GR20150100471A - Pharmaceutical aprepitant-containing formulation and preparation method thereof - Google Patents

Abstract

Amorfous solid dispersion significantly improving the aprepitant-associated solubility problems is disclosed. Final pharmaceutical forms and preparation method thereof are also disclosed.

Description

PHARMACEUTICAL PREPARATION ACTIVE CONTENT AND METHOD OF PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an immediate release preparation for oral administration containing Aprepitant in the form of an amorphous solid dispersion as well as the method of preparing the above preparation.

BACKGROUND OF THE INVENTION

Substance P (SP) is a peptide consisting of a chain of 11 amino acid residues and a member of the tachykinin neuropeptide family. It is a neuropeptide, which functions as both a neurotransmitter and a neuromodulator. It is an important element of pain perception as it is considered to be related to the transmission of pain information to the central nervous system. In addition to their potential as analgesics, SP receptor antagonists have important therapeutic applications in the treatment of a number of stress-related diseases.

Aprepitant is an antiemetic chemical that belongs to the "SPA" class of drugs, i.e. substance P antagonists. Its action occurs through inhibition of the neurokinin 1 (NK1) receptor. It is a white to off-white, non-hygroscopic crystalline powder that is practically insoluble in water and partially soluble in ethanol and isopropyl acetate as well as sparingly soluble in acetonitrile.

The very low solubility in water is a major problem in the process of preparing pharmaceutically acceptable formulations with this active substance. The relevant literature reports various solubility improvement methods used in the pharmaceutical industry. Some of the most common methods are particle reduction, pH modification in case solubility depends on pH, use of surfactants and/or solubilizers, complexation with formulations containing cyclodextrins and lipids.

European patent 1455765 uses the technique of reducing the particle size in a pharmaceutical formulation where nanoparticles with an average size not exceeding one micron are used.

Patent WO 2007/112457 relates to preparations of polymorph Aprepitant with cyclodextrin.

None of the formulations of the previous technological generation relate to an Aprepitant formulation like that referred to in the present invention.

SUMMARY OF THE INVENTION

The present invention relates to innovative pharmaceutical preparations of Aprepitant. The above preparations manage to solve the problem of the low solubility of the specific medicinal substance. An alternative formulation is provided which is easy to prepare and economical.

Through the following detailed description, other advantages and objectives of the present invention will become apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The Aprepitant molecule has the following structure:

and is a tachykinin receptor antagonist used to treat disorders primarily related to the central nervous system. Its molecular structure is C23H21F7N4O3 and its molecular weight is 534.43.

The main objective of the present invention is the development of a durable and stable immediate release pharmaceutical form, which contains Aprepitant with improved solubility. The solution provided here is to create an amorphous solid dispersion. The above method was chosen because it is common, simple and reproducible.

For the purposes of the present invention it is considered that a pharmaceutical preparation consisting of an active substance is "stable" if the said substance degrades less or more slowly than in its own known pharmaceutical preparations.

In general, amorphous pharmaceutical active substances contain more energy than crystalline ones. This results in better solubility and potentially better bioavailability. For Aprepitanti it has been reported that from a thermodynamic point of view the most stable type is the crystalline type I, therefore, even if the amorphous type is initially chosen, in the long run all its advantages will be lost as it will inevitably transform into the more stable crystalline type.

The process of amorphizing the crystalline Aprepitant by transferring it to an internal carrier was chosen to maintain the desired state of the active substance. For this purpose both spray drying and melt extrusion proved to be adequate preparation methods while remaining relatively simple and cost effective.

Applicants have found that the amorphous solid dispersion of Aprepitant with polyvinyl caprolactam-polyvinyl ethyl ester and polyethylene glycol copolymer significantly improves solubility and at the same time provides a pharmaceutical formulation that is stable on long-term storage and therefore avoids unwanted impurity that would compromise product efficiency or the patient's health.

