GR1010059B - Process and apparatus for preparing viscous pharmaceutical formulations - Google Patents

Abstract

The present invention relates to a process for the preparation of viscous pharmaceutical formulations and to an apparatus for implementing the process. A gellable material is introduced into one chamber, a vehicle is introduced in the other and by alternately applying force to each chamber, mixing and homogenization takes place. The internal diameter of the connection equipment of the two chambers is equal to the outlet internal diameters of the chambers. And each chamber is chosen to have different diameter, with the first chamber being larger than the second chamber, so as to allow the process to be executed in a simple and more convenient manner.

Description

PROCESS AND APPARATUS FOR THE PREPARATION OF THICKENED PHARMACEUTICAL FORM

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the method of preparing viscous pharmaceutical forms as well as a device for implementing the above method. More specifically, the present invention describes the preparation of viscous pharmaceutical forms, such as hydrogels, using a device with specific design features.

BACKGROUND OF THE INVENTION

Controlled-release formulations improve the efficacy of drug therapy by enhancing the therapeutic efficacy of the drug and reducing the frequency of administration, while at the same time less symptomatic exposure occurs through lower plasma concentration levels of the controlled-release drug, which reduces the intensity of side effects. When the above pharmaceutical forms are administered by injection, they are called controlled release injectable pharmaceutical forms.

A well-known category of controlled-release injectable pharmaceutical form is storage preparations. For certain drugs which i) have a broad therapeutic spectrum, ii) require a small dose to be taken on a daily basis and iii) are intended for long-term use to treat a disease, controlled-release injectable formulations that create depots, such as microparticles, suspensions and the semi-solid preparations may provide an alternative method of administration, potentially providing the possibility of administering some medicine, which under other conditions cannot be administered. Storage formulations exhibit potential advantages such as protecting peptides, proteins and other biologically active substances by stabilizing them from rapid inactivation and thus enabling the maintenance of pharmacological performance and administration in small doses. Additional advantages of depot formulations include the reduction of unwanted side effects thanks to their ability to deliver smaller doses, the reduction of the total number of administered doses as well as the possibility of controlled and targeted release of the active substances.

One of the most interesting storage devices are gels, especially hydrogels. Hydrogel formulations provide several advantages related to less frequent dosing, sustained drug release, and fewer side effects. The method of the present invention provides pharmaceutical formulations which form sustained release storage devices within the patient without requiring on-site dissolution or pretreatment prior to administration of the formulation. An important quality element of hydrogel pharmaceutical forms is their homogeneity. Hydrogels are also referred to in the literature as semi-solid forms.

Hydrogels, which are also biodegradable, provide a number of advantageous formulations, since the use of biodegradable systems eliminates the need to remove the "ghost" system for drug release after all the drug has been completely released. Biodegradable hydrogel systems provide unique advantages in drug release, such as improved biocompatibility and greater flexibility in controlling the stability and diffusion properties of protein drugs. In addition, the use of biodegradable hydrogel systems makes it possible to target the drug to a specific area of the body.

There are four different classes of hydrogel formulations: (i) those with well-organized lamellar structures, which include lyotropic hydrocrystalline phases: (ii) those with carrier (solution)-swelled cross-linked polymer networks, in these phases the polymer chains are non- organized, (iii) those with polymeric networks, in which the chain-to-chain interactions are physical, the chains may be predominantly disordered, but there may also be regions that are locally organized (especially where there are interactions within the chain), and (i) those having particulate disorganized structures, which include materials whose gel networks are composed of fibrils.

Hydrogel formulations are an example of the preparation of viscous pharmaceutical formulations exhibiting viscosity values such as those listed below.

In general, in the preparation of gel and hydrogel formulations, laminar flow appears to dominate turbulent flow, where laminar flow refers to a type of fluid (gas or liquid) flow in which the fluid passes uniformly or in defined paths, as opposed to turbulent flow, in which the fluid undergoes disordered fluctuations and mixing. The successful mixing of viscous liquids requires specially designed mixing equipment. Briefly, vane devices, anchor vanes, auger blades, and kneading mixers have been used in the past to improve mixing and create a homogeneous final formulation. Two special impellers, known as Z blades or sigma blades, are used to improve mixing in the area closest to the agitation tank walls along with a narrow gap between the impeller blades and the agitation tank wall to achieve maximum efficiency mixing.

Despite any modifications made to improve the mixing of viscous liquids, several problems still exist, such as: (i) elevated temperature due to mechanical agitation, (ii) difficulty in collecting the final product and submitting it to a single-dose filling process (human intervention), (iii) power consumption due to the large power required to adequately mix the semisolid formulations, (v) difficulties arising from the nature of the lyophilized powders often used in the preparation of semisolid formulations, and (v) problems related to sufficient homogeneity of the viscous mixture, which affect batch-to-batch consistency, a property that is particularly critical for the controlled release of pharmaceuticals.

In addition to the above challenges, mixing equipment for the preparation of thickened dosage forms must consist of hermetically sealed systems with minimal headspace to minimize any loss of water and/or product mass that dries during preparation.

