Extended-release pharmaceutical composition and preparation process

Abstract

The present invention is in the field of pharmacy. More specifically, the present invention discloses an extended-release pharmaceutical composition comprising trazodone and / or its salts as a water-soluble active compound, a lipophilic matrix-forming agent selected from the group consisting of glyceryl behenate and hydrogenated castor oil, and povidone in an amount of less than 10% by weight. Additionally, a process for producing said composition is disclosed.

Description

TITLEEXTENDED-RELEASE PHARMACEUTICAL COMPOSITION AND PREPARATION PROCESSFIELD OF THE INVENTION

[0001] The present invention is in the field of pharmacy. More specifically, the present invention discloses an extended-release pharmaceutical composition comprising trazodone and / or its salts as a water-soluble active compound, a lipophilic matrix-forming agent selected from the group consisting of glyceryl behenate and hydrogenated castor oil, and povidone in an amount of less than 10% by weight. Additionally, a process for producing said composition is disclosed.BACKGROUND OF THE INVENTION

[0002] Trazodone is indicated for the treatment of depression with or without episodes of anxiety, diabetic neuropathy-associated pain, and other types of chronic pain, and for the treatment of major depression. This compound acts by selectively inhibiting the reuptake of serotonin in the brain. Possible adverse reactions associated with its use include: sedation, headache, dizziness, fatigue, dry mouth, nausea, night sweats, edema, blurred vision, dyspnea, paranoia, acute myocardial infarction, among other disorders.

[0003] Extended-release formulations are delivery systems that are capable of more efficiently delivering drugs that are already well-established in therapy. For example, frequent dosing of immediate-release trazodone can result in fluctuations in drug release and undesirable concentration peaks, which in turn are associated with a higher risk of adverse effects. On the other hand, extended- release formulations allow the maintenance of the drug concentration in the blood for a longer period, which reduces concentration fluctuations and associated adverse effects. In addition, extended-release formulations provide a reduction in the frequency of doses, which positively influences patient adherence totreatment.

[0004] To achieve these results, extended-release formulations differ from immediate-release formulations due to several factors, such as the amount of active ingredient, excipients and even the production process. Each of these factors can affect several aspects of the medication produced, such as the uniformity of the pharmaceutical form and the properties of the tablets, such as appearance, hardness, friability, disintegration, and dissolution. More specifically, the proportion of the components of the formulation, the particle size, the hygroscopicity, cohesiveness and compressibility of the ingredients, the fluidity of the powders, the equipment used and the compression and granulation process are some examples of factors that influence the final product. In this context, specific studies of the mixing processes, consolidation of powders into solids and compression processes are particularly important to ensure that effective and safe medications of interest are obtained.

[0005] In the search for the state of the art in scientific and patent literature, the following documents were found that discuss the topic:

[0006] Document WO2017189947 relates to pharmaceutical forms for delivering abuse-prone drugs, as well as a process for producing them. More specifically, this document discloses a composition comprising at least one abuse-prone active agent in amounts of 10 to 60% by weight, at least one binder in an amount of about 10% to about 40% by weight of the composition and, optionally, other excipients. WO2017189947 does not disclose an extended-release composition comprising less than 10% by weight of a binder, nor does it have its process for preparing by means of fluidized bed drying.

[0007] Document Pentewar et al. “Formulation and in-vitro Evaluation of Modified Release Delivery of Trazodone Hydrochloride Tablets". Asian Journal of Pharmaceutical Technology & Innovation, 02 (09); 2014; 95 - 105 relates to sustained-release tablets of 52.8% w / w Trazodone Hydrochloride as the active agent, 8.5-28% w / w Carnauba wax as the water-insoluble matrix ingredient, 2- 14.5% w / w of different grades of Hydroxypropylmethyl Cellulose (HPMC,Methocel) and / or 8.5-30% w / w Polyvinylpyrrolidone as release delay polymers. This document does not disclose an extended-release composition comprising less than 52.8% Trazodone Hydrochloride, less than 10% by weight of a binder and glyceryl behenate or hydrogenated castor oil as matrix forming agents, preferably in an amount of 15% by weight. Furthermore, the process disclosed by Pentewar et al. does not comprise the use of ethanol in the wet granulation step.

