(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date Χ 15 December 2011 (15.12.2011) WO 2U11/154U12 A l
(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/415 (2006.01) A61K 9/20 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/DK201 1/050207 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 10 June 201 1 (10.06.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: PA 2010 00506 10 June 2010 (10.06.2010) DK Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): LIFE- GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, CYCLE PHARMA A S [DK/DK]; Kogle Alle 4, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, DK-2970 H0rsholm (DK). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): SKAK, Nikolaj SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, [DK/DK]; Guldregnvaenget 11, DK-2830 Virum (DK). GW, ML, MR, NE, SN, TD, TG). KRISTENSEN, Jakob [DK/DK]; Fyrrevaenget 21, DK-3520 Farum (DK). Published: (74) Common Representative: LIFECYCLE PHARMA A/ with international search report (Art. 21(3)) S ; Kogle Alle 4, DK-2970 Heirsholm (DK).
o o (54) Title: MINI-TABLETS COMPRISING POROUS ADSORBENT MATERIAL (57) Abstract: A loadable tablet comprising a porous adsorbent material and having a volume of from to 50 mm 3 may be loaded with an ingredient, such as oils, excipients, pharmaceutically active ingredients; the mini-tablet is useful e.g. for administering low doses of a pharmaceutically active ingredient to research or pre-clinical animals or to humans in phase I clinical trials or for pedi atric use. MINI-TABLETS COMPRISING POROUS ADSORBENT MATERIAL
The present invention relates to a loadable mini-tablet (or small-volume tablet) comprising a porous adsorbent material as well as such a mini-tablet loaded with an ingredient, such as oils, excipients, pharmaceutically active ingredients etc. The invention also provides a method for the preparation of such loadable mini-tablets, methods of loading with an ingredient and uses of the mini-tablet.
BACKGROUND OF THE INVENTION Many known and future drug substances may exhibit undesirable properties especially with respect to e.g. water solubility and oral bioavailability. Therefore, novel technologies, which enable especially therapeutically and/or prophylactically active substances to be delivered in vivo in a relatively easy manner and at the same time enables the desired therapeutic and/or prophylactic response, is highly needed. Drugs or pharmaceutical compositions usually comprise one or more active substances and various excipients. One reason for preparing such pharmaceutical compositions is to manipulate the availability of the active compound in the body of the patient after ingestion of the pharmaceutical composition. Pharmaceutical compositions for oral administration are conventionally provided as granules incorporating the active pharmaceutical ingredient or substance. Such granulate or granules may be compressed into tablets or filled into capsules. One commonly used technique for granulation is a wet granulation, where a mixture of powders including the active compound is mixed with a liquid, usually an aqueous liquid, under mechanical influence for the preparation of granules. Usually the granules prepared by wet granulation are dried before use. Other known techniques for the preparation of granules are melt agglomeration and controlled agglomeration. WO2006/000229A2 discloses the preparation of a tablet solely containing inert pharmaceutically acceptable excipients (although in some cases it may be suitable also to incorporate an active substance therein). When this tablet is immersed in or contacted with a pharmaceutically acceptable liquid formulation e.g. containing the active pharmaceutically ingredient (substance), the tablet will due to its porosity - absorb the liquid formulation (adsorbed to the walls of the inert tablet pores). This loading of an inert tablet takes place within a relatively short period of time and is reproducible, i.e. the same amount of liquid formulation is sorbed when the same type and size of tablet and liquid formulation is used. Typically, the pharmaceutically acceptable liquid formulation containing the active substance is described as an oil or an oily-like material, and it is intended that the oil or oily-like material containing the active substance remains in the tablet until administration to a mammal or human subject, and hereafter release occurs.
