WO2019129341A1 - Method of generating medication in aerosol form - Google Patents

Abstract

The invention relates to methods for producing a medicinal aerosol. The problem of developing an effective method of delivering a medication in aerosol form is solved by a method of generating a medication in aerosol form that comprises delivering atmospheric air evenly to a heating channel via a micropump, passing heated air through a chamber containing a medication, thermally sublimating a starting material of the medication with the subsequent nucleation of the resulting supersaturated steam and the growth of the formed aerosol particles by condensation, additionally delivering atmospheric air to the resulting aerosol, and delivering the aerosol through an outlet tube into the lungs of a patient. The advantageous effect of the proposed method is achieved by the use of a micropump for delivering air at a constant rate to an evaporation chamber containing a medication. When the patient inhales, an additional stream of air mixes with the aerosol stream via special openings in an aerosol formation chamber without disturbing the flow of air through the evaporation chamber. Advantages: maintaining a constant aerosol particle size and a constant mass rate of delivery of the aerosol into the patient's lungs, thus making it possible to control the dosage of an aerosol form of a medication.

Description

 The method of generating drugs in the form of an aerosol

Do you have technology

The invention relates to methods for generating medicinal aerosol and can be used in medicine for treatment, as _. respiratory diseases and systemic diseases.

 Prior art

 Aerosol therapy is becoming increasingly popular means of treating various diseases. This method of drug delivery is used to treat both respiratory [X-3] and systemic diseases [4- 73. When administering systemic drugs, aerosol inhalation has several advantages over oral route of administration. In particular, respiratory administration avoids gastrointestinal losses and liver metabolism. Unlike injections, inhalation therapy is non-invasive, and therefore more comfortable and safe. On the other hand, aerosol delivery has no restrictions associated with the use of water-insoluble drugs in contrast to injection therapy.

 The efficiency of aerosol particle delivery to the alveolar region is a function of particle size. Particles with a diameter of 10–20 nm have the highest deposition efficiency.

It is known from published materials [8 - 15]. First of all, it is of interest to investigate the effect of particles on the body in a given size range. Currently, metered dose inhalers, powder inhalers and nebulizers are available on the drug delivery systems market. All of these inhalers make it possible to obtain an aerosol of no less than 1 micron in size. It is obvious that for effective aerosol therapy it is necessary to develop alternative methods for the generation of nanoparticles, such as the thermocondensation method based on the nucleation of supersaturated steam [16,17]. The advantage of the thermocondensation method is the high concentration of aerosol particles (up to 1Q ⁸ cm ^-3 }, while traditional inhalers allowing to achieve a concentration of not more than 10 ⁵ cm ". ^3. In addition to TOGO, thermo-condensation generators have high stability, which is very important for precise control of the therapeutic dose. Such high stability, as a rule, cannot be given by nebulizers due to the use of solutions with different volatility of components. Because of due to different volatility, the concentration of the solution during the inhalation process is monotonously changing. Even worse is stability in powder inhalers due to the inevitable heterogeneity of the powder substance and in the metered dose inhaler the instability of spraying at high pressures. In addition to the obvious advantage of the above termokondensatsionnyh generators is simple and smooth adjustment of the size and concentration of particles.

 The correct calculation of the dose of the drug is one of the most important tasks in medicine. The importance of correct dosing is determined by the fact that an insufficient dose makes therapy ineffective, and if the dose is exceeded, the risk of toxic effects increases. Unfortunately, in modern medical practice, a high error rate is recorded when dispensing drugs, which causes almost 70% of undesirable drug reactions, which could have been prevented with the right dosage [18-21].

 To date, published descriptions of thermocondensation devices allowing the sublimation of drugs with the formation of an aerosol. There is a method of generating an aerosol using the evaporation of drugs in a tube furnace, followed by cooling the resulting steam by diluting it with air or inert gases [22]. The disadvantage of this device is the difficulty of determining the mass of vzognannogo drugs.

A device for generating medicinal aerosol is known, in which the element of generating steam is presented in the form of compressed expanded graphite impregnated with a liquid composition containing medicinal substances [23]. The disadvantage of this device is the complexity of manufacturing the element of generation of steam, the variability of the composition of the aerosol during evaporation and the impossibility the use of substances originally in solid form.

 A portable electronic inhaler is known [24] in which an aerosol of a drug is formed as a result of heating a liquid substance, which leads to the formation of supersaturated vapor followed by aerosol formation and condensation growth of particles. The disadvantage of this device is the formation of air flow through the evaporative unit of the inhaler by suction of air when the patient inhales. As a result, the flow rate continuously changes during inhalation, which leads to a strong variation in the evaporation temperature and the vapor generation rate of the drug substance. Due to temperature variation, the size distribution function of aerosol particles varies greatly during the inhalation of the patient, which does not allow to determine the inhalation dose with the required accuracy.

 A personal aerosol inhaler [25] is known, comprising a housing with a channel made from the suction port of outside air to the mouthpiece, capsule or ampoule with a liquid filler, which is a medicinal solution for aerosol formation, a heating device located in the housing for heating the drug solution and vapors from the capsule or ampoule along the specified channel to the mouthpiece along with the flow of inhaled air when sucked through the mouthpiece. The disadvantage of this inhaler is a strong change in the dispersion of the generated aerosol during inhalation.

