WO2004075817A2 - Suspendable pharmaceutical composition - Google Patents

Suspendable pharmaceutical composition Download PDF

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Publication number
WO2004075817A2
WO2004075817A2 PCT/EP2004/001852 EP2004001852W WO2004075817A2 WO 2004075817 A2 WO2004075817 A2 WO 2004075817A2 EP 2004001852 W EP2004001852 W EP 2004001852W WO 2004075817 A2 WO2004075817 A2 WO 2004075817A2
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WO
WIPO (PCT)
Prior art keywords
tablet
tablet according
water
suitable amount
comprised
Prior art date
Application number
PCT/EP2004/001852
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French (fr)
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WO2004075817A3 (en
Inventor
Jacqueline Plaizier-Vercammen
Margriet Gabriels
Original Assignee
Vrije Universiteit Brussel
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Publication of WO2004075817A2 publication Critical patent/WO2004075817A2/en
Publication of WO2004075817A3 publication Critical patent/WO2004075817A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of the pharmacology and clinical biology.
  • the present invention relates to a tablet for pharmaceutical use, suitable for being suspended in water.
  • the invention also relates to the use of such tablet in the treatment of malaria.
  • oral dosage form is generally the preferred route of administration of many pharmaceutical agents because it provides for easy, low-cost administration, compared to parenteral dosage forms.
  • Oral dosage forms may comprise tablets.
  • Liquid dosage forms are therefore a good alternative administration form for pharmaceuticals.
  • a suspension is the preferred liquid dosage form to prepare.
  • low dose suspensions containing less than 20 mg/ml active compound, are difficult to prepare, as they need higher requirements for physical stability.
  • suspensions have the disadvantageous characteristic that rests of active compound may remain on a beaker or glass, wherein the suspension is made, so that the pharmaceutical is not completely taken in by the patient.
  • uncomplete uptake of the medication may have disadvantageous effects.
  • a suspension is mostly prepared or will be reconstituted at the start of and for the whole period of treatment.
  • One embodiment of the present invention is a tablet for pharmaceutical use, suitable for forming a stable suspension in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents, wherein the addition of a predetermined amount of liquid thereto provides a suspension having a Brookfield yield value greater than or equal to 90 Pa.
  • Another embodiment of the present invention is a tablet as described above, wherein said therapeutically active compound consists of artemisinin or derivatives thereof selected from the group consisting of artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
  • Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 20 % w/w.
  • Another embodiment of the present invention is a tablet as described above wherein the quantities of therapeutically active compound, disintegrating agent and suspending agent are such that the tablet disintegrates within 40 seconds after the addition of water.
  • Another embodiment of the present invention is a tablet as described above, wherein said disintegrating agent is selected from the group consisting of natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross- linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof.
  • said disintegrating agent is selected from the group consisting of natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross- linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof.
  • Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said disintegrating agent is comprised between 30 and 90 % w/w.
  • Another embodiment of the present invention is a tablet as described above, wherein the ratio of the therapeutically active compound to said one or more disintegrating agents is comprised between 1 :2 and 1 :20.
  • Another embodiment of the present invention is a tablet as described above, wherein said suspending agent is selected form the group consisting of xanthane gums and clays, Veegum®, Bentonite, Laponite®.
  • Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said suspending agent is comprised between 5 and 40 % w/w.
  • Another embodiment of the present invention is a tablet as described above, wherein the ratio of the therapeutically active compound to said one or more suspending agents is comprised between 1 :400 and 1 :4.
  • Another embodiment of the present invention is a tablet as described above, wherein the ratio of said one or more suspending agents to said one or more disintegrating agents is comprised between 1 : 18 and 4:3.
  • Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of water-insoluble excipients selected from the group comprising water insoluble fillers/binders, organic fillers, water insoluble lubricants or any combinations thereof.
  • Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of water-soluble excipients including compression sugars, flavouring agents, sweeteners, pH adjusting agents, binders and soluble inorganic salts or combinations thereof.
  • Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of one or more glidants.
  • Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said glidants is comprised between 0.1 and 5 % w/w.
  • Another embodiment of the present invention is a tablet as described above, having a hardness higher than 20 N.
  • Another embodiment of the present invention is a tablet as described above, having a mean weight variance that is lower than 10%.
  • Another embodiment of the present invention is a tablet as described above, having a friability that is lower than 1 %.
  • Another embodiment of the present invention is a tablet as described above, suitable for being suspended in water such that the disintegration time of said tablet in water is below 60 seconds.
  • Another embodiment of the present invention is a tablet as described above, suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour which is higher than 0.4.
  • Another embodiment of the present invention is a tablet as described above, whereby said tablet is obtainable by compressing a mixture of its components using a compression force comprised between 500 and 1000N.
  • Another embodiment of the present invention is a tablet as described above, wherein the dose of the therapeutically active compound in said tablet is suitable for a single administration.
  • Another embodiment of the present invention is a tablet as described above, wherein said tablet is breakable in portions such that each tablet portion contains a dose of the therapeutically active compound which corresponds to a certain body weight of a patient.
  • Another embodiment of the present invention is a tablet as described above, wherein said tablet is in the form of a chewing tablet.
  • the present invention relates to a pharmaceutical dosage form, comprising the characteristics of a quick disintegrating tablet and a powder for the preparation of a ready- to-use suspension.
  • the invention relates to a tablet for pharmaceutical use, suitable for being suspended in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents.
  • a tablet By combined use of one or more disintegrating agents and one or more suspending agents a tablet is obtained which shows many advantageous characteristics.
  • a tablet according to the invention quickly and fully disintegrates into a powder when brought into contact with water. Furthermore, this powder very rapidly disperses in order to form a suspension.
  • this combined use of disintegrating agents and suspending agents enables to obtain a tablet having quick disintegration, but having slow precipitation or sedimentation of the suspension, properties which are essentially contradictory.
  • a tablet according to the invention when dissolving a tablet according to the invention in water, a suspension is obtained, which is physically stable over a long period after reconstitution up to the moment of intake. Because of this improved stability, a tablet according to the invention provides a suspension that is particularly suitable for use under extreme, e.g. tropical, conditions.
  • a tablet according to the invention is particularly suitable for preparing suspensions having low doses because the suspension does not sediment.
  • the therapeutically active compound consists of artemisinin or derivatives thereof selected from the group comprising artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
  • a tablet according to the present invention is particularly suitable for use in the treatment of various diseases.
  • Those skilled in the art will immediate recognize the many advantages and the numerous possibilities for end uses of the present tablet formulation from the detailed description and examples provided below. Detailed description of the figures
  • Figures 1 to 5 represent contour plots obtained following a Doehlert design in order to determine the optimum concentration of a suspending agents and compression force required for preparing a tablet according to the present invention.
  • Fig. 1 represents the contour plot with respect to the hardness parameter.
  • Fig. 2 represents the contour plot with respect to the friability parameter.
  • Fig. 3 represents the contour plot with respect to the sedimentation parameter.
  • Fig. 4 represents the contour plot with respect to the disintegration time parameter.
  • Fig. 5 represents the contour plot with respect to mean weight parameter.
  • the invention aims to provide a solid dosage form, from which a liquid dosage form that is easy and suitable to administer, can be prepared.
  • the invention provides a tablet, which disintegrates very quickly and which subsequently rapidly forms a suspension. These properties are particularly required when "small dose" compositions are to be prepared.
  • such tablet is suitable to provide a "small dose” suspension in a small amount of water, e.g. 5 ml in a spoon.
  • the suspension will assure the total intake of the small dose of active compound.
  • a powder mixture having the characteristics of fast disintegration and fast development of a suspension was created. This powder mixture can be compressed into a tablet form as will be explained below.
  • Tablets are made from powdered materials that are mixed together and compressed.
  • Various excipients i.e. inactive ingredients, are required for facilitating the manufacturing process: to hold a tablet together; to keep active ingredients from reacting together; to promote disintegration of the tablet in a recipient; to make tablets easier to swallow; to maintain reasonable taste, odor, color and appearance.
  • the present invention provides a tablet that is able to rapidly disintegrate, and to rapidly form a suspension, having a considerably improved physical stability.
  • the invention relates to a tablet wherein said therapeutically active compound consists of artemisinin or derivatives thereof selected from the group comprising artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
  • artemisinin derivatives as used herein comprises ester-like compounds such as artesunate, ether-like compounds such as arteether and artemether, and artelinic acid, and the reduced lacton derivative of artemisinin, dihydroartemisinin
  • DHA artechol
  • DHA is the active schizonticidal metabolite of artemisinin and the mentioned derivatives.
  • artemisinin and its derivatives can be regarded as pro-drugs for DHA.
  • the term “artemisinin derivatives” also refers to alpha or beta epimers of the mentioned derivatives.
