WO2023128913A1

WO2023128913A1 - A process for the preparation of dry powder compositions for inhalation

Info

Publication number: WO2023128913A1
Application number: PCT/TR2021/051667
Authority: WO
Inventors: Ali Ihsan SECKIN; Devrim Celik; Turgay KACAR; Emine Yilmaz
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2023-07-06

Abstract

The invention relates to a simple, rapid, cost-effective, time-saving and industrially convenient process for the preparation of dry powder pharmaceutical compositions comprising a platelet inhibitor as active agent. Further, the present invention also relates to the dry powder pharmaceutical compositions administered by means of inhaler devices comprising a platelet inhibitor and at least one pharmaceutically acceptable excipient.

Description

A PROCESS FOR THE PREPARATION OF DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

Background of the Invention

Platelet aggregation inhibitors work in different places of the clotting cascade and prevent platelet adhesion, therefore no clot formation. It irreversibly inhibits the enzyme cyclooxygenase, which leads to reduction in thromboxane synthesis in platelets and prostacyclin in vascular endothelial cells. The vascular endothelium recovers and can synthesize more prostacyclin but thromboxane synthesis only recovers after new platelets are formed.

Dipyridamole is a platelet inhibitor that is primarily recognized as an antithrombotic agent.

The inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5-1.9 pg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3', 5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet collagen and adenosine diphosphate (ADP). Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3', 5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).

Dipyridamole appears to act in vivo by synergistically modifying several biochemical pathways, including: a) inhibition of platelet cAMP-phosphodiesterase; b) potentiation of adenosine inhibition of platelet function by blocking reuptake by vascular and blood cells, and subsequent degradation of adenosine; and possibly, c) potentiation of PGI2 antiaggregatory activity and enhancement of PGI2 biosynthesis. These independent processes inhibit platelet function by increasing platelet cAMP through both a reduction in enzymatic cAMP- degradation, and stimulation of cAMP formation via activation of adenylcyclase by adenosine and possibly PGI2. Only the inhibition of cAMP phosphodiesterase appears to be involved in the dipyridamole inhibition of isolated platelets in vitro, since adenosine and PGI2 originate in vivo from tissues other than platelets and any blood concentrations existing in vivo will disappear before platelet-rich plasma has been prepared for in vitro platelet studies. The antithrombotic effects of dipyridamole in a baboon model of arterial thromboembolism are unaffected by simultaneous administration of dazoxiben, a specific thromboxane synthetase inhibitor, but are optimally potentiated by the simultaneous addition of aspirin in doses of 20 mg/kg/day. Since this dose of aspirin has no detectable antithrombotic effects when used alone, but blocks vascular PGI2 synthesis, the antithrombotic effects of dipyridamole, at least in this model, appear to be independent of prostacyclin.

Dipyridamole has a chemical name 2,2’,2",2"’-[(4,8-Dipiperidinopyrimido [5,4-d] pyrimidine- 2,6-diyl)dinitrilo]-tetraethanol and is represented by structural Formula I. It is commercially available in the form of oral tablets of 25, 50 and 75 mg strengths under the brand name PERSANTINE™, and as extended release capsules of 200 mg strength under the brand name PERSANTIN RETARD™. It is also available as a combination product of aspirin and dipyridamole (25 mg/ 200 mg) in the form of extended release capsules under the brand name AGGRENOX™. Boehringer Ingelheim manufactures these products.

Formula I

Dipyridamole is an orally dosed drug (available as a extended release capsule, tablet) which is FDA- approved for the treatment of as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement. In the recent years, it is known that the human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction. It is indicated in some studies that using Dipyridamole in coronavirus treatment benefits by reducing viral replication, suppressing hypercoagulability and enhancing immune recovery. Dipyridamole supplementation was associated with significantly decreased concentrations of D-dimers, increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes. It is stated to be used as orally 75 mg twice dailly in the treatment of above in coronavirus patients.

There is a need to develop a process that will allow dipyridamole to be administered at a lower dose by inhalation rather than orally in high doses, and to provide higher utilization through the lungs.

