WO2004047799A2

WO2004047799A2 - Pellets containing non-aqueous fluids and the process for their preparation

Info

Publication number: WO2004047799A2
Application number: PCT/SI2003/000042
Authority: WO
Inventors: Judita Sirca; Stanko Srcic; Rok Dreu
Original assignee: Lek Pharmaceuticals D.D.
Priority date: 2002-11-27
Filing date: 2003-11-25
Publication date: 2004-06-10
Also published as: AU2003302380A8; WO2004047799A3; SI21353A; AU2003302380A1

Abstract

Pellets characterized in that an agglomerating fluid used for their preparation is liquid polyhydroxy alcohol which may be in a mixture with water or another pharmaceutically acceptable solvent which is more easily volatile than said polyhydroxy alcohol and further characterized in that said agglomerating fluid completely or partly remains in a finished pharmaceutical dosage form.

Description

Title of the invention

Pellets containing non-aqueous fluids and the process for their preparation

Field of the invention

The present invention belongs to the field of pharmaceutical technology and relates to pellets. More particularly, the present invention relates to pellets and a process for their preparation where polyhydroxy alcohol is used as an agglomerating fluid. Still more particularly, said invention relates to pellets and a process for their preparation using an agglomerating fluid of appropriate physical and chemical properties and in a quantity to minimize the drying process or to avoid it during the manufacturing process of the pellets.

Technical problem

There is a constant need for solid pharmaceutically dosage forms wherein water should be avoided because of a nature of a pharmaceutical active substance; or a pharmaceutical active substance is poorly-water soluble; or a lipophilic active substance which may be dissolved is to be incorporated in a pharmaceutical dosage thereby improving its bioavailability; or to prepare a pharmaceutical dosage form first by suspending or emulsifying a pharmaceutically active substance; or to increase the stability of a pharmaceutical active substance by combining it with another ingredient; or to achieve rapid disintegration of a solid pharmaceutically dosage form in the gastrointestinal tract; or to incorporate a thermolabile pharmaceutical active substance in a pharmaceutical dosage form. Prior art

In the pharmaceutical industry pellets can be defined as small, spherical agglomerates comprising at least one excipient and may contain at least one pharmaceutically active substance.

One of the most suitable methods for the preparation of pellets is extrusion - spheronization, comprising first the preparation of a dry mixture of excipients and pharmaceutically active substances, followed by wet granulation whereby by wetting with a suitable wetting agent, which is usually water, the mixture is changed into a plastic mass which can be extruded. Extruded cylindrical extrudates are then transferred to a spheronizer where they are spheronized while still wet and therefore deformable until desired spherical properties are achieved. The process is followed by drying wherein used liquid is evaporated, and the pellets acquire the desired hardness. [Ghebre-Sellassie; Knoch, Encyclopaedia of Pharmaceutical Technology, Dekker] Thus, the preparation of the pellets comprises four successive sub- processes: preparation of a plastic mass, extrusion, spheronization and drying.

The preparation of spherical agglomerates is a known process. Manufact. Chem. & Aerosol News (Jun. 1970), 40 discloses a detailed description of the process from blending the mixture and preparation of the plastic mass via cylindrical extrudates to oval pellets and lists the suitable equipment for performing said process.

The various types of extruders have the common feature of forcing the extrudate from a wide cross-section through the restriction die. The force required and the characteristics of the extrudate produced are dependant on the reological properties of the extrudate, the design of the die, and the rate at which the material is forced through the die (Fielden KE, Newton JM: Extrusion and Extruders; In: Swabrick J, Boylan JC, eds; Encyclopedia of Pharmaceutical Technology, vol 5; Marcel Dekker, New York, 1995: 395 - 441 ).

