CN112336703A - Isoniazid dry powder inhalant for treating pulmonary tuberculosis - Google Patents
Isoniazid dry powder inhalant for treating pulmonary tuberculosis Download PDFInfo
- Publication number
- CN112336703A CN112336703A CN202011412789.3A CN202011412789A CN112336703A CN 112336703 A CN112336703 A CN 112336703A CN 202011412789 A CN202011412789 A CN 202011412789A CN 112336703 A CN112336703 A CN 112336703A
- Authority
- CN
- China
- Prior art keywords
- dry powder
- isoniazid
- leucine
- inhalant
- lactose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an isoniazid dry powder inhalant for treating pulmonary tuberculosis, which comprises isoniazid micro powder and carrier micro powder or not, wherein the particle size of the isoniazid micro powder is processed to be 0.1-10 mu m by a fluidized bed supersonic airflow pulverization method or a spray drying method. Preferably, the dry powder inhalant is added with auxiliary materials such as leucine, mannitol or phospholipid to enhance the granulation rate of the particles, and is added with auxiliary materials such as magnesium stearate, mannitol, leucine and/or lactose to improve the flowability of the medicine and reduce the agglomeration phenomenon of the particles. The dry powder inhalant has simple preparation process, and can be used for preparing isoniazid dry powder inhalant with higher stability. The dry powder inhalant can effectively deliver drugs to alveoli to effectively kill and inhibit tubercle bacillus in respiratory tract, and is particularly suitable for treating patients with pulmonary tuberculosis with impaired liver function.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to an isoniazid dry powder inhalant for treating pulmonary tuberculosis, a preparation method thereof, and application thereof in preparing medicaments for treating various types of pulmonary tuberculosis.
Background
Tuberculosis is a highly contagious pulmonary disease that is highly destructive to the lungs, long lasting, often over half a year. The current clinical treatment means of the pulmonary tuberculosis are usually oral administration by adopting a tetrad therapy of isoniazid, rifampicin, ethambutol and pyrazinamide. The isoniazid has strong antibacterial activity on mycobacterium tuberculosis, is a very effective and rapid mycobacterium tuberculosis bactericide, achieves very good antibacterial and bactericidal effects when the effective concentration is 0.3-10 mu g/mL, but has stronger hepatotoxicity and is difficult to achieve and maintain effective or higher drug concentration in tracheal, bronchial and alveolar secretions. In the clinical use process, the isoniazid injection can be used for adjuvant therapy of pulmonary tuberculosis by atomization and inhalation, and the atomization means is mentioned in the use instruction of the isoniazid injection, the guidelines for preventing and treating tuberculosis and the consensus of tuberculosis treatment experts.
Despite much research, there is currently no isoniazid formulation specifically for clinical inhalation. CN1102093A discloses an isoniazid aerosol, a spray and a preparation method thereof, wherein the content of the aerosol is prepared from a medicament of isoniazid; diluent and specific gravity regulator anhydrous sodium sulfate or anhydrous lactose; span-85 as a suspending agent and ethyl oleate; a latent solvent trichlorofluoromethane; propellant dichlorodifluoromethane, dichlorotetrachloroethane, etc., wherein the content of the spray is composed of isoniazid; boric acid (salt) and phosphate as pH regulators; osmotic pressure regulator sodium chloride, glucose, solvent water, etc. However, isoniazid aerosol and spray have the defects of complicated process and low delivery rate, and the dosage of the isoniazid aerosol and spray is only 2-5mg per press, while the dosage of dry powder inhalant can be 10-50mg per time.
CN101684116A discloses an isoniazid lipid derivative and a composition thereof, which is characterized in that the structure of the isoniazid lipid derivative is as follows: INH-THTT-R, wherein INH is isoniazid, THTT is thiadiazinethione, and R is a long aliphatic chain with 6-20 carbon atoms. The isoniazid lipid derivative can be prepared into tablets, capsules, injections, aerosols, dry powder inhalers and high-dispersion dosage forms. According to the application, isoniazid is chemically synthesized and modified into a lipid derivative of isoniazid, so that the in-vivo absorption of isoniazid is improved, but the method is complex in preparation process, poor in preparation stability and high in difficulty in process production amplification.
