WO2020055356A2

WO2020055356A2 - Inhalation compositions comprising anti-bacterial agents

Info

Publication number: WO2020055356A2
Application number: PCT/TR2019/050564
Authority: WO
Inventors: Ali Turkyilmaz; Irem Yenice; Devrim Celik; Arzu CAYIR
Original assignee: Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2018-07-20
Filing date: 2019-07-11
Publication date: 2020-03-19
Also published as: EP3823602A4; EP3823602A2; WO2020055356A3

Abstract

The invention relates to dry powder pharmaceutical compositions administered by means of inhaler devices comprising at least one anti-bacterial agent wherein the composition is free of lubricant and surfactant.

Description

INHALATION COMPOSITIONS COMPRISING ANTI-BACTERIAL AGENTS

Technical Field

Background of the Invention

An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria and antifungals are used against fungi. They can also be classified according to their function. Agents that kill microbes are called microbicidal, while those that merely inhibit their growth are called biostatic. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

Oxazolidinones are mainly used as antimicrobials. The antibacterial effect of oxazolidinones is by working as protein synthesis inhibitors, targeting an early step involving the binding of N-formylmethionyl-tRNA to the ribosome. Some of the most important oxazolidinones are the last generation of antibiotics used against gram-positive pathogens, including superbugs such as methicillin-resistant Staphylococcus aureus. These antibiotics are considered as a choice of last resort where every other antibiotic therapy has failed.

Some of the oxazolidinones are linezolid, posizolid, tedizolid, radezolida and cycloserine.

The first ever used oxazolidinone was cycloserine (4-amino-1 ,2-oxazolidin-3-one), a second line drug against tuberculosis since 1956. Developed during the nineties when several bacterial strains were becoming resistant against such antibiotics as vancomycin. Linezolid is the first approved agent in the class under the trade name Zyvox®.

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug resistant tuberculosis. It is used either by injection into a vein or by mouth.

As a protein synthesis inhibitor, it affects the ability of bacteria to produce protein. This either stops growth or results in bacterial death. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the start of protein production, rather than one of the later steps.

Its chemical name is N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1 ,3-oxazolidin-5- yl]methyl]acetamide and its chemical structure is shown in Formula I.

Formula I

Linezolid was discovered in the mid1990s and was approved for commercial use in 2000. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Linezolid is available as a generic medication. It appears to be more cost-effective than alternatives such as vancomycin, mostly because of the ability to switch from intravenous use to administration by mouth sooner.

In the prior art, there are various formulations suggested for the intravenous administration of linezolid. Patent document numbered WO2018055581 A1 , which is one of them, mentions parenteral formulations of oxazolidinones. The invention specifically relates to a stable concentrated linezolid injection composition comprising hydroxypropyl^-cyclodextrin for intravenous administration which further comprises sugar, buffer agent, pH modifier and process for the preparation method thereof. On the other hand, administration of linezolid through the inhalation route, which has a faster effect comparing the other dosage forms present in the market, has also been investigated in the literature.

One of the patent documents numbered W02012017405A1 relates to a biodegradable, inhalable microparticle formulation to treat pulmonary tuberculosis, multi drug resistant tuberculosis (MDRTB), methicillin resistant Staphylococcus aureus (MRSA) pneumonias and methicillin sensitive Staphylococcus aureus (MSSA) pneumonias. The invention is also about a method of delivering the microparticle formulation to a mammal in need thereof, wherein the formulation is administered by inhalation for pulmonary delivery. The formulation subjected to the invention essentially comprises a biodegradable lipid which provides the drug delivery, wherein the ratio of drug to lipid is 1 :15 to 1 :25. Linezolid is also mentioned in a group of active agents.

Another patent document numbered CN106580915 focuses on sustained-release microsphere dosage forms carrying rifapentine and linezolid combination. It is also stated that the formulation further comprises a carrier which is polylactide-glycolic acid. The sustained-release microspheres can be used for the treatment of pulmonary tuberculosis by local administration through bronchoscopes.

