RU2785565C2 - Method and device for production of solid dispersion - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics; it can be used for the production of a solid dispersion of nicardipine. A method for extrusion from a melt for the production of a solid dispersion containing a pharmaceutically active ingredient, a polymer binder, and optionally one or more auxiliary substances includes: a) placement in portions of certain amount of the polymer binder, the active ingredient, and optionally the auxiliary substance (substances) to a vessel for melting; melting of the polymer binder in the vessel for melting, while shaking for dispersion of the active ingredient in the polymer binder to obtain a molten pre-dispersion; b) supply of pre-dispersion to an extruder for homogenization of the pre-dispersion, and release of the melt through a head; and c) provision for the melt of a possibility for curing. At the same time, the active ingredient is selected from nicardipine, its pharmaceutically acceptable salt, hydrate, or solvate, and the polymer binder contains (i) poly(copolymer of lactide and glycolide) having molecular weight distribution centered around average molecular weight Mn2, and (ii) poly(copolymer of lactide and glycolide) having molecular weight distribution centered around average molecular weight Mn1, where Mn1 is in a range from 2000 to 3000 g/mol, and the ratio of Mn1/Mn2 is from 1.8 to 3.5.

EFFECT: method provides for high homogeneity of active substance in a dispersion with minimum efforts.

9 cl, 3 tbl, 2 ex

Description

The present invention relates to a melt extrusion process and apparatus for producing a solid dispersion containing a pharmaceutically active ingredient, a polymeric binder, and optionally one or more adjuvants.

In general terms, the melt extrusion process is carried out in conventional extruders known to the person skilled in the art.

The melt extrusion process includes the steps of obtaining a melt of one or more pharmaceutically active ingredients, a polymeric binder and adjuvants and cooling the melt until it solidifies. "Melting" means the transition to a liquid or elastic state, in which one component can be homogeneously incorporated into another. In addition, melt extrusion is a fast, continuous production process without the need for further drying or intermittent processing steps. This provides a short thermal exposure and therefore allows heat sensitive active ingredients to be processed. Process temperatures can be lowered by adding plasticizers. This requires comparatively less investment in equipment compared to other processes.

According to a conventional procedure, such as that described in US Pat. No. 5,7924,447, one or more pharmaceutically active ingredients, a polymeric binder, and optional adjuvants are dry blended to form a powder mixture which is transferred to an extruder. Rotating extruder screws move the mixture through a heated extruder barrel, causing the powder mixture to melt and the molten dispersion product to be discharged through the die. It is then allowed to cool to form an extrudate. Shaking the powder mixture, which occurs during processing, contributes to the homogeneity of the extrudate. The formation of the extrudate can conveniently be carried out using a calender with two counter-rotating rollers with mutually coinciding depressions on their surface. A wide range of tablet shapes can be achieved by using rollers with different recess shapes. Alternatively, the extrudate is cut into pieces before, during or after solidification. It can be further processed into suitable pharmaceutical dosage forms.

However, active ingredient particles tend to aggregate prior to extrusion due to high surface energy, even if they have been dry blended with polymeric binders and optionally auxiliaries. In addition, due to different specific gravity and different entry characteristics of the components into the extruder receiver, the powder mixture may separate before the mixture is melted. This can lead to non-homogeneous distribution of the drug within the solid dispersion and difficult to achieve uniformity in the contents of the dosage forms.

The problems are exacerbated when the solid dispersion formulation contains components that are semi-solid, sticky and/or viscous at ambient temperature, such as plasticizers or low melting binders. It is practically impossible to uniformly distribute such components in the melt during extrusion. For this reason, a granulation step is typically used in which the plasticizer is granulated with one or all of the other solid components of the composition prior to extrusion. However, the granulation step complicates the process. In addition, very sticky or viscous components are difficult to handle and difficult to granulate with solid components.

WO 02/094226 describes a method for obtaining in the absence of a solvent a homogenized product, especially for implants or microparticles, whereby at least one polymer and at least one active ingredient in raw material form are homogenized at or below the glass transition temperature of the polymer(s), especially at cryogenic temperatures. Cooling to the temperature used in cryogenic technology can be carried out, especially to the temperature of dry ice or liquid gas, especially to the temperature of liquid nitrogen.

The present invention provides a solid dispersion of a pharmaceutically active ingredient that provides high content uniformity with minimal effort, for example, without a significant increase in investment in equipment, especially in cases where the solid dispersion formulation contains semi-solid, sticky and/or viscous components.

This is achieved by a melt extrusion process to produce a solid dispersion containing a pharmaceutically active ingredient, a polymeric binder and optionally one or more adjuvants, including

a) batchwise placing a predetermined amount of polymeric binder, a predetermined amount of active ingredient and optionally a predetermined amount of adjuvant(s) in a melt vessel; melting the polymeric binder with shaking to disperse the active ingredient in the polymeric binder to form a molten predispersion;

b) feeding the predispersion into an extruder to homogenize the predispersion and releasing the melt through the die; and

c) allowing the melt to solidify.

