palmitostearate
  • glyceryl behenate ethers of fatty alcohols, esters of fatty acids, hydrogenated oils, polyethylene glycols (PEGs), polyoxyethylenated derivatives, phospholipids and any derivatives thereof.
  • the low melting point ingredient, used as fusible (meltable) binder is a solid material at ambient temperature with a melting point or a melting range lower than 95 0 C, preferably lower than 80 0 C, preferably between 30 0 C and 75°C, more preferably between 45 0 C and 55 0 C.
  • the gas generating system may consist of one or more substances known to produce carbon dioxide (e.g. sodium or potassium hydrogen carbonate, calcium carbonate, sodium glycine carbonate) or sulphur dioxide (e.g. sodium sulfite, sodium bisulfite or sodium metabisulfite) upon contact with gastric fluid.
  • the composition of the invention may further comprise acidic substances, preferably organic acids (e.g. tartaric acid, citric acid) to increase the gas generation in fed conditions even when the gastric pH is substantially increased, i.e. in presence of high fat meals.
  • the acid source may be one or more of an edible organic acid, a salt of an edible organic acid, an edible mineral acid, a salt of an edible mineral acid or mixtures thereof.
  • the drug may be pharmacologically or chemotherapeutically active itself, or may be converted into a pharmacologically or chemotherapeutically active species by a chemical or enzymatic process in the body (prodrug) .
  • the floating solid dosage forms of this invention are particularly useful for drugs which have narrow absorption window, drugs having a higher solubility in the stomach than in the intestine, drugs having a local action in the stomach or drugs absorbed by a saturable transport process.
  • Illustrative examples of drugs that are predominately absorbed from the upper part of the gastrointestinal tract include ofloxacin, ciprofloxacin, metoprolol, oxprenolol, allopurinol, baclofen, cyclosporin, sumatriptan, benazepril, enalapril, quinapril, imidapril, benazeprilat, cilazapril, delapril, moexipril, indolapril, olindapril, retinapril, pentopril, perindopril, altiopril, ramipril, spirapril, lisinopril, zofenopril, captopril and the like.
  • the present invention can be used for drug substances active against Helicobacter pylori like bismuth salts such as rantidine bismuth citrate, bismuth subsalicylate, tripotassium dicitratobismutate and the like; H-2 receptor antagonists such as cimetidine, ranitidine, famotidine, nifentidine, roxatidine, nizatidine, bifentidine, erbrotidine and the like ; antacids like aluminium hydroxide, magnesium oxide, magnesium carbonate and the like ; cytoprotective agents such as misoprostol, carbenoxolone sodium, sucralfate and the like ; antimuscarinic agents like propantheline bromide, pirenzepine , telenzepine and the like ; antibiotics and anti-parasite agents such as amoxycillin, clarithromycin, minocycline, tetracycline, metronidazole and the like.
  • H-2 receptor antagonists
  • the present invention can be used for drug substances having higher solubilities in acidic pH or one with absorption site in upper part of the gastro-intestinal tract and those that are subjected to gastrointestinal first pass metabolism.
  • antihypertensive agents like nicardipine, nimodipine, amlodipine, nifedipine, verapamil, dilthiazem, cinnarizine, propranolol, atenolol, prazosin, ketanserin, hydralazine, guanabenz acetate, carvedilol and the like ;
  • Antivirals like acyclovir, inosine pranobex, gancyclovir, zidovudine, vidarabine, tribavirin and the like ; lipid lowering agents like atorvastatin, pravastatin, simvastatin, lovastatin and the like ; And others therapeutic agents like
  • the drug itself or its pharmacologically active salt, ester or pro-drug can be used in the present invention.
  • combination of two or more active drugs or doses combinations may be included as the drug component.
  • the release of each active ingredient may be identical or different (for instance combination of two active ingredients in which the first one is presented as an immediately release form and the second one as a controlled release.
  • a combination of immediate release and controlled release form may also be obtained for the same active ingredient, in order to provide a rapid and sustained effect.
  • the floating compositions according to this invention are compressed into mini-tablets, whose composition and individual size characteristics permit also to modulate both the floating and the dissolution properties of the mini-tablet dosage form.
  • Mini-tablets can be present as single layered or multi-layered dosage forms in order to separate different active ingredients or dosages of active ingredient (s) .