SUMMARY OF THE INVENTION

As stated above, despite any modifications made to improve mixing of viscous liquids, there continues to be a need for an improved and direct method of preparing viscous dosage forms with improved homogeneity and consistency that will solve some and/or all of the problems that were mentioned above.

The present invention provides a reliable, reproducible and direct method of preparing viscous pharmaceutical forms and formulations consisting of a combination of a gelable material and a carrier using a two-chamber apparatus, wherein one chamber contains the gelable material gel and the other chamber contains the carrier, and which device continuously moves the contents of one chamber to the other chamber, the chambers having a specific ratio of internal diameters. The gelable material can be a non-active substance or an active substance with self-forming properties and inherent gel-forming properties.

More specifically, the device consists of an interconnected two-chamber system equipped with the means required to apply force to either chamber. Applying force to each chamber in turn causes a reciprocating motion that moves the contents of one chamber to the other. The means for exerting force on the contents of the chambers may be pneumatic means using a compressed gas, such as compressed air, acting directly on the contents of the chamber, or the application of pressure may be achieved by means of a movable piston placed within the chamber with some means for urging the piston to move along the chamber and thereby move the contents of one chamber into the other chamber.

The material that turns into a gel, e.g. some active substance with gelling properties is introduced into one chamber, a carrier is introduced into the other chamber and by applying force alternately in each chamber, mixing and homogenization takes place. The inner diameter of the connecting equipment of the two chambers is equal to the inner diameter of the mouth of the chambers. Each chamber is chosen to have a different diameter, with the first chamber being larger than the second, so that the process can be carried out in a simple and more user-friendly way, thus overcoming the need for high power consumption and excessive mechanical force.

The present invention provides a homogeneous viscous pharmaceutical form by means of a method having one and/or more of the following advantages: (i) small number of processing steps, (ii) absence of stagnant regions within the interconnected system of the two chambers, (iii) saving function energy during homogenization, (i) facilitating the collection of the final thick pharmaceutical formulation without human intervention, (v) shorter preparation time, and (vi) batch-to-batch consistency.

DEFINITIONS

For purposes of this application and claims, the following terms shall have the meanings assigned to them below. It is to be understood that when reference is made herein to a general term such as formulation, excipient, etc., those skilled in the art may make specific choices based on the definitions below or based on industry references that are common general knowledge.

The term "controlled-release injectable form or storage preparation" refers to a product for subcutaneous or intramuscular injection, which contains an active substance and releases the active substance over a specific period of time.

The term "controlled release pharmaceutical form" refers to a wide range of technologies, which modify the pharmacokinetic profile of the drug avoiding the immediate release of its active substance.

The term "carrier" or "pharmaceutical carrier" refers to some carrier or inactive substance used, in which the active substance is formed or administered, such as a solvent (or diluent).

The term "gelable material" refers to a substance, active or non-active, which when added to a suitable carrier produces a gel formulation or viscous pharmaceutical formulation.

The term "gel formulation" refers to a pharmaceutical formulation resulting from the swelling of a substance (active or excipient) in the presence of a liquid medium. When swelling takes place in the presence of water then the gel is called a hydrogel.

Additionally, it is to be understood in the methods of preparation and claims herein that the indefinite articles "a, one, an", where they are used to denote a reagent, such as "a base", "a solvent", etc. should be understood as "at least one" and thus include, where necessary, both individual reagents and mixtures of reagents.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates an example of a two-chamber device according to the invention.

Figure 2 illustrates the preferred approach of the invention, with an extension tube.

Figure 3 illustrates a still preferred approach to the invention, in which the extension tube is partially made of glass.

Figure 4 illustrates another preferred approach of the invention, in which the pressurizing means are pistons.

Figure 5 illustrates another preferred approach of the invention, in which the pressure means is conical in shape.

Figure 6 illustrates a still preferred approach of the invention, in which the multiple connection element is a three-position connection means.

Figure 7 illustrates another preferred embodiment of the invention with different dimensions than Figure 1.

Figure 8 illustrates another preferred approach of the invention, in which the chambers are syringes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention aims at the preparation of pharmaceutical preparations suitable for use as controlled release pharmaceutical forms. My preferred thick formulations are gels, even better hydrogels, and ideally biodegradable hydrogels.

The method for the preparation of a viscous pharmaceutical form takes place in a two-chamber device, in which the first (1), (21), (31) and the second chamber (2), (22), (32) are connected via a manifold element connection (5), (20), (25), (35) and which method includes the following steps:

a) filling the first chamber with material that turns into a gel (1), (21), (31),

b) filling a carrier in the second chamber (2), (22), (32),

c) transfer of the carrier from the second chamber (2), (22), (32) to the first chamber (1), (21), (31),

d) staying the combined content in the first chamber (1), (21), (31) for a certain period of time,

e) transferring the combined contents from the first chamber (1), (21), (31) to the second chamber (2), (22), (32)

f) transferring the combined contents from the second chamber (2), (22), (32) to the first chamber (1), (21), (31);

g) repeating steps e) and f) until homogeneity is achieved;

where the ratio of the inner diameter of chamber CD1 (6), (26), (36) of the first chamber (1), (21), (31) to the inner diameter of chamber CD2 (7), (27), ( 37) of the second chamber (2), (22), (32) is greater than 1.

