WO2007106960A1

WO2007106960A1 - Controlled-release floating dosage forms

Info

Publication number: WO2007106960A1
Application number: PCT/BE2007/000028
Authority: WO
Inventors: Francis Vanderbist; Phillippe Baudier; Arthur Deboeck; Karim Amighi; Jonathan Goole
Original assignee: Laboratoires Smb S.A.
Priority date: 2006-03-21
Filing date: 2007-03-20
Publication date: 2007-09-27
Also published as: WO2007106957A1; WO2007106960A9

Abstract

An oral pharmaceutical controlled release floating composition comprising : - mini-tablets comprising at least one active drug, one fusible binder and one gas generating agent, and - a coating layer surrounding said mini-tablets, said coating layer comprising a water insoluble polymer and a plasticizer, said coating layer representing at least 20% of the weight of the uncoated mini-tablet.

Description

Controlled-release floating dosage forms

ABSTRACT

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.

It is further related to the unigue composition of 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. To provide optimal floating properties and prolonged release of the drug, a coating layer is added on the mini-tablets. Advantageously, the amount of dry coating is equal or superior to 20% (w/w) of the mini-tablets weight. Preferably, the coating comprises also a pharmaceutically acceptable plasticizer.

BACKGROUND OF THE INVENTION

[001] Among the different routes of drug administration, the oral route has achieved the most- attention, partly due to the ease of administration and the important flexibility in dosage-form design [reference 1] . Unfortunately, in most cases, the important variability of gastrointestinal tract's physiology and of its transit time leads to an unpredictable bioavailability and non reproducible therapeutic effects.

[002] An orally administrated drug delivery system is exposed to a wide range of highly variable conditions as pH, agitation, intensity and gastric emptying times. [003] 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] .

[004] 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.

[005] The development of 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]

[006] Several approaches have been pursued to increase the retention of an oral dosage form in stomach.

[007] For instance, expandable gastro retentive dosage forms which don't pass the pylorus sphincter because of there large sizes have been proposed. The final size is obtained by swelling or unfolding process in the gastric juice following ingestion [reference 7]

These types of drug delivery systems were specially made for veterinary applications but it' s possible to use them for humans. Furthermore, their preparation seems to be long and hard to make.

[008] In the same way, swelling tablets are made to swell in the stomach following ingestion, as a result of single gelling or coupled with carbon dioxide emission trapped into hydrocolloid agent [reference 7] . [009] The use of passage-delaying excipients incorporated into and released from the delivery system has been proposed to delay or slow down the gastric transit. This is based on the fact that fatty acids and/or anticholinergic agents can reduce the motility of the stomach [reference 8] . Their use is not harmless because the normal transit is affected.

[0010] 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] . [0011] 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] . [0012] Magnetic systems and superporous biodegradable hydrogel systems are also described [reference 9] .

[0013] The floating drug delivery systems (FDDS) offer the more effective and rational protection against early and random gastric emptying compared to the other means proposed to prolong the GRT of solid dosage forms. [0014] 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. [0015] Most of the floating systems reported in literature are single-unit systems, which are generally unreliable and non-reproducible in prolonging the GRT, owning to their unpredictable all-or-nothing emptying process. On the other hand, multiple-unit dosage forms appear to be better suited since they are claimed to reduce inter-subject variability in absorption and a lower dose-dumping probability [reference 10] .

[0016] 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] . [0017] ^" 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] .

[0018] Iannucelli et al. (1998) have described an air compartment multiple-unit system in which, each unit was formed by coated beads composed of a calcium alginate core separated by an air compartment from a calcium alginate/polyvinyl alcohol membrane [reference 13].

[0019] 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] .

[0020] 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] . [0021] 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] .

[0022] 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. 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] .

[0023] 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. 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] .

[0024] 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, while the second one contains a volatile liquid, such as cyclopentane that vaporizes at physiological temperature, enabling drug reservoir to float [references 20 and 21] . [0025] 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. [0026] As an example, 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, however, 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] .

[0027] 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.

[0028] Floating Drug Delivery systems (Shweta et al - 2005) [reference 32] have been reviewed, with discussions on approaches to design floating dosage forms. The authors have classified the Floating Drug Delivery Systems in the effervescent floating dosage forms and the non-effervescent floating dosage forms. It appears from said review that the floating and release of the form depend from many parameters. [0029] Accordingly, none of the oral controlled drug delivery systems described hereinbefore is completely satisfactory, for ensuring a controlled or sustained release of one or more active agents for 12 hours or more, advantageously for 16 hours or more, preferably for about 24 hours or more.

