WO2010028843A1

WO2010028843A1 - Tablets for subsequent nanoparticle suspension filling using ultrasound

Info

Publication number: WO2010028843A1
Application number: PCT/EP2009/006615
Authority: WO
Inventors: Odon Planincek
Original assignee: Univerza V Ljubljani
Priority date: 2008-09-11
Filing date: 2009-09-11
Publication date: 2010-03-18
Also published as: WO2010028843A4; SI22860A

Abstract

To increase the fullness of empty placebo tablets with nanoparticles that contain the active ingredient the innovator has, via direct tabletting, produced porous tablets comprised only of excipients that are stable in a suspension of organic solvent with nanoparticles that with the use of ultrasound at the same time do not decay for at least 1 minute. With the use of the nanoparticle suspension in organic solvent and the use of ultrasound, the filling yield has been significantly improved compared to the conventional method used for this purpose. This invention enables the procedure of filling tablets with nanoparticles of the active substance that can be active ingredients, substances that are used in diagnostics, minerals, vitamins, or substances for peroral vaccination.

Description

Tablets for Subsequent Nanoparticle Suspension Filling using Ultrasound

Field of the invention

The porous tablets for subsequent nanoparticle filling with an active substance using ultrasound are the subject of this invention. The tablets that are the subject of this invention are produced with direct compression from excipients that enable subsequent pharmaceutical tablet filling with an active substance suspension in an organic solvent or water. After the use of ultrasound there is no dissolution for at least one minute. For the therapeutic effect to be achieved the active substance must be integrated into the appropriate therapeutic system or drug. In this invention, the basic tablets are comprised only of excipients used in pharmacy; the active substance itself is added subsequently as a suspension of nanoparticles in an organic solvent or water. The tablets filled with nanoparticles enable fast active substance release, its absorption or peroral vaccination. The tablets and the filling method with the use of ultrasound enable a large-scale series production on an industrial level.

Technological Background

Tablets are one of the most frequently used pharmaceutical forms. They are solid pharmaceutical forms that contain one dosage of one or more active substances. The tablets are usually produced by compressing a uniform volume of particles into a tablet. An older method of tablet production is granulation. The development of new excipients and the modification of old ones however, have enabled the production by direct compression. The greatest advantage of direct compression is its lower price when compared to granulation. A lesser amount of time, equipment and space, less validations and energy is required for their production. However disadvantages to direct compression do exist, generally these include:

- difficulties in ensuring a uniform distribution of components and prevention of mixing between formulations and low dosage active substances;

- fillers used in direct compression are more expensive than fillers for granulation;

- restrictions in production of coloured tablets;

- problems with powdering.

The tablets with high active-substance content can have only few excipients added that do not contribute sufficiently to improving their quality and do not make direct compression impossible. Direct compression therefore requires careful selection of excipients, adequate flow properties, homogenous component distribution within the tablet production mass and knowledge on formulation and production parameters that impact the compactibility and active substance release from the tablets.

Filling of Porous Substances with Solution or Substance Suspension

In the field of pharmacy the filling with SiO₂ particles and the active substance is well- known: they are mixed with an excess of the solution or suspension in an adequate solvent (water, acetone, chloroform). After equilibrium has been established the particles are washed in pure solvent and dried under normal or reduced pressure (Otsuka M, Tokumitsu K, Matsuda Y. Solid dosage form preparation from oily medicines and their drug release. Effect of degree of surface modification of silica gel on the drug release from phytonadione-loaded silica gels. J Control Release 2000; 67: 369-384, Chen J, Ding H, Wang SJ, Park JB. Preparation and characterization of porous hollow silica nanoparticles for drug delivery application. Biomaterials 2004; 25: 723-727). The downside of such particle filling is the use of the substance excess which is lost by the washing process, this is why the process can be modified using only a minimal solution or suspension required for a complete adsorption and absorption. The active substance filling procedure can be repeated several times and so the pores in the particles are filled further and the effectiveness is increased. A content of 500 mg of active substance per 1 g of carrier can be achieved (Ohta KM, Fuji M, Takei T, Chikazawa M. Development of a simple method for the preparation of a silica gel based controlled delivery system with a high drug content. Eur J Pharm Sci 2005; 26: 87-96).