  • alpha and beta epimer distinguishes two compounds, from which the spatial orientation of the different groups provided on only one carbon atom C10 differs.
  • the term “artemisinin derivatives” also refers to salts of the above-mentioned compounds.
  • the invention provides a tablet wherein the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 20 % w/w. In a more preferred embodiment, the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 10% w/w, and even more preferred between 0.2 and 8% w/w.
  • disintegrating agents are defined herein as compounds that allow the tablet to disintegrate quickly and uniformly in contact with water.
  • a tablet according to the invention comprises a suitable amount of at least one disintegrating agent.
  • said agent causes the tablet to disintegrate within 40 seconds as can be determined from the method described in the European Pharmacopea.
  • a tablet according to the invention comprises a suitable amount of at least one disintegrating agent selected from the group comprising natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross- linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof.
  • modified starches or “modified celluloses” as used herein refers to starches or celluloses, respectively, that have undergone certain biological, chemical, or physical treatment which changes their viscosity and/or chemical characteristics.
  • disintegrating agent tends to weaken a tablet's structure leading to poor friability values.
  • "Friability” is an index, which provides a measure of the ability of a tablet to withstand both shock and abrasion without crumbling during handling of manufacturing, packaging, shipping, and consumer use.
  • an optimal concentration of disintegrating agents can be provided which enables rapid disintegration of the tablet, without leading to poor friability.
  • the invention provides a tablet wherein the suitable amount of said disintegrating agents is comprised between 30 and 90% w/w. In a more preferred embodiment, the suitable amount of disintegrating agents is comprised between 40 and 85% w/w, even more preferred between 50 and 80% w/w.
  • said disintegrating agents consist of Explotab® and Compressil®.
  • said agents are used in a ratio of Explotab® to Compressil® comprised between 1:1 and 1:3, and even more preferred in a ratio comprised between 1 :1.5 and 1 :2.5.
  • Explotab®, a starch derivative and Compressil®, comprising magnesium silicate as active compound can be purchased at Mendell Group, and Usine Chimique d'lvry-la-Bataille, respectively.
  • a tablet wherein the ratio of the therapeutically active compound to said one or more disintegrating agents is comprised between 1 :2 and 1 :20. In a preferred embodiment, said ratio is comprised between 1:4 and 1:15, and more preferred between 1 :5 and 1:12.5.
  • suitable suspending agents are any that exhibits thioxtropic properties.
  • suitable suspending agents are any which, when added to a liquid, raise its viscosity with plastic behaviour.
  • the viscosity of the suspension of a tablet is such that its' Brookfield yield value (stress) is greater than or equal to 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 or 200 Pa, and preferably greater than or equal to 90 Pa.
  • the Brookfield yield value may be measured using a Brookfield RVT viscometer which measures the torque necessary to rotate a spindle through a liquid sample at speeds of 0.5 to 100rpm.
  • the Brookfield yield value is an extrapolation of measured values to a shear rate of zero.
  • the invention is not limited to the measurement of viscosity using a Brookfield RVT viscometer - other known and equivalent tests may be applied to the suspension, and a suitable conversion applied to the results thereof to obtain the
  • the Brookfield yield value applies to the suspension resulting from the total components of a tablet according to the invention, which includes the therapeutically active compound, disintegrating agent and suspending agent.
  • the quantity of suspending agent in a suspension used for determining the Brookfield yield is greater than or equal to 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.9, 0.95, 1% w/w.
  • the quantity of suspending agent in a suspension used for determining the Brookfield yield is in the range 0.01 to 1 , 0.02 to 0.8, 0.05 to 0.8, 0.05 to 0.6, 0.05 to 0.5, 0.05 to 0.4, 0.05 to 0.3, 0.05 to 0.2, or 0.05 to 0.1% w/w.
  • a mass of liquid in which a tablet is suspended to provide a Brookfield yield value may be equal to or less than 500 g, 400 g, 300 g, 200 g, 100g, 50 g, 20 g, 10 g, 6 g, 5 g, 4 g, 3 g, 2 g, 1 g, between 1 and 20 g, between 1 and 10 g, between 1 and 100 g, 1 and 200 g, 1 and 300 g, 1 and 400 g, 1 and 500 g, 10 and 300 g, 10 and 400 g, 50 and 400 g, 100 and 300 g.
  • suitable suspending agents are any selected form the group comprising xanthane gums and clays, Veegum®, Bentonite and Laponite®.
  • said suspending agent is Veegum®.
  • Veegum® comprising aluminium and magnesium silicate as active compound, can be purchased at Alpha Pharma.
  • Laponite® can be purchased at Laporte (UK).
  • the invention provides a tablet wherein the suitable amount of said suspending agents is comprised 5 and 40 % w/w. In a more preferred embodiment, the suitable amount of suspending agents is comprised between 10 and 35% w/w, and even more preferred between 15 and 25% w/w. In yet another embodiment, a tablet is provided wherein the ratio of the therapeutically active compound to said one or more suspending agents is comprised between 1 :400 and
  • said ratio is comprised between 1 :350 and 1 :1 and even more preferred between 1 :125 and 1 :2.
  • Another embodiment of the present invention relates to a tablet, wherein the ratio of said one or more suspending agents to said one or more disintegrating agents is comprised between 1 :18 and 4:3. In a preferred embodiment, said ratio is comprised between 2:17 and 7:8 and even more preferred between 3:16 and 1:2.
  • said tablet further comprises a suitable amount of water-insoluble excipients selected from the group comprising water-insoluble fillers/binders, organic fillers, water insoluble lubricants or combinations thereof.
  • fillers refers to an inert substance used to "fill-out" a tablet to a size and shape that can easily be processed.
  • Water-insoluble fillers/binders as used herein may include water-insoluble salts, such as calcium phosphates and sulfates, or Emcompress® (Mendell Group), a hydrated dicalcium phosphate.
  • Organic fillers as used herein may for instance include microcristalline celluloses.
  • binder refers to an inert substance that helps hold the tablet powders together. Binders may be vegetable cellulose, derived from plant fibres and natural vegetable gums.
  • lubricants refers to an ingredient that permits a compressed tablet to be properly ejected from a compression machine.
  • a tablet according to the present invention further comprises a suitable amount of water-soluble excipients including compression sugars, such as lactose, flavoring agents such as fruit tasting agents, sweeteners such as saccharinate, cyclamate, aspartame, pH adjusting agents such as inorganic and organic acids, binders such as PEG, soluble hydroxyalkylcelluloses, polyvinyl pyrrolidon, gelatine, natural gums, and soluble inorganic salts or combinations thereof.
  • compression sugars such as lactose
  • flavoring agents such as fruit tasting agents
  • sweeteners such as saccharinate, cyclamate, aspartame
  • pH adjusting agents such as inorganic and organic acids
  • binders such as PEG, soluble hydroxyalkylcelluloses, polyvinyl pyrrolidon, gelatine, natural gums, and soluble inorganic salts or combinations thereof.
  • the tablet according to the invention further comprises, in another embodiment, a suitable amount of one or more glidants.
  • glidant refers to an ingredient which is used to facilitate the flow of the powders in the tableting process and may for instance include magnesium stearate (Federa Brussels), or Aerosil ® 200 (Federa Brussels), talc or silicium dioxide.
  • the suitable amount of said glidants in said tablet is comprised between 0.1 and 5 % w/w.
  • the suitable amount of said glidants is comprised between 0.2 and 3% w/w, and even more preferred between 0.4 and 2% w/w.
  • a tablet is obtained which is characterized by different parameters, including tablet hardness, uniformity of the tablet weight and mean weight variance, friability, disintegration time of the tablet when dissolved in water.
  • the suspension obtained when dissolving the tablet according to the invention is characterized by a particular sedimentation volume parameter.
  • Tablet hardness can be determined by measuring the crushing strength of said tablet in Newton/surface units using a Heberlein Schleuniger instrument (model 2E, Dr. K. Schleuniger, CH-Z ⁇ rich).
  • the invention provides a tablet, having a hardness higher than 20 N.
  • a tablet is provided having a hardness higher than 40 N, and even more preferred higher than 50 N.
  • the uniformity of the tablet weight can be determined by separately weighing 20 randomly selected tablets on a Sartorius Analytic type A 200 S balance according to the instructions of the Pharm. Eur. 2000 (Mon crossing Pharm. Eur IV 2.9.5. Uniformity of mass of single- dose). Variation coefficient or relative standard deviation (RSD) of the tablet weight can then be calculated according to the below provided formulas:
  • the invention provides a tablet, having a mean weight variance that is lower than 10%.
  • a tablet is provided having a mean weight variance that is lower than 7.5%, and even more preferred lower than 5%.