[0030] When a granulation step is used, wet granulation is probably the most popular way to obtain granules from hydrocolloids and bicarbonate sodium after drying to evaporate solvents.

[0031] 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. [0032] 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

(solubility) properties [reference 22 and 23] . [0033] One of the major limitations for the development of tabletted floating systems is probably the difficulty to modulate both the desired time period for buoyancy and the rate of drug release. Several authors have proposed the use of bilayer or multilayer tabletted systems in which, the buoyancy formulation layer is separated from the drug release formulation layer, and thus, a greater flexibility is possible in release profile adjustment. But the main difficulty is to avoid the separation of the different layers, when the composition is put in contact with gastrointestinal fluids. [0034] Tablets can be presented as a single-unit dosage form or multiple-unit dosage form. According to Hwang et al. (1998), 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. On the other hand, 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.

[0035] In vivo investigations show that the presence of food, rather than buoyancy and/or particulate size, is the most important factor affecting the GRT of floating forms. The GRT of buoyant units depends not only on the initial density but also, on the evolution of their density as function of time

[reference 9] .

[0036] 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. First, floating granules are fabricated by melt (thermoplastic) granulation in a high shear mixer. As the manufacture method is very simple and well reproducible, the buoyant properties as well as the release properties of the controlled release dosage forms of the invention did substantially not vary from one production batch to another production batch.

[0037] 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.

[0038] ■ 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.

BRIEF DESCRIPTION OF THE lϋJVENTION

[0038] 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: ^•

- one or more mini-tablets, advantageously at least two mini-tablets, said mini-tablet (s) having a maximum size comprised between lmm and 7mm_r 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. The compositions of the present invention, advantageously in the form of multiple units floating sustained-release systems, 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. [0039] 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.

[0040] Advantageously, the mini-tablet form comprises a core comprising at least one active drug, one fusible binder, one gas generating agent and a swelling agent. [0041] Preferably, 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.

[0042] According to an advantageous embodiment, the fusible binder has a melting point or a melting range lower than 95⁰C, preferably lower than 80⁰C, preferably between 30 ⁰C and 75⁰C, more preferably between 45 ⁰C and 55⁰C. 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. [0043] Advantageously, 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.

[0044] Preferably, the unit forms which are mini- tablets have a weight average length from 1.5mm to 5mm, advantageously between 2.5mm and 4mm. [0045] According to a preferred embodiment, the composition is a multiple unit form, advantageously a capsule comprising the mini tablets.

[0046] The composition comprises advantageously several mini tablets, for instance more than 3, preferably more than 5 and more preferably more than 8. [0048] According to advantageous embodiment, 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

(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. 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. [0049] 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.

[0050] The composition advantageously further comprises a second gas generating agent. [0051] The organic acid is advantageously tartaric acid, citric acid, ascorbic acid or a mix thereof.

[0052] 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. [0053] 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. [0054] The composition of the invention is advantageously formulated in a form suitable for a once-a-day or twice-a-day administration in humans. [0055] According to an embodiment, 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. For example 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. Advantageously, the first and second generating agents are selected so as to react therebetween in presence of an aqueous medium. When using unit forms with different composition, the active agent content is advantageously the same, so as to ensure a correct active agent content of the final composition, for example of the capsule. [0056] According to another possible embodiment, one or more mini-tablets comprise a first active agent, while one or more other mini-tablets comprise another active agent .

[0057] According to still another embodiment, 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. [0058] According to a further embodiment, the composition further comprises an immediate release form of the same active drug or of another active agent. [0059] According to a specific example, 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.

[0060] The composition advantageously further contains one or more classical pharmaceutical excipients like fillers, disintegrants, lubricants, pigments, anti-taching, and combinations thereof.

[0061] 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, one fusible binder and one gas generating agent, and are characterized by a coating layer surrounding one or more mini-tablets, said coating layer comprising a water insoluble polymer in adequate proportions, a plasticizer and optionnally a swelling agent. [0062] Advantageously, 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. According to preferred embodiments, 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. [0063] Preferably, the unit form of the invention further comprises one or more organic acids.

