Patent Description:
Solid dosage forms are preferential in pharmaceutical industry, especially tablets. To attain tablets of a sufficient quality pharmaceutical excipients which do not possess pharmacologic activity are used and are added to active pharmaceutical ingredient, in particular to enhance tableting properties that are essential for production of tablets.

Important group of pharmaceutical excipients are fillers, comprising different sugars, wherein lactose is the most extensively used in a pharmaceutical industry. In pharmaceutical processing is vital that said fillers demonstrate suitable properties, in particular good flowability and compressibility, especially with regard to tablets (<NPL>). Commercially accessible types of lactose for direct compression are prepared by different methods, therefore they possess different physicochemical properties with an intention to improve process difficulties with regard to poor flowability and/or compressibility. Lactose is frequently produced with crystallization in the first stage, followed by milling and/or sieving in the second, respectively. The outcomes of the milling process are often particles with sharp edges, irregular form and small size that can have poor tableting properties, therefore are commonly subject of improvement. This is often achieved by procedures comprising: granulation, spray drying, physical modification of particles (dehydration, partial pregelatinization, etc.), co-processing, etc. (<NPL>; <NPL>). Additional stages of manufacturing of lactose particles after crystallization are time consuming and less economical, therefore there is a substantial need for a plain, convenient and more economical process for a production of directly compressible lactose particles. Spherical crystallization, and more particularly, spherical agglomeration is considered as an adequate alternative technique to aforementioned methods. Spherical agglomeration is a complex process, wherein crystallization of primary particles and agglomeration of said primary particles occur concurrently leading to formation of spherical agglomerates. Spherical agglomeration is only possible within maintained narrow crystallization conditions, therefore the parameters which lead to suitable conditions are difficult to discover. For effective spherical agglomeration process a plurality of, but not limited to, parameters are essential, such as composition of solvents, viscosity of a crystallization system, supersaturation of a solute solution, temperature of the crystallization system and stirring parameters that establish adequate hydrodynamic conditions. An appropriately guided process results in spherical agglomerates with adequate flow properties for tableting, high intrapartical porosity and brittleness that demonstrate great compressibility (Kovačič B, Vrečer F, Planinšek O. Spherical crystallization of drugs. Acta Pharmaceutica <NUM>; <NUM>: <NUM>-<NUM>).

The preparation of agglomerated crystals of lactose is also described in article "<NPL>), wherein to the lactose solution in water various volumes of ethanol was added.

The object of the present invention is to provide particles of spherically agglomerated lactose for direct compression with good flowability and compressibility produced in uniform process of spherical agglomeration without additional process stages (e.g. granulation, spray drying, etc.) required for improving flowabiltiy and compressibility.

Characteristics of particles are critical for adequate flow and compression properties of a tableting mixture in production of solid dosage forms like tablets. Flowability of a tableting mixture depends on particle size, its shape and morphology. Particles with smooth and round morphology with particle size larger than <NUM> are desired. Porosity of particles affects compression properties. The strength of tablets depends on number and potency of intraparticle and interparticle contact points that are formed during the production of dosage form, thus particles with large specific surface area and highly brittle particles are desired. Higher tablet strength prevents or minimizes very common tablet defects such as lamination and capping. Additionally, mechanical properties of tablets for handling and packaging are improved.

The simplest and most economical way of producing tablets is direct compression as it consists of two stages - blending of final tableting mixture and compression of said mixture into a tablet. Initial particles of which a tableting mixture is made of have often poor flowability and compressibility, therefore direct compression is not feasible. Hence, appropriate treatment of particles with granulation is necessary to obtain particles with good flowability and compressibility. Granulation is undesirable because specific equipment is necessary and many process stages are required to obtain tablets in comparison to direct compression.