The closest to the claimed invention is a method of generating a medicinal aerosol using rapid heating of the original substance of drugs, applied in a thin layer on the hard surface of a metal cylinder [26]. This method allows for the time from 50 to 300 ms to carry out the evaporation of the applied substance and its transformation into an aerosol ranging in size from several nanometers to several microns. The disadvantage of this method is the inability to maintain a stable concentration of the aerosol for several minutes. Disclosed® Inventions

 The task of the invention is to develop an effective method of drug delivery in the form of an aerosol, using the evaporation of the original substance of the drug, and allowing to maintain a constant average size and distribution function of the generated aerosol in size during inhalation administration and to ensure a constant mass flow rate of aerosol to the lungs.

 The proposed method of generating a medicament in the form of an aerosol, comprising heating and feeding the atmosphere to the original drug substance, evaporating the original drug substance, followed by nucleation of the resulting supersaturated vapor, condensing the growth of the formed particles and feeding them into the lungs to the patient in the form of an aerosol. According to the invention, the supply of atmospheric air is forcibly provided at a constant speed, while the individual (required) rate of entry of a particular patient is provided by an additional supply of atmospheric air, spirit into the area of aerosol formation.

 The positive effect of the proposed method is achieved through the use of forced supply of atmospheric air at a constant speed for the evaporation of the drug by any of the known devices, for example, a micro-fan or micropomp. To ensure the individual inhalation speed of a particular patient, during his inhalation, additional air flow is supplied to the aerosol formation area, which does not disturb the air flow in the evaporation area. As a result, a constant size of aerosol particles and a constant mass flow rate of the aerosol to the patient’s lungs is maintained, which, as a result, allows precise control of the dosage of the aerosol form of the drug.

The method of generating aerosol drug is as follows. At the entrance to the inhalation device forcibly with a constant volumetric flow rate in the range from 0.2 to 2.0 l / min aerosol generation. Next, the air is heated to the required temperature indicated in the graphs (see Fig. 1-3). For a wide range of drugs, the temperature of air heating is in the range from 80 to 220 ° C. Then heated air is supplied to the original substance of the drug. As a result of the evaporation of the drug, the formation of saturated steam occurs. Then the steam enters the aerosol formation area together with the air flow, where it cools down. As a result, the vapor becomes supersaturated, which leads to homogeneous nucleation, i.e. to aerosol formation is the phase transition stage. Further, the vapor is deposited on the surface of the formed particles, which leads to their condensation growth, then the condensation growth ends, due to the exhaustion of the steam. During inhalation of the patient through the nozzle, the atmospheric air is additionally mixed into the aerosol in the area of aerosol formation, in the amount necessary for. ensuring the required (individual) rate of inhalation of a particular patient. At the same time, the constant air supply rate to the evaporation area is not disturbed, which ensures the constancy of the evaporation temperature and the steam generation rate. As a result, the medicinal aerosol has a constant size distribution function and a constant mass flow rate into the patient’s lungs, which ensures precise control of the dose of the drug administered.

 Brief Description of the Drawings

 In Fig.1 is a graph of the temperature dependence of the heating air flow from the supply voltage of the heater;

 In Fig.2 is a graph of the concentration of the aerosol obtained by the sublimation of the drug isoniazid, on the heating temperature of the air stream;

 Fig. 3 is a graph of the dependence of the average size of isoniazid aerosol on the heating temperature of the air stream.

Var _& n® implementation of the invention

An example of the method of generation of aerosol drugs. Experiments were conducted to confirm the implementation of the method with the drug - isoniazid in the form of tablets. The method of generating the drug isoniazid aerosol was performed in a laboratory setup. Resistive heater is made of nichrome with a resistance of 3 ohms. The results of experimental studies are shown in FIG. Figures 1 to 3 show the dependence of the heating temperature of the air flow on the heater supply voltage, as well as the concentration and average diameter of aerosol particles on the heating temperature of the air flow. To control the concentration and size of aerosol particles of drugs, an aerosol spectrometer was used [27]. The spectrometer is equipped with a pump that sucks air at a constant volumetric rate .1. l / min to the measuring system.

 A positive result is that when using the proposed method, the generation of a medicinal product in the form of an aerosol is carried out with a stable distribution of the size of the medicinal product and with a constant mass feed rate to the patient’s lungs, without disturbing the flow of air through the evaporation chamber.

 Advantages: maintaining a constant size of aerosol particles and a constant mass flow rate of aerosol into the patient’s lungs, which, as a result, allows you to precisely control the dosage of the aerosol form of the drug,

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Claims

Claim  A method of generating a drug in the form of an aerosol, which includes heating and supplying atmospheric air to the original drug substance, evaporating the original drug substance, followed by nucleation of the resulting supersaturated steam, condensing growth of the formed particles and feeding them into the patient’s lungs as an aerosol, о®flowing® EN, the air flow is forcibly provided at a constant speed, while the individual (required) inspiration rate of the patient is provided to olnitelnoy feed air in the aerosol.