SUMMARY OF THE INVENTION The inventors of the present invention have found that small tablets (mini- tablets hereinafter also denoted LLMT) having a volume of 1-50 mm3, such as a volume of 4-20 mm3, and comprising a porous adsorbent material (carrier material) as described herein are very advantageous for specialty uses. The small mini-tablets of the present invention are loadable with different ingredients depending on the application and thus have a variety of uses once the mini tablets have been produced. Some of the porous adsorbent materials used herein, e.g. Zeofree, does not require magnesium stearate as lubricant for production of mini tablets, which is unusual. Magnesium stearate is incompatible with a number of substances, both ingredients having no pharmaceutical use as well as pharmaceutically active ingredients. No other excipients are necessarily required, and thereby the influence from these can be avoided in, e.g., tox studies. Very scarce amount of pharmaceutically active ingredient often limits formulation development activities in the preclinical phase. The LLMT can administer low doses of pharmaceutically active ingredients to animals in research or in pre-clinical, e.g. rodents, very precise and accurate. This is possible by either varying the loading ratios relative to the LLMT loading capacity or the concentration of dissolved pharmaceutically active ingredient in the loading solvent or by changing the number of LLMT dispensed. It is therefore possible to provide the exact amount of pharmaceutically active ingredient to each individual animal using the LLMT technology (as illustrated in example 1). The LLMT is easy to handle and administer to for instance animals during research compared to generally used alternatives (suspension, liquids, powder in a bottle or hand-filled capsules). The LLMT technology also provides a possibility to coat/sugar coat the mini- tablets for stability improvement or to facilitate use in animal feeds in pre-clinical testing.
Several alternative applications with these new mini tablets exists, in particular the LLMT can be used to easy adjustment of doses to both animals and humans by weighing the required amounts of LLMT for dosing relative to body mass and the LLMT can therefore also be used for the first human dose clinical trials. The LLMT are very easy to dispense at the Phase I clinical trial site compared to for example powder or hand-filled capsules. Furthermore the LLMT can be coated to mask taste, color etc, or enteric coated for targeted drug delivery if needed. No formulation change is required from pre-formulation to marketed product. This is possible because the preclinical LLMT formulation can be up-scaled to a marketed product, such as the porous composition described in WO2006/000229A2, without changing the composition and only changing the volume of the tablet (including the size). Another particular advantageous use of the mini-tablet of the present invention is pediatric use, since children should typically receive less pharmaceutical active ingredient than adults, and such mini tablets will increase compliance, when dealing with pediatric patients (children, infants, toddlers).
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to very small tablets having a volume of from about 1 to about 50 mm3, and typically is a cylindrical tablet with a diametrical size of 3 mm or less (as used herein, "size" measured in mm denotes the diameter of a tablet), which tablet can be loaded with ingredients, such as inert or inactive ingredients, or oils, or pharmaceutically active ingredients. As used herein the term "tablet" is intended to include solid dosage forms that have a predefined shape, and can be produced by various technologies known to the skilled person, such as tabletting, compacting, molding. The tablet as used herein may have different shapes, such as cylindrical, spherical, oval, triangular, square, etc. When for instance a cylindrical shape is used it should not be interpreted limiting, and may comprise such cylindrical tablets where at least a part of the tablet is cylindrical, e.g. the mid-section is cylindrical whereas the top and bottom parts are curved. In one aspect, the present invention relates to a loadable tablet comprising a porous adsorbent material, wherein said tablet has a volume of from about 1 to about 50 mm3. In a further embodiment the tablet has a volume of from about 4 to about 20 mm3. Such loadable tablet may be prepared as described in WO 2006/000229A2 using the porous adsorbent material as defined herein.