According to an advantageous embodiment, the fusible binder has a melting point or a melting range lower than 95⁰C, preferably lower than 80⁰C, preferably between 30 ⁰C and 75°C, more preferably between 45 ⁰C and 55°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.

[0064] Advantageously, 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.

[0065] Advantageously, 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/cm² , preferably less than 6 kg/cm² , most preferably less than 4 kg/cm². The hardness is advantageously greater than about 0.7kg/cm², and thus most preferably comprised between 0.7 kg/cm² and 3 kg/cm². 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.

[0066] According to an advantageous embodiment, 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.

[0067] According to another detail of an advantageous embodiment, the coating layer comprises at least one anti-foaming agent. [0068] According to a further detail of an advantageous embodiment, the coating layer comprises at least one detackifying agent.

[0069] According to an advantageous embodiment, 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.

[0070] 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.

[0071] Advantageously, the process for manufacturing composition of the invention or mini-tablets of the invention comprises at least

- the step of mixing and melt granulating the drug, the fusible binder and the gas generating agent together,

- to compress the granulates into mini tablets to coat the mini tablets with at least a water insoluble polymer, a plasticizer and advantageously an anti foaming agent.

[0072] 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. Alternatively, pellets can be produced after or during melt granulation. Said pellets can thereafter be compressed into mini-tablets.

[0073] 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. A swellable agent

(gel forming polymers) may optionally be added.

BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 shows the dissolution profile (n=5) of the mini- tablet containing 40 % and 53 % of ciprofloxacine in the core. 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. [0075] Figure 2 shows the influence of the mini- tablet diameter on the resultant-weight results and thus, on the floating properties (n=3) . The pharmaceutical composition of the granulates is given in Table 1 and 2 [0076] Figure 3 shows the influence of the pharmaceutical composition of the core, in the case of coated mini-tablets, on the drug release profiles (n=5) . The pharmaceutical compositions of the core and the formulation used in the coating are shown in Table

4.

[0077] Figure 4 shows the influence of the pharmaceutical composition of the core, in the case of coated mini-tablets, on the resultant weight profile

(n=l) . The pharmaceutical compositions of the core and the formulation used in the coating are shown in Table

4.

[0078] Figure 5 shows the influence of the coating level, in the case of coated mini-tablets, on the drug release profiles (n=5) . The pharmaceutical composition of the core and the formulation used in the coating are given in Table 6.

[0079] Figure 6 shows the influence of the coating level, in the case of coated mini-tablets, on the resultant weight profile (n=l) . The pharmaceutical composition of the core and the formulation used in the coating are given in Table 6.

[0080] Figure 7 shows the influence of the formulations used in the coating, in the case of coated mini-tablets, on the drug release profiles (n=5) . The pharmaceutical composition of the core and the formulations used in the, coating are shown in Table 8.

[0081] Figure 8 shows the influence of the formulations used in the coating, in the case of coated mini-tablets, on the resultant weight profile (n=l) .

The pharmaceutical composition of the core and the formulations used in the coating are shown in Table 8.

[0082] Figure 9 shows that is possible to obtain a sustained-release profile with several different drugs (n=5) . The pharmaceutical compositions are given in Table 10 (uncoated mini-tablets) . [0083] Figure 10 shows the resultant-weight profiles obtained with 3 mm floating mini-tablets and HBS dosage form (n=l)

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0084] 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. [0085] The present invention provides preferably coated floating controlled-release (CR) mini-tablets that can be filled into capsules.

[0086] 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. [0087] 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 ) .

[0088] Furthermore, 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.

[0089] The swellable agents and the coating can also preserve the cohesion of the system.

[0090] 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.

[0091] Advantageously, 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. mono-, di-, and tri-glycerides, in particular, 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.

[0092] Advantageously, 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 95⁰C, preferably lower than 8O⁰C, preferably between 30 ⁰C and 75°C, more preferably between 45 ⁰C and 55⁰C.

[0093] Advantageously, 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.

[0094] Although application of the present invention has not to be limited to any medicament or class of medicaments. 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. [0095] 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.

[0096] Advantageously, 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.