[0008] Document Rosiaux Y, et al. Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO. Drug Dev Ind Pharm. 2015;41 (10): 1738-44. doi: 10.3109 / 03639045.2014.1002410. Epub 2015 Feb 5. PMID: 25652358 refers to the evaluation of granulation processes for production of high dose-tablets of micronized pharmaceutical actives through a composition comprising the active in a lipid matrix prepared by four wet granulation processes: wet granulation in mortar and pestle, planetary mixer process, high shear mixer process, and fluidized bed process. More specifically, Rosiaux Y, et al. discloses a composition comprising niacin as an active agent, magnesium stearate as a lubricant, polyvinylpyrrolidone as a binder and glyceryl behenate as a matrix agent. However, this document does not disclose an extended-release composition comprising Trazodone Hydrochloride, binder in an amount of less than 10% by weight, glyceryl behenate or hydrogenated castor oil in an amount of about 15% by weight and sucrose as a pore-forming agent. Additionally, this document does not disclose a production process for the composition of the present invention comprising the steps of wet granulation of a mixture in ethanol and drying in a fluidized bed.

[0009] The present invention provides an alternative extended-release composition comprising high dose trazodone.

[0010] Thus, from what can be inferred from the literature researched, no documents were found anticipating or suggesting the teachings of the present invention, so that the solution proposed herein has novelty and inventive step compared to the state of the art.SUMMARY OF THE INVENTION

[0011] Thus, the present invention solves the problems of the prior art with a composition comprising a high dose of trazodone, glyceryl behenate or hydrogenated castor oil as lipophilic matrix-forming agents and povidone as binder. Furthermore, the present invention presents an optimized process for the preparation of said composition.

[0012] In a first object, the present invention presents an extended-release pharmaceutical composition comprising:- Trazodone and / or its salts as a water-soluble active compound;- lipophilic matrix-forming agent selected from the group consisting of glyceryl behenate and hydrogenated castor oil;- povidone as binder, wherein the binder is in an amount of less than 10% by weight.

[0013] In a second object, the present invention presents a process for preparing an extended-release pharmaceutical composition, as defined herein, comprising the steps of: a) mixing the powders of the water-soluble active compound, lipophilic matrix-forming agent and sucrose using povidone in ethanol to form a wet mass; b) dry the wet mass formed in a) directly in a fluidized bed dryer; c) mix the granules formed in b) with magnesium stearate; and d) compression.

[0014] These and other objects of the invention will be immediately appreciated by those skilled in the art and will be described in detail below.DETAILED DESCRIPTION OF THE INVENTION

[0015] The large amount of the active ingredient in the formulation poses major challenges in the production of extended-release compositions in solid form. For example, the amount of excipients that help adjust parameters (e.g., fluidity, compressibility) to obtain the desired quality of attributes such as hardness,disintegration, friability, stability, and drug release profile are limited. In this context, the present invention discloses a composition comprising high doses of trazodone, a lipophilic matrix-forming agent, and povidone as a binder. Furthermore, due to its hygroscopic characteristic, povidone tends to absorb water from the medium and, thus, plays a key role in helping the swelling of the lipophilic matrix. Thus, povidone in combination with the lipophilic matrix-forming agent promotes the release of Trazodone at the appropriate speed and time, similar to the reference drug DONAREN® Retard, whose safety and efficacy have already been proven.

[0016] In a first object, the present invention presents an extended-release pharmaceutical composition comprising:- Trazodone and / or its salts as a water-soluble active compound;- lipophilic matrix-forming agent selected from the group consisting of glyceryl behenate and hydrogenated castor oil;- povidone as binder, wherein the binder is in an amount of less than 10% by weight.

[0017] In an embodiment, the extended-release pharmaceutical composition comprises the water-soluble active compound in an amount greater than 32% by weight, preferably in an amount greater than 32% and less than 52.8% by weight, more preferably in an amount of 50% by weight.

[0018] In an embodiment, the extended-release pharmaceutical composition comprises the lipophilic matrix-forming agent in an amount above 10% and below 20% by weight.

[0019] In an embodiment, the extended-release pharmaceutical composition further comprises a water-soluble pore-forming agent.

[0020] In another embodiment, the water-soluble pore-forming agent is sucrose.

[0021] In an embodiment, the extended-release pharmaceutical composition comprises:- 50% by weight of trazodone hydrochloride;- 15% by weight of glyceryl behenate;- 8% by weight of povidone;- 26% by weight of sucrose;- 1 % by weight of vegetable magnesium stearate; and- 9.20% by weight of ethyl alcohol 96%.

[0022] In another embodiment, the extended-release pharmaceutical composition comprises:- 50% by weight of trazodone hydrochloride;- 15% by weight of hydrogenated castor oil;- 8% by weight of povidone;- 26% by weight of sucrose;- 1 % by weight of vegetable magnesium stearate; and- 9.20% by weight of ethyl alcohol 96%.

[0023] In the context of the present invention, the term “extended” refers to modified pharmaceutical forms that release the drug over a long period to obtain a prolonged therapeutic effect.