CN103110633A relates to a dry powder inhalant for preventing the respiratory tract transmission of tubercle bacillus, which is prepared by 9.9-80% isoniazid slow release microspheres, 19.9-90% rifampicin slow release microspheres and 0.1-5% glidant by weight, wherein the isoniazid slow release microspheres, the rifampicin slow release microspheres and the glidant are mixed together and filled in gelatin, plastic capsules or aluminum-plastic bubble caps or packaged in a multi-dose dry powder inhalant device in a storage mode. In order to enable the two medicines to play a slow release role, a large amount of gelatin auxiliary materials are used, the gelatin is derived from animals, some immunogenicity possibly exists when the gelatin enters the lung, the safety cannot be guaranteed, and in addition, the amount of the added auxiliary materials is large, and the drug-loading rate can be reduced.
Therefore, the clinical requirement on the isoniazid inhalation dosage form is not met, and the currently known isoniazid inhalation dosage forms have the problems of low delivery efficiency, poor preparation stability, incapability of ensuring safety, low drug loading rate and the like in different degrees.
Disclosure of Invention
In order to solve the defects of the prior art, the inventor prepares an isoniazid dry powder inhalant with high stability and high drug loading capacity by using a modern preparation technology, and inhales isoniazid powder into the trachea and the lung by means of an inhalation device so as to treat various types of tuberculosis. The isoniazid dry powder inhalant prepared by the method is particularly suitable for treating pulmonary tuberculosis and bronchial tuberculosis of patients with impaired liver function.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention relates to an isoniazid dry powder inhaler for the treatment of tuberculosis, characterized in that: the dry powder inhalant comprises isoniazide micro powder and carrier micro powder or not, and the particle size of the isoniazide micro powder is processed into d by fluidized bed supersonic gas flow grinding method or spray drying method10＝0.1-3μm、d503-7 μm and d90The dry powder inhalant comprises 7-10 mu m of carrier micro powder, wherein the carrier micro powder is prepared from an internal auxiliary material, the internal auxiliary material is amino acid, mannitol or phospholipid, and the dry powder inhalant further comprises an external auxiliary material, and the external auxiliary material is selected from one or more of amino acid, phospholipid, sugar or magnesium stearate.
In one embodiment, the amino acid is selected from leucine, valine, glycine or isoleucine, preferably leucine.
In another embodiment, the saccharide is selected from mannitol, lactose, maltose, trehalose or sucrose, preferably lactose or mannitol.
In a more preferred embodiment, the lactose is one or more of type Inhalac 120, Inhalac 140, Inhalac 230, or Inhalac 400.
In a further preferred embodiment, the internal auxiliary material is leucine, and the addition amount of the leucine is 0-30% of the total weight of the dry powder inhalant, preferably 2-10%.
In another further preferred embodiment, the additional excipient is leucine and/or lactose and/or magnesium stearate and/or mannitol, the leucine is added in an amount of 0-30%, preferably 2-10%, and the lactose is added in an amount of 0-50%, preferably 10-30%, of the total weight of the dry powder inhaler. The addition amount of the magnesium stearate accounts for 0-10%, preferably 1-5% of the total amount of the dry powder inhalant, and the addition amount of the mannitol accounts for 0-50%, preferably 10-30% of the total amount of the dry powder inhalant. .