Compared to other pulmonary drug delivery systems, DPIs offer several advantages, including enhanced drug stability, greater accuracy in dosing, elimination of hand-to-mouth coordination, breath-actuated delivery, and consequently, an overall improvement in patient compliance.

Dry powder compositions, that are suitable to be used via DPI, must fulfill a number of demands. With the aim of fulfilling these demands, it would be highly advantageous to provide a formulation exhibiting good uniformity of distribution of the active ingredient, small drug dosage variation (in other words, adequate accuracy of the delivered doses), good flowability, adequate physical stability. Dry powder formulations are usually prepared by mixing the micronized drug particles with larger carriers and other suitable particles.

Contriving the compositions is based on containing the active ingredient along with the carrier and other suitable particles having the particle sizes capable of carrying said active ingredient to the respiratory system. On the other hand, carrier particle size enabling conveying the active ingredient to the respiratory system in the desired levels is also critical.

It is a pre-condition for the medicament to possess content uniformity, in terms of user safety and effectiveness of the treatment. The difference of the particle sizes between the carrier used is important in order to ensure content uniformity. This difference to be beyond measure hampers to achieve the desired content uniformity. Another potential problem is to be unable to achieve the dosage accuracy present in each cavity in the blister or capsule. And this is of vital importance in terms of the effectiveness of the treatment. Small drug particles are likely to agglomerate. Said agglomeration can be prevented by employing suitable carrier and carrier mixtures. It also assists in controlling the fluidity of the drug coming out of the carrier device and ensuring that the active ingredient reaching to lungs is accurate and consistent.

In addition to this, the mixture of the drug particles adhered to the carrier and other suitable particles such as lubricant/glidant should be homogeneous. Adhesion should be quite strong as the drug could not detach from the carrier and other suitable particles. Moreover, lower doses of powder should also be filled into the device and the drug should always be released in the same way. Therefore, it has been found to be very important to employ the fine (small) and coarse (large) particles of the selected carrier in the compositions of the present invention in an accurate ratio.

Also, it is known that the addition of lubricant/glidant to the carrier-based dry powder compositions increases the aerosolization efficiencies of dry powder inhaler formulations, by decreasing the drug-excipient adhesion and thus facilitating the drug detachment upon device actuation.

Particle sizes of the selected carrier and glidant/lubricant (if needed) of a drug to be administered by inhalation and their ratio in the formulation are very important to obtain the desired FPF results.

In order to meet all these requirements, the process for preparing dry powder inhalation compositions should be adapted.

Thus, there is still a need for a dry powder composition of dipyridamole for inhalation, which provides high stability and at the same time ensures fluidity, content uniformity and dosage accuracy.

In this invention, to overcome these problems mentioned above, the process for preparing dry powder inhalation compositions comprising dipyridamole is provided. Also, an inhalation composition has been developed by using standard techniques which is a simple and cost- effective method. Objects and Brief Description of the Invention

The main object of the present invention is to provide a novel process for preparing dry powder inhalation compositions which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation with enhanced uniformity and homogeneity.

Another object of the present invention is to provide a novel process for preparing dry powder inhalation compositions with increased uniformity and homogeneity, enhanced fine particle dose (FPD) and fine particle fraction (FPF).

Another object of the present invention is to obtain inhalation compositions having high homogeneity and uniformity with appropriate rotational speeds.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which eliminates the requirement of sieving and saves time, provides one-pot manufacturing accordingly.

Another object of the present invention is to obtain dry powder inhalation compositions provided by the above-mentioned process comprising a platelet inhibitor.

Another object of the present invention is to obtain inhalation compositions comprising dipyridamole or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring content uniformity and dosage accuracy in each blister or capsule.

Another object of the present invention is to obtain inhalation compositions having appropriate particle size and ratios of both carriers and active agents ensuring that effective doses of active agents reach the alveoli.

A further object of the present invention is to obtain inhalation compositions which can be administered in blister pack or in capsule using an inhaler. A further object of the present invention is to obtain a blister pack filled with the above- mentioned dry powder inhalation compositions.

A further object of the present invention is to obtain a capsule filled with the above-mentioned dry powder inhalation compositions.

Detailed Description of Invention

In accordance with the objects outlined above, detailed features of the present invention are given herein.

