Patent Application
20200009334
The present invention relates to a preparation for inhalation use in form of dry powder comprising particles of Ambroxol and/or hydrochlorides thereof as single active principle and optionally a suitable pharmaceutically acceptable excipient, wherein said particles have a geometrical diameter equal to or smaller than 5 μm, wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof in the composition has a geometrical diameter from 3 to 5 μm. The present invention further relates to the methods for the preparation of such composition and uses thereof. The present invention thanks to the very fine particles of dry powder, having sizes equal to or smaller than 5 μm constitutes a composition for inhalation use with optimum performances which, combined to the inhaler action, reaches and acts directly on the bronchi or on the damaged respiratory tract. The local action and the quick absorption of the drug guarantee good features of bioavailability. The decrease in the dosage of Ambroxol with respect to the other existing oral or injectable formulations allows to reach locally and safely the therapeutic target.
Ambroxol or most used hydrochlorides thereof, such as for example Ambroxol hydrochloride, is an expectorant mucolytic drug. Ambroxol is an active metabolite of bromhexine which can favour the secretion of pulmonary surfactants and the mucosal secretions of the respiratory tract. Ambroxol fragments the mucopolysaccharide chains in the sputum, it dissolves mucus, reduces significantly viscosity of the mucosal secretions, increases the mucociliary clearance and favours expectoration. It improves ventilation and breathing difficulties. Its effectiveness as mucolytic agent is significantly higher than that of bromhexine, with low toxicity and good tolerability. Drug variants are included in the European Pharmacopoeia (EP), in the United States Pharmacopoeia (USP), in the British Pharmacopoeia (BP), in the Chinese Pharmacopoeia (CP) and others.
Currently, Ambroxol still occupies a privileged role among the mucolytic agents, with several formulations and dosages available on the market, in form of tablets, capsules oral solutions, syrups, injections, liquid solutions for aerosol, etc. For adults and children over 12 years, the usual dose of oral administration: 30 mg-3 times a day; of intravenous injection, intramuscular injection and subcutaneous injection: 15 mg/twice a day; inhalation of liquid aerosol: 15 mg/2 ml, twice a day. The oral preparations work slowly, they enter the gastrointestinal tract, they are absorbed by the blood flow to perform a systemic role and they cannot ease quickly the patient disease. The parental administration route, although it provides a quick therapeutic effect, plays a systemic role, it is relatively difficult to be administrated and causes pain in patient. The nebulized inhalants request the use of voluminous atomizers to atomize the liquid and then to inhale it, such devices are uncomfortable to be used and transported. The drug absorption rate by dry powder inhalation is second only to the intravenous injection. Especially for the diseases of bronchi and lungs it can act directly on the site of the lesions, which contributes to improve the bioavailability of the drugs and to exert a safe and effective therapeutic effect. At the same time, it favours stability and portability of the drugs.
Then, the need was very felt in the art for proposing new administration forms of Ambroxol and methods for the preparation thereof not having the disadvantages described in the known art.
Based upon the deficiencies of the several existing preparations and above-mentioned administration forms, the inventors succeeded to obtain a dry powder of Ambroxol and/or hydrochlorides thereof as single active principle and optionally a suitable pharmaceutically acceptable excipient, for inhalation use with bronchial target, with particles having a geometrical diameter equal to or smaller than 5 μm, wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof in the composition has a geometrical diameter from 3 to 5 μm. The present invention adopts a daily dosage form of dry powder for inhalation use equal to 1 up to 14.9 mg of the dry powder as defined in the present description and in the claims, in absence of propellants, with a good stability, with reduced interactions and interferences. The present invention will be preferably used with an inhaler device combined with blister or single-dose capsule, preferably blister made of aluminium, so that Ambroxol, through the inhaler, activated by the generation of an air flow due to the aspiration by the patient, could directly be inhaled to reach the bronchi and the damaged respiratory tracts, with a quick and safe effect.
The invention also relates to processes for the preparation of the dry powder comprising particles of ambroxol as defined in the present description and in the claims, and the products obtainable by means of said processes.
The present invention then relates to a method for preparing a pharmaceutical composition for inhalation use in form of dry powder of ambroxol and/or hydrochlorides thereof as single active principle, wherein at least 85% of the particles of ambroxol has a geometrical diameter from 3 to 5 μm comprising
a) to micronize ambroxol and/or hydrochlorides thereof by means of Jet Milling,
b) to collect the particles separated from the cyclone generated by said jet milling having a satisfying size, wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof has a geometrical diameter from 3 to 5 μm,
c) to mix the so obtained particles together with a suitable excipient thus obtaining the dry powder for inhalation use.