For the production of pharmaceutical products various polar solvents can be used, however all substances and products must be tested for solvent content that is most likely present in such products after the production procedure. The purpose of solvent content restrictions in pharmaceutical products is the protection of the patient. In drug production the use of less toxic, toxicologically acceptable solvents and residues in products is desired. Residue solvents are defined as volatile organic compounds used or produced during the active substance and excipient production procedure. According to the possible health consequences for humans these are classified in three groups. Class 1 solvents are carcinogenic, very probably carcinogenic and harmful to the environment. These solvents are to be avoided. Class 2 solvents are not genotoxic and do not cause irreversible toxicity, such as neurotoxicity or teratogenicity. These solvents can be toxic to a certain degree, however their toxicity is reversible. Their use is restricted. The content level for each of these solvents in pharmaceutical products is known. These solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethane, dichloromethane, 1 ,2-dimethoxyethane, N,N- dimethylacetamide, N,N-dimethylformamide, 1 ,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, methyl butyl ketone, methylcyclohexane, N- methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene and xylene. Class 3 solvents have a low toxic potential. The permissible level with which a daily dosage solvent, which can be ingested by humans in a day, is determined is 50 mg or more, where the risk of the effect to the health of a human is very low. These solvents are: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, t-butyl methyl ether, isopropylbenzene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl fumarate and formic acid (European Pharmacopoeia).

WO 00/38655 (Alza Corporation) describes the pharmaceutical form composed of porous particles. The dose form can be in the form of tablets produced by mixing porous particles with a fluid such as propylene glycol. This patent application does not include inert tablets, these have the capability of absorbing the active substance in the form of a liquid or solvent that contains the active substance in repetitive form.

US 6,399,591 (Yung-Shin Plarmaceutical Ind. Co. Ltd.) describes the inert tablets that contain an absorbent, disintegrant, glidant and filler or binder, or a mixture of filler and binder. An active substance in fluid form is added into an inert or empty tablet. In the cases described a 13% tablet filling with an active substance was achieved.

In the patent application WO 2006/000229 (Holm Per, Holm Jannie Egeskov, Ruhland Thomas, Nielsen Simon Dalsgaard) the authors describe tablets, the technique for tablet filling with an active substance solution or suspension which is taken in by the tablets due to their own porosity. The fluid most often stays in the tablet after the filling. Technical Issues

The disadvantage of a wide variety of active substances is their low solubility and biological usability. New technologies enable a positive improvement in these characteristics with nanoparticle preparation. These particles are the size of 50 nm to 1000 nm. The nanoparticles can be used dry or as a suspension. There are several ways of nanoparticle drying. One can use lyophilization or a diffusion drying process, that both require a vast energy input and which can affect nanoparticle stability, especially when these contain proteins. The problem can be solved with the use of inert tablets that are immersed in the suspension of nanoparticles with which the tablets are to be filled. The yields of such a filling process are too low if an appropriate filling method is not used.

Description of the drawings

Fig. IA shows a cross section of a tablet filled with ZnS nanoparticles according to example

2.

Fig. IB shows a cross section of a tablet filled with ZnS nanoparticles according to example 2 and the chemical analysis for the element Zn.

Fig. 2A shows a cross section of a tablet filled with ZnS nanoparticles according to a comparative example 2.

Fig. 2B shows a cross section of a tablet filled with ZnS nanoparticles according to a comparative example 2.

Detailed Description of the Invention

The inert tablets are impossible to fill repetitively with a large amount of nanoparticles without the use of an adequate procedure. The inventor has solved this problem by filling inert tablets with a suspension of nanoparticles using ultrasound which particularly improves the number of particles taken up by the tablet. Tablets produced in such a manner that contain nanoparticles can be used in disease treatment, diagnostics, in application of minerals and vitamins or for peroral vaccination, especially in countries with high atmospheric temperatures where a stable solid pharmaceutical form is desired for treatments.

Tablets for Subsequent Nanoparticle Suspension Filling using Ultrasound In the scope of the described innovation the term "inert tablet" is used to describe a tablet that contains only components that are inert relating to their therapeutic effect. More specifically, such tablets contain pharmaceutically acceptable excipients in a selected group comprised of fillers, thinners, binders, glidants, lubricants etc. Other excipients can also be pH regulatory substances, buffer capacity increasing substances, wettability improving substances, solubilizers, antioxidants and other substances. The term "tablets for subsequent nanoparticle suspension filling using ultrasound" used in this text pertains to inert tablets as described above and have the adequate porosity of minimally 30 volume percent, which ensures an appropriate filling with the suspension. These tablets are primarily inert and intended for subsequent filling, which means that they do not contain active substances before the filling process. At the same time such tablets must be durable enough to withstand at least one minute of immersion in the solvent with the simultaneous impact of ultrasound.