[0097] Advantageously, 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. [0098] These are 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 ascorbic acid, folic acid, riboflavin, cyanocobalmin, prednisolone, diazepam, levodopa, methyldopa, carbidopa, isosorbide, quinidine, sotalol, theophylline, salbutamol, alendronate, glipizide, metformine, prazosin, ketanserin, selegiline, midalozam, mriseofulvine, terfenadine aspirin, Ibuprofene, Diclofenac, Indomethacine and Ketoprofene. Advantageously, the drug itself or its pharmacologically active salt, ester or pro-drug can be used in the present invention. Moreover, combination of two or more active drugs or doses combinations may be included as the drug component. In this case, 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. Similarly, 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.

[0099] 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.

[0100] 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) .

[0101] 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.

[0102] 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 (30⁰C to 9O⁰C), 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. [0103] Granulates can be incorporated in a one, two or multiple layered mini-tablets.

[0104] 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 hyproraellose capsules with or without disintegrating agent (for example: Ac-Di- Sol®, croscarmellose sodium NF, FMC Corporation, PhiladeIphie) . When it's necessary, 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 . [0105] 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. Examples of those forms are mini tablets contained in a capsule, 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) , ...

[0106] It's supposed that the Gastric Residence Time of the compositions of the invention depends on presence of food like all floating forms. In fed condition, the gastric mixing is increased and the peristaltic movements are decreased. These physiological processes allow the floating of dosage form. [0107] 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.

[0108] These dosage forms have sufficient mechanical stability and hardness so that they will withstand the normal stress of production, packaging and dispensing. [0109] The optimum concentration of therapeutic agent depends of its physical properties, chemical properties and its optimum therapeutic dosage. [0110] 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. [0111] The fusible binder of the invention may be any lipophilic, hydrophilic or amphiphilic agent having a melting range between 30⁰C and 8O⁰C, preferably between 45⁰C and 65⁰C 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.

[0114] 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 μm, preferably inferior to 200 μm) 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.

[0115] 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.

[0116] 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. Thus, 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] . [0117] 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. To retain the gas generated in 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.

[0118] As used herein, the term "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.

[0119] As used herein, the term "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.

[0120] As used herein, the term "detackifying agent" refers to a compound whose presence in the coating composition reduces the stickiness or adhesion of the coated dosage form. [0121] Depending on the pharmaceutical form and the floating and dissolution properties required, 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) .

[0122] 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. Preferably, the anti-agglomerating agent comprises about 5% to 50% by weight of the dry coating composition. [0123] 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. Preferably, the amount plasticizer is between 0% to about 20% by weight of the dry coating composition.

[0124] Additives commonly used in coating dispersion are pigments, water-soluble materials, less water- soluble materials, no water-soluble materials, pore- forming agents. Their amount in the coating composition, if any, depends on the physicochemical properties required. [0125] 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. However, the addition of sugars in the compositions of the present invention are not mandatory.

[0126] Hydrophilic, lipophilic or inert, pH-dependent or -independent coating agents can be used. [0127] There may also be incorporated into these sustained-release formulations additional edible nontoxic ingredients recognized in pharmaceutical compounding such as excipients, preservatives, stabilisers and tabletting lubrifiants or lubricants. [0128] The choice, the amount and/or the composition of each agents described above depend on the pharmaceutical dosage form properties wanted by the formulator .

[0129] A swellable agent and a coating can possibly be used together to retain the generated gas inside the dosage form.

[0130] The procedure of making unit dosage form or mini-tablets of the invention includes preferably at least three steps. [0131] 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. During the process, 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". A jump of the torque, because of the melting of the lipidic binder, indicates the formation of the granules. Than, IS is generally decreased and CS is generally increased. From this moment, the massing time (MT) begins. The size of granulates increases by increasing the massing time. In order to reduce the total duration of the process, to obtain granules having acceptable diameters and to avoid sticking, 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.

[0132] After granulation, 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. Preferably, a specific granulates fraction is selected, for example by sieving for the preparation of the mini-tablets. [0133] 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.

[0134] All excipients generally used for compression process can be employed. [0135] The third step is the coating of the mini- tablets with a coating composition comprising a water insoluble polymer, and advantageously a plasticizer. [0136] For the coating, 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. [0137] The mini-tablets (for example 80Og) were transferred into a fluidized bed coating apparatus

(Uni-Glatt, Glatt GmbH, Germany) equipped with a bottom-spray coating process in a Wϋrster column.