In a second aspect, the present invention relates to a process for the preparation of the above-described isoniazid dry powder inhaler for the treatment of tuberculosis, said process comprising the steps of: preparing isoniazide micropowder by fluidized bed supersonic gas flow pulverization, taking isoniazide micropowder, mixing lactose and isoniazide micropowder according to a certain proportion, adding leucine after mixing, then packaging the mixed powder in capsules or bubble caps, or packaging the mixed powder in a multi-dose dry powder inhalation device in a storage mode, or the method comprises the following steps: dissolving isoniazid in a certain amount of solvent, adding leucine to prepare clear transparent solution, spray-drying the solution, collecting micropowder in a cyclone dryer, continuously drying for a period of time, adding lactose and/or magnesium stearate, continuously mixing for a period of time, and packaging the mixed powder into capsules or bubble caps, or packaging in a multi-dose dry powder inhalation device in a storage form.
In a preferred embodiment, the solvent is selected from purified water, propylene glycol or ethanol, preferably purified water.
In a more preferred embodiment, the spray drying inlet air temperature is from 100 ℃ to 180 ℃, preferably from 120 ℃ to 150 ℃; the fan frequency is 30Hz-40Hz, preferably 34Hz-38 Hz; the rotating speed is 5rpm-40rpm, preferably 8rpm-20 rpm; the atomization pressure is 0.20MPa-0.30MPa, preferably 0.24MPa-0.28 MPa; the size of the spray hole is 0.5mm-1.2mm, preferably 0.8mm-1 mm.
In another more preferred embodiment, the drying time is 5h to 48 h; the mixing time is 0.5h-1 h.
In a third aspect, the present invention relates to the use of a dry powder inhaler as described above or prepared by the preparation method described above in the preparation of a medicament for the treatment of tuberculosis.
In a preferred embodiment, the tuberculosis is a tuberculosis in a patient with poor liver function, or the tuberculosis is a bronchial nodule.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention adopts a dry powder inhalation formulation, has higher drug delivery rate and can deliver 10-50mg of drug each time. The dry powder inhalant has higher drug-loading rate, and 50 percent, even more than 75 percent of the medicinal preparation is the active ingredient isoniazid.
(2) The dry powder inhalant has higher preparation stability and simple preparation process, can quickly prepare the isoniazid dry powder inhalant, and can meet the requirement of scale-up production.
(3) The isoniazid dry powder inhalant prepared by the method is particularly suitable for treating pulmonary tuberculosis and bronchial tuberculosis of patients with impaired liver function.
Drawings
FIG. 1: scanning electron microscopy results for isoniazid dry powder inhaler of example 6 are shown. The bulk of the figure is lactose, on which raw material of isoniazid Active Pharmaceutical Ingredient (API) is adsorbed.
FIG. 2: scanning electron microscopy results for isoniazid dry powder inhaler of example 8 are shown. The figure shows that after the addition of magnesium stearate, the particles are more dispersed and agglomeration is reduced.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
1. Preparation examples
The following isoniazid dry powder inhalants were prepared and used in various effect experiments described below.
Example 1: subjecting 10.0g isoniazid to fluidized bed supersonic jet milling to obtain granules with size d10＝0.5-2.0μm、d50＝2.0-5.0μm、d90Mixing Inhalac 140 type lactose and isoniazid micropowder at a weight ratio of 1:1 with isoniazid micropowder of 5.0-9.5 μm; adding leucine as an additional auxiliary material after mixing, wherein the leucine accounts for 5 percent of the total weight of the preparation.
Example 2: subjecting 10.0g isoniazid to fluidized bed supersonic jet milling to obtain granules with size d10＝0.5-2.0μm、d50＝2.0-5.0μm、d90Mixing Inhalac 230 type lactose and isoniazid micropowder at a weight ratio of 1:1 with isoniazid micropowder of 5.0-9.5 μm; adding leucine as an additional auxiliary material after mixing, wherein the leucine accounts for 5 percent of the total weight of the preparation.
Example 3: subjecting 10.0g isoniazid to fluidized bed supersonic jet milling to obtain granules with size d10＝0.5-2.0μm、d50＝2.0-5.0μm、d90Mixing Inhalac 230 type lactose and isoniazid micropowder at a weight ratio of 2:1 with isoniazid micropowder of 5.0-9.5 μm; adding leucine as an additional auxiliary material after mixing, wherein the leucine accounts for 5 percent of the total weight of the preparation.