Significant problem of a direct compression process is an occurrence of segregation or stratification of tableting mixture which has a significant influence on uniformity of content in a tablet and stability of the process itself. Segregation is commonly encountered during blending of tableting mixture, transport of tableting mixture, transfer of said mixture from blender to hopper and during tableting process because of elevated vibrations of tablet press, especially during higher tableting speeds. Segregation is mostly a consequence of difference in particle size, shape, density and adhesion forces among particles of different components in a tableting mixture. It can be limited by transformation of particles into granules but granulation is undesirable because specific equipment is necessary and many process stages are required to obtain tablets in comparison to direct compression. Segregation can be reduced or prevented by employing adequate excipient, therefore there is a substantial need for an excipient, with particles having porous structure and demonstrate suitable morphologic properties, like increased particle outer contact surface that prevents segregation.

Many different types of lactose for direct compression are available on the market. They differentiate in particle size, shape, porosity, etc. (<NPL>; <NPL>; <NPL>). Some types of lactose for direct compression possess good flowability but poor compressibility at the same time, or vice versa. Therefore, there is a substantial need for lactose particles which possess as many as possible favourable tableting properties, such as reduction or prevention of segregation and concurrently have good flowability and compressibility.

Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention along with the presented drawings.

The object of the present invention are particles of spherically agglomerated lactose for direct compression with favourable tableting properties produced in simple, economic and uniform process of spherical agglomeration. The first aspect of the present invention are porous particles of spherically agglomerated lactose with an average particle size of <NUM> to <NUM>, more preferably of <NUM> to <NUM> and most preferably of <NUM> to <NUM>. Due to the production method of said particles of spherically agglomerated lactose, said particles demonstrate characteristic radial arrangement of prism-like primary particles, i.e. the primary particles are in a form of prism and/or in a form similar to prism, that form spherical agglomerate of lactose and furthermore enable improved tableting properties. Because of their typical structure particles of spherically agglomerated lactose possess high brittleness, are more prone to fragmentation upon compression and have higher specific surface area in comparison to commercially accessible types of lactose particles for direct compression. Another aspect of the present invention are particles of spherically agglomerated lactose with a specific surface area of <NUM>,<NUM> to <NUM>,<NUM><NUM>/g, more preferably of <NUM>,<NUM> to <NUM>,<NUM><NUM>/g and most preferably of <NUM>,<NUM> to <NUM>,<NUM><NUM>/g.

Particles of spherically agglomerated lactose of the present invention are highly compressible by means of more rapid reduction of porosity and volume, respectively. The result of a rapid reduction of volume and porosity are tablets of higher strength and higher tensile strength, respectively. It is not possible to determine the compressibility of lactose particles only due to the fact that the tablet produced of only lactose particles is not suitable for further handling and performing evaluation tests. For adequate measurement and determination of the compressibility additional pharmaceutical excipients have to be added. Hence, for determination of compressibility of tablets obtained from particles of spherically agglomerated lactose of the present invention the following tableting mixture composition was employed: <NUM>,<NUM> w/w % of particles of spherically agglomerated lactose of the invention and <NUM>,<NUM> w/w % of other pharmaceutical excipients. Compressibility was determined with modified out-die Walker analysis (<NPL>; <NPL>). The Walker coefficient for tableting mixture composed of particles of spherically agglomerated lactose of the invention is between <NUM>,<NUM> to <NUM>,<NUM> % and more preferably between <NUM>,<NUM> to <NUM>,<NUM> %.

Lactose particles, intended for use as a pharmaceutical excipient are commonly formed with crystallization procedures, followed by milling and additional processing (e.g. spray drying, granulation, etc.) for improving flowability and/or compressibility of particles. Surprisingly and unexpectedly it has been found out that with a following method we can obtain lactose particles having good flowability and compressibility, without further processing requirement to improve these properties.

Another aspect of the present invention is a method of producing particles of spherically agglomerated lactose, said method comprising the following steps:.

Lactose used to obtain lactose solution may be present in a solid state in any isomer form (a-lactose monohydrate, anhydrous lactose and β-lactose) or in a combination of two or more isomer forms in all ratios. Nonsolvent in the present invention is selected from a group comprising ethanol, n-propanol and <NUM>-propanol. More preferable nonsolvent is <NUM>-propanol and most preferable ethanol. Nonsolvent may also be a mixture of selected alcohols and/or a mixture of water and selected alcohol and/or mixtures of the several selected alcohols and water, wherein the mass ratio of alcohol in resulted mixture of water and alcohol/alcohols is higher than <NUM> %.