  • Friability is an index, which provides a measure of the ability of a tablet to withstand both shock and abrasion without crumbling during handling of manufacturing, packaging, shipping, and consumer use. Friability (Fr) can be determined in a Roche friabilator by turning 10 tablet units with a known total weight in the apparatus at 25 rotations per minute for 4 minutes. The total weight of the tablets after the experiment can be measured. The Fr-factor is calculated as follows:
  • the invention provides a tablet, having a friability that is lower than 1%.
  • a tablet is provided having a friability that is lower than 0.5% and even more preferred lower than 0.1%.
  • the parameter "disintegration time" of a tablet refers to the time requested for a tablet to completely disperse in a suitable volume of water.
  • the disintegration time of a tablet can be determined using a disintegration apparatus.
  • the temperature is preferably lowered to 19-21°. This temperature corresponds to the temperature of the water, used in the preparation of a suspension, in which a tablet according to the invention can disintegrate.
  • the volume in the dissolution beaker in the apparatus, immersed in a thermostatic water bath (20°C +/-1), is preferably was adjusted to 200 ml.
  • a tablet is preferably able to disintegrate at 1.5 cm of the paddle, when placing the tablet at the waterfront.
  • the paddle velocity was preferably set at 100 +/- 5 rpm.
  • a basket consisting of a plastic tube with a grind at the bottom, having mazes of 2 mm, was preferably placed in a fixed position just below the water surface.
  • the invention provides a tablet, suitable for being suspended in water such that the disintegration time of said tablet in water is below 60 seconds.
  • a tablet is provided suitable for being suspended in water such that the disintegration time of said tablet in water is below 50 seconds, and even more preferred below 40 seconds.
  • the parameter "sedimentation volume” as used herein refers to the ratio of the final, equilibrium volume of a sediment to the total volume one hour after dissolving a tablet in water.
  • the sedimentation volume of a tablet can be determined by dispersing a tablet of preferably 125 mg in 2.5 ml water. Subsequently, a 50 ml suspension volume is decanted in a cylinder of 100 ml having diameter of 2.65 cm. After one hour, the sedimentation volume F can be determined.
  • the invention provides a tablet, suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour, which is higher than 0.4.
  • a tablet is provided suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour, which is higher than 0.5, and even more preferred higher than
  • the first method comprises the steps of preparing a powder mixture comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one ore more suspending agents, adding one or more glidants to said powder mixture, and directly compressing the mixture to form a tablet.
  • a tablet according to the invention can be prepared by mixing a compound having a therapeutic activity with one or more disintegrating agent, at one or more suspending agent in a PVC box for 5 minutes in a Turbula mixer (model T2A, W.A. Bachofen Maschinenfabrik, CH- Basel).
  • a glidant e.g. magnesium stearate can be subsequently added to the preparation and the mixing is continued for 1 minute.
  • Another glidant such as e.g. Aerosil ® 200 can be added and mixed with the powder for 1 minute. Tablets can be subsequently prepared on a single punch tabletting machine Baby S-728 from Courtoy N.V. (B-Halle) using a Piezo electric cell to measure the compression force.
  • another method referred to as the wet granulation method, comprises the steps of preparing a powder mixture comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one ore more suspending agents, adding a suitable amount of water or solvent, preferably alcohol, to the powder mixture, granulating the wetted mixture, followed by drying and when dried further sieving the dried mixture in order to obtain granulates. Said granulates are subsequently compressed to form a tablet.
  • the wet granulation method is comparable to the direct compression method with respect to mixing of the excipients and tabletting of the mixture. However, this method comprises an extra granulation step in the preparation.
  • the mixed powder To the mixed powder, a small amount of water or alcohol, depending on the excipients used in the preparation and sufficient for wetting the powder mixture, is added.
  • the wetted powder can be subsequently dried at room temperature in a dry chamber. Afterwards, the dried, sticky powder can be sieved with a granulating apparatus Erweka AR 400 (D-Heusenstamm) with a sieve to get a granulate with good glidant properties.
  • the granulate can thereafter be compressed to form a tablet.
  • the invention provides a tablet, whereby said tablet is obtainable by compressing a mixture of its components using a compression force comprised between 500 and 1000N.
  • the compression force is preferably comprised between 650 and 950N.
  • the invention in another embodiment, relates to a tablet wherein the dose of the therapeutically active compound in said tablet is suitable for a single administration, or a single dose, also called mono-dose.
  • the tablet according to the invention is prepared in such a way as to provide single-dose-suspensions, suspensions of an active compound, which can be readily made before use.
  • the invention relates to a breakable tablet.
  • a breakable tablet according to any of the invention can be provided such that each tablet portion contains a dose of the therapeutically active compound which corresponds to a certain body weight of a patient.
  • the invention relates to a tablet, breakable in a certain portion, preferably in 2, 3 or 4 units.
  • the tablet according to the invention can thus provide possibilities to treat patients with an exact dose, by taking the number of tablet portions corresponding to their body weight.
  • Each portion in said breakable tablets preferably corresponds to a certain body weight of 1 kg to 5kg.
  • a tablet according to the invention may be administered as such, without suspending it into water.
  • a tablet according to the invention is in the form of a chewing tablet.
  • a tablet according to the invention is used in the treatment of malaria.
  • Such tablet according to the invention is intended to cure malaria in all their forms: i.e. non-complicated, complicated, non-severe, severe, cerebral and multi- resistant malaria.
  • Malaria is caused by protozoa of the genus Plasmodium.
  • the four species of Plasmodium that infect humans are Plasmodium vivax, P. malariae, P. ovale and P. falciparum, the last one is responsible for producing severe complications and cerebral malaria, which can cause the patient to lapse into a coma and ultimately leads to death.
  • some resistance of strains of P In some parts of the world, some resistance of strains of P.
  • a suspendable tablet according to the present invention may constitute an important solution to this problem, since the tablet can already be administered to the patient in a very early stage of the disease, without need to go to a hospital, which considerably enhances the survival chances of the patient.
  • a tablet according to the present invention is particularly suitable for use in the treatment of malaria of small children since it can be easily administered in the form of a suspension. Such tablet may also be administered as a chewing tablet. In these administration modes, it guarantees a complete intake of the active compound. Moreover, the dosage of the active compound can be perfectly determined. For instance, in neonates and children the suggested dosage regimen of artemether consists of 3.2 mg/ kg body weight orally on day one and 1.6 mg/kg body weight for the next 4 days. In severe malaria, it may be necessary to increase the initial loading dose and to prolong treatment for seven days.
  • a tablet according to the invention can for instance be prepared as a breakable tablet. In such formulations, the tablet can be broken in portions and a particular number of portions can correspond to the doses of active compound required at a particular day of the treatment.
  • a suspension of the required portion(s) may be prepared, in an example with
  • Example Example 1 Preparation of a tablet and suspension according to the present invention
  • a suitable tablet composition according to the present invention is prepared, comprising artemether as therapeutically active compound.
  • Different powder mixtures were prepared comprising the active compound artemether (Arenco), disintegrants Compressil® (Usines Chimiques d'lvry-la-bataille) and Explotab® (Mendell group); suspending agent Veegum® (Alpha Pharma), water-insoluble excipients Emcompress® (Mendell group), and water-soluble excipients sodium saccharinate (Alpha Pharma) and tutti-frutti (Firmenich), in different concentrations as shown in Table 1.
  • tablets were prepared from these powder mixtures, either by using a direct compression method or by applying a wet granulation method.
  • As glidants magnesium stearate (Federa Brussel) and Aerosil® (Federa Brussel) were applied in this example. Obtained tablets were characterized by means of different parameters as indicated in Table 2.
  • a silicate i.e. Aerosil R 200
  • Some negative effects on the suspending characteristics were noticed by use of the precipitated Aerosil. Improvement of the tablet characteristics was observed in experiments 6 to 9, wherein Aerosil®200 was used and the tabletting method was changed.
  • Example 2 Determination of the suitable concentration of Veegum® and compression force for preparing a tablet
  • suitable concentration of Veegum® and suitable compression forces which can be used for preparing a tablet composition according to the invention were determined using a model system, the 2 2 factorial Doehlert design (Hu and Massart, 1989, J. Chromatogr: 485: 311-323).
  • the Doehlert design the effects of two adjustable variables, i.e. the amounts of Veegum® and compression force used for obtaining suitable tablets with suitable suspension characterisctics.
  • the Doehlert design consists of a hexagon (for 2 factors), containing 6 corner points, each one prepared once, and one central point, the replicate which is prepared two times.
  • the parameters of the optimization design were the Veegum® concentration, which varied in this example from 20 to 26% w/w, and the compression force which varied in this example within the interval [600-1000].