Example 4: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 5% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 15rpm, the fan frequency at 35Hz, the air outlet temperature at 135 ℃, and collecting particles in a cyclone separator. Continuing drying for 5h, adding Inhalac 120 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 5: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 10% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 10rpm, the fan frequency at 35Hz, the air outlet temperature at 135 ℃, and collecting particles in a cyclone separator. Continuing drying for 5h, adding Inhalac 120 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 6: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 10rpm, the fan frequency at 35Hz, and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. Continuing drying for 15h, adding Inhalac 140 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 7: dissolving 10.0g of isoniazid in 300mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 10rpm, the fan frequency at 35Hz, and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. Continuing drying for 15h, adding Inhalac 140 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 8: dissolving 10.0g of isoniazid in 300mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 10rpm, the fan frequency at 35Hz, and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. And continuously drying for 15h, adding magnesium stearate, and mixing for 30min, wherein the magnesium stearate accounts for 2.5% of the total weight of the preparation.
Example 9: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 25rpm, the fan frequency at 35Hz, and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. Continuing drying for 5h, adding Inhalac 140 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 10: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 10% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 150 ℃, the rotating speed at 25rpm, the fan frequency at 45Hz, and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. Continuing drying for 5h, adding Inhalac 140 lactose, and mixing for 30min, wherein the lactose accounts for 30% of the total weight of the preparation.
Example 11: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 120 ℃, the rotating speed at 10rpm, the fan frequency at 45Hz and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. And continuously drying for 5 h.
Example 12: dissolving 10.0g of isoniazid in 200mL of purified water, adding leucine with the concentration of 8% (w/v, g/mL) to prepare a clear transparent solution, carrying out spray drying on the solution, setting the air inlet temperature at 120 ℃, the rotating speed at 10rpm, the fan frequency at 45Hz and the air outlet temperature at 130 ℃, and collecting particles in a cyclone separator. Further oven drying for 5 hr, adding magnesium stearate and Inhalac 140 lactose, mixing for 30min, wherein magnesium stearate accounts for 2.5% of the total weight of the preparation, and lactose accounts for 30% of the total weight of the preparation
2. Characterization of isoniazid micropowder particles in isoniazid dry powder inhalant
The shape of the isoniazide micro powder particles is observed by adopting a scanning electron microscope, the particle size of the powder is determined by adopting a dry method, and the dose of the fine particles of the isoniazide micro powder particles is determined by adopting an NGI method. The scanning electron microscope results of example 6 and example 8 are shown in fig. 1 and fig. 2, respectively. The results are shown in Table 1.
Table 1: characterization of isoniazid micropowder particles in isoniazid dry powder inhalant
The above results indicate that the Fine Particle Dose (FPD) values of the above batches all reach the values specified in the chinese pharmacopoeia (> 10%), both micronization and spray drying techniques can meet the requirements, but different lactose additions may cause variation in fine particles, example 3 illustrates that the addition of a certain amount of fine lactose has certain advantages over the addition of large lactose, but when the amount of lactose is excessive, the FPD value will be significantly reduced, probably because a large amount of fine raw material is sucked into the surface, and the fine particles are deposited in the throat with the lactose, reducing the FPD. In addition, the change of spray drying process parameters can cause the particle size change of the particles, the FPD value of the particles is improved when the rotating speed is selected to be lower, the FPD value of the particles is improved when the concentration of API is lower, the FPD value of the particles can be obviously improved by adding magnesium stearate, and the interaction between the particles is reduced probably related to good lubrication and flow aid effects of the particles. However, as shown in examples 9 and 10, when the rotation speed is too high, the influence of the adjustment of other parameters on the FPD of the particles is small, and the rotation speed is closely related to the size of the particles obtained in pursuit.
