WO2015051811A1

WO2015051811A1 - Stable triflusal powder formulation for oral administration and method of preparation thereof

Info

Publication number: WO2015051811A1
Application number: PCT/EP2013/003039
Authority: WO
Inventors: Evangelos Karavas; Efthimios Koutris; Vicky Samara; Amalia DIAKIDOU; Louiza KONSTANTI
Original assignee: Expermed S.A.
Priority date: 2013-10-10
Filing date: 2013-10-10
Publication date: 2015-04-16
Also published as: MX2016004445A; EP3054922A1; KR20160067175A

Abstract

The present invention relates to a dispersible pharmaceutical formulation in the form of granules for oral administration comprising Triflusal together with at least one pharmaceutically acceptable excipient and a method for manufacturing thereof.

Description

STABLE TRIFLUSAL POWDER FORMULATION FOR ORAL ADMINISTRATION AND METHOD OF PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an improved stable pharmaceutical dosage form for oral administration comprising Triflusal as the active pharmaceutical ingredient. The dosage form shows increased stability, has a pleasant taste and overcomes limitations related to poor water solubility of the drug. The composition of the present invention is preferably in the form of powder/granules/particles contained in sachets. A method of preparing such formulation is also provided.

BACKROUND OF THE INVENTION Platelet aggregation inhibitors are a class of drugs widely used nowadays to inhibit thrombus formation and decrease the formation of platelet in the arteries of patients. One of the "oldest" members of this pharmaceutical drug category is Triflusal. Triflusal acts by inhibiting prostanoid synthesis, which causes an irreversible blockage of cyclooxygenase. This in turn prevents the synthesis of anti-aggregation factors and pro-aggregation factors. Numerous studies compared Triflusal to another well known anti-thrombotic and anti-coagulant drug, acetylsalicylic acid. The results show no significant difference between Triflusal and acetylsalicylic acid in terms of efficacy and safety profile, with some data showing better efficacy for Triflusal.

Triflusal is practically insoluble in water, very soluble in ethanol and acetonitrile and freely soluble in methylene chloride. Low-solubility drugs, such as Triflusal show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Furthermore, Triflusal is incompatible with most of the excipients commonly used in pharmaceutical formulation technology. There are two types of Triflusal formulations currently on the market; a capsule and an oral solution. The oral solution formulation shows a number of administration problems such as unpleasant taste and stability issues mostly due to the fact that the active pharmaceutical ingredient is incompatible with excipients of the solvent. The capsule formulation on the other hand has also problems related to administration due to the size of the capsule which may cause additional difficulties to patient compliance, especially to the pediatric and geriatric population.

Furthermore, EP-A-2508187 proposes a stable Triflusal compound powder for oral administration together with a cyclodextrin as a stabilizing agent. The preferred cyclodextrin used is β-cyclodextrin and the formulation can be used for producing granules, tablets or for - filling sachets. However, the use of cyclodextrins in the formulation will greatly increase the cost and this is a great disadvantage for large-scale production. US patents 4,343,789; 4,404,183; 4,673,564 all have the same disclosure of a sustained release composition of the vasolidator nicardipine comprising a solid amorphous dispersion of the drug in microcrystalline cellulose, polyethylene oxide, polyvinyl pyrrolidone and the cellulosic polymers hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose phthalate. However the preferred method of forming the dispersion is by extensive and time-consuming ball-milling, and there is no recognition of the concentration-enhancing and drug-stabilizing properties of ionizable cellulosics for forming the drug dispersion.

It is also known in the art the formulation of solid dispersions containing polymers by other methods, such as milling, grinding or solvent evaporation. A major problem with current solid dispersions of drugs is that even though the dispersions may show enhanced bioavailability of the low-solubility drug when administered shortly after preparation, bioavailability typically decreases over time in a typical storage environment. Such solid dispersions are often physically unstable in that the drug present in the dispersion reverts to the crystalline form upon storage, particularly at elevated temperature and humidity. Accordingly the dispersion cannot be used to provide proper dosing of the drug because the bioavailability of the drug changes over time.