Porous adsorbent material The tablet according to the invention comprises one or more pharmaceutically acceptable excipients. It is however, important that a least one pharmaceutically acceptable excipient has the right properties with respect to providing a tablet with a porosity of 30% v/v or more, such as 50% v/v or more, typically 70% v/v or more, and that this excipient is present in a sufficient amount so that the tablet obtained also has the desired porosity. Such pharmaceutically acceptable excipients are herein denoted "a porous adsorbent material". Below is provided a list of porous adsorbent materials that have suitable properties that may provide a loadable tablet according to the invention. The porous adsorbent materials may be used alone or in combination provided that the overall aim is obtained with respect to porosity. To this end, it should be noted that the tablets are compressed into tablets by use of a certain compression force. However, the compression force may not be so low that the requirements with respect to hardness and friability of the tablets are compromised, i.e. these requirements ensure that the tablets are sufficiently robust. Suitable pharmaceutically acceptable excipients that can be used to obtain tablets having a porosity of 30% v/v or more are selected from the group consisting of metal oxides, metal silicates, metal carbonates, metal phosphates, metal sulfates, sugar alcohols, sugars and cellulose and cellulose derivatives. The metal is typically selected from the group consisting of sodium, potassium, magnesium, calcium, zinc, aluminum, titanium and silicon (silicium). A suitable metal oxide for use according to the invention may be selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, aluminium oxide, titanium dioxide including Tronox A-HP-328 and Tronox A-HP-100, silicon dioxides including Aerosil, Cab-O-Sil, Syloid, Aeroperl, Sunsil (silicon beads), Zeofree, Sipernat, and mixtures thereof. In a specific embodiment, the metal oxide is a titanium dioxide or a silicon dioxide or mixtures thereof. The silicates can be divided in the following groups: • Hydrous aluminium silicates or alkaline earths. Neusilin belongs to this group and is based on synthetic polymerisation (magnesium aluminium metasilicate). • Silicon dioxides are subdivided into porous and nonporous silicas
o Nonporous colloidal silicas e.g. Aerosil (fumed silicas)
o Porous silicas gels e.g. Syloid, Porasil, Lichrosorp
o Others e.g. Zeopharm S170, Zeopharm 6000, Aeroperl 300.
Accordingly, a loadable tablet according to the invention may contain a metal oxide that is a non-porous silicate including fumed silicas of the Aerosil type, and/or a porous silicate including e.g. Syloid, Porasil and Lichrosorp. In other embodiments the pharmaceutically acceptable excipient for use according to the invention is a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthetic calcium silicate such as, e.g., Hubersorp, microporous calcium silicate, such as Florite, zinc silicate, aluminum silicate, sodium aluminosilicate such as, e.g., Zeolex, magnesium aluminum silicate, magnesium aluminum metasilicate, aluminium metasilicate, Neusilin SG2 and Neusilin US2 and mixtures thereof. The aluminum silicate is a highly porous material having a typical average pore size of 30 to 80, such as 50-60 angstrom and a surface area of from 250 to 400 m2/g, such as about 300 m2/g. The composition of the present invention typically has a porosity of 30 % v/v or more, which is necessary for absorption of a suitable amount of a pharmaceutically active ingredient. In further embodiments the porosity is 40 % v/v or more, 50 % v/v or more, 60 % v/v or more, 70 % v/v or more, 80 % v/v or more, or 90 % v/v or more. The porosity is measured on the aluminum silicate, such as Neusilin, and then it is calculated how much aluminum silicate and an optional pharmaceutically acceptable excipient, utilize of the porosity. The porosity of the tablets before loading is calculated on basis of the density of ε the granule or tablet pt and the "true density" ps of the ingredients. The porosity of the tablet is calculated according to the Equation 1.
ε = - — Equation 1. P s The density of the tablet is based on the ratio between weight and volume of the granule or tablet. The "true density" of the ingredients is based on the gas pycnometric density determined in helium using Micromeritics Accupyc 1330. In a further embodiment the tablet of the present invention the aluminum silicate is typically present in a concentration of about 20% w/w or more. It is apparent that the higher porosity desired the higher the concentration of the aluminum silicate, thus in further embodiments of the tablet of the present invention the aluminum silicate is present in a concentration of about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 60% w/w or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 98% or more, in the unloaded tablet. The aluminum silicate typically, has an average pore size of 30 to 80, such as 50-60 angstrom and a surface area of from 250 to 400 m2/g, such as about 300 m2/g. In an embodiment the aluminum silicate is selected from magnesium aluminum metasilicate, magnesium aluminum silicate, and aluminium metasilicate, and mixtures thereof. Typical examples of aluminum silicates are Neusilin SG2, and Neusilin US2, and mixtures thereof, in particular A I20 3.Mg0.ySi0 2. xH20 , wherein y is from 1.5-2, and x is 1-10, preferred is magnesium aluminum metasilicate, e.g. A I2O3.MgO.2SiO 2. 