3. Stability research of isoniazid dry powder absorbent
The powders collected in examples 11 and 12 were placed in a stability test chamber, and the dry method was performed at 40 ℃. + -. 2 ℃/75%. + -. 5% for 0 month, 1 month, 2 months, and 3 months, respectively, and the NGI was performed for fine particle size measurement and the loss-on-drying method for powder moisture measurement. The results are shown in tables 2 and 3, respectively.
Table 2: stability results for isoniazid dry powder inhaler prepared in example 11
Table 3: stability results for isoniazid dry powder inhaler prepared in example 12
The result shows that when the spray drying technology is selected, the method is more uniform than the particles prepared by a fluidized bed supersonic speed airflow pulverization method, the balling property of the raw materials can be enhanced by adding the antistatic agent internally, the particle size of the medicine is reduced, the medicine and the auxiliary materials are uniformly distributed, the fluidity and the dispersibility of the powder are further optimized by adding the glidant magnesium stearate or lactose, and the prepared powder is more stable and is easy to fill.
4. Plasma concentration of isoniazid dry powder inhalant in rat and distribution in rat tissue
Taking 12 SD rats (200g +/-20 g), and carrying out intragastric administration on 6 isoniazid tablets; isoniazid inhalation aerosol powder set (example 6): 6 pieces of the Chinese herbal medicine are taken. Isoniazid was given in equal amounts in both groups, 5.4 mg/mouse. Respectively for 10min, 30min, 1h, 2h, 4h, 6h, 8h and 12 h. Plasma drug concentrations were determined using LC-MS.
Taking 64 SD rats (200g +/-20 g), and feeding 32 gastric isoniazid tablets; isoniazid inhalation aerosol powder set (example 6): 32 are provided. Both groups were dosed with an equal amount of isoniazid, 5.4 mg/mouse. Respectively for 10min, 30min, 1h, 2h, 4h, 6h, 8h and 12 h. Each group was dissected 4 times and liver and lung tissue drug concentrations were determined using LC-MS. The results are shown in tables 4, 5 and 6, respectively.
Table 4: plasma drug concentration of isoniazid in rats in isoniazid dry powder inhalant and isoniazid tablet
Table 5: drug concentration of isoniazid in rat lung tissue in isoniazid dry powder inhalant and isoniazid tablet
Table 6: drug concentration of isoniazid in rat liver tissue in isoniazid dry powder inhalant and isoniazid tablet
As shown in Table 4, the results of the drug concentration in plasma show that the inhaled powder varies in the drug concentration in plasma like an injection, and is rapidly absorbed into blood, and CmaxHigher than the gavage group CmaxHas the advantage of rapid blood entering. As shown in Table 5, the results of the drug concentration in lung tissue show that the inhaled powder also varied in drug concentration in lung tissue similarly to the injection, except CmaxCan achieve the gavage group CmaxAbout 3 times of that of the isoniazid powder inhalation, which indicates that the isoniazid powder inhalation can rapidly reach higher concentration in lung tissues to kill mycobacterium tuberculosis in the lung. As shown in table 6, the results of drug concentration in liver tissue showed that the drug concentration of inhaled powder in liver tissue varied little from the gavage group, but the retention time in liver tissue was relatively long in the gavage group, > 1 μ g/mL group, the gavage group lasted from 10min to 6h, while the inhalation group lasted from only 10min to 2 h. Isoniazid has the potential advantage of reducing hepatotoxicity after inhalation.
5. Pharmacodynamic experiment result of isoniazid dry powder inhalation in mice
Aerosol infection of acute mouse tuberculosis model, using PBS + 0.04% Tween 80 to dilute the frozen Mycobacterium tuberculosis H37Rv (storage concentration should be > 10)8cfu/mL), the frozen Mycobacterium tuberculosis H37Rv was diluted to a concentration of 5X 106cfu/mL. 24 BALB/C mice (18-20g) to be infected were loaded into the nebulization chamber, the chamber was closed and the bacterial solution was aspirated into the nebulizer. Preheating for 15min, atomizing for 30min, reducing smoke for 30min, and purifying for 15min for atomization infection and sterilization. Mice were housed in cages after infection in negative pressure infected animals, 3 mice were dissected on day 3 after infection and viable lung count was performed to determine whether the infection was successful. 3 mice were dissected 10 days post infection and provided a baseline for viable lung count at the start of treatment.