Amount and properties of added agglomerating or granulating liquid largely influences reological properties of wet mass intended for extrusion. Properties of and interactions of used active substance or excipients with agglomerating or granulating liquid further influence reological properties of wet mass. Different types of extruders define the maximum pressure that can be applied during extrusion and as consequence they define the lower amount of granulating liquid that can be used in formulation. Die diameter largely influences the size of end pellets but also defines the minimum pressure needed to commence and to achieve steady-state flow of extrudated mass. L/R (length to radius ratio) of the die define the pressure needed for steady-state extrusion at given reological properties of the wet mass and chosen extrusion rate (Fielden KE, Newton JM: Extrusion and Extruders; In: Swabrick J, Boylan JC, eds; Encyclopedia of Pharmaceutical Technology, vol 5; Marcel Dekker, New York, 1995: 395 - 441). Upper and lower value of granulating liquid that can be used in formulation is further restricted by spheronisation process. Extrudate must possess sufficient mechanical strength when wet, yet it must be brittle enough to be broken down to short lengths in the spheroniser, but not to be so friable that it disintegrates completely. To achieve a narrow size distribution of spheres, the extrudate is ideally reduced to cylindrical rods of uniform length equal to approximately one and a half times their diameter. The extrudate must be sufficiently plastic to enable the cylindrical rods to be rolled into spheres by the action of the friction plate in the spheroniser. The extrudate must be non-adhesive to itself in order that each spherical granule remain discrete throughout the process (Fielden KE, Newton JM: Extrusion and Extruders; In: Swabrick J, Boylan JC, eds; Encyclopedia of Pharmaceutical Technology, vol 5; Marcel Dekker, New York, 1995: 395 - 441 ).

The patent application WO 0134684 discloses a method for the preparation of microcrystalline cellulose granules wherein a mixture of water and flammable polar organic solvents was used a granulating fluid for the preparation of the granulation mixture. The granules obtained were partly dried; extrusion and spheronization, respectively, was not included in the method of preparation. The described granules are porous as a consequence of the use of a combination of solvents of which one may be volatile and is rapidly evaporated during drying leaving pores in the structure of granules and according to said patent application useful as a component of modified release pharmaceutical dosage forms. US Patent No. 2002/0127275 discloses modified release pharmaceutical dosage forms where a dry mixture of cellulose polymer with a hydrophobic substance was prepared, blended with a granulating fluid and the resulting wet mixture was dried.

All these general processes include the step of drying which is not suitable for certain pharmaceutically active substances because some of these do not withstand an impact of temperature especially when in contact with water. If said method for granulation of microcrystalline cellulose using a mixture of water and alcohols, especially using i-propanol, and consequently drying under controlled conditions, i.e. drying the granules to water content less than 15%, was used for the manufacturing of pharmaceutical dosage forms comprising excipients and one or more pharmaceutically active substances, it would be possible to partly avoid said temperature impact, but because of a high proportion of water such method would be inappropriate for pharmaceutical active substances susceptible to water. Further during the preparation of a pharmaceutical dosage form, for example to a tablet by compression of described granules, migration of droplets to the surface may occur being particularly inappropriate because of low viscosity of used liquids.

Lower polyhydroxy alcohols, that is, alcohols which contain more hydroxyl groups and lower number of carbon atoms that are in a liquid state under normal conditions, for example propylene glycol and glycerol, are well known solvents that are water miscible and, in addition to their hydrotropic properties, enable dissolution of certain substances which are otherwise poorly soluble or completely insoluble in water.

Solid polyhydroxy alcohols, for example sorbitol, are also known. European patent application 432956 discloses the pharmaceutical composition in the form of granules comprising polyhydroxy alcohol, said alcohol is selected from saccharose derivates which are solid under normal conditions.

US Patent No. 5,256,362 describes the dropping device adapted to drop molten cysteamine hydrochloride onto the belt conveyer where the deposited drops are sprayed by a polyhydric alcohol-containing liquid there cooling and solidifying the cysteamine hydrochloride into granules. US Patent No. 2002/0123503 disclosed a process for the preparation of cabergoline tablets wherein said pharmaceutically active substance and excipients were granulated using non-aqueous granulating fluids with a boiling point lower than a boiling point of water, the resulting granules were dried, submitted to milling and compressed into tablets. In their strategy the authors used non-aqueous granulating fluids thus avoiding hydrolysis of said pharmaceutical active substance wherein said granulating fluid was propylene glycol. Practically all oral pharmaceutical dosage forms mentioned can be used as a pharmaceutically acceptable vehicle. The invention relates specifically to pharmaceutical compositions comprising cabergoline and in the patent as disclosed the said composition was developed aimed at preserving the stability of cabergoline and its uniform distribution in pharmaceutical dosage units with respect to its low dosage. The patent claims protect the composition manufactured by the method of wet granulation, and from the description it is evident the process comprises the following steps: preparation of granules, their drying, milling and further incorporation into a pharmaceutical dosage form.