5H2O. As mentioned above a suitable pharmaceutically acceptable excipient may be a metal carbonate such as a carbonate selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, zinc carbonate and aluminum carbonate, and mixtures thereof. Other metal salt suitable for use according to the invention are metal phosphates selected from the group consisting of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium phosphate, magnesium phosphate, zinc phosphate and aluminum phosphate. More specifically, the pharmaceutically acceptable excipient may be a calcium phosphate selected from the group consisting of dibasic anhydrous calcium phosphate, dibasic dihydrate calcium phosphate, and tribasic calcium phosphate. The dibasic anhydrous calcium phosphate is typically selected from the group consisting of A-Tab, calcium monohydrogen phosphate, calcium orthophosphate, Di- Cafos AN, dicalcium orthophosphate, E341 , Anhydrous Emcompress, Fujicalin, phosphoric acid calcium salt ( 1 :1), and secondary calcium phosphate, and mixtures thereof. The dibasic dihydrate calcium phosphate may be selected from the group consisting of Cafos, calcium hydrogen orthophosphate dihydrate, calcium monohydrogen phosphate dihydrate, Calipharm, Calstar, Di-Cafos, dicalcium orthophosphate, DI-TAB, Emcompress, phosphoric acid calcium salt ( 1 : 1 ) dihydrate, secondary calcium phosphate, Fujiclin SG. Examples of tribasic calcium phosphates are e.g. hydroxyapatite, phosphoric acid calcium salt (2:3), precipitated calcium phosphate, tertiary calcium phosphate, Tri- Cafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI-TAB. Other suitable metal salts are metal sulfates. Useful salts include sodium sulfate, sodium hydrogen sulfate, potassium sulfate, potassium hydrogen sulfate, calcium sulfate, magnesium sulfate, zinc sulfate and/or aluminum sulfate. Examples of suitable calcium sulfates are e.g. calcium sulfate anhydrous including anhydrite, anhydrous gypsum, anhydrous sulfate of lime, Destab, Drierte, E516, karstenite, muriacite, and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, mineral white, native calcium sulfate, precipitated calcium sulfate, satinite, satin spar, selenite, terra alba and USG Terra Alba. Any one of the above porous adsorbent materials are intended to be embodiments of the invention as long as they alone or in mixture provides a suitable porosity as described above. The below specified embodiments are not to be construed as limiting the invention in any way but are merely to highlight certain preferred embodiments. In a further embodiment of this invention, the porous adsorbent material is selected from porous silicon dioxide, such as sodium silicate, potassium silicate, magnesium silicate, calcium silicate, including synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof. In a further embodiment the porous adsorbent material is selected from metal carbonates and metal phosphates. Typically, the porous adsorbent material is selected from magnesium aluminum metasilicate, precipitated silicate, and microporous calcium silicate. In many instances a tablet is formed in a cylindrical shape although the tablet may not be completely cylindrical, since the punches may leave a curvature on the edges depending on the shape of the punch. In a further embodiment of the invention, the tablet has a cylindrical shape with a size of 3 mm or less, such as from 1 to 3 mm, e.g. 2 mm. In this respect, the tablet may have a height of from 1 to 5 mm, such as a height of from 2 to 4 mm.
In pharmaceutical tablet manufacture, a lubricant, e.g magnesium stearate, is often applied in the composition to avoid material adhering to the punches during tablet compression. Depending on the porous adsorbent material it may be suitable to avoid magnesium stearate in the loadable tablet of the present invention, i.e. to provide a tablet free of magnesium stearate or at least essentially free of magnesium stearate. However, this is not to be seen as limiting the invention in any way, and such choice will be for the skilled person to make in specific situations. In a further aspect the present invention relates to a tablet comprising a porous adsorbent material and having a volume of from 1 to 50 mm3, wherein said tablet is loaded with an ingredient. The ingredient may be an inert ingredient. In a certain embodiment such ingredient is glycerol. Active pharmaceutical ingredients (API) In a further aspect, the present invention relates to a tablet comprising a porous adsorbent material and having a volume of 1-50 mm3, wherein said tablet is loaded with a pharmaceutically active ingredient. The pharmaceutically active ingredient may be any of the known active ingredients or may be new compounds developed, and may typically comprise such compounds as described in WO 2006/000229A2. In a further embodiment the pharmaceutically active ingredient is selected from atorvastatin, clopidogrel, esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine, lansoprazole, candesartan, imatinib, irbesartan, ibuprofen, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine, medroxyprogesterone, meloxicam, metaxalone, nelfinavir, rofecoxib, warfarin, cabergoline, carbamazepine, clozapine, cyproterone, itraconazole, nevirapine, orlistat, valproate, benidipine, cefditoren, ebastine, epalrestat, ethyl icosapentate, flurbiprofen, gefitinib, gliclazide, ketoprofen, cilostazol, diclofenac, manidipine, menatetrenone, mosapride, nicergoline, nilvadipine, posaconazole, pranlukast, rebamipide, tamoxifen, teprenone, ticlopidine, tocopherol, ursodeoxycholic acid, azithromycin, clarithromycin, valdecoxib, efavirenz, sirolimus, indinavir, amprenavir, aprepitant, eprosartan, lapatinib, posaconazole, tipranavir, and free acids, bases, esters and salts thereof; or of mixtures thereof. The loadable of loaded mini-tablet may of course also comprise or contain other pharmaceutically acceptable excipients such as those normally employed in the manufacturing of tablets.