Nonetheless, as it will be shown in the examples, the inventor has established that tablets with considerable porosity can be filled with the use of ultrasound with a pharmaceutically acceptable fluid containing nanoparticles for therapeutic, prophylactic or diagnostic active substances, minerals or vitamins (in the text to follow termed "active substances"). Though tablets produced without the use of ultrasound contain a few milligrams of nanoparticles (comparative examples 1 through 3), the use of ultrasound enables a filling capacity of ten mg and more (examples 1, 2, 3 and 4). The nanoparticle filled tablets must be sufficiently robust to withstand handling in the steps to follow, such as coating, packing and storage, which means that they are up to the standard of pharmacopeia regarding hardness and friability.

In specific examples the tablet for subsequent nanoparticle suspension filling in this invention is produced - if tested as described in the description to follow - when filled with at least 20 weight percent, for example 25 weight percent or at least with 30 weight percent of organic solvent (calculated according to the total mass of the solid dosage form after filling). Such a test ensures that the tablet is capable of sorbation for the fluid formulation suitable for tablet production.

As stated above, the tablets in this invention are robust enough to withstand normal handling, meaning that they have a hardness of 20 N or more, for example around 25 N or more, close to 30 N or more, close to 35 N or more, close to 40 N or more, or close to 45 N or more or close to 50 N or more.

Moreover, in this invention the friability is close to 5% or less, for example close to 4% or less, close to 3% or less, close to 2% or less or 1% or less.

As mentioned above, the tablets for subsequent filling in this invention are comprised of one or more pharmaceutically acceptable excipients. Next to that it is important that at least one of the excipients has the appropriate properties, so that it produces tablets with a porosity of 30 or more volume percent and that that the amount of this excipient is sufficient to give the produced tablet the desired porosity.

In addition in the tablets for subsequent filling, the total of pharmaceutically acceptable excipients (those that posses the properties mentioned above) is at least 50 weight percent, such as at least 55 weight percent, at least 60 weight percent, at least 70 weight percent, at least 80 weight percent, at least 90 weight percent, at least 95 weight percent, at least 98 weight percent or 100 weight percent of the total tablet weight.

In the majority of cases one or more of the present excipients ensuring the porosity is present in the tablet in the concentration of 50 weight percent or more, such as, close to 60 weight percent or more, close to 70 weight percent or more, close to 80 weight percent or more, close to 90 weight percent or more, or close to 95 weight percent or more.

In the following text a list of pharmaceutically acceptable excipients with the adequate properties is given which enable subsequent filling of tablets covered in this invention. Individual pharmaceutically acceptable excipients can be used individually or in combination ensuring that the adequate porosity is reached.

The tablets are compressed with the use of appropriate compression force that must not be so low that the tablet does not meet the requirements of hardness and friability which warrant that the tablets are robust enough. Pharmaceutically acceptable excipients that can be used for the production of tablets with the porosity of 30 volume percent or more are selected form the group of metal oxides, metal silicates, metal phosphates, sugar alcohols, sugars, cellulose and cellulose derivatives. Metals are selected from the group comprised of sodium, potassium, magnesium, calcium, zinc, aluminium, titanium and silicon.

The appropriate metal oxide for the use in this invention can be selected from the group comprised of magnesium oxide, calcium oxide, zinc oxide, aluminium oxide, titanium dioxide including Tronox A-HP-328, Tronox A-HP-100, silicon dioxides including Aerosil, Cab-O- SiI, Syloid, Aeroperi, Sunsil, Zeofree, Sipernat and their mixtures.

In special cases metal oxide, titanium dioxide or silicon dioxide or their mixtures.

The silicates can be divided into the following groups:

-Bloating clays of the smectite type, e.g. bentonite, laponite

- hydrated aluminium silicates or alkali soil. Neusilin is part of the group based on synthetic polymerisation (magnesium aluminometasilicate)

-Silicon dioxides are divided into nonporous and porous silica

-Nonporous colloidal silica, e.g. aerosil (fumed silica)

-Porous gel silica, e.g. Syloid, Porasil, Licrosorp,

Others, e.g. Zeopharm S 170, Zeopharm 6000, Aeroperi 300

The tablets in this invention can contain metal oxides such as nonporous silicate, including fumed silica of the Aerosil type and/or porous silicate including e.g. Syloid, Porasil and Lichrosorp.

