WO2023022671A1

WO2023022671A1 - A process for the preparation of dry powder compositions for inhalation

Info

Publication number: WO2023022671A1
Application number: PCT/TR2021/050825
Authority: WO
Inventors: Fatih CAN; Devrim Celik; Emine Yilmaz
Original assignee: Arven Ilac Sanayi ve Ticaret AS
Current assignee: Arven Ilac Sanayi ve Ticaret AS
Priority date: 2021-08-18
Filing date: 2021-08-18
Publication date: 2023-02-23
Anticipated expiration: 2024-02-18

Abstract

The invention relates to a process for the preparation of dry powder pharmaceutical compositions for inhalation. Further, the present invention also relates to dry powder pharmaceutical compositions administered by means of inhaler devices comprising ivermectin as an active agent and at least one pharmaceutically acceptable carrier.

Description

A PROCESS FOR THE PREPARATION OF DRY POWDER COMPOSITIONS FOR INHALATION

Technical Field

Background of the Invention

Ivermectin is a semisynthetic, anthelmintic agent derived from the avermectins, a class of highly active broad-spectrum anti-parasitic agents isolated from Streptomyces avermitilis with antiparasitic activities. Upon administration, ivermectin exerts its anthelmintic effect through binding and activating glutamate-gated chloride channels (GluCIs) expressed on nematode neurons and pharyngeal muscle cells. This causes increased permeability of chloride ions, causing a state of hyperpolarization and results in the paralysis and death of the parasite. Because of this, Ivermectin is an anti-helminthic drug that is used for the treatment of many parasitic infections which include head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, lymphatic filariasis, trichuriasis, and ascariasis.

Ivermectin was discovered in 1975 and came into medical use in 1981. Ivermectin is a Food and Drug Administration (FDA)-approved as an antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. It is also being evaluated for its potential to reduce the rate of malaria transmission by killing mosquitoes that feed on treated humans and livestock. For these indications, ivermectin has been widely used and is generally well tolerated.

Ivermectin is also used to treat infection with parasitic arthropods. Scabies - infestation with the mite Sarcoptes scabies - is most commonly treated with topical permethrin or oral ivermectin. For most scabies cases, ivermectin is used in a two-dose regimen: a first dose kills the active mites, but not their eggs. Over the next week, the eggs hatch, and a second dose kills the newly hatched mites. For severe "crusted scabies", the Centers for Disease Control recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic. Both head lice and pubic lice can be treated with oral ivermectin, a 0.5% ivermectin lotion applied directly to the affected area or various other insecticides. Ivermectin is also used to treat rosacea and blepharitis, both of which can be caused or exacerbated by Demodex folliculorum mites. In addition these, ivermectin has been described in the literature to have antiviral effects. Ivermectin has antiviral effects against several distinct positive-sense single-strand RNA viruses.

Ivermectin is an approximately 80:20 mixture of two avermectin B1 derivatives, called 22,23- dihydroavermectin B1a and B1b. Its chemical name is (1 R,4S,5'S,6R,6'R,8R, 10E, 12S, 13S, 14E, 16E,20R,21 R,24S)-6'-[(2S)-butan-2-yl]-21 ,24- dihydroxy-12-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy- 4-methoxy-6-methyloxan-2-yl]oxy-5', 11 ,13,22-tetramethylspiro[3,7, 19- trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one and its chemical structure is shown in Formula I.

Formula I

As mentioned above, ivermectin is an agent used in a wide spectrum of use in animals and humans. Ivermectin can be given by mouth, topically, or via injection. It does not readily cross the blood-brain barrier of mammals due to the presence of P- glycoprotein (the MDR1 gene mutation affects function of this protein).

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 formulations, 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 in the device before use, good aerosolization performance in terms of emitted dose and fine particle fraction (FPF). The effective inhalation performance of dry powder products is dependent on the drug formulation and the inhaler device. 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 coagulation 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 carriers should be homogeneous. Adhesion should be quite strong as the drug could not detach from the carriers. Moreover, lower doses of powder should also be filled into the device and the drug should always be released in the same way. One of the main parameters for the formulation is particle size. Besides all this, it is known that dry powder inhaler products and their active ingredients/ excipients tend to become electrostatically charged. During the various manufacturing operations (mixing, transport and filling), powders accumulate electrostatic charges from inter-particulate collisions and contact with solid surfaces (e.g. vessel walls). During the pharmaceutical powder mixing process, electrostatic charges generate and accumulate unavoidably due to particle-particle and particle-wall collision. The electrostatic charge could lead to less dose homogeneity and flowabilities within a powder. Accordingly, the amount of fine particles carried to the lungs in DPI products negatively affects the capacity of the active agents to be transported to the lungs by the excipients.