In the present invention Aprepitant can have a D90 size of 1 to 20 microns, as measured by a Malvern Mastersizer device, while sizes between 1 and 10 microns are preferred and sizes between 1 and 5 microns are ideal.

The carrier used in the amorphous solid dispersion is selected from polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer, polyvinyl polypyrrolidone, polyethylene glycol, crospovidone or mixtures thereof.

The amount of the pharmaceutical active substance as a ratio by weight to the carrier used in the present invention varies between 1:1 and 1:4, while a ratio of 1:1.5 is preferred.

In addition, the pharmaceutical preparations of the present invention are likely to contain one or more excipients of the pharmaceutical form, such as diluents, disintegrants, binders, lubricants and glidants, provided that they are compatible with the active substance of the preparation so that they do not interact with the active substance in the formulation but increase the stability of the drug and the shelf life of the drug product.

As diluents, for example, dextrates, dextrose, fructose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol can be used.

Disintegrants can be selected from alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, guar gum, methylcellulose, potassium polyacrylate, polyoxamer, sodium alginate.

For example, alginic acid, carbomer, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, povidone, methylcellulose, polydextrose, polyethylene oxide can be used as binders.

In addition, at least one lubricant is incorporated into the formulation preventing the powder from adhering to the tablet compression pistons during the compression process. For example, talc, magnesium stearate, calcium stearate, glycerin behenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate can be used as lubricants.

Glidants are used to enhance powder flow by reducing friction and cohesion between particles. They are used in combination with lubricants, since they alone do not have the ability to reduce friction on the walls. For example, colloidal silicon dioxide, calcium silicate, tribasic calcium phosphate can be used as glidants.

Also provided are the methods for the preparation of the amorphous solid dispersion of Aprepitant of the present invention.

More specifically, a manufacturing method includes the following steps:

(a) dissolving the active substance and the carrier in ethanol while heating;

(b) spray drying the solution to evaporate the solvent, (c) collecting the solid material.

Another method of preparing the amorphous solid dispersion includes the following steps:

(a) simultaneous addition of the active and the carrier in a drum with high temperature and continuous mixing;

(b) once a homogenous slurry is achieved, the mixture is cooled to room temperature, pulverized and finely sieved;

(c) collecting the solid material.

The present invention also relates to the preparation method of Aprepitant preparation, which includes the following steps:

(a) mixing the solid material obtained either by the spray drying method or by the melt method described above with the additional pharmaceutically acceptable excipients such as diluents, disintegrants, glidants and lubricants;

(b) filling the mixture into a hard gelatin capsule.

The following examples illustrate the preferred embodiments according to the present invention without limiting the scope or spirit of the invention.

EXAMPLES

Example 1:

Spray drying

Spray drying experiments were performed in a Buchi B-290 spray dryer using the carriers Povidone, Copovidone or polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer.

Aprepitant to each vehicle ratios were 1:4, 1:2.5, 1:1.5 and 1:1. All solid dispersions were prepared by dissolving the active and polymer in ethanol heating to about 40°C and then spraying the solution into a spray dryer, in which the solvent is evaporated and the solid material is collected in a container.

The obtained solid dispersions were checked by X-ray diffraction (XRD) analysis to establish the solid state of the active in the solid dispersion. According to X-ray diffraction (XRD) data, solid dispersions of Aprepitant with any of the polymers mentioned above, which were prepared by the spray drying technique, contain the active substance in an amorphous form, since no from the peaks of the crystalline Aprepitant in the diffraction patterns of the solid dispersions. Furthermore, amorphization of Aprepitant is achieved at all polymer ratios from 1:4 to 1:1.

Solubility and dissolution studies

The solid dispersions prepared by spray drying were tested for their solubility and dissolution properties in comparison with the crystalline active.