Solvent in the present invention is water. A mixture of water and alcohol may be used, however this is not part of the invention, wherein alcohol in the mixture is one or more alcohols, but not limited to, selected from a group comprising methanol, ethanol, n-propanol, <NUM>-propanol, n-butanol, wherein the mass ratio of a selected alcohol/alcohols in the resulted mixture of water and alcohol/alcohols is lower than <NUM> % and more preferable lower than <NUM>%.

Those skilled in the art will appreciate that a separation of the final product, i.e. particles of spherically agglomerated lactose may be achieved by any means of separation, preferably with filtration. Drying of separated humid lactose particles may be achieved with any known technique for drying.

Another aspect of the present invention is the use of particles of spherically agglomerated lactose in powder mixtures for direct compression comprising at least one active pharmaceutical ingredient and optionally other pharmaceutical excipients usually used in production of tablets. Capping and lamination of a tablet is a common defect obtained during tableting. Those skilled in art usually avoid this defect by producing tablets with higher strength or higher tensile strength. Particles of spherically agglomerated lactose according to the invention enable production of tablets of higher strength or higher tensile strength upon compression with relatively lower force than tablets obtained from commercially available types of lactose.

The determination of tensile strength of tablets produced from lactose particles only is not possible because the produced tablet does not attain suitable properties for performing required tests; therefore the addition of other suitable pharmaceutical excipients is necessary. For determination of a tablet tensile strength, a tableting mixture composed of <NUM>,<NUM> w/w % of particles of spherically agglomerated lactose of the present invention and <NUM>,<NUM> w/w % of other pharmaceutical excipients is employed. Tablets produced from particles of spherically agglomerated lactose presented in this invention upon compression pressure of <NUM> MPa have tensile strength from <NUM>,<NUM> to <NUM>,<NUM> MPa, more preferably from <NUM>,<NUM> to <NUM>,<NUM> MPa and most preferably from <NUM>,<NUM> to <NUM>,<NUM> MPa.

Another aspect of the present invention is the use of particles of spherically agglomerated lactose for reduction or prevention of segregation that can be encountered during blending of tableting mixture, transport of tableting mixture, transfer of said mixture from blender to hopper and during tableting process because of elevated vibrations of tablet press. Particles of spherically agglomerated lactose prepared by the disclosed method has porous structure and favourable morphologic properties, like increased particle outer contact surface that enable mechanical entrapment of particles of active pharmaceutical ingredient between primary particles of spherical agglomerate. Proportion of the adhered active pharmaceutical ingredient onto the particles of spherically agglomerated lactose is increased by this way, resulting in improved homogeneity of mixture for production of solid dosage forms and thus effectively reduces or prevents segregation in comparison to other commercially available types of lactose.

Average particle size was determined with the laser diffraction method (e.g. Mastersizer S, Malvern, Great Britain) by dispersion of lactose particles in <NUM> v/v % ethanol.

Specific surface area of spherical agglomerates of lactose was determined wit adsorption BET (Brunauer, Emmett, Teller) analysis (TriStar <NUM>, Micromeritics, USA; nitrogen gas used).

Tensile strength was determined with compression of tableting mixture with the following composition: <NUM>,<NUM> w/w % particles of spherically agglomerated lactose according to the invention or commercially available types of lactose particles, <NUM>,<NUM> w/w % binder copovidone (Kollidon® VA <NUM>, BASF, Germany) and <NUM>,<NUM> w/w % anti-adhesive magnesium stearate (Ligastar MG <NUM>, Peter Greven, Germany). Those skilled in the art will appreciate that tableting mixture was prepared by known procedures, wherein preceding sieving for removal of larger particles was employed followed by addition of individual components of tableting mixture and mixing of tableting mixture to obtain proper homogeneity. Tablets with a mass <NUM> were compressed with a single punch tablet press (Kilian SP300, IMA Kilian, Germany) with a flat round punch of the diameter <NUM>,<NUM> and compression pressure range from <NUM> to <NUM> MPa. <NUM> hours after compression of tablets the strength of tablets was measured (Vanderkamp VK <NUM>) and the tensile strength of tablets compressed at <NUM> MPa was calculated (<NPL>).