More specifically, the method for preparing a viscous pharmaceutical form takes place in a two-chamber device, in which the first (1), (21), (31) and the second chamber (2), (22), (32) are connected via of a multiple connection element (5), (20), (25), (35) and which method comprises the following steps:

a) filling a gelling material in the first chamber (1), (21), (31) with an internal diameter CD1 (6), (26), (36) and an internal orifice diameter OD1 (9), (29) , (39),

b) filling a carrier in the second chamber (2), (22), (32) with internal diameter CD2 (7), (27), (37) and internal orifice diameter OD2 (10), (30), (40) ,

c) transfer of the carrier from the second chamber (2), (22), (32) to the first chamber (1), (21), (31) through a multiple connection element (5), (20), (25), (35) with inner diameter MDC (8), (28), (38), which connects the first chamber (1), (21), (31) to the second chamber (2), (22), (32 ),

d) staying the combined content in the first chamber (1), (21), (31) for a certain period of time,

e) transferring the combined contents from the first chamber (1), (21), (31) to the second chamber (2), (22), (32)

f) transferring the combined contents from the second chamber (2), (22), (32) to the first chamber (1), (21), (31);

g) repeating steps e to f until homogenization is achieved;

where

the internal diameter CD1 (6), (26), (36) is always greater than the internal diameter CD2 (7), (27), (37),

orifice inner diameter OD1 (9), (29), (39) and orifice inner diameter OD2 (10), (30), (40) are both equal to inner diameter MCD (8), ( 28), (38) of the manifold element (5), (20), (25), (35), the ratio R1 of the inner diameter MCD (8), (28), (38) of the manifold element (5 ), (20), (25), (35) to the inner chamber diameter CD1 (6), (26), (36) of the first chamber (1), (21), (31) varies between 0.10 and 0.35,

the ratio R2 of the inner diameter MCD (8), (28), (38) of the manifold (5), (20), (25), (35) to the inner diameter of the chamber CD2 (7), (27) , (37) of the second chamber (2), (22), (32) varies between 0.15 and 0.50,

and R1 is never equal to R2.

The device may optionally have other components such as valves, fittings and sensors provided to automate the process. Other optional components can be a fuse panel, a control (HMI), one or more pumps and a high precision balance.

The gelable material used in the present method may be an inactive substance, such as one or more pharmaceutical excipients with gelling properties, or one or more active substances (API) with gelling properties, or a mixture of the above. In one of the preferred approaches the gelling material consists of one or more excipients with gelling properties. In another preferred approach the gelling material consists of one or more active substances with gelling properties.

Gels consist of two interpenetrating systems containing colloidal particles called media or gelling agents, which are uniformly distributed within the dispersion medium or solution and form a three-dimensional matrix known as a gel. Gels are prepared by adding a gelling agent, which may be a natural, synthetic or semi-synthetic polymer or low molecular weight small particles, to a liquid, such as an organic, inorganic or aqueous solvent or mixture of solvent systems. Where there is water in the liquid, then the gel is called a hydrogel.

Examples of pharmaceutical ingredients with gelling properties are agar, carrageenan and xanthan gum, guar gum (polymerized mannose and galactose disaccharide), tragacanth, pectin, starch, carbomers, sodium alginate, gelatin, cellulose derivatives, polyvinyl alcohol clays, alginate compounds, carrageenan, carboxymethyl cellulose, sodium pectin. Additionally, the following polymers are mainly used for in situ injectable formulations: aliphatic polyesters, such as poly(lactic acid), poly(glycolic acid), poly(lactic glycolic acid), poly(decalactone) and poly(ε-caprolactone). Various other polymers are also used, such as methyl alcohol and hydroxypropyl methyl alcohol as well as ternary polymer systems consisting of poly(D,L-lactic acid)-block-poly(ethylene glycol)-block-poly(DL-lactic acid) and low molecular weight mixts. poly(D,L-lactate) and poly(ε-caprolactone). Blends of poly(ethylene glycol) (PEG) and poly(methacrylic acid) (PMA) as well as polymers based on poly(acrylic acid) (PAA) (carbomer, Carbopol) or its derivatives have also been used as a pH-sensitive system to achieve gelation. (Sanjana N K. et al. / Asian Journal of Research in Biological and Pharmaceutical Sciences. 4(4), 2016, 133 - 142.)

Lanreotide acetate is an example of an active with inherent gelling properties. Lanreotide acetate is a synthetic cyclic octapeptide analog of the natural hormone somatostatin, known as cyclo[S-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyll-L-lysyl -L-valyl-L-cysteinyl-L-threoninamide, acetate. The chemical structure of Lanreotide acetate is shown below:

Lanreotide is indicated for the treatment of acromegaly, as a palliative treatment for certain types of cancer and for carcinoid syndrome in adults. The product is administered every 4 weeks in the form of a semi-solid product, the appearance of which is like a gel.