  • 8 powder mixtures were prepared, tablets thereof were made according to the wet granulation method and evaluated on their tablet and suspending characteristics.
  • tablet powders as indicated in Table 3 were prepared and investigated on: friability, sedimentation, disintegration time and weight variation. Results of the
  • suitable tablets according to this example preferably contain 23.8 to 25% w/w of Veegum®, and are preferably compressed at a compression force of 600 N to 740 N, respectively.
  • suitable tablets according to this example preferably contain 23.4, to 25, to 23.2 % w/w of Veegum®, and are preferably compressed at a compression force of 760 N, to 920, to 1000 N, respectively.
  • the contour plots for sedimentation (Fig. 3) are described by a circle.
  • suitable tablets according to this example preferably contain from 23.1% to 24.9% w/w of Veegum®, and are preferably compressed at 660 N up or 940 N, respectively.
  • suitable tablets according to this example preferably contain 23 % w/w of Veegum® at a compression force of 1000 N, 24.4 % w/w of Veegum® at a compression force of 760 N or 25 % w/w of Veegum® at a compression force of 820N.
  • the mean weight variance in this example just a small zone of the plot containing point D5 of the design is excluded. Its mean weight variance exceeds the criteria of the European Pharmacopea, which suggests that the variance is preferably smaller than 7.5% for tablets having a weight between 80 and 250 mg.
  • the overlapping zone with the contour plots of the other parameters includes mean weight variations around 7.5%
  • a suitable tablet composition which preferably comprises the following compounds (Table 5).
  • the mixture was tabletted at a compression force of 925 N, applying the wet granulation method to prepare the tablets.

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Abstract

The present invention relates to a tablet for pharmaceutical use, suitable for being suspended in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents wherein the addition of a predetermined amount of water thereto provides a suspension having a Brookfield value greater than or equal to 90 Pa. In a preferred embodiment, said therapeutically active compound comprises artemisinin or derivatives thereof.

Description

Suspendable pharmaceutical composition
Field of the invention
The present invention relates to the field of the pharmacology and clinical biology. The present invention relates to a tablet for pharmaceutical use, suitable for being suspended in water. The invention also relates to the use of such tablet in the treatment of malaria.
Background
The administration of an oral dosage form is generally the preferred route of administration of many pharmaceutical agents because it provides for easy, low-cost administration, compared to parenteral dosage forms. Oral dosage forms may comprise tablets.
International Patent Application WO 92/02217 describes an antimalarial composition in the solid dosage form. Ngo et al, International Journal of Pharmaceutics, 146 (1997) pages 271 to 274 describes solid dose formulations of artemisinin.
Liquid dosage forms are therefore a good alternative administration form for pharmaceuticals. As most of the active compounds are not soluble in water, a suspension is the preferred liquid dosage form to prepare. However, low dose suspensions, containing less than 20 mg/ml active compound, are difficult to prepare, as they need higher requirements for physical stability. In addition, suspensions have the disadvantageous characteristic that rests of active compound may remain on a beaker or glass, wherein the suspension is made, so that the pharmaceutical is not completely taken in by the patient. Especially in case of low doses comprised in the suspension, uncomplete uptake of the medication may have disadvantageous effects. In addition, in most of the cases, a suspension is mostly prepared or will be reconstituted at the start of and for the whole period of treatment. Especially for treatments which are used in tropical environments, for example for the treatment of malaria, chemical stability of the active compound, especially during transport and storage, and microbiological contamination at elevated temperature, even after reconstitution at treatment start (low water quality), are a great challenge for such preparations in tropical areas.
Therefore, it is a general object of the present invention to provide an improved liquid pharmaceutical dosage form of active compounds for oral administration. It is an object of the present invention to provide an improved liquid dosage form, in particular to provide a suspension, overcoming the above-mentioned drawbacks of conventional suspensions.
Summary of the invention One embodiment of the present invention is a tablet for pharmaceutical use, suitable for forming a stable suspension in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents, wherein the addition of a predetermined amount of liquid thereto provides a suspension having a Brookfield yield value greater than or equal to 90 Pa.
Another embodiment of the present invention is a tablet as described above, wherein said therapeutically active compound consists of artemisinin or derivatives thereof selected from the group consisting of artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 20 % w/w.
Another embodiment of the present invention is a tablet as described above wherein the quantities of therapeutically active compound, disintegrating agent and suspending agent are such that the tablet disintegrates within 40 seconds after the addition of water.
Another embodiment of the present invention is a tablet as described above, wherein said disintegrating agent is selected from the group consisting of natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross- linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof.
Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said disintegrating agent is comprised between 30 and 90 % w/w.
Another embodiment of the present invention is a tablet as described above, wherein the ratio of the therapeutically active compound to said one or more disintegrating agents is comprised between 1 :2 and 1 :20. Another embodiment of the present invention is a tablet as described above, wherein said suspending agent is selected form the group consisting of xanthane gums and clays, Veegum®, Bentonite, Laponite®.
Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said suspending agent is comprised between 5 and 40 % w/w.
Another embodiment of the present invention is a tablet as described above, wherein the ratio of the therapeutically active compound to said one or more suspending agents is comprised between 1 :400 and 1 :4.
Another embodiment of the present invention is a tablet as described above, wherein the ratio of said one or more suspending agents to said one or more disintegrating agents is comprised between 1 : 18 and 4:3.
Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of water-insoluble excipients selected from the group comprising water insoluble fillers/binders, organic fillers, water insoluble lubricants or any combinations thereof.
Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of water-soluble excipients including compression sugars, flavouring agents, sweeteners, pH adjusting agents, binders and soluble inorganic salts or combinations thereof.
Another embodiment of the present invention is a tablet as described above, wherein said tablet further comprises a suitable amount of one or more glidants.
Another embodiment of the present invention is a tablet as described above, wherein the suitable amount of said glidants is comprised between 0.1 and 5 % w/w.
Another embodiment of the present invention is a tablet as described above, having a hardness higher than 20 N. Another embodiment of the present invention is a tablet as described above, having a mean weight variance that is lower than 10%.
Another embodiment of the present invention is a tablet as described above, having a friability that is lower than 1 %.
Another embodiment of the present invention is a tablet as described above, suitable for being suspended in water such that the disintegration time of said tablet in water is below 60 seconds.
Another embodiment of the present invention is a tablet as described above, suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour which is higher than 0.4.
Another embodiment of the present invention is a tablet as described above, whereby said tablet is obtainable by compressing a mixture of its components using a compression force comprised between 500 and 1000N.
Another embodiment of the present invention is a tablet as described above, wherein the dose of the therapeutically active compound in said tablet is suitable for a single administration.
Another embodiment of the present invention is a tablet as described above, wherein said tablet is breakable in portions such that each tablet portion contains a dose of the therapeutically active compound which corresponds to a certain body weight of a patient.
Another embodiment of the present invention is a tablet as described above, wherein said tablet is in the form of a chewing tablet.
The present invention relates to a pharmaceutical dosage form, comprising the characteristics of a quick disintegrating tablet and a powder for the preparation of a ready- to-use suspension.
The invention relates to a tablet for pharmaceutical use, suitable for being suspended in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents.
By combined use of one or more disintegrating agents and one or more suspending agents a tablet is obtained which shows many advantageous characteristics. A tablet according to the invention quickly and fully disintegrates into a powder when brought into contact with water. Furthermore, this powder very rapidly disperses in order to form a suspension. Unexpectedly this combined use of disintegrating agents and suspending agents enables to obtain a tablet having quick disintegration, but having slow precipitation or sedimentation of the suspension, properties which are essentially contradictory.
In addition, when dissolving a tablet according to the invention in water, a suspension is obtained, which is physically stable over a long period after reconstitution up to the moment of intake. Because of this improved stability, a tablet according to the invention provides a suspension that is particularly suitable for use under extreme, e.g. tropical, conditions.
Moreover, since the suspension obtained with a tablet according to the invention slowly sediments, the deposition of active compound on a glass or beaker or other recipient wherein the suspension was prepared, can be avoided and a complete intake of the active compound can be guaranteed. This property is of particular importance, when low doses of an active compound should be taken in. Therefore, a tablet according to the invention is particularly suitable for preparing suspensions having low doses because the suspension does not sediment.
In a preferred embodiment, the therapeutically active compound consists of artemisinin or derivatives thereof selected from the group comprising artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
A tablet according to the present invention is particularly suitable for use in the treatment of various diseases. Those skilled in the art will immediate recognize the many advantages and the numerous possibilities for end uses of the present tablet formulation from the detailed description and examples provided below. Detailed description of the figures
Figures 1 to 5 represent contour plots obtained following a Doehlert design in order to determine the optimum concentration of a suspending agents and compression force required for preparing a tablet according to the present invention. Fig. 1 represents the contour plot with respect to the hardness parameter. Fig. 2 represents the contour plot with respect to the friability parameter. Fig. 3 represents the contour plot with respect to the sedimentation parameter. Fig. 4 represents the contour plot with respect to the disintegration time parameter. Fig. 5 represents the contour plot with respect to mean weight parameter.