It is apparent that there are a number of problems that arise in developing a stable, effective and safe Triflusal formulation, and therefore still exists the need of developing an alternative formulation with improved stability in typical storage environment, pleasant taste and is manufactured in both simple and cost effective way that overcomes the deficiencies of the prior art. SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a formulation comprising a platelet aggregation inhibitor of low solubility, such as Triflusal as the active pharmaceutical ingredient. More particularly, the present invention refers to a pharmaceutical formulation in the form of granules contained in sachets, ready to be dispersed in an appropriate vehicle for oral administration.

A further object of the present invention is to provide a dosage form for oral administration comprising Triflusal which has both physical and chemical stability.

Another object of the present invention is to provide a formulation comprising Triflusal and at least one excipient selected from diluents, suspending agents, glidants, flavoring agents and sweeteners that is in the form of a powder/granule. The dosage form should have a pleasant taste and be produced by an easy and cost effective manufacturing process.

It is a further object of the present invention to provide a formulation wherein the at least one excipient is a diluent. More specifically the ratio of Triflusal to the diluent is important for providing a physically and chemically stable formulation with good taste-masking characteristics and also appropriate dispersibility of the granule in the suspension liquid. According to the present invention the preferred diluent is mannitol and the preferred ratio of Triflusal to the diluent is from 1 :1 to 3 : 1.

Furthermore, the Triflusal formulation as produced by the method of the present invention is preferably in the form of dispersible granules filled into sachets. Such dosage form enhances patient compliance and ease of administration.

The process for the preparation of the dosage form according to the present invention comprises the steps of wet granulating the active ingredient with the excipients of the internal phase by using a non-aqueous solvent, drying the granules, mixing with excipients of the external phase, lubricating and filling into the appropriate container, which most preferably is in the form of sachets. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical powder comprising Triflusal and at least one excipient selected from diluents, suspending agents, glidants, flavoring agents and sweeteners that can be filled into sachets. The dosage form of Triflusal overcomes problems with low- solubility of the active ingredient and provides a method of production that is simple and cost effective. The pharmaceutical formulation of the present invention can be dissolved to form a solution and this improves patient compliance, especially for the pediatric and geriatric population.

Unless the context clearly indicates otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be taken into as an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to".

For the purposes of the present invention a "sachet" will refer to an envelope or a bag for the compound powder containing the active pharmaceutical ingredient. The sachet needs to provide a barrier for humidity, light and atmospheric air. It should be easy to open without the use of tools, such as scissors, and it should be able to avoid the built up of static electricity. Preferably the sachet should be easy to fill, easy to open and easy to empty to improve patient compliance. The sachets of the present invention provide long storage stability, are easy to tear, and there is no built up of static electricity, which means that it can be emptied completely. A sachet comprising the following layers is preferred: i) paper; ii) bonding layer, preferably an adhesive such as polyethylene; iii) barrier layer, preferably aluminum foil; and iv) sealing layer, preferably made of low density polyethylene. The bonding layer both waterproofs and adds strength to the sachet. The aluminum layer acts as a barrier against water vapor transmission and gasses. The low density polyethylene enables the sachet to be heat-sealed.

More particularly, the present invention provides a sachet wherein the outer paper has a preferred weight per unit area of 10-100 gr/m² (gsm), preferably 30-70 gsm, more preferred 40 gsm; the bonding layer has a preferred weight per unit area of 6-20 gsm, preferably 9-15 gsm, more preferred 12 gsm; the barrier layer preferably has a thickness of 5-20 μ, preferably 6-15 μ, more preferred 8 μ; and/or the sealing layer preferably has a weight per unit area of 10-70 gsm, preferably 15-50 gsm, more preferred 25 gsm. In addition the sachet of the present invention has very low water vapor transmission rate and oxygen transmission rate avoiding hydrolytic degradation and oxidative degradation respectively.