It is obvious that there is still a need for a dry powder inhalation formulation comprising oxazolidinones, especially linezolid, for the treatment of diseases caused by Gram-positive bacterias, which shows an effect mechanism faster than the other dosage forms in the art, thus which increases the patient’s compliance and which provides high stability, fluidity, content uniformity and dosage accuracy at the same time.

Objects and Brief Description of the Invention

Present invention relates to inhalation compositions comprising anti-bacterial agents overcoming all the aforementioned problems and bringing further advantages to the technical field.

Main object of the invention is to obtain inhalation compositions comprising at least one anti bacterial agent wherein the composition is free of lubricant and surfactant.

Another object of the present invention is to obtain inhalation compositions comprising at least one oxazolidinone. Another object of the present invention is to obtain effective and stable inhalation composition applicable in pulmonary diseases caused by Gram-positive bacterias.

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

Another object of the present invention is to obtain inhalation compositions having an effective weight ratio of carriers ensuring content uniformity, dosage accuracy and fluidity.

Another object of the present invention is to obtain inhalation compositions facilitating filling process into the blister pack or into the capsule and accordingly enhancing filling rate.

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).

A further object of the present invention is to obtain inhalation compositions which can be filled in blister or in capsule which is applicable with an inhaler.

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

A further object of the present invention is to obtain capsules filled with the above-mentioned inhalation compositions.

A further object of the present invention is to obtain an inhaler which is useable with the above-mentioned blister or the above-mentioned capsules.

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 inhalation compositions comprising at least one anti bacterial agent wherein the composition is free of lubricant and surfactant. According the preferred embodiment, the said anti-bacterial agents is an oxazolidinone derivative.

Said oxazolidinone derivative is selected from the group comprising linezolid, posizolid, tedizolid, radezolid, eperezolid, posizolid, torezolid, cytoxazone or mixtures thereof.

According to the preferred embodiment, said oxazolidinone derivative is linezolid.

According to one embodiment, the amount of the oxazolidinone derivative is between 0.1 - 20%, preferably 0.2-15%, more preferably 0.5-10% by weight of the total composition.

According to one preferred embodiment, the amount of linezolid is between 0.1 -20%, preferably 0.2-15%, more preferably 0.5-10% by weight of the total composition. Accordingly, mean particle size of linezolid is between 0.1 pm - 20pm, preferably 0.5pm - 10pm and more preferably 1 pm - 4pm.

“Mean particle size” represents the d50 value of the particles which is measured by the laser diffraction method. 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.

It has been seen that these particle size ranges ensure effective doses of active agents reaching the alveoli.

According to the most preferred embodiment, the composition is free of all types of lubricant such as stearates and free of all types of surfactant such as poloxamers, since they are known to be highly hygroscopic and they carry risk of changing the chemical behavior of the composition and reducing stability in the long-term. In addition to that, they can cause the composition to clog the inhaler as clumping together.

For the present composition, it means that required moisture resistance, stability, fluidity, content uniformity and dosage accuracy are ensured even in absence of a further excipient other than carrier. It is significantly important considering the prior art in which the use of lubricants and surfactants is shown as indispensable to ensure these qualifications. In a preferred embodiment, the inhalation composition further comprises at least one carrier selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof to provide fluidity and to ensure that the active ingredients accurately and consistently reaches the lungs.

According to the preferred embodiment, the composition comprises lactose as carrier. In the most preferred embodiment, the said lactose comprises fine lactose of which the mean particle size is lower than 100pm and coarse lactose of which the mean particle size is higher than 10pm.

According to a preferred embodiment, the mean particle size of the fine lactose is ranging between 0.1 pm - 50pm and the mean particle size of the coarse lactose is ranging between 20pm - 400pm.