During the coating operations, 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+2⁰C and 32+2⁰C, 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. [0138] Up to 1990, bulk density and floating duration have been the main parameters used to describe the adequacy of the dosage forms buoyancy (= floating properties) . However, Those parameters don't reflect the magnitude of the floating forces produced by the dosage form [25] . In 1990, J. Timmermans has proposed the resultant-weight measurement concept and an in vitro measuring apparatus was conceived.

[0139] The total force acting on an immersed object, F, can be given by this equation :

F = Fjjuoy " Fgrav

Fhuoy is the buoyant force and F_grav is the gravity force exerted on the object [26]

[0140] Conventionally, 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.

[0141] 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]

[0142] 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] . [0143] With this method, it' s possible to evaluate the lag time (time period between placing the pharmaceutical composition in the medium and its floating)^', the maximal ^' system magnitude and the floating duration.

[0144] 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) .

[0145] 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. [0146] The medium used for this test is a HCl 0.1N solution containing 0.05% (w/v) of Polysorbate 20 (pH 1.2, 37⁰C) .

[0147] Drug release can be evaluated by usual measurement processes as a dissolution testing by UV spectrophotometry or HPLC analysis. In this case, 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 percentages of drug release were measured at fixed time intervals and averaged (n=5) . [0148] The present invention is illustrated by, but is by no means limited to, the following examples.

[0149] The examples described below were realized by using levodopa, ciprofloxacin and riboflavin as models of drugs which are absorbed in the upper part of small intestine.

[0150] 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] . [0151] 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.

EXAMPLES OF PREFERRED EMBODIMENTS

Example 1

[0152] 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.

table 1 uncoated tablet

The tablet were then coated with the coating solution given in Table 2.

table 2 : coating solution Eudragit RL30D : 666 g (= 200 g of dry material) Lactose : 2O g

ATEC(AcetyI triethyl citrate) : 40 g

Talc : 50 g

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 βOOrpm and the CS is increased at 2000rpm. Massing time was fixed to 5 minutes.

[0154] Mini-tablets having a diameter of 3 mm were prepared by compression of granulates.

[0155] 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.

Table 3 : coating parameters used for the mini-tablets

parameter pre coating drying heating

T° of air at the inlet 40 ⁰C 40 ⁰C 40 ⁰C

T° of air at the outlet 35 ⁰C 32 ⁰C 35 ⁰C flow > 5 g/min > 5 g/min > 5 g/min

Pressure 1 bar 1 bar 1 bar

Duration 5 min +/- 3.5 h 10 min. [0156] The mini-tablets coated were then 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 75rpm. The dissolution results are given in Figure 1. [0157] Resultant-weights were recorded as a function of time by using the apparatus described above. Results are shown in Figure 2.

Example 2

[0158] 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.

TABLE 4

Core Formulation 1 % w/w Levodopa 37.5

Glyceryl palmito-stearate (Precirol®) 12.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid 3.0 Lactose 450mesh 33.5 Core Formulation 2

Levodopa 37.5

Glyceryl palmito-stearate (Precirol®) 12.0

Calcium carbonate 5.0

Sodium bicarbonate 4.0

Tartaric acid 3.0

Lactose 450mesh 38.5

Core Formulation 3

Levodopa 37.5

Glyceryl palmito-stearate (Precirol®) 12.0

Calcium carbonate 1.7

Sodium bicarbonate 1.36

Tartaric acid 1.02

Lactose 450mesh 46.42

Coating Formulation

EUDRAGIT RL 3OD (dry basis) 20Og

Citroflex 2 40g

Talc 5Og

Antifoam 2g

Water 842g

Coating level (%) 20

[0159] Suitable parameters (described above) 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.

[0160] To perform the coating, the inlet temperature, the flow rate, the pneumatic spraying pressure and the total spraying time were controlled.

[0161] 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 3.

[0162] Lag time was determined visually for each formulation by using the horizontal shaking method described above. Results are given in Table 5. Resultant-weights were recorded as a function of time by using the apparatus described above. Results are shown in Figure 4.