For the same tableting mixtures made in the same way as defined above the compressibility was determined by an out-die Walker analysis. <NUM> hours after compression, the tablets mass and size were determined. From obtained data the Walker profile was designed. Walker profile demonstrates dependence of a specific volume with regard to the compression pressure. With a linear regression a slope of a linear part of a curve (compression pressure in range from <NUM> to <NUM> MPa) is determined that represents Walker coefficient (w').

The present invention will be described in more detail with the reference to the examples.

<NUM> of lactose is dissolved in <NUM> of purified water at elevated temperature. The solution of lactose is then regulated at <NUM>. <NUM> of ethanol-water mixture (<NUM> v/v % ethanol) is regulated at temperature of <NUM>. Aqueous lactose solution is added to ethanol-water mixture at a flow rate of <NUM>,<NUM>/min under constant stirring conditions of <NUM> revolutions per minute with a <NUM>-bladed mechanical stirrer. Crystallization system is regulated at constant temperature of <NUM>. After the addition of aqueous lactose solution stirring is continued for additional <NUM> minutes at the temperature of crystallization system <NUM>. Formed suspension is vacuum filtrated and dried in a laboratory drier for <NUM> hours at <NUM>.

Particles in Example <NUM> are prepared by the same procedure as described in Example <NUM>, except that the initial ethanol-water mixture (<NUM> v/v % ethanol) and the crystallization system are regulated at temperature of <NUM>.

Average particle size of dried particles prepared by Example <NUM>-<NUM> was measured with a laser diffraction method and is shown in Table <NUM>.

The morphology of particles prepared by Example <NUM>-<NUM> was examined using scanning electron microscope. Particle morphology is shown in <FIG>.

As seen in Table <NUM>, the temperature of the ethanol-water mixture and further crystallization system does not have significant impact on particle size. Morphology of prepared particles is similar in all examples. Particles are porous spherical agglomerates composed of many primary particles (e.g. prisms, needles, etc.) arranged radially outwards from the centre of the particle and form a bigger agglomerate structure. Particles prepared in Example <NUM> demonstrate the best tableting properties with regard to flowability and compressibility.

<NUM> of lactose is dissolved in <NUM> of purified water at high temperature. The solution of lactose is then regulated at <NUM>. <NUM> of ethanol-water mixture (<NUM> v/v % ethanol) is regulated at temperature of <NUM>. Aqueous lactose solution is added to ethanol-water mixture at a flow rate of <NUM>,<NUM>/min under constant stirring conditions of <NUM> revolutions per minute with a <NUM>-bladed mechanical stirrer. Crystallization system is regulated at constant temperature of <NUM>. After the addition of aqueous lactose solution, stirring is continued for additional <NUM> minutes at the temperature of crystallization system <NUM>. Formed suspension is vacuum filtrated and dried in a laboratory drier for <NUM> hours at <NUM>.

Particles in Example <NUM> are prepared by the same procedure as described in Example <NUM>, except that <NUM> of lactose was dissolved in <NUM> of purified water at high temperature.

Average particle size of dried particles prepared by Example <NUM>, <NUM> and <NUM> was measured with a laser diffraction method and is shown in Table <NUM>.

The morphology of particles prepared by Example <NUM>, <NUM> and <NUM> was examined using scanning electron microscope. Particle morphology is shown in <FIG>.

As seen in Table <NUM>, the initial aqueous lactose concentration has an impact on an average particle size. Lower initial aqueous lactose concentration yields smaller spherical agglomerates in comparison to higher initial aqueous lactose concentration, while morphology of all particles prepared in Example <NUM>, <NUM> and <NUM> is still adequate.