  • the present invention relates to floating sustained-release mini-tablet systems which are able to float on the surface of aqueous fluids and delivering one or more therapeutic agents incorporated therein over an extended period of time.
  • a sustained release or controlled release composition is preferably a composition suitable for a once-a-day or a twice-a-day administration in mammals, preferably in human.
  • Granulates are made by melt granulation in a high shear mixer. Melt granulation is a low cost very short solvent-free process, consisting in the blending of the drug and at least the fusible binder and the gas generating agent.
  • the fusible binder presents the property to be solid or pasty (semi-solid) at ambient temperature (20°C-25°C) and to become liquid at the temperature of the process (30 0 C to 9O 0 C), so playing the role of granulating liquid concentrations.
  • Granulates, possibly after being pelletized, are compressed, before being coated and possibly filled into capsules. Optionally a step of sieving of granulates can be added before the compression step.
  • Granulates can be incorporated in a one, two or multiple layered mini-tablets.
  • Mini-tablets present advantageously a diameter comprised between 1.5mm and 5mm, in order to be suitable for designing a multi-particulate pharmaceutical dosage form.
  • Mini-tablets can be filled into hard gelatin capsule or hypromellose capsules with or without disintegrating agent (for example: Ac-Di- Sol®, croscarmellose sodium NF, FMC Corporation, Philadelphie) .
  • disintegrating agent for example: Ac-Di- Sol®, croscarmellose sodium NF, FMC Corporation, Philadelphie
  • the disintegrant prevents the mini-tablets from sticking when hydrocolloid is swelling into capsule and thus, reduce the variability in drug diffusion through mini-tablets.
  • the new compositions described here are advantageously multiple-units dosage form for reasons described above.
  • Multiple units in the present invention refers to a pharmaceutical form (which can be monolithic like a capsule or a tablet) but containing several separate mini tablets) which will be released once the pharmaceutical form is in contact with gastrointestinal fluids.
  • a pharmaceutical form which can be monolithic like a capsule or a tablet
  • mini-tablets of the invention connected together by a water soluble polymer and/or a disintegrating agent (so as to form distinct mini-tablets when contacting gastro-intestinal fluids) , ...
  • the present invention preferably consists of one-layered mini tablets obtained by compression.
  • Granulates used for the preparation of the mini-tablets contain at least one drug, at least one fusible (meltable) binder, one or more gas generating agents, and optionally hydrophilic or lipophilic diluent (s) or inert diluent (s), preferably swelling (hydrocolloid) agent (s).
  • the mini tablets prepared by compressing granulates are then coated with an adequate amount of polymer coating.
  • These dosage forms have sufficient mechanical stability and hardness so that they will withstand the normal stress of production, packaging and dispensing.
  • the optimum concentration of therapeutic agent depends of its physical properties, chemical properties and its optimum therapeutic dosage.
  • the fusible binder concentration depends of its capabilities of binding the different powders present in the mix and the drug release properties pursued.
  • the content of the gas generating agents and the one of the several diluents, especially the hydrocolloid vary with the floating properties and the drug release capabilities pursued.
  • the amount and the composition of the coating depend on the floating properties and the drug release capabilities pursued.
  • the fusible binder of the invention may be any lipophilic, hydrophilic or amphiphilic agent having a melting range between 30 0 C and 80 0 C, preferably between 45°C and 65 0 C and which can act as binder during the melt granulation process. Lipidic agents have to be solid at ambient temperature. The HLB values of lipidic diluents and lipidic binders can be between 0 and 7, preferably around 2. They have to be chemically inert and safe for humans and animals. [0112] The fusible binder may be present in an amount from about 5% to about 80%, preferably from about 10% to about 50%, and more preferably from about 12% to about 20%, by weight of the total weight of the composition. [0113] Optionally, a lipidic diluent may be present in an amount from about 0% to 80%, preferably from about 0% to about 20%, and more preferably from about 0% to about 10%, by weight of the total weight of the composition.
  • Every agent or every mixture of agents that can produce carbon dioxide in the presence of water or gastro intestinal fluids can be used as gas generating agents.
  • Particle sizes of these agents are preferably not too big ( ⁇ 500 ⁇ m, preferably inferior to 200 um) to avoid production of too big bubbles of gas, which can reduce the system cohesion.