The present invention further relates to a method for preparing a pharmaceutical composition for inhalation use in form of dry powder of ambroxol and/or hydrochlorides thereof as single active principle, wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof has a geometrical diameter from 3 to 5 μm comprising
a. to heat and dissolve in distilled water or in distilled water containing ethanol 20% ambroxol and/or hydrochlorides thereof
b. to subject the preparation obtained in point a. to spray drying, by obtaining particles of ambroxol and/or hydrochlorides thereof wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof has a geometrical diameter from 3 to 5 μm,
c) to mix the so-obtained particles together with a suitable excipient thus obtaining the dry powder for inhalation use.
At last, the present invention relates to a method for preparing a pharmaceutical composition for inhalation use in form of dry powder of ambroxol and/or hydrochlorides thereof as single active principle, wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof has a geometrical diameter from 3 to 5 μm comprising:
a. to heat and dissolve in distilled water and/or hydrochlorides thereof and a suitable excipient
b. to subject the preparation obtained in point a. to spray freeze drying, obtaining particles of ambroxol and/or hydrochlorides thereof wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof has a geometrical diameter from 3 to 5 μm thus obtaining the dry powder for inhalation use.
As above said, any embodiment of the composition and of the medical devices provided in the present invention, can be implemented with the dry powder obtainable by anyone of the above-described or claimed methods.
The inhalation of dry powder is an effective method to act directly on bronchi and lungs. The dry powder of Ambroxol for inhalation use of the present invention, thanks to the reduced size of the particles and through the inhaler device reaches directly the site of bronchial lesion with a good targeting and a quick effect. The drug dosage is significantly reduced, it is safe and has reduced toxic and side effects.
The present invention constitutes a new administration route and a new dosage form of Ambroxol, it has the features of easy use and portability and it is an industrial product.
The hermetic insertion of the dry powder as single dose in blister made of aluminium or capsules guarantees an accurate dosage, excluding the overdosage thereof and with an optimum stability.
The inhalation of the drug in dry powder of the present invention, combined with an inhaler device also allows a patient with poor pulmonary function to use it, the procedure is simple, both elderly people and children can use it.
The advantages, features and use modes of the present invention will result evident from the following detailed description of some embodiments, shown by way of example and not for limitative purpose.
To the purpose of the present description, the term “geometrical diameter” has the meaning commonly used in the art, said geometrical diameter being determinable, for example, by means of the method shown by the European Pharmacopoeia (SPOS, Ph. Eur. 9th Ed., 2.9.31. Particle size analysis by laser light diffraction, precisely on page 349) through granulometer Accusizer™ Optical Particle Sizer Model 770 (Santa Barbara, Calif., USA).
To the purpose of the present invention the expression “comprising” can be replaced by the term “constituted by” in any embodiment of the invention provided in the present description.
Therefore, in any embodiment of the invention, the pharmaceutical composition can be constituted by the described components.
The invention also relates to a therapeutic method for treating the pathologies illustrated in the present description, comprising the administration of the composition as defined in the present description, preferably by means of the device as defined in the present description to a subject requiring it.
The present invention utilizes Ambroxol (trans-4-(2-Amino-3,5-dibromobenzylamino)-cyclohexanol) and the hydrochlorides thereof as active principle, such as for example Ambroxol hydrochloride. The present invention firstly relates to a pharmaceutical composition for inhalation use in form of dry powder comprising particles of Ambroxol and/or hydrochlorides thereof as single active principle, and optionally a suitable pharmaceutically acceptable excipient, and wherein at least 85% of the particles of ambroxol and/or hydrochlorides thereof in said composition has a geometrical diameter from 3 to 5 μm.
The composition could include one or more excipients and/or dispersants and/or glidants suitable to the inhalation use, for example excipients could be used such as lactose, mannitol, glucose or mixtures thereof, one or more among solubilization agents, such as leucine and valine and/or glidants such as for example magnesium stearate. The percentages in the present description are meant as percentages by weight.
The composition could comprise from 20 to 100% of ambroxol, in particular from 20 to 59% or from 91 to 100% and/or from 41 to 80% of excipients and/or from 0 to 9% of dispersant. The dry powder of Ambroxol for inhalation use will be advantageously inserted hermetically as single dose in blister or capsules, preferably in blister made of aluminium. According to a preferred embodiment a self-piercing blister will be used for dispensing said powder, in particular like those described in the patent in Italy 102015000063968 herein incorporated by reference.