According to the method according to the present invention, high content uniformity is achieved with minimal effort. The pre-dispersion in step a) is carried out in the presence of a molten polymeric binder. This simplifies mixing of the polymeric binder, the active ingredient, and optionally the adjuvant(s). Step a) thus provides a more uniform predispersion with less effort than prior art processes where the mixture to be fed to the extruder is a powder mixture obtained by grinding solids. Typically, in a predispersion, the components are mixed in a liquid or viscous state, and the components are at least partially dissolved in each other. This minimizes the risk of component separation in the subsequent extrusion step.

Partial homogenization is achieved by melting the polymeric binder with shaking in step a). As a consequence, the method according to the present invention requires less stringent conditions in the subsequent extrusion, whereas in the prior art processes, homogenization is carried out almost exclusively in the extrusion step. Since high homogeneity is already achieved in step a), no or only little additional homogenization is required in the extruder. In an extruder, the input of thermal and mechanical energy may be minimal, that is, sufficient to melt and create sufficient pressure to release the melt through the die.

According to the present invention, predetermined amounts of the various components, i. the polymeric binder and the pharmaceutically active ingredient and optional adjuvant(s) are placed in a melt vessel. The predetermined amounts are determined by any suitable method known to those skilled in the art, such as by weighing or measuring the volume of each of the components, which are placed in the melt vessel. Components that are solid or semi-solid at room temperature are preferably weighed, while components that are liquid at room temperature are preferably placed in a melt vessel at predetermined volumes. The term "melt vessel" means any type of vessel, in particular a closable vessel, for example any vessel which allows the various measures described in step a) to be carried out, in particular any vessel which contains at least one opening for placing a component in the vessel . The vessel is designed in such a way that the components in the vessel can be melted, eg heated, and agitated, eg mixed. The vessel is, for example, a glass, in particular a bowl such as a stainless steel bowl.

According to the present invention, in a melt vessel, the polymeric binder is melted with agitation to disperse the active ingredient in the polymeric binder to form a molten predispersion.

Melting the polymeric binder typically involves heating the contents of the melt vessel by any means known to those skilled in the art to heat the contents of the vessels, in particular by any heating operation known to those skilled in the art for heating pharmaceutical compositions, i.e. where thermal uniformity is important and critical volumes should be avoided. Heat is, for example, delivered through the melt vessel itself, for example through the bottom and/or side walls of the melt vessel. Alternatively, heat may be delivered through heating devices that are introduced into the melt vessel, such as through an opening or openings in the melt vessel, and positioned such that the heating surface of the heating device is in contact with the contents of the melt vessel.

The term "shaking" includes any operation that ensures thorough mixing of the contents of the vessel for the melt. Shaking may include movement of the melt vessel itself. The movement of the vessel for the melt may include a rotational movement or shaking. The melt vessel itself may alternatively be static. The agitation may include agitation of the contents of the melt vessel, for example with a mechanical stirrer.

Surprisingly, it has been found that ultrasonication of the predispersion can improve the efficiency of the method according to the present invention. The sonication is preferably carried out while the active ingredient is dispersed in the polymeric binder and/or after the active ingredient is dispersed in the polymeric binder. It is also possible to carry out sonication in step b). Preferably, the sonication is interrupted when the predispersion is fed into the extruder.

A systematic analysis of the solidified melt showed that gas bubbles were present in those parts of the solidified melt that did not meet the requirements for uniformity. Gas bubbles can lead to uncontrolled release of (part of) the active ingredient from solid dispersions and are thus undesirable. Preferably, only those portions of the solidified melt that are free of bubbles are used in the treatment of patients, and the rejection of those portions of the solidified melt that contain gas bubbles may limit the efficiency of the process. It is assumed that the gas is introduced from the surrounding atmosphere (usually air) when the polymer binder melts when shaken. As it turns out, the gas accumulates in the agitated contents of the melt vessel. A high predispersion gas content increases the risk of gas bubbles in the melt during processing in an extruder, in particular when the melt is processed at an elevated temperature. On the other hand, ultrasound has been shown to accelerate the release of gas from the contents of the melt vessel and therefore reduce the amount of gas entering the extruder. This results in a substantially bubble-free solidified melt.

One skilled in the art will be familiar with ultrasonic treatment and the necessary equipment.

When the melting point of the polymeric binder is low, shaking (and optional sonication) can produce sufficient heat to melt the polymeric binder without actively heating the contents of the melt vessel.

The molten predispersion typically contains at least two phases. The first phase is a solution containing a molten polymer binder. The solution contains part of the active ingredient in dissolved form. If the adjuvant(s) is/is present, the solution may further contain the adjuvant(s) in dissolved form. The other solid phase(s) is usually present in the form of dispersed particles. This solid phase(s) contains the active ingredient and optionally the adjuvant(s) which have not been completely dissolved by the molten polymeric binder.