[0024] In a second object, the present invention presents a process for preparing an extended-release pharmaceutical composition, as defined herein, comprising the steps of: a) mixing the powders of the water-soluble active compound, lipophilic matrix-forming agent and sucrose using povidone in ethanol to form a wet mass; b) dry the wet mass formed in a) directly in a fluidized bed dryer; c) mix the granules formed in b) with magnesium stearate; and d) compression.

[0025] The drying process in fluidized bed has many advantages over conventional oven drying. The synergistic combination of air flow and increased temperature (still lower than that of oven drying) accelerates the granulate drying process, thus avoiding exposure of the sample to long drying periods and high temperatures, which reduces possible degradation of thermolabile molecules. Additionally, bed drying provides greater uniformity of the active ingredient in the granulate, forming smaller and more homogeneous granules.

[0026] Furthermore, compared to other organic solvents such as dichloromethane and isopropyl alcohol, ethyl alcohol has lower toxicity.

[0027] Thus, the present invention provides an alternative extended-release composition comprising a high dose of trazodone and an optimized production process for said composition.EXAMPLE

[0028] The examples shown herein are intended only to exemplify one of the countless ways of carrying out the invention, however without limiting the scope of the invention.Example 1 - Extended-release pharmaceutical composition

[0029] For the production of an extended-release composition comprising high doses of Trazodone several tests were carried out with different excipients and excipient concentrations, among others.

[0030] Lipophilic matrix-forming agent

[0031] The choice of the concentration of the matrix-forming agent is closely related to the similarity of the drug release profile and bioeguivalence between the reference drug and the test drug.

[0032] Furthermore, this excipient influences the homogeneity, fluidity and compressibility of the granulate during the manufacturing process. Since it is a serous matrix, increase in concentration may impact possible adhesion of the tablets to the punches during the compression process. Thus, the matrix-forming agent may affect the uniformity of the pharmaceutical form and the batch as a whole.

[0033] In this context, glyceryl behenate and hydrogenated castor oil were tested, which, due to their physical properties, have a less waxy appearance than traditional carnauba wax.

[0034] During the development stage, different concentrations of these matrixforming agents were tested with the aim of achieving a balance between the drug release profile and the manufacturing process appropriate for the product.

[0035] Concentrations of 15% and 25% presented a relative difference in the dissolution curve between them, where the dissolution profiles of the 15% concentration most closely resembled the profile of the reference drug Donaren® Retard and, therefore, was the optimal concentration selected for the formulation subjected to the bioequivalence / relative bioavailability study.

[0036] Formulations with a concentration of matrix -forming agent above 25% and with 50% of the drug make it impossible to obtain dissolution curves similar to the reference drug, where the remaining space in the formulation is reduced for the use of other excipients with important functions, such as the pore former and the binder.

[0037] Binder

[0038] Considering a production process involving wet granulation, it was decided to use povidone, which is the most suitable excipient for this process, in addition to being highly adhesive at low viscosity, offering the ideal balance between adhesive strength for granule formation and ease of handling. Another characteristic taken into consideration for the use of povidone was its hygroscopicity and swelling capacity, which helps control the release of the drug from the matrix.

[0039] Tests with different concentrations of povidone (8% and 10%) demonstrated the importance of the agglutination and swelling properties of povidone in the extended-release pharmaceutical form. Amounts different from 8% povidone impacted the dissolution quality attribute due to the modification of the speed and swelling intensity of the tablets, which consequently alters the relative bioavailability and similarity to the pharmacokinetic profile compared to the reference drug Donaren® Retard.

[0040] Water-soluble pore-forming agent

[0041] Two excipients were tested to select the pore-forming agent: lactose and sucrose. These excipients differ in chemical composition, as well as in water solubility. Sucrose has greater solubility than lactose (Handbook of Pharmaceutical Excipients).

[0042] Tests with lactose demonstrated a lower pore-forming capacity when compared to sucrose. The amount of pores also impacts the dissolution attribute due to the permeability of water in the release matrix. Thus, based on the results obtained, it was possible to evaluate in the dissolution profiles the greater efficiency of sucrose in helping in the release of the drug from the hydrophilic matrix. Thus, sucrose was chosen as the pore-forming agent due to its contribution in obtaining a dissolution profile similar to the reference drug.

[0043] Thus, the following compositions with desirable characteristics were produced:

[0044] Table 1

[0045] Table 2

[0046] Essentially, all excipients used in this formulation are functional excipients and are extremely important in balancing the release of the drug from the final pharmaceutical form.Example 2 - Preparation process of an extended-release pharmaceutical composition

[0047] For the manufacture of extended-release tablets containing a salt of the antidepressant Trazodone, the wet granulation process with ethyl alcohol as a granulating solution was tested, followed by drying in a fluidized bed and compression into tablets.