The present invention also relates to an inhaler of dry powder comprising the herein described compositions, advantageously an inhaler will be used activated by means of the air flow alone due to aspiration by the patient. In particular an inhalator will be used which can produce a turbulent flow speed so that, even under lower differential pressure conditions, it succeeds in disaggregating and dispersing particles of drug to form inhalable particles. Examples of suitable inhalers which could be used are PillHaler® or those described in the patent application in Italy 102016000093878 herein incorporated by reference.
The composition in dry powder of Ambroxol for inhalation use, the present invention relates to, will be used as expectorant mucolytic agent, in particular the herein described dry powder once inhaled is able to reach effectively the target of the bronchial lesions. The dry powder of Ambroxol according to the present invention could be used as single dose with dosage significantly lower than the several formulations on the market and which thanks to the very fine particles of dry powder having sizes included within 3-5 μm and the excipients for inhalation use and the dispersing agents, produces an inhalation dry product with optimum performances which, combined to the inhaler action, reaches and acts directly on the bronchi or on the damaged respiratory tract. The single dose of dry powder of Ambroxol will be preferably comprised from 1 mg to 14.9 mg, which is only ½-⅙ of the several formulations on the market. The dosage regime could be for example one or twice a day.
The present invention also relates to the methods for preparing the herein described dry powder of Ambroxol and/or hydrochlorides thereof as well as the power obtainable by means of the said processes.
According to a first embodiment the method provides a step wherein the drug of Ambroxol and/or hydrochlorides thereof is micronized by pulverization of the air flow (jet milling), by obtaining the wished granulometry. According to an embodiment the used process gas will have a pressure of about 7 bar. The so prepared powder could be mixed uniformly with the excipients and/or the pharmaceutically acceptable dispersing agents.
The so obtained powder will be preferably inserted hermetically as single dose, in the amounts shown in the present description, in blister made of aluminium or capsules.
In a preferred embodiment of the invention mannitol is used as excipient.
According to an alternative embodiment the method provides a step a) of mixing Ambroxol and/or hydrochlorides thereof in distilled water or in distilled water and ethanol ≤20%.
The mixture prepared in step a) is subjected to a step b) of spray drying with the purpose of obtaining fine particles according to the wished granulometry, the particles obtained in step b) are then optionally mixed with one or more pharmaceutically acceptable excipients and/or dispersants.
The so obtained powder will be preferably inserted hermetically as single dose, in the amounts shown in the present description, in blister made of aluminium or capsules.
The prepared liquid is nebulized in small drops thanks to a nozzle or a rotating disc (in English nozzle or rotary atomizer). The nozzles use the pressure or the compression of a gas (for example air or nitrogen) to nebulize the prepared liquid whereas a disc atomizer uses a disc which rotates at high speed. The speed of the air and/or of the inert gases depends upon the section of the spray drier. This procedure is performed in the drying Chamber (the final size of the solid mainly depends upon the diameter of the drops produced by the atomizer). The produced drops are dried by hot air circulating in the drying chamber. The heated gas is put in contact with the small drops by using a gas spreader, thus by guiding the liquid evaporation (the contact between the nebulized drops and the hot air causes a quick evaporation of the solvent, rapidity which is determined by the very high contact area between the drops and the hot air).
During the spray drying step preferably an opening of the nozzle of the spray dryer of at least 0.7 mm and/or a gas flow between 200 and 800 L/h will be used. The temperature of inlet air preferably will be of at least 115±2° C. The solution nebulization is made to occur for example with a liquid feeding speed of about, 8 ml/min. The so obtained powder could be mixed with excipient or inserted hermetically as single dose in blister made of aluminium or capsule in the amounts shown in the present description. The powder is recovered from the outletting gas for example by using a Cyclone or a filter (bag filter).
According to another embodiment the method provides a step a) of mixing Ambroxol and/or hydrochlorides thereof with dispersant and/or excipients in solution, for example in distilled heated water. The mixture prepared in step a) is subjected to a step b) of spray freeze drying with the purpose of obtaining fine particles according to the wished granulometry. According to a preferred embodiment an opening of the freeze dryer nozzle of at least 0.7 mm and/or a spray freezing temperature lower than or equal to −15° C. and/or a freezing temperature (cryo-temperature) lower than or equal to −60° C. and/or a liquid feeding speed of at least 1.6 ml/min and/or an atomizing pressure of at least 2.7 bar will be used.
The heating temperatures preferably are 70-75° C. when the distilled water is heated and 50-55° C. when the hydroalcoholic solution containing distilled water and ethanol 20% is heated.
The so obtained powder could be inserted hermetically as single dose, in the amounts shown in the present description, in blister made of aluminium or capsule.