The "water vapor transmission rate" (WVTR), as used herein, can be defined as the measure of the passage of water vapor through a substance. The "oxygen transmission rate" (OTR), as used herein, is the measurement of the amount of oxygen gas that passes through a substance over a given period. For the specific invention it is vital that the packaging has controlled WVTR and ORT in order to achieve the required quality, safety, and shelf life. For the present invention, the WVRT and ORT of the packaging material must be less than 0.1 gr/m /day and 0.1 cc/m /day, respectively.

The composition of the present invention comprises Triflusal and pharmaceutically acceptable excipients selected from the group consisting of suspending agents, viscosity enhancers, coating agents, flavoring agents, sweeteners, diluents, taste-masking agents, lubricants, glidants, surfactants, and buffering agents.

The pharmaceutical composition is in the form of a granulate, wherein "granulate" refers to particles, granulated or spheronized particles. Triflusal may be present at up to about 70% by weight of the dry powder for suspension composition. "Dry powder", as used herein, includes any composition which is dry and flowable such as granules, flakes, spheroids and other forms which may be readily prepared and when added to a liquid vehicle and mixed, give the desired liquid suspension.

The term "suspending agent" or "viscosity enhancer" as used herein, refers to an agent or mixture of agents that help to keep the active ingredient suspended to allow accurate dosing. They can be selected from one or more cellulosic derivatives, gums, polysaccharides, alginates, acrylic acid copolymers, polyvinyl pyrrolidone, or combinations thereof. Representative suspending agents include, but are not limited to, acacia, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium, colloidal silicone dioxide, guar gum, hydroxyl ethyl cellulose, methylcellulose, maltodextrin, microcrystalline cellulose (MCC), polydextrose, polyvinyl alcohol, povidone, sodium alginate, starch, tragacanth, xanthan gum, and mixtures thereof. Preferred suspending agent or viscosity enhancer is microcrystalline cellulose, Avicel^®.

The term "flavoring agent" as used herein, refers to an agent or mixture of agents that is natural or artificial in origin and adds flavor to a mixture. Representative flavoring agents include, but are not limited to mint, banana, caramel, cherry, chocolate, strawberry, raspberry and mixtures thereof. To enhance organoleptic properties, combination of flavors may be used.

The term "sweetener", as used herein, refers to both bulk (caloric) and intense (non caloric) sweeteners, which impart sweet taste to the composition. Examples of bulk sweeteners are dextrose, fructose, glucose, isomalt, mannitol, maltose, sorbitol, sucrose, xylitol and mixtures thereof. Examples of intense sweeteners include aspartame, neohesperidin, alitame, saccharin, sucralose and mixtures thereof. Sweetener type, combination and proportion may be varied in various compositions.

The term "diluent", as used herein, refers to an agent or a mixture of agents that when added to a formulation makes the formulation thinner or less concentrated or acts as filler and may also improve manufacturability. Diluents can also serve other functions. For example, a diluent can also act as a sweetener and/or suspending agent. Representative diluents include, but are not limited to, dextrose, fructose, lactose, mannitol (Pearlitol^®), microcrystalline cellulose, sorbitol, sucrose, xylitol and mixtures thereof.

The term "solvent", as used herein, refers to an agent or mixture of agents in the form of a liquid, which is used for dissolving another liquid or solid, or as a dispersing or granulating media. Solvent employed may be aqueous, hydroalcoholic or organic in nature with varying polarity. Representative examples of solvent employed include, but are not limited to acetone, ethanol, dichloromethane, ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.

Triflusal is an active pharmaceutical ingredient well known to be prone to degradation in conditions of high temperature and humidity. Additionally, it exhibits low water solubility. A pharmaceutical composition according to the present invention manages to maintain both physical and chemical stability of the product but also an appropriate dispersibility of the granule in the suspension liquid. The dry powder for suspension composition is stable on storage and when constituted with an ingestible liquid for administration, the corresponding liquid suspension is stable physically and chemically for the duration in which the therapy is required. The preferred medium for reconstitution is water.