  • the association of acid substances permits to allow the gas generation in fed conditions even when the gastric pH is substantially increased by creating a micro acid pH area just around mini-tablets borders.
  • the gas generating component such as carbonates and bicarbonates may be present in amounts from about 0.5% to about 50%, preferably from about 3% to about 20%, an more preferably from about 3% to about 15%, by weight of the total weight of the composition.
  • the acid source may be present in an amount from about 0% to about 50%, preferably from about 0.5% to about 10%, and more preferably from about 1% to about 3%, by weight of the total weight of the composition.
  • Swellable agents hydrate and form viscous barrier when they are in contact with aqueous fluids, including gastric juice.
  • the hydrocolloid agent preserves the system cohesion, traps the carbone dioxide to acquire a dosage form density lower than one (1 g/ml) and provides a sustained-release of the drug by both diffusion and erosion.
  • the density of mini-tablets becomes lower than one (1 g/ml) when they are in contact with gastric fluid.
  • the polymer is progressively hydrated and water diffusion into the dosage form and drug diffusion through the dosage form influence the drug release. The presence of lipidic agents may also slow down the water diffusion and thus, the drug release.
  • Inert agents as Ethylcellulose or Cellulose acetate, have the same effect on water diffusion as lipidic agents.
  • the swelling or gelling agent that can be used are gum arabic, Carrageenan, Guar gum, Gum tragacanth, Agar, Sodium Carboxymethyl cellulose, Hydroxyethyl cellulose, Hydroxypropylmethyl cellulose, Sodium alginate, Chitosan, Xanthan gum, Sodium croscarmellose, pectin [2, 4].
  • the swelling agent may be present in an amount from about 0% to about 80%, preferably from about 0% to about 50%, and more preferably from about 0% to about 25%, by weight of the total weight of the composition.
  • a non- toxic film coating is used.
  • the composition and the level of the coating influence the dissolution rate of the active drug. It was interestingly discovered in the present invention that only mini-tablets coated with at least 20% of dry coating (w/w) , expressed as percentage of weight of the uncoated tablet, exhibit an adequate prolonged release profile of the active ingredient. It is hypothesized that the pressure applied by the carbon dioxide generated into the mini-tablets is high and able to destroy or destructure at least partly the coating where the thickness of the coating layer is not high enough. This phenomenon is particularly developed in example 3 and figure 5.
  • the coating composition comprises advantageously (a) at least one coating agent which may be, but is not limited to, any water insoluble polymer derivative of acrylic acid, any water insoluble polymer derivative of cellulose or a wax, and (b) a plasticizer, while further preferably comprising a detackifying agent and/or an anti-foam, or the likes. All additives commonly used in coating composition may be further used, provided they will not destroy or destructure the coating after its contact with the gastro-intestinal fluid.
  • at least one coating agent which may be, but is not limited to, any water insoluble polymer derivative of acrylic acid, any water insoluble polymer derivative of cellulose or a wax, and (b) a plasticizer, while further preferably comprising a detackifying agent and/or an anti-foam, or the likes. All additives commonly used in coating composition may be further used, provided they will not destroy or destructure the coating after its contact with the gastro-intestinal fluid.
  • coating composition refers to a mixture of designated compounds that when applied to the surface of the pharmaceutical dosage form produces a coating layer through which the drug is released, especially in a controlled manner.
  • plasticizer refers to a component of the coating composition that has a low vapor pressure and whose presence in the composition modifies the flexibility and diffusion properties of the coating composition.
  • the term "detackifying agent” refers to a compound whose presence in the coating composition reduces the stickiness or adhesion of the coated dosage form.
  • all water insoluble coating agents commonly used may be employed alone or in combination, preferably acrylic polymers or cellulosic, more preferably insoluble pH-independent acrylic polymers (e.g. EUDRAGIT ® RL, RS or NE30D) .
  • the coating agents may be available as aqueous or organic dispersions, as a powder or as granules.
  • the amount of film-coating materials should not be limited because they vary with the kind or the amount of additives .
  • the amount of dry coating (expressed as a weight percentage of the uncoated dosage form) may be comprised between 15% and 50%, preferably between 20% and 30% (w/w) .