Detailed description
The invention aims to provide a solid dosage form, from which a liquid dosage form that is easy and suitable to administer, can be prepared. Therefor, the invention provides a tablet, which disintegrates very quickly and which subsequently rapidly forms a suspension. These properties are particularly required when "small dose" compositions are to be prepared. According to the invention, such tablet is suitable to provide a "small dose" suspension in a small amount of water, e.g. 5 ml in a spoon. The suspension will assure the total intake of the small dose of active compound. According to the invention a powder mixture, having the characteristics of fast disintegration and fast development of a suspension was created. This powder mixture can be compressed into a tablet form as will be explained below.
Tablets are made from powdered materials that are mixed together and compressed. Various excipients, i.e. inactive ingredients, are required for facilitating the manufacturing process: to hold a tablet together; to keep active ingredients from reacting together; to promote disintegration of the tablet in a recipient; to make tablets easier to swallow; to maintain reasonable taste, odor, color and appearance. By specific combination of different excipients in suitable amounts, the present invention provides a tablet that is able to rapidly disintegrate, and to rapidly form a suspension, having a considerably improved physical stability.
In a preferred embodiment, the invention relates to a tablet wherein said therapeutically active compound consists of artemisinin or derivatives thereof selected from the group comprising artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin. The term "artemisinin derivatives" as used herein comprises ester-like compounds such as artesunate, ether-like compounds such as arteether and artemether, and artelinic acid, and the reduced lacton derivative of artemisinin, dihydroartemisinin
(DHA, artechol). DHA is the active schizonticidal metabolite of artemisinin and the mentioned derivatives. As a consequence, artemisinin and its derivatives, with exception of DHA, can be regarded as pro-drugs for DHA. The term "artemisinin derivatives" also refers to alpha or beta epimers of the mentioned derivatives. The term "alpha and beta epimer" distinguishes two compounds, from which the spatial orientation of the different groups provided on only one carbon atom C10 differs. In addition, the term "artemisinin derivatives" also refers to salts of the above-mentioned compounds.
In another preferred embodiment, the invention provides a tablet wherein the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 20 % w/w. In a more preferred embodiment, the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 10% w/w, and even more preferred between 0.2 and 8% w/w.
In order to obtain a faster disintegrating tablet containing particles of active compounds, one or more disintegrating agents, were provided in a tablet according to the present invention. "Disintegrating agents" are defined herein as compounds that allow the tablet to disintegrate quickly and uniformly in contact with water.
In one embodiment, a tablet according to the invention comprises a suitable amount of at least one disintegrating agent. According to one aspect of the invention, said agent causes the tablet to disintegrate within 40 seconds as can be determined from the method described in the European Pharmacopea. In another embodiment of the present invention, a tablet according to the invention comprises a suitable amount of at least one disintegrating agent selected from the group comprising natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross- linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof. The term "modified starches" or "modified celluloses" as used herein refers to starches or celluloses, respectively, that have undergone certain biological, chemical, or physical treatment which changes their viscosity and/or chemical characteristics.
The presence of the disintegrating agent tends to weaken a tablet's structure leading to poor friability values. "Friability" is an index, which provides a measure of the ability of a tablet to withstand both shock and abrasion without crumbling during handling of manufacturing, packaging, shipping, and consumer use. However, according to the present invention an optimal concentration of disintegrating agents can be provided which enables rapid disintegration of the tablet, without leading to poor friability.
In a preferred embodiment, the invention provides a tablet wherein the suitable amount of said disintegrating agents is comprised between 30 and 90% w/w. In a more preferred embodiment, the suitable amount of disintegrating agents is comprised between 40 and 85% w/w, even more preferred between 50 and 80% w/w.
In another preferred embodiment, said disintegrating agents consist of Explotab® and Compressil®. Preferably, said agents are used in a ratio of Explotab® to Compressil® comprised between 1:1 and 1:3, and even more preferred in a ratio comprised between 1 :1.5 and 1 :2.5. Explotab®, a starch derivative and Compressil®, comprising magnesium silicate as active compound, can be purchased at Mendell Group, and Usine Chimique d'lvry-la-Bataille, respectively.
In yet another embodiment, a tablet is provided wherein the ratio of the therapeutically active compound to said one or more disintegrating agents is comprised between 1 :2 and 1 :20. In a preferred embodiment, said ratio is comprised between 1:4 and 1:15, and more preferred between 1 :5 and 1:12.5.
In order to obtain a rapid development of a suspension, a suitable amount of one or more suspending agents were provided in a tablet according to the present invention. According to one embodiment of the invention, suitable suspending agents are any that exhibits thioxtropic properties.
According to another embodiment of the invention, suitable suspending agents are any which, when added to a liquid, raise its viscosity with plastic behaviour. According to one aspect of the invention, the viscosity of the suspension of a tablet is such that its' Brookfield yield value (stress) is greater than or equal to 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 or 200 Pa, and preferably greater than or equal to 90 Pa. The Brookfield yield value may be measured using a Brookfield RVT viscometer which measures the torque necessary to rotate a spindle through a liquid sample at speeds of 0.5 to 100rpm. The Brookfield yield value is an extrapolation of measured values to a shear rate of zero. The invention is not limited to the measurement of viscosity using a Brookfield RVT viscometer - other known and equivalent tests may be applied to the suspension, and a suitable conversion applied to the results thereof to obtain the
Brookfield yield value.
According to one aspect of the invention, the Brookfield yield value applies to the suspension resulting from the total components of a tablet according to the invention, which includes the therapeutically active compound, disintegrating agent and suspending agent.
According to one embodiment of the invention, the quantity of suspending agent in a suspension used for determining the Brookfield yield is greater than or equal to 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.9, 0.95, 1% w/w.
According to one embodiment of the invention, the quantity of suspending agent in a suspension used for determining the Brookfield yield is in the range 0.01 to 1 , 0.02 to 0.8, 0.05 to 0.8, 0.05 to 0.6, 0.05 to 0.5, 0.05 to 0.4, 0.05 to 0.3, 0.05 to 0.2, or 0.05 to 0.1% w/w.
According to another embodiment of the invention, a mass of liquid in which a tablet is suspended to provide a Brookfield yield value may be equal to or less than 500 g, 400 g, 300 g, 200 g, 100g, 50 g, 20 g, 10 g, 6 g, 5 g, 4 g, 3 g, 2 g, 1 g, between 1 and 20 g, between 1 and 10 g, between 1 and 100 g, 1 and 200 g, 1 and 300 g, 1 and 400 g, 1 and 500 g, 10 and 300 g, 10 and 400 g, 50 and 400 g, 100 and 300 g.
According to another aspect of the invention, suitable suspending agents are any selected form the group comprising xanthane gums and clays, Veegum®, Bentonite and Laponite®. In a more preferred embodiment, said suspending agent is Veegum®. Veegum®, comprising aluminium and magnesium silicate as active compound, can be purchased at Alpha Pharma. Laponite® can be purchased at Laporte (UK).
In a preferred embodiment, the invention provides a tablet wherein the suitable amount of said suspending agents is comprised 5 and 40 % w/w. In a more preferred embodiment, the suitable amount of suspending agents is comprised between 10 and 35% w/w, and even more preferred between 15 and 25% w/w. In yet another embodiment, a tablet is provided wherein the ratio of the therapeutically active compound to said one or more suspending agents is comprised between 1 :400 and
1 :4. In a preferred embodiment, said ratio is comprised between 1 :350 and 1 :1 and even more preferred between 1 :125 and 1 :2.
Another embodiment of the present invention relates to a tablet, wherein the ratio of said one or more suspending agents to said one or more disintegrating agents is comprised between 1 :18 and 4:3. In a preferred embodiment, said ratio is comprised between 2:17 and 7:8 and even more preferred between 3:16 and 1:2.
Other ingredients than super-disintegrants and suspending agents, for further formulation of a tablet and aesthetical aspects of the suspension can be added to the formulation. In another embodiment, said tablet further comprises a suitable amount of water-insoluble excipients selected from the group comprising water-insoluble fillers/binders, organic fillers, water insoluble lubricants or combinations thereof. The term "filler" refers to an inert substance used to "fill-out" a tablet to a size and shape that can easily be processed. Water-insoluble fillers/binders as used herein may include water-insoluble salts, such as calcium phosphates and sulfates, or Emcompress® (Mendell Group), a hydrated dicalcium phosphate. Organic fillers as used herein may for instance include microcristalline celluloses. The term "binder" refers to an inert substance that helps hold the tablet powders together. Binders may be vegetable cellulose, derived from plant fibres and natural vegetable gums. The term "lubricants" as used herein refers to an ingredient that permits a compressed tablet to be properly ejected from a compression machine.