In the case of Lanreotide, the hydrogel formulation is based on its ability to self-assemble in water into nanotubes (Valery et al, Biophysical Journal 2004, 86, 2484), forming a hydrogel with controlled release properties that can be administered subcutaneously to patients. One possible mechanism demonstrates that the formulation forms a drug depot at the injection site due to the interaction of the formulation with body fluids. Drug release can be achieved by various mechanisms, including diffusion, dissolution, passive diffusion of the drug from the storage formulation to the surrounding tissues, followed by absorption from the circulatory system. The mechanism of action of Lanreotide is thought to be similar to that of natural somatostatin.

The method of the present invention can be used for the preparation of viscous pharmaceutical preparations and in combination with other active agents, which exhibit gelling properties, as described above. The active agent is preferably a peptide, further preferred is a somatostatin analog, even more preferred is Lanreotide or a pharmaceutically acceptable salt thereof. Acetate is now preferred.

The method of the present invention can also be used for the preparation of thick pharmaceutical preparations in combination with active agents, which do not exhibit gelling properties. In this case the pharmaceutical excipient with gelling properties may be included in the gelling material together with a non-gelling active or alternatively the non-gelling active may be included in the carrier.

Viscosity is the physical property that affects many other properties, for example in the case of pharmaceuticals, injectability. The high viscosity formulation results in an increase in injection values, because the injection force increases as the viscosity increases. The release rate can be measured through in vitro release tests to determine the percentage of active substance released over time. An increase in pH leads to a decrease in the release profile (dissolution rate) of the formulation. In the Lanreotide formulation the pH is directly proportional to the acetic acid concentration and the optimal acetic acid concentration is defined and calculated from the optimal pH range, as described in EP2523653.

Injectability is an important parameter for product performance for any parenteral formulation, such as injectable emulsions, suspensions, liposomes, microemulsions, gels and microspheres, and relates to the ease with which an injectable treatment can be administered by syringe. Considered an important property for performance, safety and patient acceptance, e.g. ease of use and patient compliance. In addition, it represents the viscosity of a product. Injectability allows conclusions to be drawn as to flow uniformity and absence of syringe blockage. In general, it affects the performance of the delivery system.

Injectability is determined by measuring the pressure or force required for injection.

The method and procedure are described in detail with reference to the respective figures.

The two chambers (1), (2), (21), (31), (22), (32) consist of a main body, in which the internal diameters of the chambers (6), (26), (36) are measured , (7), (27), (37) and a part of the mouth of the chamber in which the inside diameters of the mouth (9), (29), (39), (10), (30), (40) are measured .

In one of the approaches the chambers may have some means for exerting pressure (3), (4), (16), (17), (18), (19), (23), (24), (33 ), (34). The pressurizing means has a shape complementary to the internal shape of the chamber mouth member and is adjusted to expel all of the material when the pressurizing means moves toward the chamber mouth member. This minimizes content loss. The above means of exerting pressure can be round components (3), (4) in the case of cylindrical chambers, within which force is exerted (11), (12) (Fig. 1, 2, 3, 6, 7) or pistons ( 16), (17) (Fig. 4), conical fittings (18), (19) (Fig. 5) or pistons (33), (34) (Fig. 8).

The two chambers are connected by means of a multiple connection element (5), (20), (25), (35) along their longitudinal axis. Pressure is applied in the form of an external force (11), (12) to transfer the contents of one chamber to the other chamber through a reciprocating motion. This can be done for example through a pneumatic system using compressed air. Other ways of causing reciprocating motion are through the use of a hydraulic or electric pump connected to a piston. A vacuum pump is also used as auxiliary equipment to assist in compressing the gelling material to remove entrapped air or other gas and achieve the desired volume where required. The vacuum pump, which is not shown in the Figures, can be connected to the device through the multiple connection element (5), (20), (25), (35).

The above basic arrangement of the device is also analyzed in International Patent Publication WO 96/07398.

The chamber can be any type of container compatible with the contents to be placed in it and must withstand the forces developed during the process performed on it. Therefore, it can for example be a container, as shown in Figs. 1-7 or a syringe, as shown in Fig. 8. In one of the preferred approaches one of the two chambers is cylindrical. In another preferred approach the chambers are made of metal and more ideally of stainless steel. Each chamber is characterized by chamber inner diameter (6), (7), (26), (27), (36), (37) and orifice inner diameter (9), (10), (29), (30), (39), (40). Chamber inner diameters may vary for each chamber. The internal diameters of the mouth of each chamber are equal.

The chambers are designed and equipped in such a way as to allow them to be filled with ingredients, e.g. with the gelling material and carrier (not shown in the Figures).

Chamber size is not a critical parameter. When syringes are used as chambers, then the length can be as short as the length of a syringe. Otherwise the chamber size can be adjusted to the batch size of the mixture to be produced. It can range from a few centimeters (5 cm) to a length of up to one meter. Taking into account the ratio of the inner diameter of the chamber and the corresponding length the chamber should not be too narrow nor too wide. The ratio of the length to the corresponding inner diameter of the chamber may vary between 1 and 10, more preferably between 2 and 10 and ideally between 4 and 8.