  • the detackifying agent may be, but is not limited to talc, aluminium hydrate, glyceryl monostearate, kaolin, and the like, or mixtures thereof and is used principally to reduce the incidence of tablet-to-tablet sticking that can occur during the film coating of pharmaceutical tablets and the like when aqueous dispersions are used.
  • the anti-agglomerating agent comprises about 5% to 50% by weight of the dry coating composition.
  • the plasticizer may be but is not limited to a derivative of the groups consisting of phtalic esters, citric esters, phosphoric esters, of acid esters, oils, oleic acid, stearic acid, cetylic acid, myristic acid, propylen glycol, glycerin, polyethylene glycol having a molecular weight in the range of 200 to 800, and the like or a mixture of thereof.
  • the amount plasticizer is between 0% to about 20% by weight of the dry coating composition.
  • Additives commonly used in coating dispersion are pigments, water-soluble materials, less water- soluble materials, no water-soluble materials, pore- forming agents.
  • Lactose may be used as a hydrophilic diluent.
  • Other suitable diluents are mannitol, sorbitol, glucose, microcrystalline cellulose, gelatin, starch, dicalcium phosphate, PVP, and all hydrophilic or lipophilic diluents which have no toxicity and are compatibles with other agents present in the granulation mixture.
  • the addition of sugars in the compositions of the present invention are not mandatory.
  • Hydrophilic, lipophilic or inert, pH-dependent or -independent coating agents can be used.
  • additional edible nontoxic ingredients recognized in pharmaceutical compounding such as excipients, preservatives, stabilisers and tabletting lubrifiants or lubricants.
  • the choice, the amount and/or the composition of each agents described above depend on the pharmaceutical dosage form properties wanted by the formulator .
  • a swellable agent and a coating can possibly be used together to retain the generated gas inside the dosage form.
  • the procedure of making unit dosage form or mini-tablets of the invention includes preferably at least three steps.
  • the first step consists advantageously in the manufacturing of granulates by melt granulation.
  • the granules are, for instance, made in a high shear mixer by using the appropriate operating conditions.
  • a high shear mixer is equipped with a bowl containing the mix, an impeller to mix, a chopper to break agglomerates, an optionally with infra-red temperature detector (it's also possible to use a borer directly in contact with the mix ), an air inlet (it's possible to regulate the air flow) and sometimes with a heating jacket.
  • a computer records the temperature, the impeller speed (IS) , the chopper speed (CS) and the resistance supported by the impeller during the mix. This resistance is called “the torque".
  • IS impeller speed
  • CS chopper speed
  • IS is generally decreased and CS is generally increased.
  • the massing time (MT) begins.
  • the size of granulates increases by increasing the massing time.
  • four parameters have to be controlled: the double-jacket temperature, the CS, the IS and the massing time. The granules have to provide good flow properties.
  • the granulates size distribution is advantageously measured by laser diffractometry, using a dry sampling system with a suitable SOP (Standard Operating Procedure) , (Scirocco®, Mastersizer 2000, Malvern, UK) to appreciate the size distribution.
  • SOP Standard Operating Procedure
  • a specific granulates fraction is selected, for example by sieving for the preparation of the mini-tablets.
  • the second step consists to compress the granulates into mini tablets. Mini tablets can be manufactured by using an alternative or rotative tableting machines. The choice of the punch determines the tablet's diameter. The punches can be convex or flat.
  • the third step is the coating of the mini- tablets with a coating composition comprising a water insoluble polymer, and advantageously a plasticizer.
  • a detackifying agent is advantageously previously dispersed in water in the presence of anti-foam and mixed with the others water- soluble additives commonly used in coating composition. All the components of the coating dispersions have to be blended. The stirring may be continued for one hour before starting the coating process.
  • the mini tablets are transferred in a suitable coating apparatus. The coating parameters depend on the physicochemical properties required.
  • the mini-tablets for example 80Og) were transferred into a fluidized bed coating apparatus
  • the coating dispersion has to be stirred continuously to prevent sedimentation of insoluble particles.
  • the inlet and outlet temperatures of the drying air were 40+2 0 C and 32+2 0 C, respectively.
  • the coating dispersion was pumped at a flow rate of 5ml/min and the pneumatic spraying pressure was 1 bar.
  • the total weight of the coating dispersion sprayed on the mini tablets was 1450g.
  • the coated mini-tablets were then dried in the same apparatus for lOmin at the above-mentioned temperatures.