In other cases the pharmaceutically acceptable excipient for the use in this invention is a metal silicate selected from a group comprised of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthesised calcium silicate such as e.g. Zeolex, magnesium aluminium silicate, magnesium aluminium metasilicate, Neusilin SG2 and Neusilin US2 and their mixtures. Metal silicates can be of the bloating clay smectite type, selected from a group comprised of bentonite and laponite and/or metal silicates selected from the group of alkali silicates and aluminium silicates including magnesium aluminium metasilicate. In specific cases the metal silicate is Neusilin.

As mentioned above the appropriate excipient can be a metal carbonate such as a carbonate selected from a group comprised of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, aluminium carbonate and their mixtures.

Other salts for the use in this invention are metal phosphates isolated from the group comprised of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, calcium phosphate, magnesium phosphate, zinc phosphate or aluminium phosphate.

More specifically a more appropriate excipient can be calcium phosphate selected from a group comprised of dibasic anhydrous calcium phosphate, dibasic dihydrate calcium phosphate and tribasic calcium phosphate.

The dibasic anhydrous calcium phosphate is typically selected from a group comprised of A- Tab calcium monohydrogen phosphate, calcium orthophosphate Di-Cafos AN, dicalcium orthophosphate, E341, anhydrous Emcompress, Fujicalin, salt of phosphoric acid and calcium (1 :1), secondary calcium phosphate and their mixtures. The dibasic dihydrate calcium phosphate can be chosen from the group comprised of Cafos, calcium hydrogen orthophosphate dihydrate, calcium monohydrogen phosphate dihydrate, Calipharm, Calstar, Di-Cafos, dicalcium orthophosphate, DI-TAB, Emcompress, calcium salt of phosphoric acid (1 :1) dihydrate, secondary calcium phosphate, Fujiclin SG.

The examples of tribasic phosphate are e.g. hydroxyapatite, calcium salt of phosphoric acid (2:3), precipitated calcium phosphate, tertiary calcium phosphate, TreCafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI- TAB. Other suitable metal salts are metal sulphates such as e.g. sodium sulphate, sodium hydrogen sulphate, potassium sulphate, potassium hydrogen sulphate, calcium sulphate, magnesium sulphate, zinc sulphate and/or aluminium sulphate.

The examples of calcium sulphates are e.g. anhydrous calcium sulphate including anhydrite, anhydrous gypsum, anhydrous lime sulphate, Destab, Drierte, E516, karstenite, muriacite or calcium sulphate dihydrate including alabaster, Cal-Tab, Compactol, Destab, E516, gypsum, light spar, mineral white, native calcium sulphate, precipitated calcium sulphate, satinite, satin spar, selenite, terra alba and USG Terra Alba.

In other cases the pharmaceutically acceptable excipient can be a sugar alcohol selected from the group that includes sorbitol (such as e.g. Sorbogem, SPI Pharma), xylitol, mannitol (e.g. Mannogem, SPI Pharma), maltitol, inositol, mannitol (e.g. Pealitol SP 100) and/or a sugar selected from a group including mono-, di- or polysaccharides including saccharose, glucose, fructose, sorbose, xylose, lactose, dextran, dextran derivates and cyclodextrins.

Cellulose and cellulose derivates are also pharmaceutically acceptable excipients for tablet production with a porosity of 30% or more. The examples include cellulose, microcrystal cellulose, Celaphere, including porous cellulose pearls: cellulose acetate Celluflow TA-24 and cellulose Celluflow C-25, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose etc.

Other pharmaceutically acceptable excipients for use in tablets for subsequent filling in this invention

Of course the tablets for subsequent filling can also include other pharmaceutically acceptable excipients that are generally used in tablet production.

The term "pharmaceutically acceptable excipient" denotes a material that is inert in the sense that it does not have any therapeutic and/or prophylactic effect per se. Such an excipient is added with the purpose of facilitating the production of pharmaceutical, cosmetic and/or food formulation with appropriate and acceptable properties.

The examples of excipients for use in tablet production and subsequent filling include fillers, thinners, decomposers, binders, gliders etc. and their mixtures. Since the composition of the solid dosage form in the invention can be used for various purposes, the selection of excipients depends on the purpose of use. Other excipients, suitable for use are e.g. acidifying agents, alkalizing agents, colourings, preservatives, antioxidants, buffer capacity improving agents, chelating agents, complexing agents, emulsifϊcation agents and/or solubilising agents, aromas and perfumes, humectants, sweeteners, wetting agents, etc.