The multiple connection element (5), (20), (25), (35) controls the passage of the gelling material and/or liquid and/or air through the mouth of the first or second chamber. The manifold element (5), (20), (25), (35) may for example be a valve, preferably the triple delivery valve, which provides the additional advantage of acting as an outlet for extracting the mixture after its homogenization. Its dimensions, in particular its internal diameter MCD (8), (28), (38) are adjusted to match the internal diameters of the mouth of the first (9), (29), (39) and second chamber (10) , (30), (40) and are therefore explicitly determined by them. The multiple connection element (5), (20), (25), (35) can isolate the chambers with the corresponding adjustments. In the case of a valve, for example, this is done by turning it to its side.

The entire construction must be able to provide a system that seals tightly and has a minimum void at the top to minimize losses and allow for the use of air vacuum if required.

Moreover, the manner in which the components of the structure move is not important in causing the reciprocating motion of the pressure-exerting means (3), (4), (16), (17), (18), (19), ( 23), (24), (33), (34). With reference to the external system, either the pressure means (3), (4), (16), (17), (18), (19), (23), (24), (33), (34 ) to be mobile or the rest of the device to be mobile. In each case, the relative movement of the means of exerting pressure (3), (4), (16), (17), (18), (19), (23), (24), (33), (34) towards the rest of the device is such as to create a reciprocating movement, by which the contents of one chamber are transferred to the other chamber.

In one of the preferred approaches, the device also has an extension tube (14), as shown in Figs. 2 and 3. The extension tube is suitable for transporting the contents of the chambers from the first (1), (21), (31) to the second chamber (2), (22), (32) and vice versa. It can consist of a static stirrer in its inner part. In a more preferred approach of the invention the expansion tube (14) is at least partially made of glass (15) as shown in Fig. 3, which enables control of the homogenization during the process. The extension tube has an inside diameter (13) equal to the MCD inside diameter (8), (28), (38) of the manifold (5), (20), (25), (35) and the inside diameters of mouth of chamber OD1 (9), (29), (39) and OD2 (10), (30), (40) of first (1), (21), (31) and second chamber (2), (22 ), (32). The extension tube can be connected either to the first chamber (1), (21), (31) and the manifold element (5), (20), (25), (35) or to the manifold element ( 5), (20), (25), (35) and the second chamber (2), (22), (32).

The material that turns into a gel is supplied in powder form and is transferred into the first chamber (1), (21), (31) of the device. The other end of the first chamber (1), (21), (31) is connected to the manifold element (5), (20), (25), (35).

In some formulations the final volume of material that is gelled in the chamber is a critical parameter that may affect the subsequent stages of preparation. For example, in the case of Lanreotide it has been shown that, after packaging, the active substance constituting the mass of gelling material must have its final volume in the chamber before the carrier is added, which volume is equal to or approximately equal to with the amount of carrier to be added. Thus it becomes possible to add the carrier to the total mass of the gelled material resulting in the initial formation of a semi-solid material which can be subjected to homogenization.

In one of the preferred approaches once the gelling material is introduced and isolated in the first chamber (1), (21), (31) the capacity of the chamber is adjusted by applying pressure (3), (16), (18), (23), (33) in a volume that is similar to or equal to the volume occupied by the carrier to be added. Isolation of the first chamber prevents air from entering the system. In a more preferred approach a vacuum can be used to help adjust the volume by removing air or any entrapped gas, depending on the bulk density of the material being gelled. For smaller apparent density values, which are caused by larger specific surfaces, additional vacuum assistance may be required to properly pack the material. In addition, a filter screen and an extension with a pressure gauge connected to the vacuum valve can also be connected to the manifold (5), (20), (25), (35). This avoids aspiration of the gelled material by the vacuum pump.

An appropriate amount of a carrier is added to the second chamber (2), (22), (32). The carrier may be water, including water suitable for injection or other aqueous medium, an organic solvent with or without water, an anhydrous liquid, or an injectable oil. Examples of substances that can be used as carriers in the present invention, or more specifically as solvents, are contained in EP2823808, which is incorporated herein by reference. The carrier may also contain one or more pharmaceutical excipients, which function as components of the final formulation.

The first (1), (21), (31) and second chamber (2), (22), (32) are connected by setting the manifold (5), (20), (25), (35) to a position where the carrier can be transferred from the second chamber (2), (22), (32) to the first chamber (1), (21), (31) through the multiple connection element (5), (20); (25), (35). This transfer from one chamber to another is preferably effected by reciprocating movement of the pressurizing means (3), (4), (16), (17), (18), (19), (23), (24). , (33), (34).

When the transfer is complete the first chamber is isolated again by adjusting the multi-connector (5), (20), (25), (35) in the corresponding position and sufficient time is provided for the combined contents to remain in the first chamber.