Alternatively, the molten predispersion may be a solution, ie. single phase solution. A single phase solution is obtained when the active ingredient and optionally also the adjuvant(s) are completely dissolved by the polymeric binder. In general, the solubility of the active ingredient and adjuvant(s) in the polymeric binder increases with temperature. Thus, when melting the polymeric binder with shaking, depending on the solubility of the active ingredient(s) and adjuvant(s), it may be possible to raise the temperature such that the active ingredient and, if present, also the adjuvant(s) dissolve quantitatively. in a polymer binder. The person skilled in the art can easily determine the temperature at which the predispersion becomes single phase, ie when the remaining solid or coexisting liquid phases disappear and the temperature rises very slowly.

According to the present invention, the predispersion is fed into the extruder. In general, it is preferable to feed the molten predispersion into an extruder, i.e. not allowing the predispersion to solidify before it is fed into the extruder.

Preferably, the temperature of the predispersion, as it is fed into the extruder, is above its solidification temperature.

The molten predispersion can be fed into the extruder in various ways.

According to a preferred method according to the present invention, feeding the predispersion into the extruder comprises moving the predispersion from the melt vessel through the opening of the melt vessel, the movement of the predispersion being enhanced by reducing the volume of the melt vessel available for the predispersion. The volume of the melt vessel available for predispersion is reduced, for example, by translational movement of a transfer element, such as a punch, into the melt vessel. The opening is preferably closable. The opening may be located in the bottom of the melt vessel. The forward movement of the punch is preferably towards the bottom of the melt vessel, and the predispersion moves through the orifice as the movement of the punch reduces the volume of the melt vessel between the punch and the bottom of the melt vessel.

The predispersion fed to the extruder according to the present invention has a higher degree of uniformity than those mechanically homogenized products (as described, for example, in WO 02/094226) that are usually fed to the extruder in accordance with the prior art, as indicated above. As a consequence, more extrudate can be produced with a given extruder, or a smaller extruder can be used to produce a predetermined amount of extrudate, or even higher product uniformity is achieved when extrusion is performed as described in the prior art. When the molten predispersion is a highly viscous solution, the task of extrusion is to compensate for the remaining uneven distribution of the various components in the highly viscous solution and to adjust the desired temperature, i.e. desired viscosity for release through the die.

Alternatively, the molten predispersion is allowed to solidify before being fed into the extruder.

Conveniently, the molten predispersion is portioned before it is allowed to solidify so as to obtain a solid piece of the predispersion. Portioning may include pouring the molten predispersion into mold recesses in which the predispersions are allowed to solidify. The mold and/or the dips may be elastic, for example made of a material containing silicone, to facilitate the removal of the hardened predispersion from the mold. Alternatively, the molten predispersion may be passed through calender rollers with depressions on their surface. The predispersion piece is then fed into the extruder, optionally after grinding.

The solidified predispersion or chunks of the solidified predispersion may be pulverized and the pulverized solid predispersion (which is in the form of solid particles) fed into the extruder. Grinding includes any method of reducing the size of the solidified predispersion to particles or pieces of a certain or indefinite shape, which are small enough to feed them into the extruder; for example, breaking and/or cutting the partially or completely solidified mixture into such particles or pieces. Any method for reducing the particle size of solid ingredients in pharmaceutical dosage forms is suitable for grinding a solidified predispersion.

According to the present invention, the predispersion is homogenized as it passes through the extruder. As used herein, the term "homogenized" refers to bringing the predispersion into a more homogeneous state. The melt discharged through the die has a higher degree of uniformity than the predispersion fed to the extruder. A higher degree of homogeneity is characterized, for example, by an increase in the relative amount of dissolved active ingredient(s) and/or a decrease in the average particle size of the dispersed solids. According to one embodiment of the present invention, the melt is homogeneous throughout and thermodynamically consists of only one phase.

Extrusion may, for example, include raising the temperature of the predispersion to a first target temperature and maintaining that first target temperature, lowering the temperature to a second target temperature, and maintaining the second target temperature before discharging the melt through the die.

After the first target temperature is reached, that temperature is maintained for a sufficiently long period of time to ensure complete melting of all components and their complete mixing to provide a homogeneous melt without a temperature gradient or substantially without a temperature gradient throughout the molten mass. Depending on the total weight of the components, the time period may vary from 2 minutes to 30 minutes, such as from 3 minutes to 25 minutes, from 4 minutes to 20 or from 5 minutes to 15 minutes. Preferably, the time period is as short as possible to avoid thermal damage to the melt components. A suitable time period can be readily determined by those skilled in the art.

The second target temperature is chosen in order to set a viscosity suitable for melt exit through the die. The second target outlet temperature is chosen to ensure smooth subsequent extrusion by providing melt homogeneity, sufficient viscosity to pass through the die at the selected die pressure, shape stability of the extruded mass, and a suitable solidification time. The temperature decrease must be slow enough to avoid local overcooling and the associated risk of crystallization or precipitation of one or more melt components. Depending on the heat capacity of the melt components and their total mass, the time period for cooling the melt from the first target temperature to the second target temperature may be from 3 minutes to 60 minutes, in particular from 4 minutes to 30 minutes, from 5 minutes to 20 minutes, such as for example from 5 minutes to 10 minutes.