In prior art descriptions, the terms pellets and granulates or granules are often alternatively used. The European patent application no. 653935 discloses a pelletted pharmaceutical composition named in German: »Granulierte pharmaceutische Zusammensetzung«, and the term with the same root is also in the French title »... sous forme de granules«. In the German patient claims of said patent, contrary to the term used in the title, the term pelletted pharmaceutical compositions are used.

The present invention differs from the processes referring to the preparation of granules, irregular sharp-shaped particles, as by the extrusion and spheronization technology the granulate can be completely avoided because a cylindrical extrudate is a step prior to spheronization. The pellets, already defined in first paragraphs of the description in the prior art, have the following unequivocal advantages over the granules: manufacturing of the pellets offers a high degree of adaptability during designing and development of a pharmaceutical dosage composition, in particular, pellets are suitable for the production of modified release pharmaceutical compositions; in view of their round shape and size, pellets have a low surface/volume ratio, therefore, they are suitable for film coating [Ghebre-Sellassie, Pharmaceutical Pelletization Technology, 2nd edition, Dekker, 1989]; as pellets are larger than granules, the problem of agglomeration during the coating process is decreased; a smooth surface with low porosity, low abrasion, narrow distribution of pellet size, low variability of bulk density and spherical shape of pellets which are without edges, in comparison to granules, permit a more uniform film coating producing layers smaller in thickness, Encyclopedia of Pharmaceutical Technology, vol 1, Dekker, 1988]. In particular, pellets are suitable in film coating designed for sustained release and acid resistant film coating [Chambliss, Encyclopedia of Pharmaceutical Technology, vol 5, Dekker, 1992].

US Patent no. 5,292,461 discloses a specific process for the preparation of pellets wherein a direct pelletization process in a propeller-like mixer and different wetting agents are used.

Residual liquid in pellets or granules has already been used and different effects have been obtained. For example, US Patent No. 4,261 ,942 discloses the tablets of sodium dichloroisocyanurate, produced with moisture content between 7 and 11 % having flame resistance and thermal stability to avoid chain reaction thermal decomposition. In the text of said patent forming of columnar pellets with moisture content between 15 and 30% is mentioned, however, from the text it is clear that this relates to cylindrical extrudates which are partly dried and then compacted. Residual liquid, in said example water, has such volatilizing enthalpy that by volatilizing protects incorporated sodium dichloroisocyanurate from thermal decomposition at room and higher temperature, respectively, of storage.

If pharmaceutical active substances are water susceptible, water as an agglomerating fluid should be avoided in the process for the preparation of pellets, which has already been presented in Lek patent SI 9700186 where non-aqueous ethanol was used.

The patent application WO 8303756 describes a rapidly acting analgesic pharmaceutical dosage form in combination with potassium carbonate which was prepared by wet granulation with non-aqueous solvents such as dichloromethane or alkanols, the resulting mass was extruded, spheronized and dried.

The said prior art suggest that pellets have a wide possibility of usage in the pharmaceutical industry, and that they can be prepared according to numerous processes with different excipients and by using different granulating fluids. The analysis of all published examples for the preparation of pellets also indicates that at least partial drying is necessary if a pharmaceutical composition is prepared by the process comprising wet granulation otherwise adhesion of particles and a decrease in granulation fluid content may occur in a pharmaceutical product during its aging. Processes producing pellets wherein liquids with a lower boiling point than that of water are used, do not eliminate drying but only permit performing said operation under more mild conditions.

Use of non-aqueous agglomerating fluids prevents the hydrolysis of incorporated pharmaceutical active substances, prevents swelling of superdisintegrants and liberation of carbon dioxide as the means for rapid disintegration of a dosage form. The present invention relates to pellets prepared by the extrusion and spheronization technology wherein the quantity of an agglomerating fluid used permits avoiding of drying during the process of production which is also an essential novelty regarding the known prior art processes for the preparation of pellets. By avoiding the drying after a wet agglomeration procedure, the possibility of changing the polymorph modification of an active substance or formation of a hydrate or a solvate of an active substance is minimized which otherwise may occur because of a wet agglomeration procedure [Morris et al, Adv. Drug Deliver. Rev., 48 (2001) 91-114].