  • the coated tablets or mini tablets may be cured or not.
  • F buoy is the buoyant force and F grav is the gravity force exerted on ' the object [26]
  • F is positive when the object floats and F is negative when the object sinks.
  • the resultant-weight apparatus measures F values as a function of time. When these values are divided by the experimental weighing, it is possible to obtain the resultant-weight values in percent.
  • the resultant-weight apparatus comprises a balance, a force transmitter device (FTD) , a test bath
  • the bath temperature can be regulated
  • a liquid level compensating system a digital/analog converter and a recorder (computer) [reference 26]
  • the interfering factors can be the temperature of electromagnetic measuring module, the draft and room ventilation, the magnetization of LTD, the surface tension of test solvent, the fluid density, air bubble adherence onto FTD, liquid level lowering by evaporation and the condensation of solvent vapour onto the FTD [reference 26] .
  • the lag time time period between placing the pharmaceutical composition in the medium and its floating
  • the maximal ' system magnitude and the floating duration are possible to evaluate.
  • the medium used for resultant-weight measurement is a HCl 0. IN solution containing 0.05% (w/v) of Polysorbate 20 (pH 1.2, 37°C).
  • the lag time can also be measured by an other way.
  • Pharmaceutical dosage forms can be placed in a becher containing the medium and subjected to an horizontal shaking of 100 cycles per minute.
  • the medium used for this test is a HCl 0.1N solution containing 0.05% (w/v) of Polysorbate 20 (pH 1.2, 37 0 C) .
  • Drug release can be evaluated by usual measurement processes as a dissolution testing by UV spectrophotometry or HPLC analysis.
  • dissolution studies were carried out using a Disteck 2100C USP 29 dissolution apparatus (Disteck Inc., North Brunswick, NJ, USA) Type II (paddle method) .
  • Di- potassium hydrogen phosphate/Acetic acid (0.05M each) buffer solutions containing 0.05% (w/v) Polysorbate 20 were used as the dissolution fluid at suitable pHs.
  • the volume and temperature of the dissolution medium were 900ml and 37.0 ⁇ 0.2°C, respectively.
  • the drug releases from tablets or minitablets was determined at a suitable wavelength, using an Agilent 8453 UV/visible Dissolution Testing System (Agilent, USA) .
  • the present invention is illustrated by, but is by no means limited to, the following examples.
  • Levodopa is used for the treatment of Parkinson's disease. Parkinson disease is a progressive neurological disorder with a prevalence of 1-2% in people over the age of 50. It has a world-wide distribution and has no gender preference [reference 28] .
  • Ciprofloxacin is a broad spectrum, fluoroquinolone antibiotic that is administered every 12h to treat a wide range of bacterial infections. Design of such an once daily dosage form with conventional sustained-release is problematic because ciprofloxacin is poorly absorbed in the terminal part of the small intestine and in the colon.
  • Example 1 describes the composition of the invention wherein the active ingredient is ciprofloxacin. The manufacturing process to obtain it is also described. The pharmaceutical composition is given in Table 1.
  • Emulsion silicone 2 g eau ad 1600 g [0153]
  • the manufacturing process was the following. During the granulation step, the double-jacket temperature of the mixer was set at 60 °C. Before the formation of the granulates, the IS was set at 1800rpm and the CS was set at 130rpm. After the formation of the granulates, the IS is decreased at ⁇ OOrpm and the CS is increased at 2000rpm. Massing time was fixed to 5 minutes.
  • Mini-tablets having a diameter of 3 mm were prepared by compression of granulates.
  • the mini-tablets were then coated with the coating solution described in table 2 using a fluid bed apparatus (Uni-Glatt) and with the coating parameters given in table 3. 20 % of coating (expressed as percentage of dry weight of coating to the weight of the uncoated tablet) were applied on the mini-tablets.
  • Example 2 illustrates the influence of the composition of the core, in the case of coated mini-tablets, on the drug release profiles and the floating lag time.
  • the pharmaceutical compositions of the cores and the formulation used for the coating are given in Table 4.
  • Suitable parameters were applied to granulate these formulations by melt granulation. Granulates were filled into the die of an instrumented single-punch tableting machine to produce mini tablets, using 3 mm concaved-face punches and dies. The weight and the hardness were kept constant and were 20mg and 7N, respectively.