In order to avoid concentration or temperature gradient, the melt is preferably continuously stirred while the temperature is lowered.

After the second target temperature is reached, the temperature is held constant for a period of time sufficient to ensure that a uniform or substantially uniform outlet temperature is equalized throughout the melt. Depending on the total mass of the melt and the components contained therein, the time period may vary from 2 minutes to 45 minutes, in particular from 3 minutes to 30 minutes, from 4 minutes to 20 minutes, such as about 5 minutes, about 10 minutes or about 15 min. To speed up the temperature equalization and prevent uneven distribution of the melt components, the melt is stirred during this period.

After reaching a uniform or substantially uniform target temperature to exit throughout the melt, the melt is released through the die. Extrusion parameters such as die diameter and shape and extrusion pressure will depend on the desired shape and characteristics of the solidified melt, as well as the characteristics of the melt (depending on the components it contains) and can be optimized by those skilled in the art. Preferably, the solidified melt is a one-phase mixture of the pharmaceutically active ingredient(s), the polymeric binder, and optionally one or more adjuvants. In particular, the solidified melt is clear, free of bubbles or substantially free of bubbles, and is essentially or completely free of spots when visually inspected.

The method according to the present invention provides a continuous release of the melt, starting with an intermittent, ie intermittent, production of a molten predispersion.

Step a) can, for example, be repeated using the same vessel or different vessels in order to obtain several batches, for example at least two batches of molten predispersion. These batches are fed into the extruder one by one while the extrusion continues.

When the same vessel is used to prepare each batch of predispersion, the next batch of predispersion can be prepared as soon as the previous batch of predispersion has been fed into the extruder.

In the solidified melt and in pharmaceutical dosage forms obtained by further processing of the solidified melt, i.e. in delivery systems, the pharmaceutically active ingredient is present as a solid dispersion. A solid dispersion defines a system in a solid state (as opposed to liquid or gaseous state) containing at least two components, i.e. a pharmaceutically active ingredient; and a polymeric binder, wherein one component is uniformly dispersed throughout the other component or components. For example, the active ingredient is dispersed in a matrix consisting of a polymeric binder. The term "solid dispersion" encompasses systems having small particles, typically less than 1 micron in diameter, of one phase dispersed in another phase. When said dispersion of components is such that the system is chemically and physically homogeneous or homogeneous throughout or consists of a single phase (as defined in thermodynamics), such a solid dispersion will be referred to as a solid solution or molecular dispersion. Molecular dispersions are the preferred physical systems. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS).

Solid dispersions of virtually any desired shape can be formed by forcing the melt through a suitable shaped die, optionally followed by an additional shaping or molding step, including injection molding, blow molding, extrusion, or any other shaping, molding, or casting process known in the art. of the art as suitable for forming components.

As is clear from the process of the present invention, which involves melting the polymeric binder, polymeric binders that can be melted without breaking are preferred. In this respect, polymeric binders are preferred that can be heated to at least 50K, eg at least 60K, preferably at least 80K above the highest glass transition temperature of the (components) of the polymeric binder without breaking down. "No degradation" means that the number average molecular weight of Mn changes by no more than 15%, for example, no more than 10%, preferably no more than 5%, when the polymer binder melt is maintained for 1 hour at 50 K, 60 K or 80 K above the highest glass transition temperature (components) of the polymer binder.

Preferably, at least one of the active ingredient, polymeric binder and adjuvant contains a component that is semi-solid, sticky or viscous at ambient temperature, for example, 20°C.

The person skilled in the art knows what is meant by semi-solid, sticky and viscous.

"Semi-solids" have a thermal transition, such as a glass transition, close to ambient temperature. As a rule, semi-solid substances show a glass transition temperature below 40°C, for example, below 35°C.

"Glass transition temperature" as used herein refers to the temperature at which the transition from a glassy state to a viscous or elastic state occurs. This glass transition temperature is suitably determined by differential scanning calorimetry (DSC) at a heating rate of 5 K/min. DSC plots heat flux versus temperature. In a plot of heat flux versus temperature, the glass transition is a gradual transition that occurs over a range of temperatures. At temperatures just below the transition, the heat flux is almost constant, resulting in an almost straight and slowly rising portion of the graph. Inside the junction, the heat flux increases. Thus, the graph is steeper, but nevertheless usually almost straight in the central part of the transition. The first straight line corresponds to the almost straight and slowly rising part of the graph. The second straight line is set on the steeper and almost linear part of the graph at the center of the transition. The glass transition temperature is the temperature at which these lines intersect.

The tack and viscosity of a component, such as a polymer, can be determined by routine measurements known to those skilled in the art.