In yet another embodiment, a tablet according to the present invention further comprises a suitable amount of water-soluble excipients including compression sugars, such as lactose, flavoring agents such as fruit tasting agents, sweeteners such as saccharinate, cyclamate, aspartame, pH adjusting agents such as inorganic and organic acids, binders such as PEG, soluble hydroxyalkylcelluloses, polyvinyl pyrrolidon, gelatine, natural gums, and soluble inorganic salts or combinations thereof.
The tablet according to the invention further comprises, in another embodiment, a suitable amount of one or more glidants. The term "glidant", as used herein refers to an ingredient which is used to facilitate the flow of the powders in the tableting process and may for instance include magnesium stearate (Federa Brussels), or Aerosil®200 (Federa Brussels), talc or silicium dioxide. In a preferred embodiment, the suitable amount of said glidants in said tablet is comprised between 0.1 and 5 % w/w. In a more preferred embodiment, the suitable amount of said glidants is comprised between 0.2 and 3% w/w, and even more preferred between 0.4 and 2% w/w.
According to the present invention, a tablet is obtained which is characterized by different parameters, including tablet hardness, uniformity of the tablet weight and mean weight variance, friability, disintegration time of the tablet when dissolved in water. In addition, the suspension obtained when dissolving the tablet according to the invention is characterized by a particular sedimentation volume parameter.
Tablet hardness can be determined by measuring the crushing strength of said tablet in Newton/surface units using a Heberlein Schleuniger instrument (model 2E, Dr. K. Schleuniger, CH-Zϋrich). In a preferred embodiment, the invention provides a tablet, having a hardness higher than 20 N. In a more preferred embodiment, a tablet is provided having a hardness higher than 40 N, and even more preferred higher than 50 N.
The uniformity of the tablet weight can be determined by separately weighing 20 randomly selected tablets on a Sartorius Analytic type A 200 S balance according to the instructions of the Pharm. Eur. 2000 (Monografie Pharm. Eur IV 2.9.5. Uniformity of mass of single- dose). Variation coefficient or relative standard deviation (RSD) of the tablet weight can then be calculated according to the below provided formulas:
- L V n Mean weight
" ( X|-x f
SD , 2_ n Standard deviation
vc = - P- χ ioo Coefficient of variation x
In a preferred embodiment, the invention provides a tablet, having a mean weight variance that is lower than 10%. In a more preferred embodiment, a tablet is provided having a mean weight variance that is lower than 7.5%, and even more preferred lower than 5%. "Friability" is an index, which provides a measure of the ability of a tablet to withstand both shock and abrasion without crumbling during handling of manufacturing, packaging, shipping, and consumer use. Friability (Fr) can be determined in a Roche friabilator by turning 10 tablet units with a known total weight in the apparatus at 25 rotations per minute for 4 minutes. The total weight of the tablets after the experiment can be measured. The Fr-factor is calculated as follows:
_ original weight - weight after test original weight
In a preferred embodiment, the invention provides a tablet, having a friability that is lower than 1%. In a more preferred embodiment, a tablet is provided having a friability that is lower than 0.5% and even more preferred lower than 0.1%.
The parameter "disintegration time" of a tablet refers to the time requested for a tablet to completely disperse in a suitable volume of water. The disintegration time of a tablet can be determined using a disintegration apparatus. In such apparatus, the temperature is preferably lowered to 19-21°. This temperature corresponds to the temperature of the water, used in the preparation of a suspension, in which a tablet according to the invention can disintegrate. The volume in the dissolution beaker in the apparatus, immersed in a thermostatic water bath (20°C +/-1), is preferably was adjusted to 200 ml. In this apparatus, a tablet is preferably able to disintegrate at 1.5 cm of the paddle, when placing the tablet at the waterfront. The paddle velocity was preferably set at 100 +/- 5 rpm. In this apparatus a basket, consisting of a plastic tube with a grind at the bottom, having mazes of 2 mm, was preferably placed in a fixed position just below the water surface.
In a preferred embodiment, the invention provides a tablet, suitable for being suspended in water such that the disintegration time of said tablet in water is below 60 seconds. In a more preferred embodiment, a tablet is provided suitable for being suspended in water such that the disintegration time of said tablet in water is below 50 seconds, and even more preferred below 40 seconds.
The parameter "sedimentation volume" as used herein refers to the ratio of the final, equilibrium volume of a sediment to the total volume one hour after dissolving a tablet in water. The sedimentation volume F is defined as the ratio of the final, equilibrium volume of the sediment, Vu to the total volume V0 before settling, as expressed in the following equation: F = [Vu/V0]. The sedimentation volume of a tablet can be determined by dispersing a tablet of preferably 125 mg in 2.5 ml water. Subsequently, a 50 ml suspension volume is decanted in a cylinder of 100 ml having diameter of 2.65 cm. After one hour, the sedimentation volume F can be determined. In a preferred embodiment, the invention provides a tablet, suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour, which is higher than 0.4. In a more preferred embodiment, a tablet is provided suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour, which is higher than 0.5, and even more preferred higher than
0.6.
Two methods can be applied for the preparation of a tablet according to the invention. In an embodiment, the first method, referred to as the direct compression method, comprises the steps of preparing a powder mixture comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one ore more suspending agents, adding one or more glidants to said powder mixture, and directly compressing the mixture to form a tablet. In an example, a tablet according to the invention can be prepared by mixing a compound having a therapeutic activity with one or more disintegrating agent, at one or more suspending agent in a PVC box for 5 minutes in a Turbula mixer (model T2A, W.A. Bachofen Maschinenfabrik, CH- Basel). A glidant, e.g. magnesium stearate can be subsequently added to the preparation and the mixing is continued for 1 minute. Another glidant, such as e.g. Aerosil®200 can be added and mixed with the powder for 1 minute. Tablets can be subsequently prepared on a single punch tabletting machine Baby S-728 from Courtoy N.V. (B-Halle) using a Piezo electric cell to measure the compression force.
In another embodiment, another method, referred to as the wet granulation method, comprises the steps of preparing a powder mixture comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one ore more suspending agents, adding a suitable amount of water or solvent, preferably alcohol, to the powder mixture, granulating the wetted mixture, followed by drying and when dried further sieving the dried mixture in order to obtain granulates. Said granulates are subsequently compressed to form a tablet. The wet granulation method is comparable to the direct compression method with respect to mixing of the excipients and tabletting of the mixture. However, this method comprises an extra granulation step in the preparation. To the mixed powder, a small amount of water or alcohol, depending on the excipients used in the preparation and sufficient for wetting the powder mixture, is added. The wetted powder can be subsequently dried at room temperature in a dry chamber. Afterwards, the dried, sticky powder can be sieved with a granulating apparatus Erweka AR 400 (D-Heusenstamm) with a sieve to get a granulate with good glidant properties. The granulate can thereafter be compressed to form a tablet.
In another embodiment, the invention provides a tablet, whereby said tablet is obtainable by compressing a mixture of its components using a compression force comprised between 500 and 1000N. In another embodiment, the compression force is preferably comprised between 650 and 950N.
In another embodiment, the invention relates to a tablet wherein the dose of the therapeutically active compound in said tablet is suitable for a single administration, or a single dose, also called mono-dose. The tablet according to the invention is prepared in such a way as to provide single-dose-suspensions, suspensions of an active compound, which can be readily made before use.
Alternatively, in another preferred embodiment, the invention relates to a breakable tablet. A breakable tablet according to any of the invention can be provided such that each tablet portion contains a dose of the therapeutically active compound which corresponds to a certain body weight of a patient. In a preferred embodiment, the invention relates to a tablet, breakable in a certain portion, preferably in 2, 3 or 4 units. The tablet according to the invention can thus provide possibilities to treat patients with an exact dose, by taking the number of tablet portions corresponding to their body weight. Each portion in said breakable tablets preferably corresponds to a certain body weight of 1 kg to 5kg.
In another embodiment, a tablet according to the invention may be administered as such, without suspending it into water. In yet another embodiment, a tablet according to the invention is in the form of a chewing tablet.