[0048] To perform this process, the powders of the following were first added to a high-shear granulator: active agent (trazodone hydrochloride), lipophilic matrixforming agent (hydrogenated castor oil or glyceryl behenate), water-soluble poreforming agent (sucrose) and binder (povidone). The powders must then be mixed at appropriate impeller and chopper speeds for sufficient time to homogenize the materials inside the container. In this case, these ingredients were mixed at an impeller speed of 10 to 200 rpm and at a chopper speed of 300 to 3,000 rpm for 600 seconds. The obtained mixture was humidified by adding ethyl alcohol as organic solvent by spray and the wet mass was mixed at high speed (impeller speed between 10 and 200 rpm; chopper speed between 300 and 3,000 rpm) until an adequate consistency was obtained. After granulation, the wet granulate obtained was calibrated in a mill with a 10 mm mesh at a speed between 200 and 1 ,500 rpm.

[0049] For the drying stage of the wet granules, a fluidized bed was used with air flow between 400 and 2,400 m3H and inlet air temperature and outlet air - 50 °C, for 30 minutes. Thus, obtaining a granulate with a humidity less than or equal to 1 .0%. Subsequently, the dry granulate obtained was calibrated in a mill with a 1 .0 mm coarse mesh at a speed between 200 to 1 ,500 rpm.

[0050] The vegetable magnesium stearate was then calibrated in a mill with a 0.6 mm smooth mesh at a speed between 200 and 1 ,500 rpm. The dry materials(magnesium stearate and granules) obtained were mixed in the Bin mixer at an appropriate speed and for sufficient time for adequate lubrication. In this case, these materials were mixed for 5 minutes at a speed of 15 rpm. Finally, this mixture was compressed in a compressor with an upper punch of 14.00 x 6.00 mm and a lower punch of 14.00 x 6.00 mm, oblong with double crease.

[0051] The tablets obtained by this process are white to slightly yellowish oblongs, with a double crease on both sides. In this case, the tablets had an average weight of 300.0 mg, with T 1 between 291 .0 and 309.0 mg (± 3.0%) and T2: 285.0 to 315.0 mg (± 5.0%); and thickness between 3.70 and 4.30 mm. The ideal hardness is between 3.0 Kp - 6.0 Kp and the tablets obtained had a hardness of 4.5 Kp. The friability of the tablets is less than 1.0%.

[0052] Those skilled in the art will appreciate the knowledge presented herein and will be able to reproduce the invention in the modalities presented and in other variants and alternatives, covered by the scope of the following claims.

Claims

CLAIMS1. Extended-release pharmaceutical composition characterized by comprising:- Trazodone and / or its salts as the water-soluble active compound;- lipophilic matrix-forming agent selected from the group consisting of glyceryl behenate and hydrogenated castor oil;- povidone as binder, wherein the binder is in an amount of less than 10% by weight.

2. Extended-release pharmaceutical composition according to claim 1 , characterized in that the water-soluble active compound is in an amount greater than 32% by weight, preferably in an amount greater than 32% and less than 52.8% by weight, more preferably in an amount of 50% by weight.

3. Extended-release pharmaceutical composition according to claim 1 or 2, characterized in that the lipophilic matrix-forming agent is in an amount above 10% and below 20% by weight.

4. Extended-release pharmaceutical composition according to any one of claims 1 to 3, characterized in that it further comprises a water-soluble poreforming agent.

5. Extended-release pharmaceutical composition according to claim 4, characterized in that the water-soluble pore-forming agent is sucrose.

6. Extended-release pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises:- 50% by weight of trazodone hydrochloride;- 15% by weight of glyceryl behenate;- 8% by weight of povidone;- 26% by weight of sucrose;- 1 % by weight of vegetable magnesium stearate; and- 9.20% by weight of ethyl alcohol 96%.

7. Extended-release pharmaceutical composition according to any one ofclaims 1 to 5, characterized in that it comprises:- 50% by weight of trazodone hydrochloride;- 15% by weight of hydrogenated castor oil;- 8% by weight of povidone;- 26% by weight of sucrose;- 1 % by weight of vegetable magnesium stearate; and- 9.20% by weight of ethyl alcohol 96%.

8. Process for preparing an extended-release pharmaceutical composition, as defined in any one of claims 1 to 7, characterized by comprising the steps of: a) mixing the powders of the water-soluble active compound, lipophilic matrix-forming agent and sucrose using povidone in ethanol to form a wet mass; b) drying the wet mass formed in a) directly in a fluidized bed dryer; c) mixing the granules formed in b) with magnesium stearate; and d) compression.

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