The invention is described hereinafter in details in the following examples which are only by way of example without limiting the conferred protective scope.
In this preparation method the micronizer is used: DECMCOne model. The drug of Ambroxol hydrochloride is micronized by pulverization of the air flow.
The air flow pulverizer uses a “process gas” 7 bar 0.09 Nm3/min (3.18 CFM) the ambient temperature in white chamber is 20° C. and the temperature in the area dedicated to the micronizer unit is 12° C. Through grinding and crushing at high pressure and the centrifugal force generated by the turbine, the rough particles are separated from the fine ones. The particles satisfying the size requirements enter the cyclone separator and are herein collected. It is preferred that at least 85% of particles has a diameter smaller than 5 μm, preferably from 3 to 5 μm. Reproducing and distributing uniformly excipient and dispersant in an inhalation level from 50 to 100 μm to obtain a good sliding capability. During inhalation the flow generates turbulences which disperse the particles to form micronized particles which can be inhaled to reach the bronchi. The percentage by weight ratio of the particles of active principle and the particles of excipient is 40%:60%. The deriving powder is inserted hermetically as single dose in blister made of aluminium or capsules.
The excipient used in the above-mentioned example preferably is mannitol.
In this preparation method the mini spray dryer BUCHI B-290 is used. The opening of the spray dryer nozzle: 0.7 mm, compressed gas flow: 5˜8 bar, 200˜800 L/h, temperature of inlet air 115±2° C., liquid feeding speed: 1.8 ml/min, nebulization air speed: 473 litres/hour, atomization pressure: 2 bar, air flow: 0.55 m3/min, drying time≤1.5-seconds. Ambroxol and/or hydrochlorides thereof are dissolved in distilled water comprising or not 20% of ethanol, the spray-drying method is used with the solution obtained by adjusting the nebulization air speed to control the size of the particles of atomized small drops to prepare particles of micronized powder with a good form. It is preferred that at least 85% of particles has a diameter smaller than 5 μm, preferably from 3 to 5 μm and that 40% of the particles of excipient has a diameter from 15 to 100 μm mixed uniformly to obtain a good sliding capability. During inhalation the flow generates turbulences which disperse the particles to form micronized particles which can be inhaled to reach the bronchi. The deriving powder is inserted hermetically as single dose in blister made of aluminium or capsules.
In this preparation method the freeze dryer Pilotech YC-3000 is used.
Opening of the freeze dryer nozzle: 0.7 mm, temperature of spray freezing: ≤−15° C., cryo-temperature: ≤−60° C., liquid feeding speed 1.6 ml/min, atomization pressure: 2.7 bar. Based upon the percentage by weight of the components of the end mixture, 91% of Ambroxol hydrochloride and 9% of mannitol are dissolved in distilled heated water. The size of the particles of the atomized small drops is controlled by freeze dryer method to prepare particles of micronized powder with a good form. It is preferred that at least 85% of particles has a geometrical diameter from 3 to 5 μm. The particles are mixed uniformly with ≤0.5% of dispersant to obtain a good sliding capability. During inhalation the flow generates turbulences which disperse the particles to form micronized particles which can be inhaled to reach the bronchi. The deriving powder is inserted hermetically as single dose in blister made of aluminium or capsules.
The physical and chemical properties of the dry powder for inhalation use obtained with the herein described preparation methods, the present invention relates to, were determined by meeting the standards related to the European Pharmacopoeia (EP). Determination of the water content by thermogravimetric analysis (Ph. Eur. 9th Ed, 2.2 Thermal analysis). Morphological characterization of the powder: characterization of the surface morphology of the powder by means of scanning electron microscopy. Several preparation methods generate different surface morphologies of the powder. The product prepared with the micronization method has an irregularly wrinkled aspect, whereas the one obtained through spray drying process will have a spherical shape. Size characterization of the particles: the particle sizes were determined with the method illustrated by the European Pharmacopoeia (SPOS, Ph. Eur. 9th Ed., 2.9.31. Particle size analysis by laser light diffraction, described in detail on page 349) through granulometer Accusizer™ Optical Particle Sizer Medel 770 (Santa Barbara, Calif., USA). 85% of the obtained powder particles has a diameter smaller than 5 μm, preferably from 3 to 5 μm. Measurement of the aerodynamic diameter of the powders by cascade impactor (Ph. Eur. 9th Ed., 2.9.18. Preparations for inhalation: aerodynamic assessment of fine particles). Study of the sliding properties and density of the powders by measuring the tap density and angle of repose according to the European Pharmacopoeia (Ph. Eur. 9th Ed., 2.9.34. Bulk density and tapped density of powders; 2.9.36. Powder flow].