By "tacky" is meant that the material has a tack of at least 0.7 ns at ambient temperature (as measured by a texture analyzer such as TA-XT2i).

The term "viscous" means that the material has a dynamic viscosity of 0.2 to 100 Pa.s at ambient temperature.

The polymeric binder may contain one or more polymeric binder components. When the polymeric binder contains two or more polymeric binder components, it is generally preferred to use binder components capable of forming a single phase mixture. "Single-phase mixture" means a polymer mixture in which polymers are mixed with each other at the molecular chain level and are able to form a chemically and physically homogeneous mixture, that is, to form a "single phase".

Most preferably, the polymeric binder comprises a semi-solid polymeric binder component with a glass transition temperature below 40°C, eg below 35°C, and a solid polymeric binder component.

The semi-solid component of the polymeric binder may, for example, have a glass transition temperature in the temperature range from -30 to 30°C, preferably from -20 to 20°C, in particular from -10 to 10°C.

The glass transition temperature of the solid polymeric binder component is generally higher than the glass transition temperature of the semi-solid polymeric binder component, for example at least 10 K above the glass transition temperature of the semi-solid polymeric binder component.

The solid component of the polymeric binder may, for example, have a glass transition temperature of 10°C or higher, preferably 15°C or higher, in particular 20°C or higher, for example, in the range from 10°C to 110°C, preferably from 15 °C to 90°C, in particular from 20°C to 70°C.

According to one embodiment of the present invention, the polymeric binder is a non-liquid carrier material, such as a poly(lactide-glycolide copolymer). According to a particularly preferred embodiment of the present invention, the semi-solid polymeric binder component is a poly(lactide-glycolide copolymer) having a molecular weight distribution centered around the first number average molecular weight Mn2, and the solid polymeric binder component is a poly(lactide-glycolide copolymer) having a molecular weight distribution centered around the first number average molecular weight of Mn1, where Mn1 is in the range from 2000 to 3000 g/mol, and the ratio Mn1/Mn2 is from 1.8 to 3.5.

Poly(copolymer of lactide and glycolide) means a copolymer (or cocondensate) of lactic acid and glycolic acid. The poly(lactide-glycolide) copolymers for use in the present invention are biodegradable, that is, they are degraded in the body over time by enzymatic or hydrolytic action or similar mechanisms, thereby forming pharmaceutically acceptable degradation products, and are biocompatible, that is, they do not cause toxic or irritant effects, or immunological rejection when in contact with body fluids. The lactic acid units may be L-lactic acid, D-lactic acid, or a mixture thereof. The ratio of lactic acid units to glycolic acid units in each copolymer may be in the range from 25:75 to 75:25, preferably in the range from 40:60 to 60:40, in particular from 45:55 to 55:45.

The number average molecular weight of Mn1 is higher than the number average molecular weight of Mn2. For example, Mn1 may be in the range of 2000 to 3000, in particular 2000 to 2500. A preferred solid component of the polymeric binder is PLGA Resomer® Mn 2300. The number average molecular weight of Mn2 may be in the range of 300 to 1200, preferably 400 to 1000 , in particular from 600 to 1000. A preferred semi-solid component of the polymeric binder is PLGA RESOMER® Mn 800.

"PLGA Resomer® Mn 2300" is available from Evonik and refers to a poly(copolymer of lactide and glycolide), ie. a copolymer cocondensate of DL-lactic acid and glycolic acid, wherein the proportion of DL-lactic acid units and glycolic acid units is 50:50, with a number average molecular weight Mn=2300. "PLGA Resomer® Mn 800" is also available from Evonik and refers to a poly(copolymer of lactide and glycolide), i.e. a copolymer cocondensate of DL-lactic acid and glycolic acid, wherein the proportion of DL-lactic acid units and glycolic acid units is 50:50, with a number average molecular weight Mn=800.

In a particularly preferred method according to the present invention, the semi-solid polymeric binder component is PLGA Resomer® Mn 800 and the solid polymeric binder component is PLGA Resomer® Mn 2300.

Unless otherwise indicated or evident from the context, the molecular weight of the polymer is to be understood as the number average molecular weight of Mn.

In general, both components of the polymeric binder, for example both poly(lactide-glycolide copolymer), are monodisperse copolymers. The molecular weight distribution centered around the average defines a substantially monomodal molecular weight distribution associated with the number average of each monodisperse copolymer. In general, polymeric binder components, such as poly(lactide-glycolide copolymers), have a polydispersity index (which is the ratio of weight average molecular weight to number average molecular weight [PDI=Mw/MNn)] of at most 3.2.

The molecular weights of polymers are measured, for example, by size exclusion chromatography (SEC). Waters HPLC equipment (Waters 515) equipped with 4 coupled Waters Styragel columns as stationary phase, tetrahydrofuran at a flow rate of 1 ml/min as mobile phase and a Waters 410 refractometer as detector can be used. The molecular weight can be calculated using the system calibration software using polystyrene standards of known molecular weights.