The present invention relates to a process for preparing dry powder inhalation compositions, comprising the following steps: i. plastering the inner wall of the mixing vessel with first fraction of the first carrier and mixing with the mixer ii. adding the second carrier and active agent into the plastered mixing vessel and mixing with the mixer iii. adding second fraction of first carrier into the vessel and mixing with the mixer iv. adding third fraction of first carrier into the vessel and mixing with the mixer v. sieving the mixture vi. adding lubricant/glidant into the mixing vessel and mixing with the mixer vii. sieving the mixture

According to one embodiment, said mixer is high shear mixer. The impeller speed of 100-800 rpm, preferably 100- 600 rpm, more preferably 100- 500 rpm.

According to one embodiment, said mixer further comprises a chopper speed of 100-3000 rpm, preferably 100- 2500 rpm, more preferably 100- 2000 rpm.

According to one embodiment, chopper speed is open from the beginning to the end of the process.

One of the key points of the invention, the first carrier is divided into four equal portions. And first carrier is added to the process separately in the step numbered (i), (iii) and (iv) of the process that is the subject of the invention. After the first portion of the first carrier, second carrier and the active agent is mixed instead of the whole first carrier is included into the formulation. The purpose of this is to ensure the uniformity of the dose given to the patient and reaching the lungs by ensuring its homogeneous distribution in the formulation.

According to one embodiment, plastering the inner wall of the mixing vessel with first fraction of the first carrier is continued for at least 3 minutes. The impeller speed of the mixer in the step numbered (i) is 100-300 rpm. The first fraction of the first carrier is 25% by weight of the total first carrier.

According to one embodiment, adding the second carrier and active agent into the plastered mixing vessel and mixing with the mixer is continued for at least 10 minutes. The impeller speed of the mixer in the step numbered (ii) is 100-800 rpm.

According to one embodiment, adding second fraction of first carrier into the vessel and mixing with the mixer is continued for at least 10 minutes. The impeller speed of the mixer in the step numbered (iii) is 100-800 rpm. The second fraction of the first carrier is 25% by weight of the total first carrier.

According to one embodiment, adding third fraction of first carrier into the vessel and mixing with the mixer is continued for at least 10 minutes. The impeller speed in the step numbered (iv) is 100-800 rpm. The third fraction of the first carrier is 50% by weight of the total first carrier.

According to one embodiment, adding lubricant/glidant into the mixing vessel and mixing with the mixer is continued for maksimum 10 minutes. The impeller speed of the mixer in the step numbered (vi) is 100-300 rpm.

Impeller speed of the different steps of the process is specified according to the aim of the step. As an example at the first mixing/ plastering step (i), the impeller speed is between 100- 300 rpm in order to achieve the plastering of the coarse lactose particles to the walls of the container. But at the same time, it is aim not to charge the walls of the container by using a high mixing speed. Also, at the (vi.) step again the impeller speed is between 100-300 rpm in order to provide a convenient powder without a separation/ segregation of lubricant/glidant particles from the powder product.

According to the preferred embodiment, in the step numbered (ii), (iii), (iv) and (vi) of the process, the impeller speed is one of the most important aspects of the invention. It is surprisingly found that by using 100-300 rpm in the step numbered (i) and (vi) provides the minimum charging of the container and prevents the separation/ segregation of lubricant/glidant particles from the powder product. And by using 100-800 rpm in the step numbered (ii), (iii), (iv), the homogenization of the formulation powder is increased, the separation of the powder was prevented and thus a more homogeneous and stable composition is obtained. The desired quality profile was not achieved, when the inventors used different impeller speeds in the step numbered (i), (vi) and (ii), (iii), (iv) of the process.

According to the preferred embodiment, the first carrier mentioned in the step numbered (i), (iii) and (iv) are coarse carrier particles. Said coarse carrier particles is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof. Most preferably, said the first carrier is coarse lactose.

According to the preferred embodiment, in the step numbered (i), (iii) and (iv) of the process, a coarse lactose, such as lactose monohydrate, is applied to de-agglomerate the drug particles and optimize the deposition of the drug in the lung. The particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention. The mean particle size (D50 value) of coarse lactose is between 25-250 pm, preferably 35-100 pm.