<NUM> of lactose is dissolved in <NUM> of purified water at high temperature. The solution of lactose is then regulated at <NUM>. <NUM> of ethanol-water mixture (<NUM> v/v % ethanol) is regulated at temperature of <NUM>. Aqueous lactose solution is added to ethanol-water mixture at a flow rate of <NUM>,<NUM>/min under constant stirring conditions of <NUM> revolutions per minute with a <NUM>-bladed mechanical stirrer. Crystallization system is regulated at constant temperature of <NUM>. After the addition of aqueous lactose solution, stirring is continued for additional <NUM> minutes at the crystallization system temperature of <NUM>. Formed suspension is vacuum filtrated and dried in a laboratory drier for <NUM> hours at <NUM>.

Average particle size of dried particles prepared by Example <NUM> was measured with a laser diffraction method and morphology of particles was examined by scanning electron microscope. Particle morphology is shown in <FIG>.

Average size of particles prepared by Example <NUM> is <NUM>,<NUM>. Moreover, it is demonstrated that different stirring velocity provides particles with adequate size and adequate morphologic properties.

Example <NUM> depicts direct compression of a tableting mixture, comprising particles of spherically agglomerated lactose prepared in Example <NUM> and illustrates some important technical characteristics of spherical agglomerates in comparison to commercially available particles of lactose. Reference lactose particles are commercially available lactose particles used as fillers for direct compression. Particles of spherically agglomerated lactose according to the invention were compared to following reference lactose particles: Tablettose® <NUM> (Meggle, Germany), Tablettose® <NUM> (Meggle, Germany), Lactopress® SD250 (DFE Pharma, Germany), SuperTab® 11SD (DFE Pharma, Germany) in SuperTab® 14SD (DFE Pharma, Germany). Tablettose® particles are agglomerates of primary particles produced in a granulation process, while Lactopress® and SuperTab® particles are obtained by spray drying process.

Tableting mixtures were prepared with the following composition: <NUM>,<NUM> w/w % particles of spherically agglomerated lactose according to the invention or commercially available types of lactose particles, <NUM>,<NUM> w/w % binder copovidone (Kollidon® VA <NUM>, BASF, Germany) and <NUM>,<NUM> w/w % anti-adhesive magnesium stearate (Ligastar MG <NUM>, Peter Greven, Germany). Those skilled in the art will appreciate that tableting mixtures were prepared by known procedures, wherein preceding sieving for removal of larger particles was employed, followed by addition of individual components of tableting mixture and mixing of tableting mixture to obtain proper homogeneity. Tablets with a mass of <NUM> were compressed with a single punch tablet press (Kilian SP300, IMA Kilian, Germany) with a flat round punch of a diameter <NUM>,<NUM> and compression force range from <NUM> to <NUM> MPa. <NUM> hours after compression of tableting mixtures the strength of tablets was measured (Vanderkamp VK <NUM>) and the tensile strength of tablets compressed at <NUM> MPa was calculated (<NPL>). Tableting mixtures of the examples are named after lactose, of which they are prepared.

For the same tableting mixtures made in the same way as defined above the compressibility was determined by an out-die Walker analysis. <NUM> hours after compression, the tablets mass and size were determined. From obtained data the Walker profile was designed. Walker profile demonstrates dependence of a specific volume with regard to the compression pressure. With a linear regression a slope of linear part of a curve (compression pressure from <NUM> to <NUM> MPa) is determined that represents Walker coefficient (absolute slope multiplied with one hundred; w').

<FIG> represents graph of so obtained Walker profiles of selected tableting mixtures. Specific volume of tableting mixture prepared from particles of spherically agglomerated lactose obtained by Example <NUM> is significantly higher in comparison to the reference tableting mixtures, composed of commercially available lactose particles. Significantly higher specific volume of tableting mixture prepared from particles of spherically agglomerated lactose obtained by Example <NUM> may be due to higher intraparticle porosity, as is clearly observed from scanning electron microscope photos, while interparticle porosity is similar among all tableting mixtures. Furthermore, particles of spherically agglomerated lactose prepared by Example <NUM> are increasingly more compressible as the specific volume is reduced more rapidly compared to the reference lactose particles which is demonstrated in significantly steeper slope and greater Walker coefficient (w', Table <NUM>).