Development and validation of a UV (Ph. Eur. 9th Ed., 2.2.25. Spectrophotometry, ultraviolet and visible absorption) or HPLC (Ph. Eur. 9th Ed., 2.2.29. Liquid chromatography) method for the quantitative determination of Ambroxol hydrochloride. The content of Ambroxol hydrochloride is 95%-105% with respect to the illustrated amount.
Determination of the content uniformity of the prepared mixtures (Ph. Eur. 9th Ed. 2.9.40. Uniformity of dosage units).
Determination of the emptying speed:
Determination of the powder fraction emitted by using the apparatus Glass Twin Stage Impinger (Ph. Eur. 9th Ed., 2.9.18. Preparations for inhalation: aerodynamic assessment of fine particles) by following the guidelines of EMA. A dry powder inhaler device will be for example used which activates only thanks to the air flow alone generated by the patient's inhalation, including inside blister made of aluminium the formulations obtained with the herein described preparation methods.
10 accurately weighed products (W1) are collected. The inhalation of one product at a time is measured at an air flow di 60L±5 L for 5 seconds to identify then each weight thereof (W2). Then, any residue is eliminated to obtain the value of the tare (W3). Through the following formula the value of the fraction of emitted powder will be obtained:
[(W1−W2)/(W1−W3)]×100%.
Fraction of powder emitted by the product of the present invention: from 91 to 100%.
Determination of the pulmonary deposit through FPF analysis:
Glass Twin Stage Impinger (Ph. Eur. 9th Ed., 2.9.18. Preparations for inhalation: aerodynamic assessment of fine particles) of distribution of the dry powder for inhalation use, to measure the deposition level of Ambroxol hydrochloride in the simulated respiratory and pulmonary tract. By using for example a dry powder inhaler device which activates thanks to the air flow alone generated by the patient's inhalation, containing inside blister made of aluminium the formulations obtained with the herein described preparation methods. The content of Ambroxol hydrochloride is determined and the device is validated through high performance liquid chromatography (HPLC).
10 samples of this product are collected and the dry powder inhaler device is used, by using for example a dry powder inhaler device which activates thanks to the air flow alone generated by the patient's inhalation, containing inside blister made of aluminium the formulations obtained with the herein described preparation methods, the results are compared to the shown amount of this product to obtain the powder distribution quantity. The FPF deposit rate of this product is 0-50%.
Conclusion: From the evaluation of the dynamic particles of the product it is clear that the powder particles of the present invention are suitable for the administration to the bronchi. The selected excipients and their ratio with the drug show a good disaggregation level of the particles and then an optimum drug release. Most particles succeed in reaching the bronchial site.
To 18 laboratory rats, weighing 250 g, divided into two groups, three doses of product were administered separately and diluted in the respective dose for injection of Ambroxol hydrochloride. The plasmatic concentration and the effect on the bronchi of the same dose of product for injection of Ambroxol hydrochloride is thus determined. Test methodology: all rats were anaesthetized with isoflurane, one group received separately three doses of product by using a micronized atomizer of animal lung similar to a syringe. A method for the direct administration of a nebulized powder to a trachea of a rat with the needle and the other group was subjected to intravenous injection of the same dose of Ambroxol hydrochloride by injection. Then, from the eye socket of the animal blood was collected to determine the plasmatic concentration in 15 minutes of the same dose of product and of the same dose by injection in the same time. From the drug concentration in the blood the absorption speed and level of the inhaled product can be evaluated, with the purpose of deducing the product effect and target. The experimental results show that the product target has been reached, the targeted administration of the drug is effective and allows to reduce the dose thereof, thus reducing the side effects. The container for the drug, used for implementing the present invention, preferably is in blister made of hermetic aluminium, as the dry powder preparation can be pre-packaged in an established single dose and inserted in the blister made of sealed aluminium by guaranteeing the powder tightness and its chemical-physical protection. Such packaged formulations can remain stable for a long period of time and they are also very advantageous from the economic and commercial point of view.
The inhalation device used for the administration of the present invention is a tool for inhaling dry powder PillHaler® which is fed exclusively by the inspiratory air flow of the patient, in combination with the blister made of sealed aluminium to form a unique product. The drug powder is effectively dispersed in the turbulence of the air flow produced by the inhalation of the patient and it is easily inhaled in the body. Even the patients with poor lung functionality can use it as the procedure is simple. It can be easily used by elderly people and children.
The present invention also relates to all products obtainable according to anyone of the herein described embodiments of the methods.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102018000006909 | Jul 2018 | IT | national |