Treatment started on day 10 post infection, blank control group (6): 0.5% hydroxymethyl cellulose (CMC), positive control (6): gavage of isoniazid tablets (5.4 mg/mouse, concentration 54mg/mL, 0.1mL per gavage), positive treatment group (6 mice): isoniazid dry powder inhalation group (example 7 formulation, dose of about 10mg of drug powder per dose, isoniazid content about 60%, corresponding to about 6mg administered), 5.4mL per mouse endotracheal tube was nebulized using mini-lung dust nebulizer. Mice from each group were sacrificed 1 time daily for 4 weeks, the day after 28 doses, and the mice were weighed and counted for viable lung bacteria. The results are shown in Table 7.
Table 7: viable count (log10cfu) of different treatment groups
The result shows that a large amount of tubercle bacillus still grows in the lung on the 3 rd day, the number of the tubercle bacillus is increased on the 10 th day, and after four weeks of treatment, the counting result of the bacteria in the lung tissue shows that the number of the bacteria in the treatment group is obviously reduced compared with that in the control group, wherein the suction treatment mode can obviously reduce the tubercle bacillus in the tissue, and the suction treatment mode proves that the suction treatment mode has a good local sterilization effect compared with the intragastric administration treatment. And the trend of weight change has a certain correlation with the bacterial number in the lung, and the more the bacterial number is, the lighter the weight of the mouse is, and the growth state of the mouse can be influenced by the growth of the bacteria in the lung. The isoniazid powder inhalation is suspected to have the potential advantage of improving the life condition of the tuberculosis patients clinically.
In conclusion, the dry powder inhalant has higher drug loading rate, and 80 percent and even more than 95 percent of the medicinal preparation are active ingredient isoniazid. The dry powder inhalant has higher preparation stability and simple preparation process, can quickly prepare the isoniazid dry powder inhalant, and can meet the requirement of scale-up production. The isoniazid dry powder inhalant prepared by the method is particularly suitable for treating pulmonary tuberculosis and bronchial tuberculosis of patients with impaired liver function, and has important clinical significance.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. An isoniazid dry powder inhalant for treating pulmonary tuberculosis, which is characterized in that: the dry powder inhalant comprises isoniazide micro powder and carrier micro powder or not, and the particle size of the isoniazide micro powder is processed into d by fluidized bed supersonic gas flow grinding method or spray drying method10＝0.1-3μm、d503-7 μm and d90The dry powder inhalant comprises 7-10 mu m of carrier micro powder, wherein the carrier micro powder is prepared from an internal auxiliary material, the internal auxiliary material is amino acid, mannitol or phospholipid, and the dry powder inhalant further comprises an external auxiliary material, and the external auxiliary material is selected from one or more of amino acid, phospholipid, sugar or magnesium stearate.
2. The dry powder inhaler according to claim 1, wherein: the amino acid is selected from leucine, valine, glycine or isoleucine, preferably leucine, the saccharide is selected from mannitol, lactose, maltose, trehalose or sucrose, preferably lactose or mannitol.
3. The dry powder inhaler according to claim 2, wherein: the lactose is one or more of Inhalac 120, Inhalac 140, Inhalac 230 or Inhalac 400.