Thus, there is still a need for a dry powder process of ivermectin for inhalation that reduce static loads, 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, a process for the preparation of dry powder pharmaceutical compositions for inhalation comprising ivermectin 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 compositions for inhalation which eliminate all aforesaid problems and bring additional advantages to the relevant prior art.

The main object of the present invention is to distribute the active agent more homogeneously by purifying it from static loads in the production process and to ensure that the active agents/ excipients reach the lower parts of the lungs more.

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

Another object of the present invention is to provide a novel process for preparing dry powder compositions for inhalation with enhanced uniformity and homogeneity. Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation in which the active agent(s) and carrier are added in more than one portions together or separately.

Another object of the present invention is to provide a novel process for manufacturing dry powder compositions for inhalation which decrease contamination in the powder mixture depending on the process time and steps.

Another object of the present invention is to obtain inhalation compositions comprising at least one macrocyclic lactone or a pharmaceutically acceptable salt thereof.

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

Another object of the present invention is to obtain effective and stable inhalation composition applicable in the treatment or the prophylaxis of COVID- 19, SARS-CoV-2, SARS-CoV-2 infection.

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.

Another object of the present invention is to obtain inhalation compositions comprising two types of carriers in terms of particle size.

Another object of the present invention is to obtain inhalation compositions having appropriate active agent particle size range ensuring that effective doses of active agents reach the alveoli, in other words inhalation compositions providing enhanced aerosolization performance in terms of emitted dose and fine particle fraction (FPF).

Detailed Description of Invention

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

The invention relates to a process that prevents the powder particles from being loaded with static charges during the mixing process of active agent and carriers. This process is carried out with a static eliminator. Static eliminator is applied directly on the bulk powder after the addition steps, sieving step and while the process continues. Further, these can be including glass beakers, spatulas, spoons, sieves.

The present invention relates to a process for preparing dry powder inhalation compositions comprising active agent, first carrier and second carrier, said process comprising the following steps: i. adding and mixing active agent, first carrier and second carrier into the mixing vessel ii. sieving and mixing the obtained composition wherein the static charges of the mixing vessel, active agent, first carrier and second carrier are discharged with a static eliminator.

Active agent or a pharmaceutically acceptable salt and pharmaceutically acceptable carrier can be mixed using any suitable blending apparatus which is selected from the high shear mixer (for example a QMM, PMA or TRV series mixer) or a low shear tumbling mixer (a Turbula mixer). If the high shear mixer is selected for mixing, the rotational speed is 75-1000 rpm, preferably 100-800 rpm, more preferably 200-600 rpm. If the low shear mixer is selected for mixing, the rotational speed is 11 to 45 rpm, preferably 16 to 32 rpm.

According to one embodiment, said mixer further comprises a chopper with a rotation speed of 0-3000 rpm, preferably 50-2000 rpm, more preferably 100-1000 rpm.

According to the preferred embodiment, the step number (i) comprises the following steps: a) the total amount of the first carrier is divided into five fractions and the first fraction of the first carrier is put into a mixing vessel and it is mixed to cover the inside of the wall of the mixing vessel b) the total amount of ivermectin and a second carrier are put into a mixing vessel and mixed c) the second fraction of the first carrier is put into a mixing vessel and mixed d) the third fraction of the first carrier is put into a mixing vessel and mixed

According to the preferred embodiment, the duration of the step numbered (i) (a) is at least 3 minutes. According to the preferred embodiment, the duration of the step numbered (i) (b), (c), (d) is at least 10 minutes.

According to the preferred embodiment, the step number (ii) comprises the following steps: a) the fourth fraction of the first carrier is put into a mixing vessel, sieved with a sieve and mixed b) the fifth fraction of the first carrier is put into a mixing vessel, sieved with a sieve and mixed c) the obtained composition is sieved with the sieve and mixed

According to the preferred embodiment, the duration of the step numbered (ii) (a), (c) is at least 10 minutes.

According to the preferred embodiment, the duration of the step numbered (ii) (b) is at least 60 minutes.

According to the preferred embodiment, the active agent is a macrocyclic lactone in the process. Said macrocyclic lactone is selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin, moxidectin or mixtures thereof.

According to the preferred embodiment, said macrocyclic lactone is ivermectin.

