Technical Field

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

Background of the Invention

A dopamine receptor agonist is a compound that activates dopamine receptors. Dopamine receptor agonists activate signaling pathways through trimeric G-proteins and b-arrestins, ultimately leading to changes in gene transcription.

Today, for several dopamine receptor subtypes (Di, D ₂ , D ₃ ) agonists are known, that differentially address these signaling pathways. They are called biased agonists.

Some medical drugs act as dopamine agonists and can treat hypodopaminergic (low dopamine) conditions; they are typically used for treating Parkinson's disease (PD), attention deficit hyperactivity disorder (in the form of stimulants) and certain pituitary tumors (prolactinoma), and may be useful for restless legs syndrome (RLS). Dopamine agonists can be classified under three groups which are partial agonists, full efficacy agonists and indirect agonists.

Apomorphine, which is a full efficacy agonist, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D ₂ -like and, to a much lesser extent, D _r like receptors. It also acts as an antagonist of 5-HT ₂ and a-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix relates to it being a morphine derivative. Currently, it is used in the treatment of Parkinson's disease. It is a potent emetic and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances. Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland. It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex Parkinson's has also been found to have excess iron at the sites of neurodegeneration; both the R- and S- enantiomers of apomorphine are potent iron chelators and radical scavengers.

Apomorphine also reduces the breakdown of dopamine in the brain (though it inhibits its synthesis as well). It is a powerful upregulator of certain neural growth factors, in particular NGF and BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.

Its chemical name is (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline -10,11- diol and its chemical structure is shown in Formula I.

Formula I

Its subcutaneous dosage forms are marketed under brand names such as Apokyn, Ixense, Spontane and Uprima. These drugs are known to reduce or cease the patient’s complaints in about 20 minutes. Another dosage form of apomorphine is sublingual tablet which takes 30- 45 minutes to show the pharmaceutical effect of apomorphine.

Besides, the maximum amount of active agent in a single dose of subcutaneous injection is 10mg and the total daily amount should not exceed 100mg for the patient’s safety. However, frequent apomorphine injections at low doses are often insufficient to control symptoms. In this case, repeated injections can cause pain and decrease the patient compliance. On the other hand, powder forms of dopamine agonists for inhalation, which are meant to take effect faster than the other dosage form present in the market, have also been studied in the patent literature.

One of the documents in the prior art, patent document numbered US2014377189A1 , reveals an aerosol formulation comprising a dopamine agonist, a propellant and a cosolvent. The document is claiming that the suggested formulation is stable at room temperature for at least one week. It is also stated that the dopamine agonist is rotigotine.

Another patent document numbered US2013287854A1 suggests a method for the treatment or the prevention of the symptoms of Parkinson’s disease comprising the administration of apomorphine in combination with levodopa and/or a dopamine agonist other than apomorphine by inhalation. It is stated that the inhalation formulation further comprises a carrier and an additive material such as magnesium stearate which has lubricative properties.

Yet another patent document in the prior art, namely US6193954B1 , presents a method of administering a dopamine agonist by inhalation. The pharmaceutical formulation by which the method is performed further comprises a propellant and a poloxamer as surfactant and it is mentioned that surfactants are necessary to prevent aggregation of the formulation.

However, additive materials such as lubricants and surfactants which are used in the state of art are known to be highly hygroscopic. One of the biggest challenges for the pharmaceutical dosage forms, especially for dry powder formulations, is the moisture in the air; since it changes the chemical behavior, reduces stability and damages the long-term performance of the product. In addition to that, it causes for dry powder inhalation formulations to clump together and clog the inhaler.

Inhalation compositions show activity by reaching directly to the respiratory system. Contriving the compositions is based on containing the active ingredient along with the carrier and the extender 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. Difference of the particle sizes between the carrier and the extender used is important in order to ensure the 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 effectiveness of the treatment.

Small drug particles are likely to agglomerate. Said coagulation can be prevented by employing suitable carrier or 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 should be homogeneous. Adhesion should be quite strong as the drug could not detach from the carrier particle. 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 the particle size. Therefore, it has been found to be very important to employ the fine (small) and coarse (large) particles of the selected carrier in the formulations of the present invention in an accurate ratio.

In order to meet all these requirements, dry powder inhaler (DPI) formulations should be adapted especially by carefully choosing the employed carriers. In order to meet these requirements, the inhalable, fine or micro-fine particles of the active compounds are mixed with carriers. By means of mixing process, particle size of the carrier can be changed in order that a certain amount thereof to become inhalable. Particle size of employed carrier depends on the requirements and specifications of the powder inhaler used for application of the formulation.

Thus, there is still a need for a powder formulation of dopamine agonists for inhalation, which is free of lubricant and surfactant, thus which provides high stability and at the same time which ensures fluidity, content uniformity and dosage accuracy.

Objects and Brief Description of the Invention

Present invention relates to inhalation compositions comprising dopamine agonists overcoming all the aforementioned problems and bringing further advantages to the technical field. Main object of the present invention is to obtain effective and stable inhalation composition which comprises at least one dopamine agonist wherein the composition is free of lubricant and surfactant.

Another object of the present invention is to obtain effective and stable inhalation composition applicable in Parkinson's disease.

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 dopamine agonist wherein the composition is free of lubricant and surfactant.

Said dopamine agonist is selected from the group comprising apomorphine, bromocriptine, cabergoline, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, lisuride, pergolide, piribedil, pramipexole, propylnorapomorphine, quinagolide, ropinirole, rotigotine, roxindole, sumanirole or mixtures thereof.

According to the preferred embodiment, said dopamine agonist is apomorphine.

According to this embodiment, the amount of apomorhine 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 apomorphine 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 30pm.

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. However, 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 90-97% by weight of the total composition.

The weight ratio of the fine lactose to the coarse lactose is in the range of 0.01 :1 to 0.2:1 , preferably 0.03:1 to 0.1 :1 , more preferably 0.04:1 to 0.07:1. It has been also seen 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 apomorphine

- 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 apomorphine 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 the Parkinson’s disease.