In general, in the process of the present invention, the relative amounts of the semi-solid polymeric binder component and the solid polymeric binder component can vary over wide ranges. The polymeric binder components can, for example, be used at a weight ratio of semi-solid polymeric binder component and solid polymeric binder component of 1:20 to 2:1, for example 1:10 to 1.5:1, preferably 1:4 to 1: one. These weight ratios are preferred particularly when the semi-solid polymeric binder component is PLGA Resomer® Mn 800 and the solid polymeric binder component is PLGA Resomer® Mn 2300.

Predetermined amounts of the various components may be placed in the melt vessel in any desired order. Preferably, at least a portion of the polymeric binder, e.g., at least a portion of the semi-solid component of the polymeric binder, is placed in the melt vessel and is at least partially melted before the active ingredient and optional adjuvant(s) are placed in the melt vessel. . Most preferably, the semi-solid polymeric binder component is placed in the melt vessel and is at least partially melted before the solid polymeric binder component, active ingredient, and optional adjuvant(s) are placed in the melt vessel.

It is possible to add those components of the predispersion which melt at an elevated temperature, for example above 20° C., such as, for example, the active ingredient, in the form of particles of any size. The particle size is reduced when the polymeric binder melts while dispersing the active ingredient in the polymeric binder. The person skilled in the art knows how to adapt the agitation so that the mechanical forces are sufficient to break even large particles of the active ingredient into small particles.

It is possible to grind the pharmaceutically active ingredient and/or at least a portion of the polymeric binder, for example the solid component of the polymeric binder, before it is placed in the melt vessel. This is necessary in order to accelerate the formation of the molten predispersion in step a). When at least part of the solid components are placed in the melt vessel in the form of small particles, that is, in the form of a pulverized product, a homogeneous melt predispersion will be formed even more easily.

Any kind of pharmaceutically active ingredient (or combination of pharmaceutically active ingredients) can be used in the method of the present invention.

According to one embodiment of the present invention, the polymeric binder and the pharmaceutically active ingredient together constitute at least 80 wt.%, such as at least 85 wt.% or at least 90 wt. % of the total mass of the predispersion. According to another embodiment of the present invention, the pharmaceutically active ingredient (or combination of pharmaceutically active ingredients) may comprise from 1 wt.% to 25 wt.% of the total weight of the solid dispersion product, such as from 5 wt.% to 20 wt.%, from 10% by weight to 15% by weight or about 10% by weight.

In certain embodiments of the present invention, the active ingredient may be selected from non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, NMDA antagonists, endothelin receptor antagonists, antioxidants, neurotrophic factors, and calcium channel blockers. Examples of non-steroidal anti-inflammatory drugs include aspirin, acetaminophen, indomethacin and ibuprofen. Examples of steroidal anti-inflammatory agents include cortisone, prednisone, prednisolone, and dexamethasone. Examples of NMDA antagonists include magnesium sulfate and dextromethorphan. Examples of endothelin receptor antagonists include clazosentan and bosentan. Examples of antioxidants include superoxide dismutase, catalase, nitric oxide, mannitol, allopurinol, and dimethyl sulfoxide. Examples of neurotrophic factors include endorphins and citicholin.

A particularly preferred method according to the present invention is a method for preparing a solid dispersion product suitable for the treatment and/or prevention of cerebral vasospasm, such as cerebral vasospasm associated with traumatic brain injury or subarachnoid hemorrhage. Accordingly, the pharmaceutically active ingredient is a calcium channel blocking agent, e.g., a calcium channel blocking agent, which is effective for treating and/or preventing cerebral vasospasm, such as cerebral vasospasm associated with traumatic brain injury or subarachnoid hemorrhage.

Cerebral vasospasm refers to the temporary or permanent narrowing of blood vessels (particularly arteries) located anywhere in the brain. In the human context, the cerebrum contains the telencephalon (in particular the cerebral cortex), the diencephalon, the midbrain, the hindbrain (in particular the cerebellum), and the medulla oblongata. Specifically, cerebral vasospasm refers to temporary or permanent narrowing of the blood vessels in the cerebellum and cerebral hemispheres (in particular the cerebral cortex).

Examples of calcium channel blockers include nimodipine, nifedipine, verapamil, nicardipine and isradipine. A particularly preferred active ingredient is selected from nicradipine, a pharmaceutically acceptable salt, hydrate or solvate thereof. The most preferred active ingredient is nicardipine.

Another calcium channel blocking agent or one or more active ingredients other than the calcium channel blocking agent may be used in addition to the calcium channel blocking agent, for example in addition to nicardipine. A predetermined amount(s) of the additional active ingredient(s), for example, may be placed(s) in a melt vessel in order to obtain a molten predispersion containing the additional active ingredient(s).