Excipients used in the current formulation were chosen to be compatible with the active pharmaceutical ingredient. The composition of the present invention comprises at least one suspending agent, at least one diluent, at least one sweetening and/or flavor agent and optionally one glidant. The appropriate amount of suspending agent was found to be in the range of 5% to 30% w/w of the total weight of the composition. An amount of suspending agent outside the above mentioned limits results in poor suspendability of the granular formulation.

The diluent should be in the range of 20% to 35% w/w of the total weight of the composition. An amount of diluent outside the above mentioned limits results in excess amount of unwanted impurities related to stability problems for the pharmaceutical formulation. In addition, the ratio of Triflusal to the diluent should be in the range of 1 : 1 to 3 : 1. This ratio is important for masking the unpleasant taste of Triflusal and in addition to provide good suspendability of the formulation in the reconstitution medium. A common problem associated with pharmaceutical dosage forms for suspension is the often disagreeable taste of a drug. Sometimes, the taste of the drug in the dosage form may be overpowered by adding sweeteners or flavoring agents, however, these agents are not totally effective in concealing the unpalatable taste of pharmaceuticals. Additionally, poorly formulated pharmaceutical suspensions allow the drug to settle out as sediment, thereby reducing the therapeutic concentration of drug in the suspension. This results in under dosing or over dosing of the patient, which may seriously compromise the patient's recovery.

Furthermore, the pharmaceutical granule for suspension should be readily pourable so that the dosage is easy to administer. In view of these difficulties it would be desirable to develop a ready-to-use pharmaceutical suspension with a high degree of stability and good taste-masking characteristics. The present invention discloses a stable aqueous suspension system for pharmaceutical actives, which can be combined with sweeteners and flavoring agents to provide a palatable dosage form. This dosage form is also physically and chemically stable and especially well suited for both geriatric and pediatric applications. According to the present invention, those characteristics are achieved with the use of a diluent and a suspending agent. The diluent preferably used is mannitol, especially mannitol having a population of particles of not more than 20% with a size of greater than 500 microns and a population of particles not less than 85% of particles with a size of 100 microns measured by laser light diffraction. The diluent is used intragranularly in the composition and the ratio of API to the diluent is from 1 :1 to 3:1. The method of incorporation of mannitol in the current dosage form provides a protective coat to Triflusal. With the formation of said coat it is feasible to overcome the low water solubility issue related to this specific active agent and on the same time it stabilizes it chemically and masks the unpleasant taste of Triflusal.

The suspending agent preferably used is microcrystalline cellulose especially that having a nominal mean particle size of around 100 microns. The suspending agent is used extragranularly. The interaction between microcrystalline cellulose and mannitol-coated particles of Triflusal allow the powder formulation to remain suspended in the liquid of administration. The selected particle size of the two excipients has also an important role on the suspendability of the formulation.

The dry powder for suspension composition may be prepared by conventional mixing and fabrication techniques. Examples of such techniques include but are not limited to i) Dry blending, ii) Wet Granulation, iii) Fluid bed granulation, of Triflusal and pharmaceutically acceptable excipients selected from the group consisting of suspending agents, viscosity enhancers, coating agents, flavoring agents, sweeteners, diluents, taste masking agents, lubricants, glidants, surfactants and buffering agents.

Most preferably the manufacturing process of the present invention comprises the steps of:

Sieving Triflusal and all the excipients

Mixing the active pharmaceutical ingredient with at least one diluent for an appropriate time

- Kneading the granule with a solvent other than water

Drying the granules

Mixing with at least one dispersing agent, a sweetener and a flavoring agent

Mixing the resulting granules with a glidant

Filling the appropriate container with the granules. The whole process for manufacturing the composition of the present invention takes place under controlled conditions. Temperature is between 15°C and 25°C, while relative humidity is between 30% and 70%. However, particularly the filling of the granule in the container takes place in relative humidity that is below 30%.