For the solubility study, an amount of the solid dispersion equivalent to 10.0 mg of Aprepitant was dissolved in a 100 ml volumetric flask with postprandial simulated gastric fluid (FeSSIF) dissolution medium at a concentration of 0.1 mg/ml. The solution was magnetically stirred for 30 min and centrifuged at 4000 rpm for 5 min before being injected into the HPLC. Finally, drug concentration equates to drug solubility.

Table 1: Solubility of solid dispersion prepared according to Example 1

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The ratio and extent of drug dissolution was studied using a USP type II apparatus (vanes) at 50 rpm. The dissolution medium was FeSSIF at pH 5.0. The release rates of the solid dispersions were compared with those of the pure active substance and the results are presented in Table 2 below.

Table 2: Dissolution results of various ratios of active to poly Aprepitant.

of amorphous solid dispersions for the parts compared to those of the neat

According to the results presented above, a significant improvement in the dissolution of Aprepitant is achieved through the amorphous solid dispersions, which provide almost instantaneous dissolution. The solid dispersion of Aprepitant to polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer showed a sufficient release rate at all ratios studied, from 1:1 to 1:4.

Final pharmaceutical form

The powders prepared by spray drying were further processed with other excipients and filled into capsules to improve their physical properties, such as flowability and dissolution properties, which were also tested. Without being limited thereto, the solid dispersion of Aprepitant to polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer in a ratio of 1:1.5 was tested.

The spray-dried powders are mixed with a diluent, such as lactose, mannitol, or microcrystalline cellulose, and a disintegrant, such as crospovidone. In addition, colloidal silicon dioxide was used as a glidant and magnesium stearate as a lubricant.

Preparation method:

1. The solid dispersion obtained through the spray drying process is finely sieved through a 40 mesh sieve.

2. The powder is mixed with the diluent, Crospovidone and

Colloidal silicon dioxide.

3. Finally, the mixture is mixed with magnesium stearate and then

paid in capsules.

As shown in Table 4 above, the use of flow enhancers improves the flow properties of the powder resulting from spray drying and thus can be prepared into its final pharmaceutical form more easily. Additionally, lactose provided the best results among all diluents tested.

Table 4: Flow properties of the formulations of example 1

According to the data presented, the solubility and dissolution properties (table 5) of the solid dispersion of Aprepitant/polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol dispersion were improved, proving that the existence of other soluble versions, such as lactose or mannitol, enhances the dissolution of Aprepitant from the solid dispersion.

Table 5: Dissolution profile of the formulations of example 1

Stability

To study the physical and chemical stability of solid dispersions prepared by spray drying, samples were stored in normal and accelerated storage conditions (25°C/60% RH and 40°C/75% RH respectively) in powder form as well as in the final pharmaceutical form.

The physical stability was studied by X-ray diffraction (XRD) analysis of the active substance in its solid state. According to the results, the amorphous state of Aprepitant in solid dispersions with polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol and Copovidone copolymer is maintained after 6 months of storage under normal and accelerated storage conditions.

Also, the chemical stability was studied for impure impurities and the results are presented below.

Table 6: Results of impurity analysis after 6 months of storage under normal and accelerated storage conditions

Example 2:

Melt mixing

Another method applied to prepare solid dispersions of Aprepitant was the melt blending technique whereby Aprepitant is incorporated into a carrier/polymer, which melts and molecularly disperses into the polymer forming the solid dispersion.

The melting point of Aprepitant is at 253°C. Such high temperatures are required to allow mixing with the polymer/carrier during its melt. Povidone has a high glass transition temperature (Tg= 167 °C). This Tg value demonstrates that high temperatures are required to prepare solid dispersions by melt extrusion. Therefore, to lower the Tg value of polyvinylpyrrolidone (PVP), and thus lower the extrusion temperature, plasticizers such as low molecular weight polyethylene glycol (PEG) can be used. Polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer has a low glass transition temperature (Tg≈ 70 °C), is easy to extract, and therefore does not require the addition of a plasticizer to the formulation. It also has good thermal stability, good flowability and low toxicity.