Compression characteristics can be characterized with a compactibility profile, as shown on <FIG>. It demonstrates that particles of spherically agglomerated lactose have greater compactibility in comparison to the reference lactose particles. Tensile strength of tablets made out of tableting mixture composed of particles of spherically agglomerated lactose by Example <NUM> is significantly higher within all pressure range compared to the reference lactose particles. Higher tensile strength prevents very common tablet defects like capping and lamination, and at the same time provides increased mechanical resistance necessary for further tablet handling and packaging. Values of tensile strength measured at compression pressure <NUM> MPa are presented in Table <NUM>.

Compression properties of selected tableting mixtures are presented in Table <NUM> in the form of Walker coefficient and tensile strength at compression pressure of <NUM> MPa. Particles of spherically agglomerated lactose prepared by Example <NUM> have superior compression properties compared to the reference lactose particles, defined with higher compressibility as well as higher compactibility (higher tensile strength). They show much desired qualities with regard to compression properties of particles. Particles of spherically agglomerated lactose according to the invention are highly porous and because of their characteristic radial structure are more brittle and highly breakable, hence the number of contact points between particles upon compression is increased which increases tensile strength of tablets.

Average particle size and BET specific surface area of reference (spray dried and agglomerated) lactose particles that gave highest tensile strength of tablets and particles of spherically agglomerated lactose obtained by Example <NUM> were measured. Results are shown in Table <NUM>.

Particles of spherically agglomerated lactose obtained by Example <NUM> have significantly higher specific surface area compared to reference lactose particles. This represents one of the essential characteristics of particles of lactose according to the invention and is attributed to their characteristic internal structure. Particle of spherically agglomerated lactose is composed of many prism-like primary particles which are radially organised in a characteristic structure that significantly increase specific surface area compared to the reference lactose particles.

Example <NUM> presents the use of particles of spherically agglomerated lactose prepared by Example <NUM>.

Atorvastatin, lactose, microcrystalline cellulose, polyvinylpyrrolidone and croscarmellose sodium are sieved through sieve <NUM>, weighted and homogenously mixed. Magnesium stearate is added and obtained powder mixture additionally mixed for <NUM> minutes. Tableting mixture is compressed into tablets with a theoretical mass of <NUM>,<NUM>.

Example <NUM> presents the use of spherical agglomerates of lactose prepared by Example <NUM>.

Fluoxetine, lactose, microcrystalline cellulose and sodium starch glycolate are sieved through sieve <NUM>, weighted and homogenously mixed. Magnesium stearate is added and obtained powder mixture additionally mixed for <NUM> minutes. Tableting mixture is compressed into tablets with a theoretical mass of <NUM>,<NUM>. Tablets may be optionally coated to assure prolonged release.

Prednisolone, <NUM>,<NUM> of lactose for granulation, microcrystalline cellulose and corn starch are sieved through sieve <NUM>, weighted and placed into a high-shear mixer. Granulation is achieved with water addition. Wet granules are sieved and dried. Silicon dioxide, sodium starch glycolate and lactose (by Example <NUM>) are extragranularly added to dried granules and mixed homogenously. In so obtained powder mixture magnesium stearate is added and again mixed homogenously. Tableting mixture is compressed into tablets with a theoretical mass of <NUM>,<NUM>.

Example <NUM> presents the comparison between the proportion of adherence of a model substance tartrazine onto the particles of spherically agglomerated lactose obtained by Example <NUM> and the proportion of adherence onto the reference commercially available lactose particles for direct compression. Particles of spherically agglomerated lactose obtained by Example <NUM> were compared to Tablettose® <NUM> (Meggle, Germamy) and Flowlac® <NUM> (Meggle, Germany).