% 25 of the first carrier is added in the (i) step, % 25 is added in the (iii) step and the % 50 is added in the (iv) step. By this amount of portions, a geometric increment process is applied to the powder product in order to achieve a homogeneous mixture.

According to the preferred embodiment, the active agent mentioned in the step numbered (ii) is a platelet inhibitor. The platelet inhibitor is selected from the group comprising dipyridamole, cangrelor, clopidogrel , prasugrel , ticagrelor, ticlopidine, cilostazol, vorapaxar or a pharmaceutically acceptable salt thereof.

According to this preferred embodiment, said platelet inhibitor is dipyridamole.

According to this preferred embodiment, dipyridamole has a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm.

According to the preferred embodiment, the second carrier mentioned in the step numbered (ii) is fine carrier particles. Said fine carrier particles is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof. Most preferably, said second carrier is fine lactose. The mean particle size (D50 value) of fine lactose is between 0.01-25 pm, preferably 0.01-20 pm.

According to one embodiment, the choice of carrier is essential in ensuring that the device works correctly and delivers the right amount of active to the patient. Therefore, to use lactose as a carrier in two different particle sizes (fine and coarse) is essential.

Particle size distribution of the carrier plays a crucial role for the qualification of the composition subjected to the invention. As used herein, ‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis).

Laser diffraction measures particle size distributions by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. The particle size is reported as a volume equivalent sphere diameter.

According to this measuring method, the D50 value is the size in microns that splits the distribution with half above and half below this diameter.

In the preferred embodiment of the invention, said lactose monohydrate is present in the composition in two parts. One of these parts is lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm. The other part is lactose monohydrate having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 pm.

Coarse carrier particles are used to prevent agglomeration of the active agent particles having mean particle size lower than 10 pm. During inhalation, as the active agent and the carrier particles need to be separated from each other, shape and surface roughness of the carrier particles are especially important. Particles having smooth surface will be separated much easier from the active agents compared to the particles in the same size but having high porosity.

Active agent particles will tend to concentrate on the regions having higher energy as the surface energy does not dissipate on the coarse carrier particles evenly. This might prevent separation of the active agent particles from the coarse carrier after pulmonary administration, especially in low dose formulations. In this sense, fine carrier particles are used to help the active agents to reach to the lungs easier and in high doses. As the high- energy regions of coarse carrier particles will be covered by fine carrier particles, the active agent particles will be attaching to low energy regions; thus, the amount of active agent particles detached from the coarse carrier particles will potentially increase.

According to the preferred embodiment, sieving mentioned in the step numbered (v) and (vii) is performed by a sieve having 125-500 pm, preferably 125-400 pm, more preferably 125- 350 mesh size. According to the preffered embodiment, sieving mentioned in the step numbered (v) is performed by a sieve having 250 pm and sieving mentioned in the step numbered (vii) is performed by a sieve having 315 pm.

Also, it is known that the addition of lubricant/glidant to the carrier-based dry powder formulation increases the aerosolization efficiencies of dry powder inhaler formulations, by decreasing the drug-excipient adhesion and thus facilitating the drug detachment upon device actuation.

In a preferred embodiment, lubricants/glidants are selected from the group comprising magnesium stearate, sodium stearate, calcium stearate, zinc stearate, lithium stereate, sodium stearyl fumarate, silicon dioxide, talc, colloidal silicon dioxide, corn, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulfate, behenic acid, erucic acid, lauric acid, oleic acid, palmitic acid, glyceryl behenate, aluminum dioxide, starch, titanium dioxide, sodium stearoyl lactylate, dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI), phosphatidylglycerol (PG), lecithin, soya lecithin, laxiric acid, triglycerides, hydrogenated castor oil waxy powder, l-leucine, isoleucine, trileucine, lysine, methionine, phenylalanine, valine, aspartame, and acesulfame potassium or mixtures thereof.

According to the preferred embodiment, lubricant/glidant is magnesium stearate.