In one preferred approach, sufficient time is provided for the carrier and gelling material to interact. In an even more preferred approach, sufficient time is provided for the carrier to hydrate the gelling material. Sufficient time means between a few minutes and several hours, preferably between 10 minutes and 3 hours, more preferably between 15 minutes and 2 hours and most ideally between 30 and 60 minutes.

In the next stage the first chamber (1), (21), (31) is connected again to the second chamber (2), (22), (32) and the homogenization process begins. The combined content is transferred from the first chamber (1), (21), (31) to the second chamber (2), (22), (32) and then the hydrated mixture is transferred from the second chamber (2), (22) , (32) in the first chamber (1), (21), (31). The combined content continues to be transferred from the first chamber (1), (21), (31) to the second chamber (2), (22), (32) and vice versa through the manifold element (5), (20), (25), (35) until the mixture is homogeneous.

In one of the approaches, the transfer of the contents of the first chamber to the second chamber and vice versa is carried out through a reciprocating movement of the pressure exerting means (3), (4), (16), (17), (23), (24), ( 33), (34).

During the homogenization process Fmax and Faverage are measured. The maximum force (Fmax) is the largest force measured from the point where the profile of the force required for injection begins to reach a plateau (displacement versus force) and until the piston completes its stroke of the front end of the syringe or container (before the sudden force increase caused by the compression of the plunger on the end of the syringe). The Dynamic Gliding Force (DGF or Faverage) is calculated as an average over the fixed plane region of the data corresponding to the displacement ranges of the various syringes.

The standard injectability test measures the force required to move the syringe plunger so that the contents of the syringe exit the needle. The profile shows an initial sharp increase in the force required in the first few millimeters of displacement and then a stabilization region (steady-state region). The steady level is observed until the final spike in applied force, which corresponds to the point where the plunger completes its travel at the front end of the syringe (eg, after the syringe contents have been expelled). To evaluate a pharmaceutical device and then a pharmaceutical formulation through injectability measurements three parameters are considered. Breakaway Force (BLF), Maximum Force (Fmax) and Dynamic Glide Force (DGF).

Figure 1: A typical injection measurement combining the red dotted area denoting the Release Force (BLF), the dotted and dashed area where the Maximum Force (Fmax) is observed, and the dotted dashed area denoting the area of Dynamic Gliding Force (DGF).

The first parameter is the Release Force (BLF) and is observed during the first centimeters of piston displacement. The BLF corresponds to the maximum force required to overcome the adhesion forces developed between the inner barrel of the syringe and the rubber stopper. The BLF study is useful for stability reasons where rubber stopper interactions with the pharmaceutical formulation may alter the level of initial force required to initiate delivery.

The most important factor is the Dynamic Gliding Force (DGF), which is defined as an average force calculated over the region of the fixed plane. This corresponds to the force required to maintain the uninterrupted transfer of content at a constant displacement rate. This is the most critical metric for evaluating the device, primarily as it relates to ease of administration to the patient. By comparing DGF between different formulations information can be extracted regarding viscosity, concentration and other characteristics. Finally, the Maximum Force (Fmax) is defined as the maximum force observed at the fixed level during the injection measurement. The above factor can provide information about the homogeneity of the mixture, possible clogging, etc. when combined with the Dynamic Gliding Force (DGF).

The inventors unexpectedly discovered that the homogeneity of the viscous pharmaceutical formulation can be affected by the specific dimensions of the chambers. More specifically, the internal diameters of the chambers CD1 (6), (26), (36) and CD2 (7), (27), (37), the diameters of the orifices OD1 (9), (29), (39) and OD2 (10), (30), (40) and the corresponding ratios were found to play an important role for the homogenization process. Since orifice inner diameter OD1 (9), (29), (39) and orifice inner diameter OD2 (10), (30), (40) are both equal to inner diameter MCD (8) , (28), (38) of the manifold element (5), (20), (25), (35) it is easier to make a general reference to the inner diameter MCD (8), (28), (38).

To determine the optimum dimensions, the bulk amount of gel prepared by the method of the present invention was subjected to injectability and viscosity tests by taking samples from different parts thereof. Adequate homogeneity is considered to have been achieved when the deviation between the analytical results of the different samples is not significant (see Table 1).

Optimum results are obtained when the ratio R1 of the MCD (8), (28), (38) of the manifold element (5), (20), (25), (35) to CD1 (6), (26) , (36) of the first chamber (1), (21), (31) is between 0.10 and 0.35, and the R2 ratio of the MCD (8), (28), (38) of the manifold element (5 ), (20), (25), (35) to CD2 (7), (27), (37) of the second chamber (2), (19) varies between 0.15 and 0.50. Additionally, the inner diameter CD1 (6), (26), (36) is always larger than the inner diameter CD2 (7), (27), (37) and R1 must never be equal to R2.

The inventors consider the above parameters to be critical and determine the physical characteristics of the final gel formulation which in turn affect the degradation rate and thus the release characteristics of the prepared formulation. The proposed diameter ratios allow the process to be completed in about 2-3 hours, during which about 60 transfer cycles are carried out from the first to the second chamber and vice versa. Nevertheless, there are cases in which the preparation time can reach up to 15 hours to achieve satisfactory homogenization.