In the present context, the term "pharmaceutically acceptable excipient" is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect perse. Such an excipient may be added with the purpose of making it possible to obtain a pharmaceutical, cosmetic and/or foodstuff composition, which have acceptable technical properties. Examples of suitable excipients for use in a loadable or loaded tablet of the invention include fillers, diluents, disintegrants, surfactants, binders, lubricants etc. or mixture thereof. As the composition or solid dosage form according to the invention may be used for different purposes, the choice of excipients is normally made taken such different uses into considerations. Other pharmaceutically acceptable excipients for suitable use are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc. Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray- dried lactose, a-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L- hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g.
Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A , Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc. Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tri-basic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc. Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc. Examples of surfactants are: iCremophor RH40 iPolyoxyl 40 hydrogenated castoer oil iCremophore ELP iPolyoxyl 35 castoer oil
iPolysorbate 20, Tween 20, Polyoxyethylene Sorbitan iMontanox 20 PHA Fatty Acid Ester based on Laurie acid
iPolysorbate 80, Tween 80, Polyoxyethylene Sorbitan !Montanox 80 VG PHA iFatty Acid Ester based on Oleic acid Labrafil M 1944 CS iOleoyl macrogol-6-glycerider iLabrafil M 2125 CS iLauroyl Macrogol-6 glycerider iLabrasol iCaprylocaproyl macrogolglycerides Lutrol F127 iPoloxamer 407
!Lutrol F68 iPoloxamer 188 iMontane 20 PHA iSorbitan monolaurate, Span 20 iSpan 60 pharma iSorbitan monostearate iMontane 80 VG PHA iSorbitan monooleate, Span 80 iSoluplus i'Polyvinyl-caprolactam-polyvinyl acetat' !Solutol HS 15 iPolyoxyl 15 Hydroxystearate !Speziol TPGS Pharma iVitamin E TPGS iTranscutol HP piethylene glycol monoethyl ether
Glidants and lubricants may also be included in the tablet. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, colloidal silicon dioxide (Aerosil) talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc. Specific examples of disintegrants are e.g. croscarmellose sodium, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl stare and mixtures thereof (e.g. Primogel® and Explotab®) etc. Any one of these disintegrants is intended to be specific embodiments and may be combined with any one of the aspects and/or embodiments of the present invention. Typically, the concentration of disintegrant is from 1 %w/w to 20 %w/w, such as 1 %w/w to 10 %w/w, such as 2 %w/w to 15 %w/w, such as 2.5 %w/w to 8 %w/w (based on the total weight of the composition before loading).
Other excipients which may be included in a loadable tablet of the invention are e.g. flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc. Other additives the loadable or loaded tablet of the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain e.g. stabilizing agents. The concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w. Any one of these excipients is intended to be specific embodiments and may be combined with any one of the aspects and/or embodiments of the present invention.
Uses The loadable mini-tablet of the present invention is useful for several purposes.