In another preferred embodiment, a tablet according to the invention is used in the treatment of malaria. Such tablet according to the invention is intended to cure malaria in all their forms: i.e. non-complicated, complicated, non-severe, severe, cerebral and multi- resistant malaria. Malaria is caused by protozoa of the genus Plasmodium. The four species of Plasmodium that infect humans are Plasmodium vivax, P. malariae, P. ovale and P. falciparum, the last one is responsible for producing severe complications and cerebral malaria, which can cause the patient to lapse into a coma and ultimately leads to death. In some parts of the world, some resistance of strains of P. falciparum was noticed for chloroquine, mefloquine, halofantrine, quinine and combination of sulfadoxine with pyrimethamine, the trusted drugs of choice for control of malaria. Likewise P. vivax infections resistant to chloroquine are emerging in different countries. More than 270 million people suffer from the disease, and 1.2-1.7 million deaths occur yearly. Mortality is more among children under 5 years of age who are particularly sensitive because of their lack of immunity to the disease.
Young children generally do not have a swelling reflex or may have difficulties to swallow. Conventional oral administration modes, mostly tablets and capsules for adults, do not comprise the dose for children and do not contain excipients masking the bitter taste of artemisinin and derivatives thereof, having therapeutic effects on malaria are therefore not suitable for this part of the population. Furthermore, other conventional administration modes, including intramuscular administration, intravenous injection of solutions of artemisinin or its derivatives, are generally not suitable for application on small children. In addition, bad environmental conditions, especially in tropical areas, do not enable good administration of such preparations on adults as well as on children. Also, the bioavailability of the active compounds in these modes of administration is generally low. Moreover, generally small doses of therapeutically active compounds need to be administered to children, and such doses are difficult to administer with currently known administration modes. Furthermore, in acute cases, especially in small children with severe cerebral malaria, early treatment of the disease may be crucial. Failure to immediately treat a patient may lead to the patient suffering sometimes immensely, resulting in loss of life. In areas where hospitals are lacking, or where hospitals are located far away from habitation zones, the rapid administration of IM injections is not feasible. A suspendable tablet according to the present invention may constitute an important solution to this problem, since the tablet can already be administered to the patient in a very early stage of the disease, without need to go to a hospital, which considerably enhances the survival chances of the patient.
A tablet according to the present invention is particularly suitable for use in the treatment of malaria of small children since it can be easily administered in the form of a suspension. Such tablet may also be administered as a chewing tablet. In these administration modes, it guarantees a complete intake of the active compound. Moreover, the dosage of the active compound can be perfectly determined. For instance, in neonates and children the suggested dosage regimen of artemether consists of 3.2 mg/ kg body weight orally on day one and 1.6 mg/kg body weight for the next 4 days. In severe malaria, it may be necessary to increase the initial loading dose and to prolong treatment for seven days. A tablet according to the invention can for instance be prepared as a breakable tablet. In such formulations, the tablet can be broken in portions and a particular number of portions can correspond to the doses of active compound required at a particular day of the treatment. A suspension of the required portion(s) may be prepared, in an example with
2.5ml water per portion, just before administration.
The following non-limiting examples illustrate preferred embodiments of tablets according to the present invention.
Example Example 1 Preparation of a tablet and suspension according to the present invention
In this example, a suitable tablet composition according to the present invention is prepared, comprising artemether as therapeutically active compound. Different powder mixtures were prepared comprising the active compound artemether (Arenco), disintegrants Compressil® (Usines Chimiques d'lvry-la-bataille) and Explotab® (Mendell group); suspending agent Veegum® (Alpha Pharma), water-insoluble excipients Emcompress® (Mendell group), and water-soluble excipients sodium saccharinate (Alpha Pharma) and tutti-frutti (Firmenich), in different concentrations as shown in Table 1. In this example, tablets were prepared from these powder mixtures, either by using a direct compression method or by applying a wet granulation method. As glidants, magnesium stearate (Federa Brussel) and Aerosil® (Federa Brussel) were applied in this example. Obtained tablets were characterized by means of different parameters as indicated in Table 2.
Table 1 Powder mixture compositions (in % w/w)
Figure imgf000017_0001
a = Aerosil R 200; b = precipitated aerosil R; 1 = Direct compression method; 2 = Wet granulation method using 17.5 ml alcohol; 3 = wet granulation using 1% (g/g) PVP (BASF) on total tablet powder, dissolved in 10 ml alcohol; further wetting with 7.5 ml alcohol
Table 2 Characterising parameters
Figure imgf000018_0001
In the present experiments, amounts of Veegum® used in the tablet powders comprised 12, 18 or 21 % w/w. In experiments 1 to 3, it can be seen that using higher concentrations of Veegum®, did not significantly improved hardness of the prepared tablets in this example. At higher concentrations of Veegum®, the sedimentation volume F1u was 20% better up to 0.63. Compared to the lowest content of Veegum® (exp. 1-12% w/w), disintegration was slightly increased with 7 seconds up to 23 seconds in experiment 3. However, in these experiments, higher amounts of Veegum® had negative effects on the friability values. When comparing tablets and prepared suspensions in this example containing 18 or 21% g/g Veegum®, the last ones were more suitable and their suspension was less flocky than in the previous experiments.
To enhance the flowability of powder and the hardness of the respective tablets prepared in this example, a silicate, i.e. Aerosil R 200, was added to tablet mixtures of this example (experiments 4 to 9). Some negative effects on the suspending characteristics were noticed by use of the precipitated Aerosil. Improvement of the tablet characteristics was observed in experiments 6 to 9, wherein Aerosil®200 was used and the tabletting method was changed.
In experiment 4, hardness was increased up to 44.8 N. Friability was lowered from 2.68% w/w (experiment 3) down to 1.88% w/w (experiment 4), and the disintegration time was also improved with a few seconds compared to previous experiment 3. In these experiment 4 the F1u value was not influenced but it was visually observed that one of the powders in the reconstituted suspension very quickly precipitated, namely the precipitated Aerosil powder. In experiment 5, tablet mixtures prepared with Aerosil®200 could not be tabletted using the direct compression method. In experiment, 6 to 9, a wet granulation method was applied to prepare tablets from the provided powder mixtures. In experiments, 6 and 7 the method comprised wetting the powder mixtures with 17.5 ml alcohol, mixing and drying. Then Aerosil®200 and the magnesium stearate were added. From this mixture, tablets were compressed at 550 and 1000 N compression force. At both compression forces, tablets could be made. Suitable results for disintegration time and friability could be obtained (see Table 2).
In experiments 8 and 9, 1% w/w of PVP was added to the alcohol used for the wetting of the powder mixture in the preparation method. The obtained results in this example showed that PVP did not improve tablet characteristics. Friability results in these experiments were poor at high compression force. Moreover the disintegration time was strongly enhanced.
Example 2 Determination of the suitable concentration of Veegum® and compression force for preparing a tablet
In a second example, suitable concentration of Veegum® and suitable compression forces which can be used for preparing a tablet composition according to the invention, were determined using a model system, the 22 factorial Doehlert design (Hu and Massart, 1989, J. Chromatogr: 485: 311-323).
In this Doehlert design the effects of two adjustable variables, i.e. the amounts of Veegum® and compression force used for obtaining suitable tablets with suitable suspension characterisctics. The Doehlert design consists of a hexagon (for 2 factors), containing 6 corner points, each one prepared once, and one central point, the replicate which is prepared two times. The parameters of the optimization design were the Veegum® concentration, which varied in this example from 20 to 26% w/w, and the compression force which varied in this example within the interval [600-1000]. In this example, 8 powder mixtures were prepared, tablets thereof were made according to the wet granulation method and evaluated on their tablet and suspending characteristics.
Since said variables are not expressed in the same unit and level, it is difficult to define the extent of the variable's influence on the response. Therefore, coded (normalized) values for these variables were used. The general form of the quadratic model, which describes the effect of the variables, is presented in the following formula: Y = bo + b1X1 + b2X2 + bn X,2 + b22X2 + b12X1X2 in which X, is the Veegum® concentration in this example, and X2 is the applied compression force, both in normalized values, and XiX2 is the interaction term between them. By multiple linear regression, the values of the model coefficients (bj) were calculated.
In this example, tablet powders as indicated in Table 3 were prepared and investigated on: friability, sedimentation, disintegration time and weight variation. Results of the
Doehlert design are represented in Table 4.
Table 3 Tablet compositions of each point of the Doehlert design
Figure imgf000020_0001
Table 4 Responses of the measurements performed on the different tablets
Figure imgf000020_0002
Based on the obtained results, models were calculated, which describes the effect of the variables on the different parameters. These models were represented as a contour plot.
In each contour plot, zones are indicated, which are conform to assumed limits for each parameter. Overlapping zones were selected, from which a suitable composition for a tablet according to the invention can be derived. Models for each studied parameter comprised: for hardness: Y = 64.76 + 19.78X2- 13.08X-,2- 7.52X2 2+ 17.09X-,X2 for friability: Y = 1.46 + 0.7893X! - 0.9163X2 + 0.3813X-,2 - 1.058X^2 for sedimentation: Y = 0.64 - 0.0495 X.,2 - 0.0705 X2 2 for disintegration time: Y = 42.39 + 6.877X-, + 17.25X2 - 10.67^ 2 for mean weight variance: Y = 2.27 - 3.069^ + 2.401X! + 4.25X1 2+ 3.42X2 2- 4.99X^2.