Description of the solution of the technical problem including examples

With the aim to optimize the process for the preparation of pellets and solving the problem of the production of pellets where water should be avoided because of a nature of a pharmaceutical active substance; or a pharmaceutical active substance is poorly-water soluble; or to prepare a pharmaceutical dosage form first by suspending or emulsifying a pharmaceutical active substance; or to increase the stability of a pharmaceutical active substance by combining it with another ingredient; or to achieve rapid disintegration of a solid pharmaceutical dosage form in the gastrointestinal tract; or to incorporate a thermolabile pharmaceutical active substance in a pharmaceutical dosage form, we have directed our research into testing of new agglomerating fluids which would partially or completely substitute water.

Surprisingly we have found that using polyhydroxy alcohols as agglomerating fluids which remain in a pharmaceutical composition, more specifically, using propylene glycol and glycerol, respectively, we can prepare a novel pharmaceutical dosage form, we named pelliquettes. They exhibit undisputable advantages over conventionally prepared pellets. Further, our process has a great advantage over conventional processes for the preparation of pellets because the process of drying is minimized or avoided. In some presented examples the pellets, according to present invention, were also dried under mild conditions, the aim of drying was removal of easily volatile components or bound moisture of the components and not removal of the agglomerating fluid. We have found it is possible to prepare pellets which have satisfactory mechanical properties, shape and surface if an agglomerating fluid as described is used in amount for example approximately equal to the dry mass of excipients and other ingredients.

Further, we have found that it is not necessary to dry the pellets prepared with the needed quantity of a fluid according to the present invention to suffice for the preparation of the plastic mass suitable for extrusion that has an essential impact on economy of the pelletization process. Likewise, surprisingly it was not necessary to dry the pellets prepared with up to around 10% more agglomerating fluid.

In our invention, this fluid, apart from having a classical role of wetting and with fluid bridges bonding a dry agglomeration mixture, it also has a role of the pharmaceutical active substance reservoir in which the active substance is dispersed, dissolved or emulsified; the role of providing the plastic properties of produced pellets or the role of the medium miscible with water and by water penetration into the pellet structure permiting rapid disintegration or formation of a porous form.

As also other excipients besides granulating liquid and much needed microcrystalline cellulose influences mechanical strength, plasticity and self-adhesiveness, the upper and lower amount of granulating liquid can only be firmly defined when all other formulation components are defined. Therefore values of used granulating liquid as disclosed in examples only define frame interval of percentage of polyhydroxy alcohol that can be used during granulation.

The pellets, prepared by the process which is the object of the present invention, can be further film coated or they can be layered with an active substance or a mixture of active substances and excipients.

Detailed description of the invention

To prepare the pelliquettes according to the present invention, an agglomerating fluid is added with constant stirring to at least one excipient which may be in a mixture with at least one pharmaceutical active substance, and the homogeneously wetted mixture is transferred to the extruder and extruded through the screen openings. The exact amount of added agglomerating fluid depends on nature of fluid, excipients and active ingredients and can be for example between 30% and 70% of the total weight of a dosage form, preferably when polyhydroxy alcohols having around 3 carbon atoms are used the amount can be between 45% and 60%, most preferably when glycerol and microcrystalline cellulose are used the amount is around 50 ± 3 %. The extrudate is transferred to the spheronizer and upon spheronization, the spherical agglomerates with uniform distribution of particle size, suitable physical and mechanical properties (such as, e.g. flow properties, tapped and bulk density, suitable crushability, disintegration and tensile strength) which permit easy handling, for example, poring, weighing, capsule filling; and chemical properties which are appropriate for pharmaceutical active substances to be used in the described pharmaceutical dosage form. Optional procedure of preparing pellets comprises tempering of spheronized product, produced only by use of glycerol or propylene glycol, at temperature of 70°C for 90 min. It is cennceivable that this is a non-drying process. Drying may be defined as the vaporization and removal of water or other liquid from solution, suspension, or other solid-liquid mixture to form a dry solid (Ganderton D, Hickey AJ: Pharmaceutical Process Engineering; In: Swabrick J ed; Drugs and the pharmaceutical sciences, vol 112; Marcel Dekker, New York, 2001). In our case we do not remove granulating liquid substantially, which can be explained by values of vapour pressure of glycerol and propylene glycol which are well under vapour pressure of water at 20°C. The purpose of product tempering at higher temperature for example at around 70°C can be a redistribution of incorporated agglomeration liquid within as viscosity and surface tension of most liquids including glycerol and propylene glycol are both lower at higher temperature, for example at around 70°C in comparison with values at lower temperature, for example at around 20°C. Reduced surface tension (improved wettability) and viscosity facilitate the redistribution of granulating liquid inside the matrix structure an therefore the homogeneity of the product.