TABLE 5

Example 3

[0163] 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

Formulation of the core % w/w

Levodopa 37.5

Glyceryl palmito-stearate (Precirol®) 12.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid 3.0

Lactose 450mesh 33.5

Formulation used for the coating

EUDRAGIT RL30D (dry basis) 20Og

Citroflex 2 4Og

Talc 5Og

Antifoam 2g

Water 842g

Coating level (%) 0 - 11 - 15 - 20

[0164] 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 mini-tablets, using 3 mm concaved-face punches and dies. The weight and the hardness were kept constant and were 20mg and 7N, respectively.

[0165] To perform the coating, the inlet temperature, the flow rate, the pneumatic spraying pressure and the total spraying time were controlled. [0166] 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. Advantageously, the 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. While we don't want to be bound by any theory, it is an hypothesis that 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.

[0167] Lag time was determined visually for each coating level by using the horizontal shaking method described above. Results are given in Table 7. Resultant-weights were recorded as a function of time by using the apparatus described above. Results are shown in Figure 6. TABLE 7

Coating level ( % ) 0 11 15 20

Lag time (min) Early breaking 7 5 10

Example

[0168] 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 .

TABLE 8

Formulation of the core % w/w

Levodopa 37.5

Glyceryl palmito-stearate (Precirol®) 12.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid 3.0

Lactose 450mesh 33.5

Formulations used for the coating

Coating 1 Coating 2 Coating 3

Acrylic polymer (dry basis) 20Og 20Og 20Og

Methocel® E5 Og 2Og 40g

Citroflex 2 40g 40g 4Og

Talc 5Og 50g 50g

Antifoam 2g 2g 2g

Water 842g 822g 802g

Coating level (%) 20 20 20 [0169] Suitable parameters (described above) were applied to granulate this formulation 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 harness were kept constant and were 20mg and 7N, respectively.

[0170] To perform the coatings, the inlet temperature, the flow rate, the pneumatic spraying pressure and the total spraying time were controlled. [0171] 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 7. [0172] Lag time was determined visually for each formulation used for the coating by using the horizontal shaking method described above. Results are shown in Table 9.

Resultant-weights were recorded as a function of time by using the apparatus described above. Results are shown in Figure 8.

TABLE 9

Example 5

[0173] 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.

TABLE 10

Formulation 1 % (w/w)

Levodopa 37.5

Glyceryl palmito-stearate (Precirol^®) 12.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid 3.0

Hydroxypropyl methylcellulose (Methocel® K15M) 25.0

Lactose 450 mesh 8.5

Formulation 2 % (w/w)

Ciprofloxacin 31.25

Glyceryl palmito-stearate (Precirol^®) 18.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid 3.0

Hydroxypropyl methylcellulose (Methocel® K15M) 25.0

Lactose 450 mesh 8.75

Formulation 3 % (w/w)

Riboflavin 5.0

Glyceryl palmito-stearate (Precirol^®) 12.0

Calcium carbonate 10.0

Sodium bicarbonate 4.0

Tartaric acid. 3.0

Hydroxypropyl methylcellulose (Methocel® K15M) 25.0

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 40πιg. [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.

TABLE 11

Example 6

[176] The composition of the invention containing levodopa as active ingredient (composition of example 4 - coating 1) has been compared, in term of floatibility using the resultant-weight apparatus described above, to the commercial HBS dosage form (PROLOPA HBS^®, Roche) .

[177] The HBS capsule system presented no lag time due to its very low initial density. Its maximal resultant-weight value (~45πιg/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.

List of References

[1] K.Soppimath et al., Microspheres as floating drug-^" delivery systems to increase gastric retention of drugs, Drug Metabolism Review, 33 (2) (2001) , 149-160

[2] M. Franz, M. Oth, Sustained release bilayer buoyant dosage form, US Patent 5, 232, 704, August 3, 1993

[3] S.Desai, S.Bolton, Floating sustained release therapeutic compositions, US Patent 4, 814, 179, March 21, 1989

[4] Hoffmann La Roche, Sustained-Release formulations, CA Patent 1, 073, 358, GB Patent, 1, 546, 448, May 23, 1979

[5] A.Dhamne, M.Avachat, Gastric Floating system, WO Patent 02, 102, 415, December 27, 2002

[6] P.Seth, J.Tossounian, Novel sustained release tablet formulations, US Patent 4, 167, 558, September 11, 1979

[7] E.Klausner et al., Expandable gastroretentive dosage forms, J. Controlled Release 90 (2003) 143-162