The calcium channel blocking agent can be from 1 wt. % up to 25 wt. % of the total weight of the solid dispersion product, such as from 5 wt.% to 20 wt.%), from 10 wt.%) to 15 wt.% or about 10 wt.%. In the case where more than one calcium channel blocking agent is present, the combined total weight of all calcium channel blocking agents is between 1 wt.% and 25 wt.% of the total weight of the solid dispersion product, as previously determined.

In a preferred method according to the present invention, the semi-solid polymeric binder component is PLGA Resomer® Mn 800 and the solid polymeric binder component is PLGA Resomer® Mn 2300 and the active ingredient is nicardipine, a pharmaceutically acceptable salt, hydrate or solvate thereof. These components are preferably used at a weight ratio of 50-80 parts by weight of PLGA Resomer® Mn 2300: 27-48 parts by weight of PLGA Resomer® Mn 800: 9-21 parts by weight of nicardipine (calculated as the free base of nicardipine). For these weight ratios, a suitable second target temperature can be easily determined by those skilled in the art and can range from 40°C to 100°C, such as from 50°C to 90°C, in particular from 60°C to 80°C. .

The method according to the present invention can be carried out using only a polymeric binder and an active ingredient. It is possible to include one or more adjuvants in the predispersion, for example by placing a predetermined amount(s) of adjuvant(s) in the melt vessel or by adding the adjuvant(s) at a later stage of the process.

Suitable adjuvants are known in the art and examples include antibacterial and antifungal agents, stabilizers, isotonic agents and pH adjusting agents. Auxiliaries may be included in the solid dispersion and/or the solid dispersion may be coated with the aids to prevent or delay chemical or physical changes during storage (eg by moisture or oxygen penetration) or to maintain the shape of the solid dispersion. The adjuvants are biodegradable and biocompatible. Examples of suitable adjuvants include natural polymers such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, polysaccharides and artificial polymers such as polyesters (polylactic acid, polylactic-polyglycolic acid), polyethylene glycol, poloxamers, polyanhydrides and polyoxamers.

The solid dispersion according to the present invention is characterized by a particularly high degree of uniformity with respect to its composition, in particular with respect to the distribution of the pharmaceutically active ingredient(s) in the solid dispersion product and with respect to the release of the pharmaceutically active ingredient(s) from the solid dispersion product.

In the method according to the present invention, measures conventional in the art can be taken to avoid contamination by polluting organisms or infectious agents (such as eukaryotic cells, bacteria or viruses) or harmful substances (such as chemicals or endotoxins), followed by packaging in sealed containers or the like to prevent subsequent contamination.

The solidified melt can be further processed into implants for the treatment and/or prevention of cerebral vasospasm. This may include, for example, cutting, shaping and/or sterilizing the solidified melt. For example, sterilization is carried out by gamma radiation. The implants may consist of a solid dispersion product.

The implants may have various shapes, such as substantially spherical shapes, such as balls and ellipsoids, or may be elongated, such as rods or tubes (with a circular cross section), flattened tubes (with an oval cross section), triangular, rectangular or polygonal bars or tubes (with a substantially triangular, rectangular or polygonal cross section) where the surfaces may be convex or concave. The implants may in particular be shaped to mimic the topology of the surface of the subarachnoid compartment and may, for example, have an elongated triangular shape with convex surfaces to facilitate their deposition and/or fixation in or on the grooves formed by the cerebral convolutions or on the blood vessels in these areas. Implants of the desired shape can be formed by injection molding, blow molding, extrusion, or any other shaping, molding or molding process known in the art as being suitable for molding the components.

The present invention also relates to a melt extrusion apparatus comprising an extrusion unit, a melt vessel with an opening, a shaking unit and a transfer element, wherein

the shaking unit is positioned so that the contents of the melt vessel can be agitated, e.g. agitated, in the melt vessel, and

the transfer element is positioned such that it can move the contents from the melt vessel through the opening by reducing the volume of the melt vessel available to the contents, and where

the melt vessel is connected to the extrusion unit such that the content conveyed through the opening enters the extruder assembly through the feed opening of the extruder assembly.

The melt extrusion apparatus may further comprise an ultrasound source which is positioned such that the contents of the melt vessel can be sonicated while agitated.

The present invention is further further illustrated by the following examples, which should not be construed as limiting the present invention.

Example 1

PLGA Resomer® Mn 2300 (98.42 g) and PLGA Resomer® Mn 800 (37.49 g) were weighed directly into the mixing and melting beaker at 90°C. After about ten minutes, the polymers were thin enough that a portion of the nicardipine base (15.28 g) could be incorporated into the melt. After the nicardipine base was melted and incorporated with shaking, the predispersion was processed in a beaker with an ultrasonic device at a temperature of 100°C. After 5 minutes of sonication at 20 kHz, the lid was closed and the molten predispersion was transferred by a punch to a twin screw extruder (type: Mini CTW). The extrusion was carried out at 68°C, while the temperature of the cap 70°C.