The examples of fillers, thinners and/or binders include lactose (e.g. diffusion dried lactose, α-lactose, β-lactose, Tabletoza®, various types of Avicel®, Elcema®, Vivacel, Ming Tai® or Solka Floe®), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metoloza SH Shin Etsu Ltd such as e.g. 4000 cps grade Methocel E and Metoiose 60 SH, 4000 cps grades Methocel F and Metholose 65 SH, 4000, 15000 and 100000 cps grades Methocel K and 4000, 15000, 39000 and 100 0000 grades Metholose 90 SH), methylcellulose polymers (e.g. Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethyl cellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, corn starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate, calcium carbonate, sodium alginate, collagen, etc.

Specific examples of thinning substances are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystal cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinised starch, sucrose sugar etc.

Specific examples of decomposing agents are e.g. alginic acid or alginates, microcrystal cellulose, hydroxypropyl cellulose and other cellulose derivatives, sodium salt of croscarmellose, crospovidone, potassium salt of polacrilin, sodium starch gylcolate, starch, pregelatinised starch, carboxymethyl starch (e.g. Primogel® and Explotab®).

Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethyl cellulose, microcrystal cellulose, dextrin, ethylcellulose, gelatine, liquid glucose, guarane, hydroxypropyl methylcellulose, methylcellulose, pectin, polyethyleneglycol (PEG), povidone, pregelatinised starch etc.

Glidants and lubricants can also be included in the tablet. Examples include stearic acid, magnesium stearate, calcium stearate, and other metal stearates, talcum, waxes and glycerides, also mineral oil, PEG, glyceryl behenate, colloid silica, hydrogenated vegetable oil, com starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulphates, sodium benzoate, sodium acetate etc.

Other excipients that may also be included in the tablet for subsequent nanoparticles filling in this invention are for example substances for taste enhancement, colourings, taste masking agents, pH modifying agents, buffer capacity enhancers, preservatives, stabilisers, antioxidants, wetting agents, humidity controlling agents, surface active agents, suspension agents, absorption modifying agents, release modifying agents etc.

Other excipients in the composition of a solid pharmaceutical form in this invention can be antioxidants, such as ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hydrophosphoric acid, monothioglycerol, potassium metabisulphite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulphate, sulphur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier ingredients can also contain stabilisers that amount to 1 to 5 weight percent.

The composition of the solid dose in this invention can contain one or more surface active agents or substances that have surface active properties. It is expected that these substances have a greater effect on weakly soluble active substances and therefore contribute to improving the solubility properties of active substances. Examples of surface active substances are given in the text to follow.

Excipients suitable for use in tablets for this invention are e.g. amphiphilic surfactants disclosed in WO 00/50007 under Lipocaine Inc. Examples of such surfactants include: i) polyethoxylated fatty acids such as mono or diester fatty acids with polyethyleneglycol or their mixtures, for example mono or diester of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, linoleic acid and polyethylene glycol that can be selected among PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEGlO, PEG12, PEGl 5, PEG20, PEG25, PEG30, PEG32, PEG40, PEG45, PEG50, PEG55, PEGlOO, PEG200, PEG400, PE600, PEG800, PEGlOOO, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, PEGlOOO, PEG10,000, PEG 20,000, PE 35,000; ii) fatty acid ethers with polyethylene glycol glycerol, these are esters, as mentioned before, but in the form of glyceryl esters with individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters e.g. with vegetable oils, such as e.g. hydrogenated castor oil, almond oil, palm seed oil, castor oil, apricot seed oil, olive oil, peanut oil, hydrogenated palm seed oil and similar; iv) polyglycerated fatty acids, such as polylglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate; v) esters of fatty acids with propylene glycol, such as e.g. propylene glycol monolaurate, propylene glycol ricinoleate and similar; vi) mono and diglycerides such as glyceryl monooleate, glyceryl dioleate, glyceryl mono and/or dioleate, glyceryl caprylate etc.; vii) sterols and sterol derivatives; viii) esters of polyethylene glycol sorbitan and fatty acids (fatty acid esters and PEG- sorbitan) such as PEG esters with different molecular masses as this is outlined above, as well as different Tweens; ix) alkyl esters of polyethyl polyethylene glycol, such as e.g. PEG oleyl ether and lauryl ether OE; x) sugar esters, such as sucrose monopalmitate, sucrose monolaurate; xi) polyethylene glycol alkyl phenols such as e.g. Triton® of the X or N series; xii) Polyoxyethylene- polyoxypropylene block copolymers, such as series Pluronic®, series Sanperonic®, Emkalyx®, Lutrol®, Supronic® etc. The general term for these polymers is poloxamer and the relevant examples in this context are the following Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212,

215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401,

402, 403, 407; xiii) esters of fatty acids and sorbitan, such as the series Span® or series Ariacel®, such as e.g. sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate; xiv) esters of fatty acids with lower level alcohols, such as e.g. oleate isopropyl myristate, isopropyl palmitate etc.; xv) ionic surfactants including cationic, anionic and zwitterionic surfactants, such as e.g. fatty acid salts, gall acid salts, phospholipides, esters of phosphoric acid, carboxylates, sulphates and sulphonates etc.