In particular, the mini-tablet is very suitable for use in administering low doses of a pharmaceutically active ingredient to animals, such as research or pre-clinical animals, e.g. rodents, or to humans in phase I trials, in particular first human dose trials. A further use of the mini-tablet of the present invention loaded with an active pharmaceutically ingredient is in the administration of an active pharmaceutically ingredient to infants, toddlers or children, i.e. for pediatric use. This is typically the situation in pediatric clinical trials or in an everyday treatment regime, where infants, toddlers or children are subject to treatment with medicaments, since the young subjects normally should receive a lower dose compared to adult subjects or patients. In a further aspect the present invention relates to the use of a tablet comprising a porous adsorbent material, wherein said tablet has a volume of from 1 to 50 mm3, for preparing a pediatric medicament. In a still further aspect the present invention concerns use of a tablet comprising a porous adsorbent material, wherein said tablet has a volume of from 1 to 50 mm3, for preparing a low dose of an active pharmaceutically ingredient to be administered to animals, such as research or pre-clinical animals, e.g. rodents. In another embodiment, the mini-tablets of the present invention is administered to human beings in clinical phase I trials, in particular first human dose trials.
EXAMPLES Without being limited hereto, the following examples of mini-tablets (LLMT) according to the invention, which mini-tablets are porous and able to absorb small amounts liquid substances (adsorbed to the porous, solid carrier material), with or without dissolved active ingredient(s) in a very accurate and precise manner. Examples 1 and 2 are carried out with glycerin as loading liquid and example 3 is carried out with a 10% (w/w) solution of celecoxib, an active pharmaceutical ingredient, in ethanol and illustrates that the tablets performs according to the invention. The porosity of the un-loaded LLMT is usually between 85% and 70% (90-40%) depending on tablet excipients. The LLMT can be fully loaded (100% of the loading capacity) or partially loaded (depending on the properties of the liquid to be loaded down to approx. 20% of the loading capacity). For example, a 3 mm diameter tablet with a tablet height of 2.4 mm, made with a flat tip punch, has a tablet volume of about 17 mm3. A 2 mm diameter tablet with a tablet height of 1.62 mm, made with a flat tip punch, has a tablet volume of about 5.1 mm3.
List of materials: Neusilin US2 (Fuji Chemical Industry, lot 502002) , Zeopharm 5170 (Huber, lot ETW 4/2) , Celecoxib (Euroasia, lot CBX/30301 3), Magnesium stearate (Mallinckrodt Chemicals Ltd., lot J001 19), Ethanol (Kemetyl), Glycerin (Fagron, 09H28-B01 )
EXAMPLE 1
Manufacture of 2mm loadable tablets containing Neusilin US2
2000 g of Neusilin US2 was mixed with 20.20 g of magnesium stearate in a turbula blender for 30 seconds. The tablet press (Fette, bench press) equipped with 6 multi tip punches, with a punch tip size of 2mm, was set up for production by adjusting tablet height and tablet weight to obtain a coherent tablet suitable for further processing. The porosity was calculated from the tablet volume and tablet weight and the pychnometric density of the tablet excipients.
Loading of LLMT with glycerin:
The glycerin loading for each of the ratios listed in Table 1 were calculated based on the tablet porosity, and the loading of the three batches was subsequently performed in a loading chamber. 122 g, 89.6 g respectively 5 1.2 g of glycerin was added to 7 1. 1 g og tablets. The glycerin was added to the chamber followed by addition of the tablets. The chamber rotated until the tablets were completely dry. The loading time was from 25 minutes to 1 hour depending on the amount of glycerin. Table 1:
* ) MgSt is magnesium stearate.
The results provided in Table 1 show that the actual loading of glycerin is very close to target loading.
EXAMPLE 2
Manufacture of 2 mm loadable tablets containing Zeofree 5170:
24.75 g of Zeofree 5170 was mixed with 0.25 g of magnesium stearate in a turbola blender for 30 seconds. A single punch tablet press (Diaf) equipped a multi tip punch, with a punch tip size of 2mm, was set-up for production by adjusting tablet height and tablet weight to obtain a coherent tablet suitable for further processing. 50 g of Zeofree 5170 was compressed using the same setup.
Loading of LLMT with glycerin: The glycerin loading were calculated based on the tablet porosity, and the loading of the two batches was subsequently performed in a loading chamber. 4.5 g of tablets were applied for both tablet batches. The glycerin was added to the chamber followed by addition of the tablets. The chamber rotated until the tablets were completely dry. The loading time was from 25 minutes to 1 hour depending on the amount of glycerin. Table 2 :
* MgSt is magnesium stearate
The results listed in Table 2 show that LLMT can be manufactured with and without the use of a lubricant and loaded as described herein.