The melt mixing of Aprepitant with polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer and Povidone combined with the use of PEG as a plasticizer (in ratios of 80:20 and 70:30) was carried out in ratios of 1:4, 1:2.5 and 1:1 ,5 and at temperatures from 160°C to 200°C. When cooled, the mixtures were pulverized and finely sieved with a 100 mesh sieve. The table below shows the solid dispersions prepared, the conditions as well as the solid state of the active substance in the solid dispersion.

Table 7: Solid dispersions prepared by melt blending

According to X-ray diffractograms, the combination of an appropriate polymer ratio and process temperature above 180°C results in the formation of an amorphous solid dispersion of Aprepitant where a temperature below 180°C is insufficient to convert the active to an amorphous form due to of its high melting point.

Solubility and Dissolution

The solid dispersions were tested for their solubility and the results are shown in the table below.

Table 8: Solubilities of solid dispersions prepared by melt blending

Solubility results confirm improvement when Aprepitant is in solid dispersion form with specific polymer to active ratio & melt mixing temperatures.

The dissolution rate of the solid dispersions showing optimum solubility was studied in a USP II apparatus, at 50 rpm, with FeSSIF medium.

Table 9: Dissolution rate of amorphous solid dispersions

The results show that solid dispersions of Aprepitant with polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol or PVP/PEG copolymers prepared by melt blending show much higher solubility than pure Aprepitant.

Final pharmaceutical form

The solid dispersion of Aprepitant with polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer 1:1.5 prepared at 200°C was also mixed with other excipients, filled into capsules (Test 2) and analyzed for its dissolution properties.

Table 10: Final formulation of Example 2

Preparation method:

1. The solid dispersion obtained by the melt mixing process is finely sieved through a 100 sieve.

2. The powder is mixed with anhydrous lactose, crospovidone and colloidal silicon dioxide.

3. Finally, the mixture is mixed with magnesium stearate and then filled into capsules.

Table 11: Dissolution profile of the formulation of example 2

Stability

The physical and chemical stability of the solid dispersions prepared by melt blending in powder form and in the final pharmaceutical form was studied by storing the samples in normal and accelerated storage conditions (25°C/60% RH and 40°C/75% RH). .

Table 12: Impurity analysis results after 6 months of storage under normal and accelerated storage conditions

According to the stability data, the melt mixing method results in physical and chemical stability of Aprepitant in its amorphous solid dispersion after 6 months of storage under normal and accelerated storage conditions.

While the present invention is described with reference to its specific approaches, those skilled in the art will realize that several changes and modifications may be made to the invention without, however, departing from the spirit and object thereof, as stated in the appendices of the claims.

Claims (7)

1. Pharmaceutical preparation containing an amorphous solid dispersion of Aprepitant with polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer. 2. A pharmaceutical preparation according to claim 1, wherein the ratio of Aprepitant to polyvinyl caprolactam-polyvinyl ethyl ester-polyethylene glycol copolymer is from 1:1 to 1:4. 3. A pharmaceutical composition according to claim 1, which also contains a diluent, a disintegrant, a glidant and a lubricant. A pharmaceutical formulation according to claim 1, wherein the diluent is lactose. 5.  A method for preparing a pharmaceutical formulation according to claim 1 by dissolving Aprepitant and the polymer in ethanol while heating, then spraying the solution into a spray dryer, where the solvent is evaporated and the solid material is collected in a container. 6.  A method for the preparation of a pharmaceutical composition according to claim 1 by melt mixing Aprepitant with the copolymer at temperatures above 180°C, mixing, cooling the mixture, pulverizing and sieving. 7.  Method for the preparation of aprepitant medicinal preparation, which includes the following steps: - Mixing the mixture of the amorphous solid dispersion according to claim 5 or 6 with a diluent, a disintegrating agent and a glidant until complete homogeneity is achieved, -further mixing with a lubricant and hard gelatin capsules. filling the resulting mixture in