After extrusion, the strip was applied to a conveyor belt to adjust the diameter by setting the speed of the belt. When the extrudate reached ambient temperature, segments (length = 10 cm) were cut and stored in appropriate desiccant vials. During extrusion, the conveyor belt speed was set to 70 mm/min (+/- 10 mm/min) while the extruder torque was balanced to 15 Ncm (+/- 3 Ncm) with a screw speed of 3 rpm. The extrusion yield was 78% (118.5 g yield with 151.2 g injection), mainly due to material loss at the beginning and end of extrusion, as well as losses during material transfer from the melt vessel to the extruder.

The homogeneity of the contents of the beaker was controlled by routine analysis of samples taken from the beaker before and after shaking and at certain points in time after the start of extrusion. The results are summarized in Table 1.

Example 2

One portion of PLGA Resomer® Mn 2300 (37.61 g) was mixed with nicardipine base (15.19 g). A second portion of PLGA Resomer® Mn 2300 (58.54 g) was weighed. A mixture of PLGA Resomer® Mn 2300 with nicardipine base and a second batch of PLGA Resomer® Mn 2300 was cryogenically milled as shown in Table 2, ie. one portion of PLGA Resomer® Mn 2300 was ground separately and a second portion of PLGA Resomer® Mn 2300 was ground with nicardipine base.

PLGA Resomer® Mn 800 (37.69 g) was directly poured into a beaker for melting and stirring until sufficient liquid was reached when applied at 80° C. for 5 minutes. The milled mixture and milled second portion of PLGA Resomer® Mn 2300 was added to the already melted PLGA Resomer® Mn 800. This mixture was melted at 90°C for 10 minutes and then homogenized using ultrasound for 5 minutes at 20 Hz and 100°C.

Transfer to an extruder and extrusion was carried out as described for Example 1.

After extrusion, the strip was applied to a conveyor belt to adjust the diameter by setting the speed of the belt. When the extrudate reached ambient temperature, segments (length = 10 cm) were cut and stored in appropriate desiccant vials. The conveyor belt speed was 95 mm/min (+/- 5 mm/min). The extruder torque was 10 Ncm (+/- 3 Ncm). A yield of 86% was achieved.

The homogeneity of the contents of the beaker was controlled by routine analysis of samples taken from the beaker before and after shaking and at certain points in time after the start of extrusion. The results are summarized in Table 3.

Table 3 shows the high uniformity of the contents of the beaker during the method according to the present invention.

It is important to note that the uniformity of the contents of the glass in table 1, that is, without cryogrinding, was completely sufficient to feed it into the extruder. This shows that it is not necessary to grind any of the ingredients before placing them in the glass.

Claims (13)

1. A melt extrusion process for producing a solid dispersion containing a pharmaceutically active ingredient, a polymeric binder, and optionally one or more adjuvants, comprising: a) batchwise placing a predetermined amount of polymeric binder, a predetermined amount of active ingredient and optionally a predetermined amount of adjuvant(s) in a melt vessel; melting the polymeric binder in the melt vessel with agitation to disperse the active ingredient in the polymeric binder to form a molten predispersion; b) feeding the predispersion into an extruder to homogenize the predispersion and releasing the melt through the die; and c) allowing the melt to solidify, wherein the active ingredient is selected from nicardipine, a pharmaceutically acceptable salt, hydrate or solvate thereof, and the polymeric binder comprises (i) a poly(copolymer of lactide and glycolide) having a molecular weight distribution centered around the number average molecular weight of Mn2, and (ii) a poly(copolymer lactide and glycolide) having a molecular weight distribution centered around the number average molecular weight of Mn1, where Mn1 is in the range from 2000 to 3000 g/mol, and the ratio Mn1/Mn2 is from 1.8 to 3.5. 2. The method of claim 1, wherein the polymeric binder and the pharmaceutically active ingredient together comprise at least 80% by weight of the total weight of the predispersion. 3. The method according to p. 1, where the mass ratio of the component (i) of the polymeric binder and component (ii) of the polymeric binder is from 1:10 to 1.5:1. 4. The method of claim 1 wherein at least a portion of the polymeric binder is placed in the melt vessel and is at least partially melted before the active ingredient and optional adjuvant(s) are placed in the melt vessel. 5. The method according to claim 1, wherein the sonication is carried out while the active ingredient is dispersed in the polymeric binder and/or after the active ingredient is dispersed in the polymeric binder. 6. The method of claim 1 wherein the temperature of the predispersion as it is fed into the extruder is above its solidification temperature. 7. The method of claim 1, wherein feeding the predispersion to the extruder comprises moving the predispersion from the melt vessel through the opening of the melt vessel, the movement of the predispersion being enhanced by reducing the volume of the melt vessel available for the predispersion. 8. The method of claim 7, wherein the volume of the melt vessel available for predispersion is reduced by translational movement of a transfer element, such as a punch, into the melt vessel. 9. The method according to any one of paragraphs. 1-8, wherein the pharmaceutically active ingredient and/or at least a portion of the polymeric binder is ground prior to being placed in a melt vessel.