The magnesium stearate is preferably used for this purpose in dry powder formulations. When magnesium stearate is used in the dry powder formulations, some of the active sites of carrier particles are occupied by magnesium stearate and the inter particulate forces (i.e. adhesive forces and cohesive forces) are balanced in the formulation, therefore not being too weak which would lead to the falling off the drug particles and forming agglomerates and not too strong which would not enable their detachment from the carrier surface. However, only some of the active sites are occupied by magnesium stearate, enabling some active sites to be occupied by the drug particles and therefore aerosolize upon actuation.

Moisture uptake can directly affect the flowability of the powders and the force to detach the micronized particles from the carrier surface. Use for magnesium stearate in the formulation of the present invention also helps to minimize the influence of penetrating moisture during the storage of said formulation and results in said formulation to be more stable against the moisture. Thus, the quality of the pharmaceutical formulation remains considerably better than conventional formulations which are free of magnesium stearate even on storage under extreme conditions of temperature and humidity. Therefore, the use of magnesium stearate also improves the moisture resistance of the dry powder formulations.

However, magnesium stearate is poorly water-soluble, its presence in such amount may raise some concerns as to a potential irritation or toxicity of this excipient, part of which can be inhaled by the patient together with the active agent. Therefore, it is important to determine the optimum concentration of the magnesium stearate that enables eliminating or minimizing potential irritation or toxicity of this excipient while getting balanced inter particulate forces between dipyridamole particles and the carrier surface which will enable maximum aerosolization deposition and minimizing the influence of penetrating moisture during the storage of the formulation.

In this invention, surprisingly high uniformity and homogeneity are provided by the specified rotational speeds of the mixer, by the inclusion of the active agent in the process by dividing it into two equal parts and by using lubricant in the step numbered (vi). Accordingly, homogeneity is increased which means the shelf life of the final product is extended. Besides, fine particle fraction and particle size distribution of the final powder mixture are enhanced which means the accurate and consistent transport of the active agents to the lungs is guaranteed. Stability is also enhanced according to the above enhanced parameters.

This preferred rotation speed of the process and its particle size distribution eliminates agglomeration of active agent particles and assures enhanced homogeneity, stability, moisture resistance, fluidity, content uniformity and dosage accuracy. According to one embodiment, the process for preparing dry powder inhalation compositions subjected to the invention are prepared by these steps: i. plastering the inner wall of the mixing vessel with %25 by weight of coarse lactose and mixing with the mixer ii. adding fine lactose and dipyridamole into the plastered mixing vessel and mixing with the mixer iii. adding %25 by weight of coarse lactose into the vessel and mixing with the mixer iv. adding %50 by weight of coarse lactose into the vessel and mixing with the mixer v. sieving the mixture vi. adding magnesium stearate into the mixing vessel and mixing with the mixer vii. sieving the mixture

The invention also defines dry powder inhalation compositions obtained by the process subjected to the invention.

According to the preferred embodiment, the dry powder composition comprises a platelet inhibitor or a pharmaceutically acceptable salt thereof.

According to a preferred embodiment, the dry powder composition comprises dipyridamole.

According to one embodiment, the amount of dipyridamole is between 0.01-60 %, preferably 0.01-40 %, more preferably 0.01-20 % by weight of the total composition.

According to one embodiment, the dose weight of dipyridamole is in the range of 0.005-15 mg, preferably 0.005-12 mg, more preferably 0.005-10 mg.

According to this preferred embodiment, the amount of the fine lactose is in the range of 0- 25%, preferably 0.5 - 20%, more preferably 1-15 % by weight of the total composition.

According to one embodiment, the amount of coarse lactose is between 13.5-99.98%, preferably 38.6-99.48%, more preferably 63.7-98.98% by weight of the total composition.

According to this preferred embodiment, the amount of the magnesium stearate is in the range of 0.01-1.5%, preferably 0.01- 1.4%, more preferably 0.01- 1.3% by weight of the total composition. According to one preferred embodiment, the process for the dry powder composition subjected to the invention comprises;

- 0.01-60 % by weight of dipyridamole

- 13.5-99.98% by weight of coarse lactose

- 0-25% by weight of fine lactose

- 0.1 -1.5% by weight of magnesium stearate

According to all these embodiments, the below-given formulations can be used as a process for preparing dry powder inhalation compositions subjected to the invention. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.