According to the most preferred embodiment, the mean particle size of the fine lactose is ranging between 0.5pm - 25pm and the mean particle size of the coarse lactose is ranging between 40pm - 200pm.

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.

In order to get drug delivery into the lungs from a DPI formulation, the drug particles have to detach from surface of the carrier particles and penetrate into the lungs. The adhesive and cohesive forces between contiguous particle surfaces affect the detachment of the drug particles from surface of the carrier particles, and thus aerosolization of respirable particles in dry powder formulation. The different surface properties of the carrier resulted in different adhesive forces between the drug and the carrier, which was reflected in the lung deposition results. During inhalation, the adhesive forces that exist between drug and carrier particles have to be overcome in order to aerosolize drug particles. The magnitude of the attachment forces during inhalation relative to the adhesive forces in the mixture determines the obtained fine particle fraction (FPF). Consequently, optimizing a dry powder inhalation system with respect to delivered fine particle dose requires careful balancing between both types of forces. The attachment forces have to be strong enough to maintain satisfactory blend homogeneity during handling, storage and transportation but weak enough to yield a high drug release from the carrier particles during inhalation.

It is known that the addition of low surface free energy materials such as lubricants and surfactants 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. Lubricants are preferably used, for this purpose, in the dry powder formulations in the state of the art. Flowever, for this invention, it has been surprisingly found that specific amounts of coarse lactose and fine lactose and their weight ratios given below surely guarantee the required and even enhanced aerosolization performance in terms of emitted dose and fine particle fraction.

According to the present invention, "emitted dose" is the total amount of the active agent emitted from the inhaler device and hence available to the user. Fine particle fraction (FPF) is defined as the percentage of active agent (<5 pm in mass median aerodynamic diameter) which is deposited into respirable regions of the lung, divided by the total amount of active agent leaving the device. For this invention, the emitted dose is above 90% and the FPF is above 15%.

According to the preferred embodiment, the amount of the fine lactose is in the range of 1 - 15%, more preferably 3-10% by weight of the total composition.

According to this preferred embodiment, the amount of the coarse lactose is in the range of 75-99%, more preferably 80-97% by weight of the total composition.

The weight ratio of the fine lactose to the coarse lactose is in the range of 1 :99 to 1 :1 , preferably 1 :50 to 1 :5, more preferably 1 :25 to 1 :15. It has been surprisingly found that this specified ratio range increases fluidity, content uniformity and thus dosage accuracy.

Since lactose is a slightly hygroscopic carrier, it enhances stability and it doesn’t cause agglomeration, thus facilitates the filling process of the composition into the blister or into the capsule.

According to one preferred embodiment, the inhalation composition subjected to the invention comprises;

- 0.1 -20% by weight of linezolid

- 1 -15% by weight of fine lactose with the mean particle size is lower than 100pm

- 75-99% by weight of coarse lactose with the mean particle size is higher than 30pm

According to one embodiment, the dosage form is capsule or blister.

According to all these embodiments, the below given formulations can be used for the inhalation composition subjected to the invention.

Example 1 : Inhalation composition

Example 2: Inhalation composition for administration with a capsule-based inhaler or a blister based inhaler

Example 3: Inhalation composition for administration with a capsule-based inhaler

Example 4: Inhalation composition for administration with a blister-based inhaler

The pharmaceutical compositions subjected to the invention are prepared by these steps:

- Plastering the inner wall of a container with 4/10 by weight of coarse lactose by mixing the lactose in the container for about 3 minutes

- Adding fine lactose and linezolid into the plastered container and mixing them for 3-5 minutes

- Adding 2/10 by weight of coarse lactose and mixing for 5 minutes

- Sieving the mixture through a 250pm mesh

- Adding 4/10 by weight of coarse lactose through the same mesh and mixing the powder mixture for 15 minutes

- Sieving the mixture through a 250pm mesh

- Mixing the final powder for 90 minutes

- Filling the final powder mixture into blisters or capsules 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 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 (a single dose) contains 5mg inhalation composition subjected to the invention. In another preferred embodiment, one capsule contains 25mg 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 5 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 of pulmonary diseases caused by Gram-positive bacteria.