EXAMPLE 3
Loading of LLMT with a 10% w/w solution ofcelecoxib
10 g of celecoxib was dissolved in 90 g ethanol. 10 mini-tablets (LLMT), manufactured as describe above in Example 1 were dried in an incubator at 110°C until constant mass just before loading. The loading capacity of the min-tablets was determined by submerging 20 tablets in the solvent for 30 minutes and determining the increase in mass. The dried un-loaded tablets were placed in a closed container together with 22.620 mg of the 10% (w/w) solution of celecoxib for 1 hour corresponding to a 90% loading capacity. The container was opened and placed in an incubator (Memmert, Model 100-800) at 110°C until constant mass. The loading of celecoxib was calculated based on mass differences. Table 3 :
The results in Table 3 show that the loadable mini-tablets of the present invention can be accurately loaded with very small amounts of active ingredients in small scale (10 tablets). Here the tablets were actually loaded with 114 micrograms, while the target loading was 113 micrograms. CLAIMS
1. A loadable tablet comprising a porous adsorbent material, wherein said tablet has a volume of from 1 to 50 mm3, preferably a volume of from 4 to 20 mm3.
2 . The tablet of claim 1 comprising a porous adsorbent material in an amount of at least 50 w/w % , preferably at least 60 w/w % , more preferably at least 70 w/w % , more preferably at least 80 w/w % , more preferably at least 90 w/w % , more preferably at least 95 w/w % , more preferably at least 98 w/w % , especially at least 99 w/w % .
3 . The tablet according to claim 1 or claim 2 , wherein the tablet has a cylindrical shape and a diameter of up to 3 mm, preferably a diameter from 1 to 3 mm, e.g. 2 mm.
4 . The tablet according to any of claims 1-3, wherein the tablet has a height of from 1 to 5 mm.
5 . The tablet according to any of claims 1-4, wherein the porous adsorbent material is selected from the group consisting of metal carbonates, metal phosphates, porous silicon dioxide, magnesium silicate, calcium silicate, sodium silicate, potassium silicate, synthetic calcium silicate, microporous calcium silicate, zinc silicate, aluminum silicate, sodium aluminosilicate, hydrous aluminium silicates or alkaline earths, magnesium aluminum metasilicate, magnesium aluminum silicate, aluminium metasilicate, nonporous colloidal silicas, porous silicas gels, precipitated silicate, and mixtures thereof.
6 . The tablet according to any of the claims 1-5 being essentially free of magnesium stearate.
7 . A tablet comprising a porous adsorbent material and having a volume of 1-50 mm3, wherein said tablet is loaded with an ingredient.
8 . The tablet of claim 7, wherein the ingredient is glycerol.
9 . A tablet comprising a porous adsorbent material and having a volume of from 1 to 50 mm3, wherein said tablet is loaded with an active pharmaceutically ingredient. 10. The tablet of claim 9, wherein the pharmaceutically active ingredient is selected from atorvastatin, clopidogrel, esomeprazole, valsartan, olanzapine, risperidone, pioglitazone, quetiapine, lansoprazole, candesartan, imatinib, irbesartan, ibuprofen, aripiprazole, ezetimibe, celecoxib, lamotrigine, telmisartan, olmesartan, tacrolimus, fenofibrate, fenofibric acid, mycophenolate, bicalutamide, lopinavir, ritonavir, raloxifene, efavirenz, carvedilol, omeprazol, methylphenidate, cyclosporine, simvastatin, ziprasidone, nifedipine, glimepiride, glipizide, glyburide, hydroxyzine, isotretinoin, loratadine, medroxyprogesterone, meloxicam, metaxalone, nelfinavir, rofecoxib, warfarin, cabergoline, carbamazepine, clozapine, cyproterone, itraconazole, nevirapine, orlistat, valproate, benidipine, cefditoren, ebastine, epalrestat, ethyl icosapentate, flurbiprofen, gefitinib, gliclazide, ketoprofen, cilostazol, diclofenac, manidipine, menatetrenone, mosapride, nicergoline, nilvadipine, posaconazole, pranlukast, rebamipide, tamoxifen, teprenone, ticlopidine, tocopherol, ursodeoxycholic acid, azithromycin, clarithromycin, valdecoxib, efavirenz, sirolimus, indinavir, amprenavir, aprepitant, eprosartan, lapatinib, posaconazole, tipranavir, and free acids, bases, esters and salts thereof; or mixtures thereof.