When a surface active substance or their mixture is present in the composition of the solid dose in this invention, the concentration surface active substances is normally from 0.1 to 80%, such as for example from approximately to 0.1 % to 20 weight percent, from approximately 0.1% approximately 15 weight percent, from approximately 0.5% to approximately 10 weight percent, or alternatively from approximately 0.1% to 80 weight percent, as for example from approximately 10% to approximately 70 weight percent, from approximately 20% to approximately 60 weight percent or from approximately 30% to approximately 50 weight percent.

Tablets Filled with Fluid Nanoparticle Formulation

Tablets described above are designed in such a manner that they can be filled with a pharmaceutically acceptable formulation of nanoparticles under the action of ultrasound with a concentration of approximately 20 weight percent or more, such as approximately 25 weight percent or more, approximately 30 weight percent or more (calculated according to the total weight of the solid dosage form after filling).

Primarily the pharmaceutically acceptable fluid nanoparticle formulation is present in a concentration of approximately 20 weight percent or more, such as approximately 30 weight percent or more, approximately 40 weight percent or more (depending on the total weight of the solid dosage form after filling).

The critical parameters in connection with tablet filling under ultrasound are wetting and viscosity. Filling is performed by immersing the tablet in a suspension of nanoparticles in a solvent that wets the tablets well so as to facilitate capillary suction into the tablet.

Furthermore, the pharmaceutically acceptable fluid nanoparticle formulation has a normal melting point minimally around 0 ⁰C and maximally 250 ⁰C, such as approximately 5 ⁰C or more, approximately 10 ⁰C or more, approximately 15 ⁰C or more, approximately 20 ⁰C or more. The melting point is not such a critical temperature, because the fluid nanoparticle formulation can be heated or cooled during the ultrasound filling.

The pharmaceutically acceptable fluid nanoparticle formulation can be water-based, or based on an organic solvent base or on an oil-like solvent.

Oil-like solvents for this invention can be selected from an array of plant oils, hydrogenated plant oils or animal oils.

Suitable examples are apricot oil, almond oil, avocado oil, coconut oil, cocoa butter, corn oil, cotton seed oil, grape seed oil, jojoba oil, linseed oil, wheat oil, olive oil, palm seed oil, peanut oil, poppy seed oil, rapeseed oil, sesame oil, soy seed oil, sunflower oil, gokhru seed oil, nut tree oil, beef fat, pork fat, whale fat and their mixtures. Other examples of hydrophilic oils or oils similar to the selected group comprised of polyether glycols, such as polyethylene glycols, polypropylene glycols, polyoxyethylenes, polyoxypropylenes, poloxameres and their mixtures; or a selection from the group represented by: xylitol, sorbitol, sodium potassium tartrate, saccharose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13 and other Gelucires, such as Gelucire 44/14 etc., Gelucire 50/10, Gelucire 61/05, Sucroester 7, Sucroester 11, Sucroester 15, maltose, mannitol and their mixtures.

Oil-like substances can also be hydrophobic oils or oil-like substances selected from a group comprised of linear saturated hydrocarbons, sorbitan esters, paraffins, fats and oils, such as cocoa butter, beef fat, pork fat, polyether glycol esters, higher fatty acids, such as e.g. stearic acid, myristic acid, palmitic acid, higher alcohols, such as e.g. cetanol, stearol, waxes with lower melting-points, such as e.g. glyceryl monostearate, glycerol monooleate, hydro genated fat, myristyl alcohol, stearyl alcohol, substituted and/or non substituted monoglycerides, substituted and/or non substituted diglycerides, yellow beeswax, white wax, palm wax, castor wax, Japanese wax, acetilate monoglycerides, NVP polymers, PVP polymers, acryl polymers and their mixtures.

Suitable polyethyleneglycols usually have a molecular mass in the range of approximately 400 to approximately35000, as in approximately 800 to approximately 35000, from approximately 1000 to approximately 35000, such are polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 5000, polyethylene glycol 6000, polyethylene glycol 7000, polyethylene glycol 8000, polyethylene glycol 9000, polyethylene glycol 10000, polyethylene glycol 15000, polyethylene glycol 20000, polyethylene glycol 35000. In some situations polyethylene glycol with a molecular mass of approximately 35000 to approximately 100 000 can be used.