Claims

1. An inhalation composition comprising at least one anti-bacterial agent wherein the composition is free of lubricant and surfactant.

2. The inhalation composition according to claim 1 , wherein the anti-bacterial agents is an oxazolidinone derivative.

3. The inhalation composition according to claim 2, wherein the oxazolidinone derivative is selected from the group comprising linezolid, posizolid, tedizolid, radezolid, eperezolid, posizolid, torezolid, cytoxazone or mixtures thereof.

4. The inhalation composition according to claim 3, wherein the oxazolidinone derivative is linezolid.

5. The inhalation composition according to claim 3 or 4, wherein the amount of the oxazolidinone derivative is between 0.1 -20%, preferably 0.2-15%, more preferably 0.5- 10% by weight of the total composition.

6. The inhalation composition according to claim 4, wherein the mean particle size of linezolid is between 0.1 pm - 20pm, preferably 0.5pm - 10pm and more preferably 1 pm - 4pm.

7. The inhalation composition according to any one of the preceding claims, further comprising at least one carrier selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, maltitol or mixtures thereof.

8. The inhalation composition according to claim 7, wherein the carrier is lactose.

9. The inhalation composition according to claim 8, wherein the said lactose comprises fine lactose of which the mean particle size is lower than 100pm and coarse lactose of which the mean particle size is higher than 10pm.

10. The inhalation composition according to claim 9, wherein the said lactose comprises fine lactose of which the mean particle size is ranging between 0.1 pm - 50pm and coarse lactose of which the mean particle size is ranging between 20pm - 400pm.

11. The inhalation composition according to claim 9, wherein the said lactose comprises fine lactose of which the mean particle size is ranging between 0.5pm - 25pm and coarse lactose of which the mean particle size is ranging between 40pm - 200pm.

12. The inhalation composition according to any one of the claims 9 to 1 1 , wherein the amount of the fine lactose is in the range of 1 -15%, more preferably 3-10% by weight of the total composition.

13. The inhalation composition according to any one of the claims 9 to 1 1 , wherein the amount of the coarse lactose is in the range of 75-99%, more preferably 80-97% by weight of the total composition.

14. The inhalation composition according to claim 12 or 13, wherein the weight ratio of the fine lactose to the coarse lactose is in the range of 1 :99 to 1 :1 , preferably 1 :50 to 1 :5, more preferably 1 :25 to 1 :15.

15. The inhalation composition according to any one of the preceding claims, wherein the composition comprises;

- 0.1 -20% by weight of linezolid

- 1 -15% by weight of fine lactose with the mean particle size which is lower than 100pm

- 75-99% by weight of coarse lactose with the mean particle size which is higher than

30pm

16. The inhalation composition according to claim 15, wherein the dosage form is capsule or blister.

17. A process for preparing the inhalation composition according to claim 16, comprising the following steps:

- Plastering the inner wall of a container with 4/10 by weight of coarse lactose

- Adding fine lactose and apomorphine into the plastered container and mixing them

- Adding 2/10 by weight of coarse lactose and mixing

- Sieving the mixture through a 250pm mesh

- Adding 4/10 by weight of coarse lactose through the same mesh and mixing the powder mixture

- Sieving the mixture through a 250pm mesh

- Mixing the final powder - Filling the final powder mixture into blisters or capsules

18. The inhalation composition according any one of the preceding claims, for use in the treatment of pulmonary diseases caused by Gram-positive bacteria.

19. An inhaler for placing the capsules according to claim 16 wherein the inhaler comprises means to open capsules and to enable respective delivery of each unit dose.

20. An inhaler for placing a blister pack comprising the blisters according to claim 16, wherein the inhaler comprises means to open blisters and to enable respective delivery of each unit dose.