[8] A.J.Moes, Gastroretentive Dogase Forms, Critical Reviews™ in Therapeutic Drug Carrier Systems, 10(2) (1993), 143-195 [9] S-J Hwang et al., Gastric Retentive Drug-Delivery Systems, Critical Reviews™ in Therapeutic Drug Carrier Systems, 15(3) (1998), 243-284

[10] B.Singh et al., Floating drug delivery systems : an approach to oral controlled drug delivery via gastric retention, J. Controlled Release 63 (2000) 235- 259

[11] P.R.Seth et al., Sustained release pharmaceutical capsules, US Patent 4, 126, 672, November 21, 1978.

[12] R.M.Harrigan, Drug delivery device for preventing contact of undissolved drug with the stomach lining, US Patent 4, 055, 178, October 25, 1977

[13] V. Iannuccelli et al . , Air compartment multiple- unit system for prolonged gastric residence. Part I. Formulation study, Int. J. Pharm. 174 (1998) 47-54

[14] Y.Kawashima et al . , Hollow microspheres for use as a floating controlled drug delivery system in the stomach, J.Pharm.Sci. 81 (1992), 135-140

[15] B.C. Thanoo et al., Oral sustained-release drug delivery systems using polycarbonate microspheres capable of floating on the gastric fluid, J. Pharm. Pharmacol. 45 (1993), 21-24

[16] H.Yuasa et al., Studies on the development of intragastric floating and sustained release preparation. I. Application of calcium silicate as a floating carrier, Chem. Pharm. Bull. 44 (1996) ^' 1361- 1366

[17] M.Ichikawa et al., A new multiple-unit oral floating dosage systems. I: Preparation and in vitro evaluation of floating and sustained-release characteristics, J.Pharm.Sci 80 (1991) 1062-1066

[18] L.Whitehead et al., Development of gastroretentive dosage form, Eur. J. Pharm. 4 (suppl.) (1996) S182

[19] F.Atyabi et al . , Controlled drug release from coated floating ion exchange resin beads, J. Controlled Release 42 (1996) 25-28

-[20] A.S.Michaels et al . , Integrated device for administering beneficial drug at programmed rate, US Patent 3, 901, 232, August 26, 1975

[21] A.S.Michaels et al . , Drug delivery device with self actuated mechanism for retaining device in selected area, US Patent 3, 786, 813, January 22, 1974.

[22] J.Hamdani et al., Development and evaluation of prolonged release pellets obtained by the melt pelletization process, Int. J. Pharm. 245 (2002), 167- 177

[23] J.Hamdani et al., Physical and thermal characterisation of Precirol® and Compritol® as lipophilic glycerides used for the preparation of controlled-release matrix pellets, Int. J. Pharm. 260 (2003) 47-57

[24] N. Rouge et al., Prevention of the sticking tendency of floating minitablets filled into hard gelatin capsules, Eur. J. Pharm. Biopharrα. 43 (1997) , 165-171

[25] J.Timmermans et al., How well do floating dosage forms float?, Inter. J. Pharm., 62 (1990), 207-216

[26] J.Timmermans et al., Measuring the Resultant- Weight of an Immersed Test Material, Acta Pharm. Technol. 36 (1990), 171-175

[27] Levy G. and Hewitt R. R., Evidence in man for different specialized intestinal transport mechanisms for riboflavin and thiamine, Am. Clin. Nutr. 24, 401- 404, 1971 [28] B.Shastry, Parkinson disease : etiology, pathogenesis and future of gene therapy, Neuroscience Research 41 (2001), 5-12

[29] J.Louie-Helm et al., Pharmacokinetics of Ciprofloxacin gastric retentive (GR™) tablets in healthy volunteers, Proceed. Int'l. Symp. Control. ReI. Bioact. Mater. , 28 (2001)

[30] Talwar et al., Orally administered controlled drug delivery system providing temporal and spacial control, US Patent 6,261,601, July 17, 2001 [31] US6,514,524 - Saslawski et al - Orally administerable immediate release and prolonged release galenic form comprising an absorption-promoting agent and use of this absorption-promoting agent.