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

The active agent has to be diluted with suitable carriers to prepare dry powder formulation for inhalation. Carrier particles are used to improve active agent flowability, thus improving dosing accuracy, minimizing the dose variability compared with active agent alone and making them easier to handle during manufacturing operations. Additionally, with the use of carrier particles, active agent particles are emitted from the medicament compartments (capsule, blister, etc.) more readily, hence, complete discharge of the medicament compartments by the inspiratory air during inhalation can be achieved and the inhalation efficiency in terms of emitted dose and fine particle fraction (FPF) increases. According to the preferred embodiment, the said carriers comprises fine carrier particles and coarse carrier particles. The said first carriers are coarse carrier particles and the said second carriers are fine carrier particles. Said carriers are selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. Most preferably, said carriers are lactose having fine particle and lactose having coarse particle.

According to the preferred embodiment, the said first carrier is lactose having coarse particle.

According to the preferred embodiment, the said second carrier is lactose having fine particle.

According to the preferred embodiment, a coarse carrier particle, 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. Lactose comprises lactose having coarse particle size and lactose having fine particle size. Lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35- 100 pm.

According to the preferred embodiment, lactose 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.

According to one embodiment, the choice of carrier is essential in ensuring that the device works correctly and delivers the right amount of active agent 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 15 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.

This preferred selection of carrier and its particle size distribution eliminates agglomeration of active agent particles and assures the enhanced stability, moisture resistance, fluidity, content uniformity and dosage accuracy.

In addition to all these, some of the experimental results of the inventors showing what kind of differences emerged in the invention with the use of the static eliminator are as follows:

When the results obtained by the inventors are examined, the only difference between the production with the serial number 215511301 and the production with the serial number 215511304 is that an additional static eliminator was used in the production process with the serial number 215511304. The decrease in % RSD values shows that the production with serial number 215511304 is more homogeneous.

In addition, when the transmission data to the patient from the data obtained by the inventors is examined, the FPD result of the production process with serial number 215511301 is 77.9 mcg, while the FPD result of the process of production with serial number 215511304 using the static eliminator is 118.4 mcg. It has surprisingly been found that using the static eliminator increases the FPD and FPF value.

With the invention made by the inventors, it is possible to distribute the active agent in the formulation more homogeneously by purifying it from static loads and ensure that the active agent reaches the lower parts of the lungs more.

According to one embodiment, dry powder inhalation compositions comprising active agent, first carrier and second carrier subjected to the invention are prepared by these steps: i. adding and mixing ivermectin, lactose having coarse particles and lactose having fine particles into the mixing vessel ii. sieving and mixing the obtained composition wherein the static charges of the mixing vessel, ivermectin, lactose having coarse particles and lactose having fine particles are discharged with a static eliminator.

According to one embodiment, the step numbered (i) comprises the following steps: a) the total amount of lactose having coarse particles is divided into five fractions and the first fraction of lactose having coarse particles is put into a mixing vessel and it is mixed for at least 3 minutes to cover the inside of the wall of the mixing vessel b) the total amount of ivermectin and a lactose having fine particles are put into a mixing vessel and mixed for at least 10 minutes c) the second fraction of lactose having coarse particles is put into a mixing vessel and mixed for at least 10 minutes d) the third fraction of lactose having coarse particles is put into a mixing vessel and mixed for at least 10 minutes

According to one embodiment, wherein the step numbered (ii) comprises the following steps: a) the fourth fraction of lactose having coarse particles is put into a mixing vessel, sieved with a sieve and mixed for at least 10 minutes b) the fifth fraction of lactose having coarse particles is put into a mixing vessel, sieved with a sieve and mixed for at least 60 minutes c) the obtained composition is sieved with the sieve and mixed for at least 10 minutes.

According to the preferred embodiment, 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 at least one macrocyclic lactone.

According to the preferred embodiment, said macrocyclic lactone is selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin, moxidectin or mixtures thereof.

According to the preferred embodiment, said macrocyclic lactone is ivermectin.

According to this embodiment, the amount of ivermectin is between 0.01-70%, preferably 0.02-65%, more preferably 0.03-60% by weight of the total composition.

According to one embodiment, the amount of total lactose is between 30.00-99.99 %, preferably 35.00-99.98%, more preferably 40.00-99.97% by weight of the total composition.

According to this preferred embodiment, the amount of lactose having fine particle is in the range of 0-25%, preferably 0.5-20%, more preferably 1-15 % by weight of the total composition. According to one preferred embodiment, the inhalation composition subjected to the invention comprises;

- 0.01-70% by weight of ivermectin

- 0-25% by weight of fine lactose

- 30-99.99 % by weight of total lactose

According to all these embodiments, the below given formulations can be used 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 : Inhalation composition 1

The dry powder composition subjected to the invention is suitable for administration in dosage forms such as capsules or blister packs.