Particle size fraction of lactose higher than <NUM> and particle size fraction of tartrazine below <NUM> were obtained by means of sieving. Binary mixtures of tartrazine and individual lactose were prepared in mass ratio <NUM>:<NUM>. Mixtures were blended in laboratory type mixer (Bioengineering Inversina) for <NUM> minutes with <NUM> revolutions per minute. Prepared mixtures were exposed to a mechanical stress that simulates conditions during tableting process which can lead to segregation. Prepared mixtures were sieved for <NUM> minutes (sive size <NUM>) on an agitation plate (Retsch AS <NUM>) with an amplitude <NUM>. Remaining fraction on the sieve were spectrophotometrically analysed to obtain proportion of adhered tartrazine on lactose (Table <NUM>).

Particles of spherically agglomerated lactose obtained by Example <NUM> capture significantly higher proportion of tartrazine in comparison to the reference lactose particles. Mechanical capture into intraparticle pores reduces or prevents segregation that may be a consequence of elevated vibrations of tablet press during tableting.

Transferring of tableting blend between hoppers causes a formation of cone like pile upon powder flow. Particles arrange differently considering their flow properties. Particles with better flow properties slide further on a formed pile, contrary to particles which possess worse flow properties. Example <NUM> presents results of evaluating segregation in binary mixtures of particles of spherically agglomerated lactose obtained by Example <NUM> with an active pharmaceutical ingredient carvedilol compared to the results of two reference lactose types: Tablettose® <NUM> (Meggle, Germamy) and Flowlac® <NUM> (Meggle, Germany).

Particle size fraction of lactose higher than <NUM> and particle size fraction of carvedilol below <NUM> were obtained by means of sieving. Mixtures of carvedilol and individual lactose were prepared with a mass ratio of carvedilol <NUM> % and <NUM> %. Mixtures were blended in laboratory type mixer (Bioengineering Inversina) for <NUM> minutes with <NUM> revolutions per minute. Individual binary mixture was poured into a glass funnel for measuring flow time. Flow of particles through the funnel created cone like structure. Cone piles were sampled on four symmetric locations on a circumference and one at the top. The content of carvedilol was determined spectrophotometrically and relative standard deviation of content was calculated (Table <NUM> and Table <NUM>).

Claim 1:
A production process of particles of spherically agglomerated lactose comprising radially arranged prism-like primary particles, wherein particles of spherically agglomerated lactose have an average particle size from <NUM> to <NUM> determined with the laser diffraction method by dispersion of lactose particles in <NUM> v/v % ethanol, a specific surface area from <NUM>,<NUM> to <NUM>,<NUM><NUM>/g determined with adsorption BET analysis, a compressibility from <NUM>,<NUM> to <NUM>,<NUM> %, determined as referred to in the description with Walker coefficient for a tableting mixture consisting of at least <NUM> % w/w of particles of spherically agglomerated lactose, and a tensile strength upon compression pressure of <NUM> MPa from <NUM>,<NUM> to <NUM>,<NUM> MPa, determined as referred to in the description by compression of tableting mixture consisting of at least <NUM> % w/w of particles of spherically agglomerated lactose, the process comprising the following steps:
a) preparation of lactose solution by dissolving lactose in a solvent, wherein the lactose is in any isomer form or combination of two or more forms in any ratio and the solvent is water and wherein the concentration of lactose solution is from <NUM>,<NUM> % to <NUM>,<NUM> % given as weight-weight concentration, and the temperature of lactose solution is from <NUM> to <NUM>;
b) addition of said lactose solution to a nonsolvent, wherein the nonsolvent is alcohol, selected from a group comprising ethanol, n-propanol and <NUM>-propanol, and wherein the addition of said lactose solution to the nonsolvent occurs at constant stirring and a temperature of the nonsolvent is regulated in a range from <NUM> to <NUM>, wherein the particles of spherically agglomerated lactose precipitate; and
c) separation of precipitated particles of spherically agglomerated lactose comprising radially arranged prism-like primary particles from suspension and drying.