Based on the contour plots for hardness (Fig. 1), suitable tablets according to this example preferably contain 23.8 to 25% w/w of Veegum®, and are preferably compressed at a compression force of 600 N to 740 N, respectively. Based on the contour plots for friability (Fig. 2), suitable tablets according to this example preferably contain 23.4, to 25, to 23.2 % w/w of Veegum®, and are preferably compressed at a compression force of 760 N, to 920, to 1000 N, respectively. The contour plots for sedimentation (Fig. 3) are described by a circle. Based on the contour plots suitable tablets according to this example preferably contain from 23.1% to 24.9% w/w of Veegum®, and are preferably compressed at 660 N up or 940 N, respectively. Based on the contour plots for the disintegration time (Fig. 4), suitable tablets according to this example preferably contain 23 % w/w of Veegum® at a compression force of 1000 N, 24.4 % w/w of Veegum® at a compression force of 760 N or 25 % w/w of Veegum® at a compression force of 820N. Based on the contour plot for the mean weight variance, in this example just a small zone of the plot containing point D5 of the design is excluded. Its mean weight variance exceeds the criteria of the European Pharmacopea, which suggests that the variance is preferably smaller than 7.5% for tablets having a weight between 80 and 250 mg. The overlapping zone with the contour plots of the other parameters includes mean weight variations around 7.5%
Table 5 Suitable tablet composition according to the invention
Figure imgf000021_0001
In this example, a suitable tablet composition is illustrated which preferably comprises the following compounds (Table 5). Preferably, the mixture was tabletted at a compression force of 925 N, applying the wet granulation method to prepare the tablets.

Claims

1. Tablet for pharmaceutical use, suitable for forming a stable suspension in water, comprising a suitable amount of therapeutically active compound, a suitable amount of one or more disintegrating agents, and a suitable amount of one or more suspending agents, wherein the addition of a predetermined amount of liquid thereto provides a suspension having a Brookfield yield value greater than or equal to 90 Pa.
2. Tablet according to claim 1 , wherein said therapeutically active compound consists of artemisinin or derivatives thereof selected from the group consisting of artesunate, artemether, arteether, artelinic acid, artesunic acid, and dihydroartemisinin.
3. Tablet according to claims 1 or 2, wherein the suitable amount of artemisinin or derivatives thereof is comprised between 0.1 and 20 % w/w.
4. Tablet according to any of claims 1 to 3 wherein the quantities of therapeutically active compound, disintegrating agent and suspending agent are such that the tablet disintegrates within 40 seconds after the addition of water.
5. Tablet according to any of claims 1 to 4, wherein said disintegrating agent is selected from the group consisting of natural starches, modified starches such as cross-linked polyvinyl-pyrrolidones, modified celluloses such as cross-linked sodium carboxymethylcellulose, alginic acid and alginates, cross-linked microcristalline cellulose, or combinations thereof.
6. Tablet according to any of claims 1 to 5, wherein the suitable amount of said disintegrating agent is comprised between 30 and 90 % w/w.
7. Tablet according to any of claims 1 to 6, wherein the ratio of the therapeutically active compound to said one or more disintegrating agents is comprised between 1 :2 and 1 :20.
8. Tablet according to any of claims 1 to 7, wherein said suspending agent is selected form the group consisting of xanthane gums and clays, Veegum®, Bentonite, Laponite®.
9. Tablet according to any of claims 1 to 8, wherein the suitable amount of said suspending agent is comprised between 5 and 40 % w/w.
10. Tablet according to any of claims 1 to 9, wherein the ratio of the therapeutically active compound to said one or more suspending agents is comprised between 1 :400 and 1 :4.
11. Tablet according to any of claims 1 to 10, wherein the ratio of said one or more suspending agents to said one or more disintegrating agents is comprised between 1 :18 and 4:3.
12. Tablet according to any of claims 1 to 11 , wherein said tablet further comprises a suitable amount of water-insoluble excipients selected from the group comprising water insoluble fillers/binders, organic fillers, water insoluble lubricants or any combinations thereof.
13. Tablet according to any of claims 1 to 12, wherein said tablet further comprises a suitable amount of water-soluble excipients including compression sugars, flavouring agents, sweeteners, pH adjusting agents, binders and soluble inorganic salts or combinations thereof.
14. Tablet according to any of claims 1 to 13, wherein said tablet further comprises a suitable amount of one or more glidants.
5. Tablet according to any of claims 1 to 14, wherein the suitable amount of said glidants is comprised between 0.1 and 5 % w/w.
16. Tablet according to any of claims 1 to 15, having a hardness higher than 20 N.
17. Tablet according to any of claims 1 to 16, having a mean weight variance that is lower than 10%.
18. Tablet according to any of claims 1 to 17, having a friability that is lower than 1 %.
19. Tablet according to any of claims 1 to 18, suitable for being suspended in water such that the disintegration time of said tablet in water is below 60 seconds.
20. Tablet according to any of claims 1 to 19, suitable for being suspended in water such that a suspension is obtained which has a sedimentation volume parameter after one hour which is higher than 0.4.
21. Tablet according to any of claims 1 to 20, whereby said tablet is obtainable by compressing a mixture of its components using a compression force comprised between 500 and 1000IM.
22. Tablet according to any of claims 1 to 21 , wherein the dose of the therapeutically active compound in said tablet is suitable for a single administration.
23. Tablet according to any of claims 1 to 22, wherein said tablet is breakable in portions such that each tablet portion contains a dose of the therapeutically active compound which corresponds to a certain body weight of a patient.
24. Tablet according to any of claims 1 to 23, wherein said tablet is in the form of a chewing tablet.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1795183A1 (en) * 2005-12-09 2007-06-13 Teva Pharmaceutical Industries, Inc. Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation
WO2008098586A1 (en) * 2007-02-13 2008-08-21 Dafra Pharma N.V. Pharmaceutical carrier composition and pharmaceutical composition
WO2015140709A1 (en) * 2014-03-19 2015-09-24 Novartis Ag Solid pharmaceutical dosage forms
EP1906937B1 (en) 2005-07-22 2016-10-19 Rubicon Research Pvt Ltd. Novel dispersible tablet composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002217A1 (en) * 1990-08-08 1992-02-20 Ciba-Geigy Ag Antimalarial compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002217A1 (en) * 1990-08-08 1992-02-20 Ciba-Geigy Ag Antimalarial compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NGO THU HOA ET AL: "Formulation of artemisinin tablets." INTERNATIONAL JOURNAL OF PHARMACEUTICS (AMSTERDAM), vol. 146, no. 2, 1997, pages 271-274, XP002251104 ISSN: 0378-5173 cited in the application *
TITULAER HAC ET AL: "The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers" JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 42, no. 11, 1990, pages 810-813, XP002907519 ISSN: 0022-3573 *

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Publication number Priority date Publication date Assignee Title
EP1906937B1 (en) 2005-07-22 2016-10-19 Rubicon Research Pvt Ltd. Novel dispersible tablet composition
EP1795183A1 (en) * 2005-12-09 2007-06-13 Teva Pharmaceutical Industries, Inc. Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation
WO2007067208A1 (en) * 2005-12-09 2007-06-14 Teva Pharmaceutical Industries Ltd. Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation
JP2009518395A (en) * 2005-12-09 2009-05-07 テバ ファーマシューティカル インダストリーズ リミティド Aqueous dispersions and solutions of poorly soluble compounds and methods for their preparation
US8470344B2 (en) 2005-12-09 2013-06-25 Teva Pharmaceutical Industries Ltd. Aqueous dispersions and solutions of difficult to dissolve materials and methods of their preparation
WO2008098586A1 (en) * 2007-02-13 2008-08-21 Dafra Pharma N.V. Pharmaceutical carrier composition and pharmaceutical composition
WO2008098750A1 (en) * 2007-02-13 2008-08-21 Dafra Pharma N.V. Pharmaceutical carrier composition and pharmaceutical composition
AP2734A (en) * 2007-02-13 2013-09-30 Dafra Pharma Nv Pharmaceutical carrier composition and pharmaceutical composition
US8937085B2 (en) 2007-02-13 2015-01-20 Dafra Pharma N.V. Pharmaceutical carrier composition and pharmaceutical composition
WO2015140709A1 (en) * 2014-03-19 2015-09-24 Novartis Ag Solid pharmaceutical dosage forms

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