In specific cases oils and oil-like substances can be polyethyleneoxides with a molecular mass of approximately 2000 to approximately 7 000 000, such as around 2 000 to 100 000, from approximately 5 000 to around 75 000, from approximately 10 000 to around 60 000, from approximately 15 000 to around 50 000, from approximately 20 000 to around 40 000, from approximately 100 000 to around 7 000 000, as in approximately 100 000 to around 1 000 000, from approximately 100 000 to around 600 000, from approximately 100 000 to around 400 000 or from approximately 100 000 to around 300 000.

In this invention poloxamers can also be used. These examples include Poloxamer 188, Poloxamer 237, Poloxamer 338, or Poloxamer 407, other block copolymers of ethylene oxide and propylene oxide as in the series Pluronic^® and/or Tetronic^®. The primary block of the Pluronic^® series include polymers with a molecular mass of around 3000 or more, such as approximately 4000 to 20 000 and/or viscosity measured with a Brookfield viscometer from approximately 200 to around 4000 cps, such as e.g. approximately 250 to around 3000 cps. Suitable examples include Pluronic^® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc. The primary block of copolymers of the Tetronic^® series include polymers with a molecular mass of around 8000 or more, such as from around 9 000 to around 35 000 and/or viscosity measured with a Brookfield viscometer of around 500 to 45 000 cps, such as from 600 to around 40 000. Viscosity values given above are measured at 60 ⁰C for paste-like substances at room temperature and at 77 ⁰C for substances that are solid at room temperature. In the second example, the oils and oil-like substances, sorbitan esters, such as sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate , sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate or their mixtures.

Additionally or alternatively, oils or oil-like substances, mixtures of different oils or oil-like substances can be used, such as e.g. a mixture of hydrophilic and/or hydrophobic substance or solvents semi-hard excipients such as e.g. propylene glycol, polyglycolisated glycerides including Gelucire 44/14, complex substance fatty acids of plant origin such as cocoa oil and palm wax, vegetable oils, such as almond oil, coconut oil, corn oil, cottonseed oil, soy seed oil, olive oil, castor oil, palm seed oil, peanut oil, rapeseed oil, grape seed oil, hydrogenated vegetable oils, such as hydrogenated peanut oil, hydrogenated palm seed oil, hydrogenated cotton seed oil, hydrogenated soy oil, hydrogenated castor oil, hydrogenate coconut oil, natural fats of animal origin including beeswax, lanolin, fatty alcohols including cetyl alcohol, lauryl, myrystil, palmityl, stearine fatty alcohols; esters including glycerol stearate, ethyl oleate, isopropyl myristate; fluid interesterificated semi-synthetic glycerides including Miglicol 810/812; amides or alcaloamides of fatty acids including steramid ethanol diethanolamide with fatty coconut acids, acetic acid esters with mono- and diglycerides, citric acid with mono- and diglycerides, lactic acid esters with mono- and diglycerides, polyglycerol esters of fatty acids, polyglycerol, polyricinoleate, esters of fatty acids with propylene glycol, sorbitan monostearates, sorbitan tristearates, sodium stearoyl lactylates, calcium stearoyl lactylates, diacetyltartaric acid esters with mono and diglycerides etc.

The pharmaceutically acceptable fluid formulation can also be in the form of a nanoparticle dispersion in the shape of an emulsion or micro emulsion.

Typically the concentration of a pharmaceutically acceptable fluid nanoparticle formulation in a tablet is around 4 weight percent or more, as in e.g. around 10 weight percent or more, around 15 weight percent or more, around 20 weight percent or more, around 25 weight percent or more, around 30 weight percent or more, around 35 weight percent or more, around 40 weight percent or more, around 45 weight percent or more, around 50 weight percent or more, around 60 weight percent or more, around 70 weight percent or more.

Moreover, the tablets are formulated in such a manner that they release the active ingredient immediately or via a modified process. Tablets designed for immediate release have a typical decay time of maximal 15 minutes, measured with the decay test described by Ph Eur, as for the film coated tablets, they have a decay time of 30 minutes. For the modified release, the kinetics of active substance release is important.