EXAMPLES

66.8 g of active Lanreotide with a peptide content of 92.0% and an acid content of 5.5% are introduced into the first chamber (1) and packed using a vacuum pump until a volume of 174.31 mL is reached. 216.08 g of water for injection are mixed with 3.69 g of acetic acid until a clear, colorless solution is obtained. 193.02 g of the above solution is charged into the second chamber. After packing the active 193.02 g of the aqueous acetic acid solution are transferred to the first chamber. Sufficient time is provided for proper hydration of the active (ie 60 minutes). Once the above is achieved, the two chambers are connected and the homogenization process begins, transferring the hydrated mixture from the first to the second chamber and vice versa. The homogenization process continues until the mixture is considered completely homogenized.

The homogeneity of the bulk product is evaluated based on the relative standard deviation (RSD) percentage calculated with respect to the injection from three different points of the bulk product. The small percentage of RSD indicates that the product is homogeneous.

Injectability

The gel product is filled into syringes and the force versus displacement data as well as the graph are extracted from the measurement using a Shimadzu EZ-SX food texture analyzer.

Viscosity

The rheological characterization of the sample is carried out through measurements of dynamic oscillations as a function of stress and cyclic frequency (i.e. stress and frequency sweep test) using an AR-G2 strain controlled rheometer from TA Installments.

Table 1

• Examples 1 and 2: When R1 is equal to R2 the process takes too many hours until homogenization is achieved and the results obtained are not acceptable.

• Examples 3 and 4: When one or both ratios R1, R2 have values less than 0.10 and 0.15 respectively, then the result is unsatisfactory homogenization of the samples and long preparation hours.

• Examples 5, 6 and 7: When and range between 0.10 - 0.35 and 0.15 a gel with good homogeneity is prepared.

• Example 8: When R ratios respectively, then this results in homogeneous.

the two ratios R1, R2 have values that - 0.50 respectively then within 2 — 3 hours

1, R2 have values above 0.35 and 0.05 and the product produced is not

Claims (28)