Example 1 : Dry powder composition for inhalation

Example 2: Dry powder composition for inhalation

Example 3: Dry powder composition for inhalation

Example 4: Dry powder composition for inhalation

Example 5: Dry powder composition for inhalation

Unlike processes in the art in which sieving is essential to assure stable and uniform dry powder compositions, these suggested processes don’t require any sieving step to provide such compositions. The process subjected to the invention only requires a mixer defined as in any embodiment above.

The uniformity and FPD value are enhanced by the coordinated effect of the selected rotational speed range. The increase in stability also leads the extension of the shelf life of the final composition. As FPD and FDP values are enhanced, the accurate and consistent transport of the active agents to the lungs is guaranteed.

On the other hand, as the process subjected to the invention eliminates sieving procedures required labor and production cost are considerably reduced, thus an increased production output it provided. The dry powder composition subjected to the invention is suitable for administration in dosage forms such as capsules, cartridges or blister packs.

In the preferred embodiment, the dry powder composition subjected is suitable for administration in a multi-dose system, more preferably in a multi-dose blister pack which has more than one blister with air and moisture barrier properties.

Each blister contains the same amount of active agent and carrier which is provided via content uniformity and dosage accuracy of the composition. For this invention, it is ensured by the specific selection of carriers, their amounts and their mean particle sizes. In a preferred embodiment, a blister contains 3-30 mg dry powder composition.

In the most preferred embodiment, the said blister pack is arranged to be loaded in a dry powder inhaler and the composition subjected to the invention is configured to be delivered to the lungs via the said inhaler. The inhaler has the means to open the blister and to provide the respective delivery of each unit dose.

According to a preferred embodiment, dry powder composition subjected to the invention is used in the treatment or the prophylaxis of COVID-19, SARS-CoV-2, SARS-CoV-2 infection.

Claims

1. A process for preparing dry powder inhalation compositions, comprising the following steps: i. plastering the inner wall of the mixing vessel with first fraction of the first carrier and mixing with the mixer ii. adding the second carrier and active agent into the plastered mixing vessel and mixing with the mixer iii. adding second fraction of first carrier into the vessel and mixing with the mixer iv. adding third fraction of first carrier into the vessel and mixing with the mixer v. sieving the mixture vi. adding lubricant/glidant into the mixing vessel and mixing with the mixer vii. sieving the mixture

2. The process according to claim 1 , wherein the active agent is a platelet inhibitor.

3. The process according to claim 2, wherein the platelet inhibitor is selected from the group comprising dipyridamole, cangrelor, clopidogrel, prasugrel, ticagrelor, ticlopidine, cilostazol, vorapaxar or a pharmaceutically acceptable salt thereof.

4. The process according to claim 3, wherein the platelet inhibitor is dipyridamole.

5. The process according to any one of the proceeding claims wherein said dipyridamole has a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm.

6. The process according to claim 1 , wherein said first carrier is the coarse carrier particles.

7. The process according to claim 6, wherein said coarse carrier particles is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof.

8. The process according to any one of the proceeding claims, wherein said first carrier is coarse lactose.

9. The process according to any one of the proceeding claims, wherein said the mean particle size of coarse lactose is between 25-250 pm, preferably 35-100 pm.

10. The process according to claim 1 , wherein said second carrier is the fine carrier particles.

11. The process according to claim 10, said fine carrier particles is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof.

12. The process according to any one of the proceeding claims, wherein said second carrier is fine lactose.

13. The process according to any one of the proceeding claims, wherein said the mean particle size of fine lactose is between 0.01-25 pm, preferably 0.01-20 pm.

14. The process according to any one of the proceeding claims, wherein the impeller speed in the step numbered (ii), (iii) and (iv) is 100-800 rpm.

15. The process according to any one of the proceeding claims, wherein the impeller speed in the step numbered (i) and (vi) is 100-300 rpm.

16. The process according to any one of the proceeding claims, wherein for use in the treatment or the prophylaxis of COVID-19, SARS-CoV-2, SARS-CoV-2 infection.