The following examples illustrate aspects of the present invention but are not in any way limiting the scope of invention. EXAMPLES

Example 1

Table 1 : Triflusal formulations of example 1

Seven formulations having different amounts of active pharmaceutical ingredient and excipients were evaluated according to the present invention. Composition A, according to table 1 above, was prepared by a dry granulation process. Triflusal was mixed with Pearlitol^® 400, Avicel^® 102, Noehesperidine, Stawberry flavor and Aerosil^® in multiple steps one after the other. The produced granule even though it had acceptable flowability and stability, when suspended in water, it was not homogenous. Therefore wet granulation was selected as more appropriate. Formulations B to G were manufactured according to the following steps:

- The active pharmaceutical ingredient and Pearlitol^® 400 were sieved and mixed in a drum mixer for appropriate time;

- The granule was kneaded with ethanol and subsequently dried; -Avicel 102, Neohesperidine and Strawberry Flavor were sieved and mixed with the dried granule of the previous step;

-Aerosil^®, was sieved, and added to the above granule and mixed; Triflusal was tested for its compatibility with the granulation liquid, namely ethanol and was found to conform to the requirements.

Both taste masking and re-suspendability of all formulations were satisfactory, therefore the stability of the formulations was tested. All formulations (B to G) were placed in stability chambers for 3 month at 25°C. The main degradation impurity of Triflusal is its hydroxy metabolite (HTB). The results are shown in the table below:

Table 2: Stability data of Triflusal formulations of example 1

All formulations B to G of example 1 presented acceptable values of the main impurity; however formulation G exhibited the best results.

The granule of formulation G had a suspension time in water of 1.5 minutes and a re-suspension time of three seconds. The angle of response measurement showed that the granule had excellent flow. Finally, the dissolution of the granule was measured when the quantity of a sachet was suspended in 150 ml of water and subsequently to 850ml of a buffer with pH 1.2, in order to be close to physiological everyday administration. This results in an adequate dissolution of the API in the dispensing liquid from the first ten minutes, with complete dissolution in the first thirty minutes.

Claims

1. A dispersible pharmaceutical composition in the form of granules for oral administration, which is essentially free of any cyclodextrin, comprising Triflusal together with at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, wherein said excipient is at least one of diluents, suspending agents, glidants, flavoring agents and sweeteners.

3. The pharmaceutical composition according to claim 2, wherein said diluent is mannitol.

4. The pharmaceutical composition according to claim 3, wherein mannitol is in an amount of from 20% w/w to 35% w/w of the total weight of the composition.

5. The pharmaceutical composition according to claim 3, wherein the Triflusal to mannitol ratio is from about 1 : 1 to about 3:1.

6. The pharmaceutical composition according to claim 2, wherein said suspending agent is microcrystalline cellulose.

7. The pharmaceutical composition according to claim 5, wherein microcrystalline cellulose is in amount of from 5% w/w to 30% w/w of the total weight of the composition.

8. The pharmaceutical composition according to claim 2, wherein said glidant is preferably colloidal silicon dioxide.

9. The pharmaceutical composition according to claim 2, wherein said flavoring agent is preferably strawberry and said sweetening agent is preferably Neohesperidine.

10. A process for manufacturing a dispersible pharmaceutical composition in the form of granules for oral administration, which is essentially free of any cyclodextrin, comprising Triflusal together with at least one pharmaceutically acceptable excipient, said process comprising the steps of:

Sieving Triflusal and all the excipients;

Mixing the active pharmaceutical ingredient with at least one diluent for an appropriate time;

Kneading the granule with a solvent other than water;

Drying the granules;

Mixing with at least one dispersing agent, a sweetener and a flavoring agent; Mixing the resulting granules with a glidant;

Filling the appropriate container with the granules.

1 1. The process according to claim 10, wherein the granulation solvent is preferably ethanol.

12. The process according to claim 10, wherein the container is preferably a sachet.