  • the inlet temperature, the flow rate, the pneumatic spraying pressure and the total spraying time were controlled.
  • Example 3 illustrates the influence of the coating level, on the drug release profiles and the floating lag time in the case of coated mini-tablets.
  • the pharmaceutical compositions of the core and the formulation used for the coating are given in Table 6. TABLE 6
  • Suitable parameters were applied to granulate these formulations by melt granulation. Granulates were fed into the die of an instrumented single-punch tableting machine to produce mini-tablets, using 3 mm concaved-face punches and dies. The weight and the hardness were kept constant and were 20mg and 7N, respectively.
  • the inlet temperature, the flow rate, the pneumatic spraying pressure and the total spraying time were controlled.
  • the mini-tablets were tested for dissolution in a di-potassium hydrogen phosphate/acetic acid (0.05M each) buffer solution at pH 3.0 using USP 29 Apparatus II with paddle speed at 50rpm.
  • the dissolution results are given in Figure 5.
  • the results of dissolution are very interesting since it was shown that only mini-tablets with a coating level above 15% demonstrate a suitable prolonged (or extended) release profile.
  • the formulation containing 15% (w/w) or less of coating did exhibit a non linear release of drug characterized by a slow release during the first 4 to 6 hours, followed by a rapid release of the drug.
  • compositions of the invention are coated with at least more than 15% (w/w) of coating, preferably more (or equal) to 20% (w/w) of coating.
  • w/w the weight/weight of a coating
  • the carbon dioxide generated by gas generating agents in contact with water exerts a relatively high pressure on the coating. This pressure is then able to destroy or destructure the film-coating when the amount of coating is too low.
  • the percentage of film coating applied on the mini-tablets of the present invention are consequently a very important parameter in order to control the release of the drug over an extended period of time. This influence of the coating levels on the release of a drug from floating systems has not been described up to now .
  • Example 4 illustrates the influence of the formulations used for the coating, in the case of coated mini-tablets, on the drug release profiles and the floating lag time.
  • the pharmaceutical composition of the core and the formulations used for the coating are given in Table 8 .
  • Example 5 illustrates the fact that it is possible to obtain a sustained-release profile with several different drugs.
  • the pharmaceutical compositions are given in Table 10.
  • Lactose 450 mesh 41.0 [0174] Suitable parameters (described above) were applied to granulate these formulations by melt granulation. Granulates were fed into the die of an instrumented single-punch tableting machine to produce minitablets, using 4 mm concaved-face punches and dies. The weights were kept constant and were 40mg. [0175] The mini-tablets were tested for dissolution in a di-potassium hydrogen phosphate/acetic acid (0.05M each) buffer solution at pH 3.0 using USP 29 Apparatus II with paddle speed at 50rpm. The dissolution results are given in Figure 9. [0185] Lag time was determined visually for each formulation by using the horizontal shaking method described above. Results are shown in Table 11.
  • composition of the invention containing levodopa as active ingredient has been compared, in term of floatibility using the resultant-weight apparatus described above, to the commercial HBS dosage form
  • the HBS capsule system presented no lag time due to its very low initial density. Its maximal resultant-weight value ( ⁇ 45mg/100mg) was obtained after 10 min and remained constant for about 1 hour ( Figure 10) . During this time period, the increase in volume was greater than the increase in mass during swelling. However, afterwards, its floating strength decreased as a result of the development of its hydrodynamic equilibrium. The lag time of the floating minitablets was only 1 min. From 10 min to the end of the test, the resultant-weight values were higher than those obtained with the commercial HBS dosage form. In fact, the floating capabilities of the floating minitablets did not decrease until the end of the test because carbon dioxide was continuously produced and entrapped in the swelling polymer. It seems that the incorporation of gas-generating agents improve the floating properties, especially the duration of floating.

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Abstract

La présente invention concerne une composition pharmaceutique orale flottante à libération contrôlée comprenant : - des mini-comprimés comprenant au moins un médicament actif, un agent liant pouvant fondre et un agent gazogène, et - une couche de revêtement entourant lesdits mini-comprimés, ladite couche de revêtement comprenant un polymère insoluble dans l'eau et un plastifiant, ladite couche de revêtement représentant au moins 20 % du poids du mini-comprimé non revêtu.