The essential novelty of the present invention is the use of polyhydroxy alcohols which function as an agglomerating fluid in the classical sense of the preparation of pellets, and as the finished pharmaceutical dosage form comprises them, they are also an excipient in the classical sense of the preparation of solid pharmaceutical dosage forms.

Typical such polyhydroxy alcohol is glycerol which occurs naturally in animal and vegetable fats and oils that are consumed as part of a normal diet. Glycerol is readily absorbed from the intestine and is either metabolized to carbon dioxide and glycogen or is used in synthesis of body fats. Glycerol is used in a wide variety of pharmaceutical formulations including oral, ophthalmic, parenteral, and topical preparations. Adverse effects are mainly due to the dehydrating properties of glycerol. Oral doses are demulcent and mildly laxative in action. Large doses may produce headache, thirst, nausea, and hyperglycemia. Glycerol may also be used orally in doses of 1 ,0-1 ,5 g/kg body-weight to reduce intraocular pressure. When used as an excipient or food additive, glycerol is not usually associated with any adverse effects and is generally regarded as a nontoxic and nonirritant material. Density of glycerol at 20°C is 1 ,2636 g/cm³ , its dynamic viscosity changes dramatically from 25°C where it is 2095 mPas to 70°C where it is only 22,9 mPas. On the other hand at that temperature where habitually used granulation liquids like water or ethanol would easily evaporate its vapour pressure is only 0,0035 kPa. Therefore tempering (exposing to temperature as for example drying) of the pellets prepared with glycerol as an agglomerating liquid can be easily affected at that temperature, while tempering of the pellets prepared with water would inevitably lead to removing of said liquid.

Another example of such polyhdroxy alcohol is propylene glycol. It is a better general solvent than glycerol and dissolves a wide variety of materials, such as corticosteroids, phenols, sulfa drugs, barbiturates, vitamins (A and D) most alkaloids, and many anesthetics. Propylene glycol is used in a wide variety of pharmaceutical formulations and is generally regarded as a nontoxic material. Probably as a consequence of its metabolism and excretion, propylene glycol is less toxic than other glycols. Propylene glycol is estimated to be one third as intoxicating as ethanol, with administration of large volumes being associated with adverse effects most commonly on the central nervous system, especially in neonates and children. Other adverse reactions reported, though generally isolated, include: ototoxicity, cardiovascular effects, seizures, hyperosmolarity and lactic acidosis, both of which occur most frequently in patients with renal impairment. Based on metabolic and toxicological data, the WHO has set an acceptable daily intake of propylene glycol at up to 25mg/kg body-weight.

The present invention is illustrated but in no way limited by the following examples presenting, to our knowledge, the best techniques for the preparation of pelliquettes. Example 1

To 300.00 g of microcrystalline cellulose in the mixer vessel was added 303.50 g of glycerol with constant stirring at a temperature of 35°C. After the addition of all glycerol the mixture was stirred for further 5 minutes. The wet mass was transferred to the screw extruder (PHARMEX 35T) and extruded through the screen opening size 1.00 mm at the screw speed of 60 rpm. Immediately upon extrusion, the extrudate was transferred to the spheronizer (SPHAEROMAT 250T) and spheronized on the plate at 1400 rpm for 1.5 minutes. The resulting pellets were dried in the tray dryer at T = 70°C for 90 minutes. Said drying under normal pressure and at a temperature much lower than a boiling point of used agglomerating fluid served only for elimination of moisture bound to the excipients, namely, using of pharmaceutically appropriate but not analytically pure polyhydroxy alcohols containing a small proportion of water. It is possible also to prepare satisfactorily non-sticking pellets when mass of glycerol and microcrystalline cellulose is varied ± approximately 30 g.