1. A method for preparing a viscous pharmaceutical form which takes place in a two-chamber apparatus, in which the first (1), (21), (31) and the second chamber (2), (22), (32) are connected via of a multiple connection element (5), (20), (25), (35) and which method comprises the following steps: a) filling the first chamber with material that turns into a gel (1), (21), (31), b) filling a carrier in the second chamber (2), (22), (32), c) transfer of the carrier from the second chamber (2), (22), (32) to the first chamber (1), (21), (31), d) staying the combined content in the first chamber (1), (21), (31) for a certain period of time, e) transferring the combined contents from the first chamber (1), (21), (31) to the second chamber (2), (22), (32) f) transferring the combined contents from the second chamber (2), (22), (32) to the first chamber (1), (21), (31); g) repeating steps e) and f) until homogeneity is achieved; where the ratio of the inner diameter of chamber CD1 (6), (26), (36) of the first chamber (1), (21), (31) to the inner diameter of chamber CD2 (7), (27), ( 37) of the second chamber (2), (22), (32) is greater than 1. 2. A method for the preparation of a viscous pharmaceutical form taking place in a two-chamber apparatus, in which the first (1), (21), (31) and the second chamber (2), (22), (32) are connected via of a multiple connection element (5), (20), (25), (35) and which method comprises the following steps: a) filling a gelling material in the first chamber (1), (21), (31) with an internal diameter CD1 (6), (26), (36) and an internal orifice diameter OD1 (9), (29) , (39), b) filling a carrier in the second chamber (2), (22), (32) with internal diameter CD2 (7), (27), (37) and internal orifice diameter OD2 (10), (30), (40) , c) transfer of the carrier from the second chamber (2), (22), (32) to the first chamber (1), (21), (31) through the multiple connection element (5), (20), (25) , (35) with inner diameter MDC (8), (28), (38), d) staying the combined content in the first chamber (1), (21), (31) for a certain period of time, e) transferring the combined contents from the first chamber (1), (21), (31) to the second chamber (2), (22), (32); f) transferring the combined contents from the second chamber (2), (22), (32) to the first chamber (1), (21), (31); g) repeating steps e) and f) until homogeneity is achieved; where the internal diameter CD1 (6), (26), (36) is always greater than the internal diameter CD2 (7), (27), (37), orifice inner diameter OD1 (9), (29), (39) and orifice inner diameter OD2 (10), (30), (40) are both equal to inner diameter MCD (8), ( 28), (38) of the manifold element (5), (20), (25), (35), the ratio R1 of the inner diameter MCD (8), (28), (38) of the manifold element (5), (20), (25), (35) to the inner diameter of the chamber CD1 (6), (26) , (36) of the first chamber (1), (21), (31) varies between 0.10 and 0.35, the ratio R2 of the inner diameter MCD (8), (28), (38) of the manifold (5), (20), (25), (35) to the inner diameter of the chamber CD2 (7), (27) , (37) of the second chamber (2), (22), (32) varies between 0.15 and 0.50, and R1 is never equal to R2. 3. A method according to claim 1 or 2, wherein in step d) sufficient time is provided for the carrier to interact with the gelling material. A method according to claims 1-3, wherein the first chamber comprises a pressurizing means (3), (16), (18), (23), (33) and the second chamber also comprises a pressurizing means (4), (17), (19), (24), (34) and the transfer of the contents from the first to the second chamber and vice versa is carried out by means of reciprocating movement of the pressurizing means. 5. A method according to any of the above claims, wherein after step b) and before step c) the capacity of the first chamber is adjusted to a volume approaching or equal to the volume occupied by the carrier through pressure exerted by the first means of exerting pressure (3), (16), (18), (23), (33). A method according to claim 5, wherein the regulation of the capacity of the first chamber is assisted by the use of vacuum. A method according to claim 6, wherein the vacuum is created by a filter screen. A method according to any one of the above claims, wherein one or both chambers (1), (21), (31), (2), (22), (32) are cylindrical. A method according to any one of the above claims, wherein the manifold element (5), (20), (25), (35) is a valve. A method according to claim 9, wherein the valve is a triple delivery valve (20). 1 1. A method according to any one of the above claims, wherein the extension tube (14) can be connected to the manifold (5), (20), (25), (35) and the first chamber 1), (21), (31) or in the manifold element (5), (20), (25), (35) and the second chamber (2), (22), (32). A method according to claim 11, wherein the extension tube (14) is partially made of glass (15). 13. A method according to any one of the above claims, wherein the pressurizing means is a piston or piston (16), (17), (33), (34). 14. A method according to any one of the above claims, wherein the gelling material contains an active substance with gelling properties or a pharmaceutical excipient with gelling properties or a mixture thereof. 15. A method according to any of the above claims, wherein the carrier consists of a pharmaceutical excipient and/or active substance without gelling properties. 16. A method according to any of the above claims, wherein the gelling material is Lanreotide or a pharmaceutically acceptable salt thereof, ideally an acetate. 17. A two-chamber apparatus for carrying out the method of claims 1-16, comprising: a) a first chamber (1), (21), (31) for the gelling material, b) a second chamber (2), (22), (32) for the carrier, c) a multiple connection element (5), (20), (25), (35) for controlling the path of gelling material, carrier, air or any mixture thereof from the orifice of the first or second chamber connecting the first chamber (1), (21), (31) to the second chamber (2), (22), (32); where the ratio of the inner diameter of chamber CD1 (6), (26), (36) of the first chamber (1), (21), (31) to the inner diameter of chamber CD2 (7), (27), ( 37) of the second chamber (2), (22), (32) is greater than 1. 18. A two-chamber apparatus for carrying out the method of claims 1-16, comprising: a) a first chamber (1), (21), (31) with internal diameter CD1 (6), (26), (36) and internal orifice diameter OD1 (9), (29), (39) for the material which turns into a gel, b) a second chamber (2), (22), (32) with internal diameter CD2 (7), (27), (37) and internal orifice diameter OD2 (10), (30), (40) for the carrier , c) a multiple connection element (5), (20), (25), (35) with internal diameter MCD (8), (28), (38) to control the path of the gelling material, the carrier , air or any mixture thereof from the mouth of the first or second chamber connecting the first chamber (1), (21), (31) to the second chamber (2), (22), (32), where the internal diameter CD1 (6), (26), (36) is always greater than the internal diameter CD2 (7), (27), (37), the ratio R1 of the inner diameter MCD (8), (28), (38) of the manifold element (5), (20), (25), (35) to the inner diameter of the chamber CD1 (6), (26) , (36) of the first chamber (1), (21), (31) varies between 0.10 and 0.35, and the ratio R2 of the inner diameter MCD (8), (28), (38) of the manifold (5), (20), (25), (35) to the inner diameter of the chamber CD2 (7), (27) , (37) of the second chamber (2), (22), (32) varies between 0.15 and 0.50, and R1 is never equal to R2. 19. A device according to claims 17-18, wherein the first chamber comprises pressurizing means (3), (16), (18), (23), (33) and the second chamber comprises pressurizing means (4) , (17), (19), (24), (34). A device according to claims 17-19, wherein one or both chambers are cylindrical. A device according to claims 17-20, wherein the manifold element (5), (20), (25), (35) is a valve. An apparatus according to claim 21, wherein the valve is a triple delivery valve (20). 23. A device according to claims 17-22, comprising inter alia an extension tube (14) with an inner diameter TD (13) equal to the inner diameter MCD (8), (28), (38) of the manifold element connected to the multiple connection element (5), (20), (25), (35) and the first chamber (1), (21), (31) or to the multiple connection element (5), (20), ( 25), (35) and in the second chamber (2), (22), (32). A device according to claim 23, wherein the extension tube (14) is partly made of glass (15). 25. A device according to claims 19-25, wherein the pressurizing means is a piston or plunger (16), (17), (33), (34). 26. An apparatus according to any one of the above claims, comprising inter alia means for pressurizing the first chamber. 27. An apparatus according to claim 26, further comprising a filter screen. 28. A product obtained by applying the method of claims 1-16.