[32] Shweta et al - AAPS PharmSciTech 2005; 6 (3) Article 47 - Floating Drug Delivery Systems: A Review

Claims

WHAT WE CLAIM IS ;

1. An oral pharmaceutical controlled release floating composition or floating dosage form comprising : - one or more mini-tablets, advantageously at least two mini-tablets, said mini-tablet (s) having a maximum size comprised between lmm and 7mm, 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 .

2. The composition of claim 1, in which the mini-tablet form comprises a core comprising at least one active drug, one fusible binder, one gas generating agent and a swelling agent.

3. The composition of claim 1 further comprising an organic acid, advantageously in one or more mini tablets.

4. The composition of claim 1 wherein the fusible binder has a melting point or a melting range lower than 95⁰C, preferably lower than 8O⁰C, preferably between

30 ⁰C and 75°C, more preferably between 45 ⁰C and

55°C.

5. The composition of claim 1 wherein the fusible binder^' has a HLB value lower than 7.

6. The composition of claim 1 wherein the weight ratio between the fusible binder and the gas generating agent, advantageously in the mini-tablet, is about 0.1 to 10, preferably from 0.2 to 5, most preferably from 0.5 to 2.

7. The composition of claim 1, in which the mini- tablets have a weight average size from 1.5mm and 5mm, advantageously between 2.5 and 4.5mm, preferably between 2.8 and 3.5mm.

8. The composition of claim 1, in which for the coating layer, the dry weight ratio plasticizer/water insoluble polymer is greater ^■ than 1:10, advantageously greater than 1.5:10, preferably comprised between 1.5:10 and 5:10.

9. The composition of claim 1, in which the coating layer comprises at least one anti foaming agent.

10. The composition of claim 1, in which 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 .

11. The composition of claim 1 wherein the multiple unit form is a capsule comprising the mini-tablets.

12. The composition of claim 11, which comprises several, mini tablets.

13. The composition of claim 1 wherein 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 (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, derivatives thereof and mixtures thereof.

14. The composition of claim 1 wherein the gas generating agent is 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.

15. The composition of claim 1 further comprising a second gas generating agent.

16. The composition of claim 3, wherein the organic acid is selected from the group consisting of tartaric acid, citric acid, ascorbic acid and combinations thereof.

17. The composition of claim 1, wherein the water insoluble coating polymer is selected from the group consisting of water insoluble acrylic polymers, water insoluble cellulosic polymers, waxes and combinations thereof.

18. The composition of claim 1, wherein the swelling agent is selected from the group consisting of gum arable, Carrageenan, Guar gum, Gum tragacanth, Agar, Sodium Carboxymethyl cellulose, Hydroxyethyl cellulose, Hydroxypropylmethyl cellulose, Sodium alginate, Chitosan, Xanthan gum, Sodium croscarmellose, pectin and combinations thereof.

19. The composition of claim 1 suitable for a once-a- day or twice-a-day administration in humans.

20. The composition of claim 1, wherein several unit forms are filled into a pharmaceutically acceptable capsule, preferably a hard gelatine capsule or hypromellose capsule.

21. The composition of claim 1 further comprising an immediate release form of the same active drug or of another active agent.

22. The composition of claim 1 comprising a combination of two or more active drugs with similar or different release rates of each drug

23. The composition of claim 20, wherein one drug presents .a first controlled release profile, while the other drug presents a release profile different from the first controlled release profile, advantageously an immediate release profile.

24. The composition of claim 1 further containing one or more classical pharmaceutical excipients like fillers, disintegrants, lubricants, pigments, anti- taching.

25. The composition of claim 1, which comprises less than 5% by weight of carbonate and bicarbonate in the uncoated mini-tablet (s) .

26. A mini-tablet suitable for the preparation of a composition according to any one of the preceding claims, whereby said mini-tablet comprises at least one active agent, one fusible binder and one gas generating agent, whereby the mini-tablet is surrounded with at least a coating layer comprising a water insoluble polymer and a plasticizer.

27. The mini-tablet of claim 25, said mini-tablet having one or more characteristics as disclosed in any one of the claims 2 to 24.

28. A process for manufacturing composition of any one of the claims 1 to 24 or a mini tablet of claim 25 or 26, said process comprising at least a) the step of mixing and melt granulating the drug, the fusible binder and the gas generating agent together and b) to compress the granulates into mini tablets c) to coat the mini tablets or tablets with at least a coating composition comprising a water insoluble polymer and a plasticizer.