PCT/BE2007/000028 2006-03-21 2007-03-20 Formes galéniques flottantes à libération contrôlée Ceased WO2007106960A1 (fr)

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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2489659T3 (pl) 2004-06-24 2018-06-29 Vertex Pharma Modulatory transporterów posiadających kasetę wiążącą atp
JP5409010B2 (ja) 2005-12-28 2014-02-05 バーテックス ファーマシューティカルズ インコーポレイテッド Ｎ−［２，４−ビス（１，１−ジメチルエチル）−５−ヒドロキシフェニル］−１，４−ジヒドロ−４−オキソキノリン−３−カルボキサミドの固体形態
ZA200903854B (en) * 2008-06-19 2011-02-23 Univ Of The Witwatesrand Johannesburg A gastroretentive pharmaceutical dosage form
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
US12458635B2 (en) 2008-08-13 2025-11-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US8476442B2 (en) 2009-03-20 2013-07-02 Vertex Pharmaceutical Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
CA2790164A1 (fr) * 2010-02-17 2011-08-25 Sun Pharma Advanced Research Company Ltd. Methode de traitement d'une affection sensible a une therapie par baclofene
WO2011154012A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Mini-comprimés comprenant un matériau adsorbant poreux
CA2865519C (fr) 2012-02-27 2018-01-02 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques renfermant une dispersion solide de n-[2,4-bis(1,1-dimethylethyl0-5-hydroxyphenyl-1]-1,4-dihydro-4-oxoquinolone-3-carboxamide destinees au traitement de la fibrose kystique
EP2890366A1 (fr) 2012-08-28 2015-07-08 DSM Sinochem Pharmaceuticals Netherlands B.V. Composition comprenant un antibiotique et un inhibiteur de la bêta-lactamase, au moins l'un d'entre eux se trouvant sous la forme de mini-comprimés
EP3148514B1 (fr) 2014-06-02 2024-04-17 Clexio Biosciences Ltd. Forme posologique à rétention gastrique expansible
CN104224744A (zh) * 2014-09-28 2014-12-24 严相顺 用于家蚕细菌病防治的环丙沙星泡腾片
KR20170063954A (ko) 2014-10-07 2017-06-08 버텍스 파마슈티칼스 인코포레이티드 낭성 섬유증 막횡단 전도도 조절자의 조정제의 공-결정
WO2018102799A1 (fr) 2016-12-02 2018-06-07 Clexio Biosciences Ltd. Système à résidence gastrique
EP3720537B1 (fr) 2017-12-04 2025-03-19 Clexio Biosciences Ltd. Système de résidence gastrique à action prolongée
WO2020230089A1 (fr) 2019-05-14 2020-11-19 Clexio Biosciences Ltd. Traitement de symptômes nocturnes et de l'akinésie matinale chez des sujets atteints de la maladie de parkinson
KR20220107014A (ko) * 2019-11-27 2022-08-01 디에스엠 아이피 어셋츠 비.브이. 리보플라빈을 포함하는 다중 단위 펠릿 시스템 정제
CN114760992A (zh) * 2019-11-27 2022-07-15 帝斯曼知识产权资产管理有限公司 包含核黄素的mups片剂
WO2022195476A1 (fr) 2021-03-15 2022-09-22 Clexio Biosciences Ltd. Dispositifs de rétention gastrique pour l'évaluation d'états intragastriques

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2775188B1 (fr) * 1998-02-23 2001-03-09 Lipha Forme galenique a liberation immediate ou liberation prolongee administrable par voie orale comprenant un agent promoteur d'absorption et utilisation de cet agent promoteur d'absorption
US6350470B1 (en) * 1998-04-29 2002-02-26 Cima Labs Inc. Effervescent drug delivery system for oral administration
GB0113842D0 (en) * 2001-06-07 2001-08-01 Boots Co Plc Therapeutic agents
CN1630513A (zh) * 2002-02-04 2005-06-22 兰贝克赛实验室有限公司 流体动力平衡的以两相释放的口服药物输递系统
GB0330255D0 (en) * 2003-12-31 2004-02-04 Vectura Ltd Multiparticulate formulations for oral delivery
WO2006040779A2 (fr) * 2004-10-11 2006-04-20 Natco Pharma Limited Formule à matrice flottante gastrique à libération contrôlée contenant la substance imatinib

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