Example 2

To 300.00 g of microcrystalline cellulose in the mixer vessel was added 318.70 g of glycerol with constant stirring. After the addition of all glycerol the mixture was stirred for further 5 minutes. The wet mass was transferred to the screw extruder (PHARMEX 35T) and extruded through the screen opening size 1.00 mm at the screw speed of 60 rpm. Immediately upon extrusion, the extrudate was transferred to the spheronizer (SPHAEROMAT 250T) and spheronized on the plate at 1200 rpm for 1.5 minutes. The resulting pellets were not dried. Example 3

To 300.00 g of microcrystalline cellulose in the mixer vessel was added 312.70 g of propylene glycol with constant stirring. After the addition of all propylene glycol the mixture was stirred for further 5 minutes. The wet mass was transferred to the screw extruder (PHARMEX 35T) and extruded through the screen opening size 1.00 mm at the screw speed of 60 rpm. Immediately upon extrusion, the extrudate was transferred to the spheronizer (SPHAEROMAT 250T) and spheronized on the plate at 1400 rpm for 1.5 minutes. The resulting pellets were dried in the tray dryer at T = 70°C for 90 minutes.

Example 4

To a homogeneous mixture of 150.00 g of crystalline cellulose and 150.00 g of ketoprofen in the mixer vessel was added 303.50 g of glycerol with constant stirring. After the addition of all glycerol the mixture was stirred for further 5 minutes. The wet mass was transferred to the screw extruder (PHARMEX 35T) and extruded through the screen opening size 1.00 mm at the screw speed of 60 rpm. Immediately upon extrusion, the extrudate was transferred to the spheronizer (SPHAEROMAT 250T) and spheronized on the plate at 1400 rpm for 1.5 minutes. The resulting pellets were not dried.

Example 5

The pellet cores of the identical composition as in Example 4 were prepared as described in Example 4 and in continuation of the process they were coated.

80.00 g of hydroxypropyl methylcellulose and 14.00 g of polyethylene glycol 6000 were dissolved in 1230.00 g absolute ethanol at a room temperature, 7.00 g of talc was dispersed in the solution and the prepared dispersion was sprayed on the pellet cores in the fluid bed granulator

Claims

1. A solid pharmaceutical dosage form which comprises at least one excipient and optionally comprises at least one pharmaceutically active substance, prepared by extrusion and spheronization, characterized in that an agglomerating fluid used for the preparation of an extrusion mixture is a liquid polyhydroxy alcohol which may be in a mixture with water or another pharmaceutically acceptable solvent which is more easily volatile than said polyhydroxy alcohol whereat said agglomerating fluid completely or partly remains in a finished pharmaceutical dosage form.

2. A solid pharmaceutical dosage form prepared by extrusion and spheronization, characterized in that an agglomerating fluid used for the preparation of an extrusion mixture is at least one liquid polyhydroxy alcohol whereat said agglomerating fluid substantially completely remains in a finished pharmaceutical dosage form.

3. The solid pharmaceutical dosage form according to Claims 1 and 2 characterized in that the process for its preparation does not include drying of said pharmaceutical dosage form after spheronization.

4. The solid pharmaceutical dosage form according to Claims 1 to 3 intended for oral administration.

5. The solid pharmaceutical dosage form according to Claims 1 to 4 containing from about 45% to 60% of polyhydroxy alcohol.

6. The solid pharmaceutical dosage form according to Claims 1 to 5 wherein polyhydroxy alcohol is either glycerol or propylene glycol.

7. A process for the preparation of the solid pharmaceutical dosage form comprising: a) Preparation of the mixture of excipients and pharmaceutically active substances with polyhydroxy alcohol; b) Extrusion of said mixture whereat cylindrical extrudates are formed; c) Spheronization of said cylindrical extrudates; further characterized in that the process may include drying upon spheronization obtained pharmaceutical dosage forms at a temperature at least 70°C lower than a boiling point of said polyhydroxy alcohol.

8. The process according to Claim 7 characterized in that said process does not include drying upon spheronization obtained pharmaceutical dosage forms.

9. A pharmaceutical preparation containing a plurality of dosage forms according to any one of Claims 1 to 6.