4. The dry powder inhaler according to any one of claims 1 to 3, characterized in that: the internal auxiliary material is leucine, the addition amount of the leucine accounts for 0-30%, preferably 2-10% of the total weight of the dry powder inhalant, the external auxiliary material is leucine and/or lactose and/or magnesium stearate and/or mannitol, the addition amount of the leucine accounts for 0-30%, preferably 2-10% of the total weight of the dry powder inhalant, the addition amount of the lactose accounts for 0-50%, preferably 10-30% of the total weight of the dry powder inhalant, the addition amount of the magnesium stearate accounts for 0-10%, preferably 1-5% of the total weight of the dry powder inhalant, and the addition amount of the mannitol accounts for 0-50%, preferably 10-30% of the total weight of the dry powder inhalant.
5. A method of preparing the dry powder inhaler according to any one of claims 1 to 4, the method comprising the steps of: preparing isoniazide micropowder by fluidized bed supersonic gas flow pulverization, taking isoniazide micropowder, mixing lactose and isoniazide micropowder according to a certain proportion, adding leucine after mixing, then packaging the mixed powder in capsules or bubble caps, or packaging the mixed powder in a multi-dose dry powder inhalation device in a storage mode, or the method comprises the following steps: dissolving isoniazid in a certain amount of solvent, adding leucine to prepare clear transparent solution, spray-drying the solution, collecting micropowder in a cyclone dryer, continuously drying for a period of time, adding lactose and/or magnesium stearate, continuously mixing for a period of time, and packaging the mixed powder into capsules or bubble caps, or packaging in a multi-dose dry powder inhalation device in a storage form.
6. The method of claim 5, wherein: the solvent is selected from purified water, propylene glycol or ethanol, preferably purified water.
7. The production method according to claim 5 or 6, characterized in that: the air inlet temperature of the spray drying is 100-180 ℃, and the optimal temperature is 120-150 ℃; the fan frequency is 30Hz-40Hz, preferably 34Hz-38 Hz; the rotating speed is 5rpm-40rpm, preferably 8rpm-20 rpm; the atomization pressure is 0.20MPa-0.30MPa, preferably 0.24MPa-0.28 MPa; the size of the spray hole is 0.5mm-1.2mm, preferably 0.8mm-1 mm.
8. The production method according to any one of claims 5 to 7, characterized in that: the drying time is 5-48 h; the mixing time is 0.5h-1 h.
9. Use of the dry powder inhaler according to any one of claims 1 to 4 or prepared by the preparation method according to any one of claims 5 to 8 in the preparation of a medicament for treating tuberculosis.
10. Use according to claim 9, characterized in that: the tuberculosis is a pulmonary tuberculosis in a patient with poor liver function, or the tuberculosis is a bronchial tuberculosis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011412789.3A CN112336703B (en) | 2020-12-04 | 2020-12-04 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
| PCT/CN2021/130116 WO2022116792A1 (en) | 2020-12-04 | 2021-11-11 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011412789.3A CN112336703B (en) | 2020-12-04 | 2020-12-04 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112336703A true CN112336703A (en) | 2021-02-09 |
| CN112336703B CN112336703B (en) | 2022-03-11 |
Family
ID=74427388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011412789.3A Active CN112336703B (en) | 2020-12-04 | 2020-12-04 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112336703B (en) |
| WO (1) | WO2022116792A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022116792A1 (en) * | 2020-12-04 | 2022-06-09 | 深圳善康医疗健康产业有限公司 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
| CN115581688A (en) * | 2022-11-25 | 2023-01-10 | 山东国邦药业有限公司 | Tilmicosin dry powder inhalant and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110633A (en) * | 2013-02-28 | 2013-05-22 | 郑州大学 | Dry powder inhalant capable of preventing mycobacterium tuberculosis from transmitting through respiratory tract |