11. The tablet according to any of claims 1- 10 further comprising a pharmaceutically acceptable excipient, such as a surfactant or a disintegrant.
12. The tablet according to any of claims 9-1 1 for use in administering low doses of a pharmaceutically active ingredient to animals, such as research or pre-clinical animals, e.g. rodents, or to humans in phase I clinical trials, in particular first human dose trials.
13 . The tablet of any one of claims 9-1 1 for pediatric use in administering an active pharmaceutically ingredient to infants, toddlers or children.
14. Use of a tablet comprising a porous adsorbent material and having a volume of from 1 to 50 mm3 for the preparation of a pediatric medicament.
15. Use of a tablet comprising a porous adsorbent material and having a volume of from 1 to 50 mm3 for preparation of a low dose of an active pharmaceutically ingredient to be administered to animals, such as research or pre-clinical animals, e.g. rodents, or to humans in phase I clinical trials, in particular first human dose trials. A . CLASSIFICATION O F SUBJECT MATTER INV. A61K31/415 A61K9/20 ADD.
According to International Patent Classification (IPC) or to both national classification and IPC
B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal , WPI Data, EMBASE, BIOSIS
C . DOCUMENTS CONSIDERED TO B E RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
WO 2008/114276 Al ( LUPIN LTD [IN] ; GUHA 1-15 ASHISH SHARADCHANDRA [IN] ; METKAR BHARAT RAGHUNAT) 25 September 2008 (2008-09-25) exampl es 1-5 c l aims 1-12
W0 2010/043950 A2 (AIZANT DRUG RES 1-15 SOLUTIONS PRIV [IN] ; ANAND PAVITHRA [IN] ; SATHURAPPAN) 22 Apri l 2010 (2010-04-22) exampl e 1 c l aims 1-6
W0 2007/106957 Al (SMB S A LAB [BE] ; 1-15 VANDERBIST FRANCIS [BE] ; BAUDI ER PHI LI PPE [BE] ; DEB0) 27 September 2007 (2007-09-27) exampl es 1, 3-7 c l aims 1-28 -/-
Further documents are listed in the continuation of Box C . See patent family annex.
* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle o r theory underlying the considered to be of particular relevance invention "E" earlier document but published on or after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to "L" documentwhich may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y" document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the "O" document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled in the art. "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family
Date of the actual completion of the international search Date of mailing of the international search report
15 September 2011 26/09/2011
Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Schi fferer, Hermann C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
COSIJNS ET AL: " Porous hydroxyapati t e 1-15 tabl ets as carri ers for l ow-dosed drugs" , EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVI ER SCI ENCE PUBLISHERS B.V. , AMSTERDAM, NL, vol . 67 , no. 2 , 8 August 2007 (2007-08-08) , pages 498-506, XP022190567 , ISSN : 0939-6411 , D0I : 10. 1016/J . EJPB.2007 .02 .018 page 499 , l eft-hand col umn , l i ne 2 1 - page 500, l eft-hand col umn , l i ne 40 tabl e 1
MATTSS0N S ET AL: "The use of mercury 1-15 porosimetry i n assessi ng the effect of di fferent bi nders on the pore structure and bondi ng properti es of tabl ets" , EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVI ER SCI ENCE PUBLISHERS B.V. , AMSTERDAM, NL, vol . 52 , no. 2 , 1 September 2001 (2001-09-01) , pages 237-247 , XP004301073 , ISSN : 0939-6411 , D0I : 10. 1016/50939-6411 (01)00163-1 page 238, l eft-hand col umn , l i ne 4 - page 239 , l eft-hand col umn , l i ne 3 Patent document Publication Patent family Publication cited in search report date member(s) date
WO 2008114276 A l 25-09-2008 NONE
O 2010043950 A2 22 -04 -2010 NONE wo 2007106957 A l 27 -09 -2007 W0 2007106960 A l 27-09-2007