According to an embodiment, the inhalation composition is presented in blister strips and capsules. The said capsules may be made of gelatin or a pharmaceutically acceptable polymer such as hydroxypropyl methylcellulose and it is arranged for use in a dry powder inhaler. The composition is configured to be delivered to the lungs by the respiratory flow of the patient via the said inhaler comprising means to open capsules and enabling respective delivery of each unit dose.

In a preferred embodiment, one capsule and blister strips (a single dose) contains 3-30 mg inhalation composition subjected to the invention.

According to an embodiment, the inhalation composition 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 property. The said blister pack comprises an aluminum material covering them to prevent moisture intake. Each blister is further encapsulated with a material resistant to moisture. By this means, blisters prevent water penetration and moisture intake from outside into the composition.

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 carrier, its amount and mean particle sizes. In a preferred embodiment, a blister contains 3-30 mg inhalation composition subjected to the invention.

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

In a preferred embodiment, the said inhaler further comprises a lid and a lock mechanism connected to the lid which is arranged to maintain the inhaler locked in both positions in which it is ready for inhalation and the lid is closed. According to this embodiment, the inhaler also ensures to be automatically re-set once the lid is closed.

Subsequent to opening of the device cap, a force is exerted to the device cock by the user. Afterwards, the cock is bolted by being guided by the tracks within the body of the device and the tracks on itself. Mechanism is assured to function via this action. In the end of bolting, cock is locked upon clamping and single dose drug come out of the blister is enabled to be administered. Pushing of the cock by the user completely until the locking position ensures the blister to be completely peeled off and the dosage amount to be accurately administered. As a result of this locking cock is immobilized and is disabled for a short time. This pushing action further causes the spring inside the mechanism to be compressed between the cock and the inner body of the device. Said device becomes ready to re-use following the closing of the cap by the user after the administration of the powder composition, without needing to be set again, thanks to the mechanism involved.

According to a preferred embodiment, inhalation 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 active agent, first carrier and second carrier, said process comprising the following steps: i. adding and mixing active agent, first carrier and second carrier into the mixing vessel ii. sieving and mixing the obtained composition wherein the static charges of the mixing vessel, active agent, first carrier and second carrier are discharged with a static eliminator.

2. The process according to claim 1, wherein the step numbered (i) comprises the following steps: a) the total amount of the first carrier is divided into five fractions and the first fraction of the first carrier is put into a mixing vessel and it is mixed to cover the inside of the wall of the mixing vessel b) the total amount of ivermectin and a second carrier are put into a mixing vessel and mixed c) the second fraction of the first carrier is put into a mixing vessel and mixed d) the third fraction of the first carrier is put into a mixing vessel and mixed

3. The process according to claim 1 , wherein the step numbered (ii) comprises the following steps: a) the fourth fraction of the first carrier is put into a mixing vessel, sieved with a sieve and mixed b) the fifth fraction of the first carrier is put into a mixing vessel, sieved with a sieve and mixed c) the obtained composition is sieved with the sieve and mixed

4. The process according to any one of the preceding claims, wherein the active agent is a macrocyclic lactone.

5. The process according to any one of the preceding claims, wherein said macrocyclic lactone is selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin, moxidectin or mixtures thereof.

6. The process according to any one of the preceding claims, wherein said macrocyclic lactone is ivermectin. The process according to any one of the preceding claims, wherein ivermectin has a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm. The process according to any one of the preceding claims, wherein said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. The process according to any one of the preceding claims, wherein said carriers are preferably lactose and more preferably lactose monohydrate. The process according to any one of the preceding claims, wherein said first carrier is lactose having coarse particle. The process according to any one of the preceding claims, wherein said second carrier is lactose having fine particle. The process according to any one of the preceding claims, wherein said lactose having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 pm. The process according to any one of the preceding claims, wherein 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 process according to any one of the preceding claims, wherein said ivermectin has a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm. The process according to any one of the preceding claims, wherein the duration of the step numbered (i) (a) is at least 3 minutes. The process according to any one of the preceding claims, wherein the duration of the step numbered (i) (b), (c), (d) is at least 10 minutes. The process according to any one of the preceding claims, wherein the duration of the step numbered (ii) (a), (c) is at least 10 minutes. The process according to any one of the preceding claims, wherein the duration of the step numbered (ii) (b) is at least 60 minutes. The process according to any one of the claims 1 to 18, for use in the treatment or the prophylaxis of COVID-19, SARS-CoV-2, SARS-CoV-2 infection.