Comparison of the tablets produced with the innovative procedure with the use of ultrasound and the comparative examples where a magnetic stirrer was used, shown in Table 1 proves that with the use of ultrasound a greater fullness of tablets with nanoparticles is achieved, as opposed to the filling without ultrasound or with the use of a magnetic stirrer. The result is a consequence of a far deeper trickling of nanoparticles into the pores of tablets with the use of ultrasound (Figs. IA and IB) as compared to the use of magnetic stirrer or without the use of ultrasound (Figs. 2B and 2B).

The invention will be described with added figures, a table and practical examples.

Example 1

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles of BaSO4 in the size of 190 nm were measured with a laser diffractometer Mastersizer S (Malvern^Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was submerged for one minute in the suspension and filled with the use of a ultrasound immersion tank. During that time, the tablets did not decay. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure.

Example 2

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles of ZnS the size of 170 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was submerged for one minute in the suspension and filled with the use of a ultrasound immersion tank. During that time, the tablets did not decay. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure. Example 3

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60°C. Nanoparticles of TiO₂ in the size of 600 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was submerged for one minute in the suspension and filled with the use of a ultrasound immersion tank. During that time, the tablets did not decay. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure.

Example 4

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles of ZnS the size of 170 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was submerged for one minute in the suspension and filled with the use of a ultrasound immersion tank. During that time, the tablets did not decay. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60⁰C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure. The procedure was repeated again, which yielded double filled tablets.

Comparative Example 1

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles Of BaSO₄ in the size of 190 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was immersed in the suspension and filled by using a magnetic stirrer for 20 minutes. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure.

Comparative Example 2

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles of ZnS the size of 170 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was immersed in the suspension and filled by using a magnetic stirrer for 20 minutes. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure.

Comparative Example 3

Silicised microcrystal cellulose (prosolv HD90, JRS Pharma, Rosenberg, Germany) was used for a production of tablets with a mass of 400 mg and a diameter of 12 mm. For tablet compression the tabletting machine SP3000 (Kilian, Cologne, Germany) was used. The hardness of tablets was 85 N. Before the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. Nanoparticles of TiO₂ in the size of 600 nm were measured with a laser diffractometer Mastersizer S (Malvern, Great Britain) and dispergated in ethanol (concentration 20 weight percent). An empty tablet was immersed in the suspension and filled by using a magnetic stirrer for 20 minutes. After the filling procedure, the tablets were dried for an hour in a vacuum dryer at 60 °C. The effectiveness of the filling was proven by weighing the tablets before and after the filling procedure. Test 1

To confirm the effectiveness of the of the tablet nanoparticle filling procedure with the use of ultrasound, the mass of filled and empty tablets was weighed. The results of the effectiveness of filling are given in Table 1 :

Table 1 :

Test 2

To confirm the improved efficiency of nanoparticle tablet filling with the use of ultrasound, measurements have been made with an electron microscope Supra VV35 (Zeiss, Germany) and the use of EDS detector to measure how deep into the tablet the nanoparticles have reached by preparing a cross section of the tablet.

Claims

1. Porous tablets for subsequent filling with an active substance where the base tablets are produced by known procedures, labelled by which the basic pharmaceutical tablets are comprised only of excipients used in pharmaceutical industry that are not soluble in organic solvents and decay in contact with them, and are then filled with the use of nanoparticle suspension with an active substance in organic solvent with the use of ultrasound.

2. The tablets under claim 1 above are labelled to indicate that the excipients are lactose and/or SiO₂ and/or with SiO₂ treated macrocrystalline cellulose in different ratios.

3. The tablets in claim 1 are labelled to indicate that they are stable for at least 1 minute in organic solvent with simultaneous ultrasound use.

4. The tablets in claim 1 are to be labelled to indicate organic solvents in which the dispergation of nanoparticles is carried out with the active substance are heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propylacetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, t- butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethylacetate, ethylether, ethyl fumarate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2- dichloroethane, dichloromethane, 1 ,2-dimetoxietane, N,N-dimethylacetamide, N ,N- dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamid, hexane, methanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluene, xylene or a mixture of two or more of the mentioned solvents.

5. The tablets in claim 1 are labelled to indicate that a glidant is added to the powder mixture for tabletting before the tabletting procedure.

6. The tablets in claim 4 are labelled to indicate that Mg stearate is used as glidant.

7. The tablets in claim 1 are labelled to indicate that the tablets have a mass from 50 mg to 1000 mg.

8. The procedure of porous tablet production for subsequent filling with the active substance in claims 1 through 5, labelled as the tablet bases are immersed into an excess suspension of active nanoparticle substance in organic solvent.