| CN106692116A (en) * | 2015-11-15 | 2017-05-24 | 复旦大学 | Capsule-type inhalation aerosol powder containing isoforskolin |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422457B (en) * | 2007-10-31 | 2011-01-26 | 江苏正大天晴药业股份有限公司 | Tiotropium bromide respirable dry powder composition |
| CN112336703B (en) * | 2020-12-04 | 2022-03-11 | 深圳善康医疗健康产业有限公司 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
-
2020
- 2020-12-04 CN CN202011412789.3A patent/CN112336703B/en active Active
-
2021
- 2021-11-11 WO PCT/CN2021/130116 patent/WO2022116792A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110633A (en) * | 2013-02-28 | 2013-05-22 | 郑州大学 | Dry powder inhalant capable of preventing mycobacterium tuberculosis from transmitting through respiratory tract |
| CN106692116A (en) * | 2015-11-15 | 2017-05-24 | 复旦大学 | Capsule-type inhalation aerosol powder containing isoforskolin |
Non-Patent Citations (1)
| Title |
|---|
| IMCO SIBUM等: "Characterization and Formulation of Isoniazid for High-Dose Dry Powder Inhalation", 《PHARMACEUTICS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022116792A1 (en) * | 2020-12-04 | 2022-06-09 | 深圳善康医疗健康产业有限公司 | Isoniazid dry powder inhalant for treating pulmonary tuberculosis |
| CN115581688A (en) * | 2022-11-25 | 2023-01-10 | 山东国邦药业有限公司 | Tilmicosin dry powder inhalant and preparation method thereof |
| CN115581688B (en) * | 2022-11-25 | 2023-03-10 | 山东国邦药业有限公司 | Tilmicosin dry powder inhalant and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112336703B (en) | 2022-03-11 |
| WO2022116792A1 (en) | 2022-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220296559A1 (en) | Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI) | |
| TWI228998B (en) | Method and device for delivering an active agent to the lungs | |
| CA2981038C (en) | Dry powder vancomycin compositions and associated methods | |
| CN112336703B (en) | Isoniazid dry powder inhalant for treating pulmonary tuberculosis | |
| EP1067839A1 (en) | Pulmonary and nasal delivery of raloxifene | |
| MX2014001345A (en) | Method and formulation for inhalation. | |
| Zillen et al. | Natural and bioinspired excipients for dry powder inhalation formulations | |
| EP1036562A1 (en) | Soft-pellet drug and process for the preparation thereof | |
| AU2012254999A1 (en) | Dry powder vancomycin compositions and associated methods | |
| AU2009331277B2 (en) | Dry powder pharmaceutical composition for inhalation | |
| JP2020011952A (en) | Ambroxol dry powder for inhalation use with bronchial targets | |
| CN111358773B (en) | Peramivir dry powder inhalant and preparation method thereof | |
| JP5437543B2 (en) | Asthma detection preparation | |
| CA3201551A1 (en) | Method and composition for treating pulmonary fibrosis | |
| CN109771397B (en) | Equipment integration and method for improving pulmonary inhalation medication through lactose micropowder predeposition | |
| CN102302475B (en) | Resibufogenin dry powder inhalant and preparation method and application thereof | |
| KR20070110418A (en) | Particle and preparation containing the particle | |
| MXPA01003103A (en) | Micronised pharmaceutical compositions. | |
| CN116407524A (en) | Monabivalve inhalation powder aerosol and preparation method thereof | |
| WO2023177367A1 (en) | Dosage forms of active substances used against viral diseases in dry powder inhaler device for symptoms caused by covid-19 and other viral lung diseases | |
| CN111920785B (en) | Inhalation preparation of iso-glycyrrhizic acid or salt thereof and application thereof | |
| EP4142691A1 (en) | Clofazimine composition and method for the treatment or prophylaxis of viral infections | |
| CN115137713A (en) | Amphotericin B atomization inhalation preparation and preparation method thereof | |
| WO2023187393A1 (en) | Inhalation composite and carrier based formulation combination | |
| JP2022139708A (en) | Dry powder pharmaceutical composition for inhalation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 518000 building C2, Longtian street, Pingshan District, Shenzhen City, Guangdong Province Patentee after: Shenzhen shankang Pharmaceutical Technology Co.,Ltd. Address before: 518000 building C2, Longtian street, Pingshan District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN SCIENCARE MEDICAL INDUSTRIES Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |