CN116687888A - Vardenafil and dapoxetine compound dry powder inhalation preparation and preparation method thereof - Google Patents
Vardenafil and dapoxetine compound dry powder inhalation preparation and preparation method thereof Download PDFInfo
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- CN116687888A CN116687888A CN202310649477.1A CN202310649477A CN116687888A CN 116687888 A CN116687888 A CN 116687888A CN 202310649477 A CN202310649477 A CN 202310649477A CN 116687888 A CN116687888 A CN 116687888A
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- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960002381 vardenafil Drugs 0.000 title claims abstract description 42
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- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 claims abstract description 19
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Classifications
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Otolaryngology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a vardenafil and dapoxetine compound dry powder inhalation preparation and a preparation method thereof, belonging to the technical field of dry powder inhalants. The compound dry powder inhalation preparation comprises a first active drug, a second active drug and an optional carrier; wherein the first active agent is vardenafil; the second active drug is dapoxetine; the carrier is at least one of lactose, mannose, chitosan, DPPC and DSPC. The invention introduces the preparation process of the dry powder inhalant into the traditional preparation, the active ingredients of the traditional oral preparation are easy to be destroyed in the alimentary canal, the bioavailability is low, the first pass effect of liver is achieved, the effect is slow, the traditional aerosol inhalation solution has poor portability, the drug delivery dosage is inaccurate, and the traditional injection can cause skin injury. In the dry powder inhalation preparation, the carrier component selected by the invention has the characteristics of low toxicity and small irritation, and the vardenafil and dapoxetine compound dry powder inhalation with the effect of remarkably improving male sexual dysfunction is prepared.
Description
Technical Field
The invention belongs to the technical field of dry powder inhalants, and particularly relates to a vardenafil and dapoxetine compound dry powder inhalant preparation and a preparation method thereof.
Background
Premature Ejaculation (PE) is a common male sexual dysfunction, associated with serious personal and interpersonal negative psychological consequences, and drug treatment of PE is common, effective and safe. Development and regulatory approval of drugs specifically used to treat PE will reduce reliance on off-label therapy and help to fill the unmet need for therapy, with erectile dysfunction being penile erection that fails to achieve or maintain adequate sexual activity. Vardenafil is an oral tablet for improving erectile function in men suffering from erectile dysfunction. In natural environment, i.e. by sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. Penile erection is a hemodynamic process. During sexual stimulation nitric oxide is released which activates guanylate cyclase resulting in elevated levels of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn causes smooth muscle relaxation, thereby increasing blood flow into the penis. In vardenafil tablets, vardenafil is rapidly absorbed and the maximum blood level observed in some men is reached as early as 15 minutes after oral administration. However, 90% of the time, the maximum plasma concentration was reached within 30 to 120 minutes (median 60 minutes) after oral administration in the fasted state. The average absolute oral bioavailability was 15%. After oral vardenafil, AUC and Cmax increased in proportion to the recommended dose range (5-20 mg). Dapoxetine absorbs and eliminates rapidly, resulting in minimal accumulation, has a pharmacokinetic proportional to the dose, is not affected by multiple dosing, and has no inter-ethnicity differences, dapoxetine can effectively block cloned kv4.3 potassium voltage-gated channels that are involved in neurotransmitter release regulation. Dapoxetine is an effective SSRI that can be administered on demand 1-3 hours prior to planned sexual contact. It is rapidly absorbed and eliminated, resulting in minimal accumulation, and has dose-proportional pharmacokinetics that is unaffected by multiple administrations. Dapoxetine, the first drug developed for PE, is an effective and safe drug for treating PE, representing a significant advancement in medicine.
Inhalation formulations refer to formulations which are delivered in the form of a mist to the respiratory tract and/or lungs by specific means to exert a local or systemic effect. At present, the traditional Chinese medicine composition is widely applied to the treatment of asthma and chronic obstructive pulmonary diseases, and is a recommended formulation of medical guidelines and consensus and diagnosis and treatment guidelines of authoritative specialists at home and abroad. The 2015 edition of Chinese pharmacopoeia takes the inhaled preparation as a single dosage form and describes the detection index and the detection method. Inhalation formulations can be divided into four main categories according to their administration device differences: dry Powder Inhalants (DPI), aerosols (MDI), aerosol inhalation solutions (NEB), sprays. Dry powder inhalants (dry powder inhaler, DPI), also known as powder aerosols, refer to formulations in which finely divided particulate drug is stored in capsules, vesicles or multi-dose reservoirs, alone or in combination with a carrier, and the airflow generated by the patient's inhalation is used to act on a specially designed dry powder inhalation device to cause turbulent airflow generated by the device to aerosolize and empty the drug, delivering the dispersed drug to the lungs, thereby producing a therapeutic effect. DPIs do not contain propellants and are mostly breath-driven, i.e. "passive". DPIs have numerous advantages, such as: the propellant does not contain hydrofluoroalkane, so that environmental pollution is avoided; for polypeptide and protein medicines, the dry powder has good room temperature stability and high inhalation efficiency, and is not easy to be polluted by microorganisms.
Although many researches have been carried out, there is no compound dry powder inhalation formulation of vardenafil and dapoxetine which is specially used for clinical inhalation.
Disclosure of Invention
Based on the problems existing in the background technology, the invention provides a vardenafil and dapoxetine compound dry powder inhalation preparation and a preparation method thereof, and the prepared vardenafil and dapoxetine compound dry powder inhalation can have the advantages of simple production process, portability, slight irritation to respiratory tract and improvement of bioavailability.
The invention is implemented by the following technical scheme:
a compound dry powder inhalation preparation of vardenafil and dapoxetine comprises a first active drug, a second active drug and an optional carrier.
Further, the first active agent is vardenafil;
the second active drug is dapoxetine;
the carrier is at least one of lactose, mannose, chitosan, DPPC and DSPC.
Further, the content ratio of the first active drug, the second active drug and the carrier is (5-20): (10-80): (0-80).
A method for preparing vardenafil and dapoxetine compound dry powder inhalation preparation comprises the step of adding active medicine to prepare inhalation powder aerosol, and the step of preparing inhalation particles after the added active medicine is mixed with carrier or without carrier.
Further, the preparation method of the inhalation particles comprises the following steps:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with a carrier to obtain a third component;
s03, preparing the third component into a dry powder preparation, and loading the dry powder preparation into a corresponding device for standby.
Further, in step S01, the micronization process includes, but is not limited to, jet milling, spray drying, spray freeze drying, recrystallization, or ball milling; in step S02, the mixing process includes, but is not limited to, high shear mixing, air flow mixing, or three-dimensional mixing; in step S03Devices include, but are not limited toDevice(s)>Device, all guarantee->Devices or apparatusAnd (3) a device.
Further, the particle diameter D90 of the first active medicine and the second active medicine is 1-10um; the carrier particle diameter D90 is 3-200um, and the D50 is 0.5-100um.
Further, in steps S01 and S02, the first active drug, the second active drug are micronized by a pulverizing and mixing device, after which the first component, the second component and the carrier are mixed by a pulverizing and mixing device;
the crushing and mixing device comprises a shell, wherein a crushing box is arranged in the shell, the crushing box is in sliding connection with the inner walls of the left side and the right side of the shell, two bilaterally symmetrical feeding pipes are arranged on the crushing box, the feeding pipes extend upwards out of the crushing box, the feeding pipes are in sliding connection with the extending positions of the crushing box, a driving motor is fixedly arranged at the upper end of the shell, the lower output end of the driving motor is fixedly connected with a rotating rod, the rotating rod downwards penetrates through the shell and extends into the crushing box, the rotating rod is in rotating connection with the extending positions of the shell, a reciprocating screw rod is fixedly arranged at the extending positions of the rotating rod and the crushing box, the reciprocating screw rod is in threaded connection with the crushing box, a filter screen is arranged at the lower end of the crushing box, the rotating rod is in rotating connection with the filter screen, and a plurality of cutting knives are fixedly arranged on the rotating rod;
still install the circulation air pump on the casing, two bilateral symmetry's outlet duct is installed to the circulation air pump downside, the outlet duct downwardly extending advances in the casing, and outlet duct and casing extended position fixed connection, fixedly on the casing upside inner wall be equipped with the inlet tank, inlet tank and outlet duct link up and be connected, the dwang passes the inlet tank downwards, and the dwang passes the position with the inlet tank and rotate to be connected, be equipped with a plurality of through-holes in the inlet tank, the dwang sets up to the cavity, a plurality of through-holes are installed on the dwang, smash the incasement and be equipped with a plurality of fumaroles, a plurality of fumaroles are installed on the dwang.
Further, the lower end of the crushing box is provided with a receiving box which is in through connection with the crushing box, the through position of the receiving box and the crushing box is provided with a filter screen, the left side and the right side of the receiving box are in through connection with a powder outlet pipe, the other end of the powder outlet pipe is in through connection with an auxiliary box, the auxiliary box is fixedly arranged on the inner walls of the left side and the right side of the shell, a bag type filter screen is arranged in the auxiliary box, the bag type filter screen is in sliding connection with the inner wall of the auxiliary box, one side of the bag type filter screen, which is mutually close, is fixedly provided with a driving rod, a through groove is formed in one side wall of the auxiliary box, which is mutually close, the driving rod penetrates through the through groove to extend out of the auxiliary box, the driving rod is in sliding connection with the through groove, and a sealing gasket is arranged on the through groove and used for sealing the through groove when the driving rod moves;
grooves are formed in the left side wall and the right side wall of the crushing box, an air pipe is connected to the upper side of the auxiliary box in a penetrating manner, the air pipe penetrates through the grooves upwards to extend out of the shell, the air pipe is fixedly connected with the extending position of the shell, and the other end of the air pipe is connected with a circulating air pump in a penetrating manner;
the rotating rod is fixedly provided with a first bevel gear, the left side and the right side of the first bevel gear are connected with a second bevel gear in a meshed mode, one side, away from each other, of the second bevel gear is fixedly connected with a rotating shaft, the rotating shaft is rotationally connected with the auxiliary box, and a cam is fixedly arranged on the rotating shaft and is in contact fit with the driving rod.
Further, an opening is formed in the inner wall of the lower side of the shell, a mixing box is mounted at the opening, carrier pipes are connected to the left side and the right side of the mixing box in a penetrating manner, the carrier pipes extend out of the shell and are fixedly connected with the extending position of the shell, component pipes are further connected to the left side and the right side of the mixing box in a penetrating manner, the component pipes are connected with the lower surface of the auxiliary box in a penetrating manner, a rotating rod extends downwards into the mixing box, the rotating rod is connected with the extending position of the mixing box in a rotating manner, two stirring rods which are symmetrical left and right are fixedly arranged at the lower end of the rotating rod, scraping plates are fixedly arranged at the ends, away from each other, of the stirring rods, and the scraping plates are abutted to the inner wall of the mixing box;
the fixed dead lever that is equipped with a plurality of evenly distributed on the mixing box upside inner wall, the dead lever lower extreme is fixed to be equipped with fixed circle shell, has seted up a plurality of first mixed grooves on the fixed circle shell, still is equipped with rotatory circle shell in the mixing box, and rotatory circle shell is fixed to be equipped with a plurality of blades on the inner wall, and the other end of a plurality of blades is fixed to be equipped with the ring, and ring fixed mounting is on the dwang, and rotatory circle shell cooperatees with fixed circle shell.
The invention has the beneficial effects that:
the invention introduces the preparation process of the dry powder inhalant into the traditional preparation, the active ingredients of the traditional oral preparation are easy to be destroyed in the alimentary canal, the bioavailability is low, the first pass effect of liver is achieved, the effect is slow, the traditional aerosol inhalation solution has poor portability, the drug delivery dosage is inaccurate, and the traditional injection can cause skin injury. In the dry powder inhalation preparation, the carrier component selected by the invention has the characteristics of low toxicity and small irritation, and the vardenafil and dapoxetine compound dry powder inhalation with the effect of remarkably improving male sexual dysfunction is prepared. Experiments prove that the prepared vardenafil-dapoxetine compound dry powder inhalant can effectively improve the bioavailability and improve the clinical use effect.
Drawings
FIG. 1 is a schematic structural view of a pulverizing and mixing apparatus of the present invention;
FIG. 2 is an enlarged view of FIG. 1 at A in accordance with the present invention;
FIG. 3 is a schematic view of the cam of the present invention;
FIG. 4 is a schematic diagram illustrating the cooperation of a rotary shell and a stationary shell according to the present invention;
fig. 5 is an internal structural view of the rotary round shell of the present invention.
In the figure: 1. a housing; 2. a crushing box; 3. a cutting knife; 4. a feed pipe; 5. an air outlet pipe; 6. a circulation air pump; 7. a driving motor; 8. an air inlet box; 9. an air pipe; 10. a reciprocating screw; 11. a rotating lever; 12. a gas injection hole; 13. a filter screen; 14. a bag filter screen; 15. an auxiliary box; 16. a carrier tube; 17. a mixing box; 18. a support column; 19. a stirring rod; 20. rotating the round shell; 21. fixing the round shell; 22. a scraper; 23. a fixed rod; 24. a component tube; 25. a powder outlet pipe; 26. a rotating shaft; 27. a receiving box; 28. a first bevel gear; 29. a second bevel gear; 30. a first mixing tank; 31. a driving rod; 32. a cam; 33. a circular ring; 34. a blade; 35. a second mixing tank.
Detailed Description
The technical scheme of the present invention will be further described in detail with reference to the following specific examples, but the scope of the present invention is not limited to the following examples.
Example 1
The vardenafil and dapoxetine compound dry powder inhalation preparation of the embodiment comprises the following raw materials: a first active agent, a second active agent, and a carrier;
wherein the first active medicine component is vardenafil, which accounts for 15 mass percent of the total amount, and the grain diameter D90 is 5um;
the second active medicine component is dapoxetine, which accounts for 60 mass percent of the total amount, and the grain diameter D90 is 5um;
the carrier is lactose, the weight percentage of the carrier is 25 percent of the total amount, the particle diameter D90 is 150um, and the D50 is 50um.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with a carrier to obtain a third component;
s03, preparing the third component into a dry powder preparation, obtaining a uniform mixture, and selecting a bubble cap type device Device) was dispensed 20mg.
Wherein the feed pressure of the jet milling in S01 is 8bar, and wherein the discharge pressure of the jet milling is 8bar;
the mixing mode in S02 is air flow mixing, the feeding pressure of air flow mixing is 6bar, and the discharging pressure of crushing is 1bar.
Example 2
The vardenafil and dapoxetine compound dry powder inhalation preparation of the embodiment comprises the following raw materials: a first active agent, a second active agent, and a carrier;
wherein the first active medicine component is vardenafil, the mass percentage of the first active medicine component is 10 percent of the total amount, and the particle size D90 is 5um;
the second active medicine component is dapoxetine, which accounts for 35 mass percent of the total amount, and the particle diameter D90 is 5um;
the carrier is lactose, the weight percentage of the carrier in the total amount is 55 percent, the grain diameter D90 is 5um, and the D50 is 3um.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with a carrier to obtain a third component;
s03, preparing the third component into a dry powder preparation, obtaining a uniform mixture, and selecting a capsule type deviceDevice) was dispensed 20mg.
Wherein the feed pressure of the jet milling in S01 is 8bar, and wherein the discharge pressure of the jet milling is 8bar; the mixing mode in S02 is high shear mixing, the mixing speed is 600rpm, and the mixing time is 30min.
Example 3
The vardenafil and dapoxetine compound dry powder inhalation preparation of the embodiment comprises the following raw materials: a first active agent, a second active agent, and a carrier;
wherein the first active medicine component is vardenafil, the mass percentage of the first active medicine component is 10 percent of the total amount, and the particle size D90 is 5um;
the second active medicine component is dapoxetine, which accounts for 35 mass percent of the total amount, and the particle diameter D90 is 5um;
the carrier is lactose, the weight percentage of the carrier in the total amount is 55 percent, the grain diameter D90 is 5um, and the D50 is 3um.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with a carrier to obtain a third component;
s03, preparing the third component into a dry powder preparation, obtaining a uniform mixture, and selecting a capsule type deviceDevice) was dispensed 20mg.
Wherein the feed pressure of the jet milling in S01 is 8bar, and wherein the discharge pressure of the jet milling is 8bar; the mixing method in S02 is three-dimensional mixing.
Example 4
The vardenafil and dapoxetine compound dry powder inhalation preparation of the embodiment comprises the following raw materials: a first active agent and a second active agent;
wherein the first active pharmaceutical ingredient is vardenafil, accounting for 20% of the total mass; the second active medicine component is dapoxetine, which accounts for 80 percent of the total mass.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, carrying out spray drying on the first active medicine to obtain a first component, wherein the particle size D90 is 4.6um;
s02, carrying out spray drying on the second active medicine to obtain a second component, wherein the particle size D90 is 4.3um;
s03, mixing the first component and the second component through air flow, obtaining a uniform mixture by mixing, and selecting a capsule type deviceDevice) was dispensed 20mg.
Wherein, the spray drying conditions in step S01 are: the concentration of the aqueous solution is 0.5% (W/V), the inlet temperature is 120 ℃, the outlet temperature is 83 ℃, the sample flow rate is 200mL/h, and the atomization pressure is 0.3MPa;
the spray drying conditions in step S02 are: the concentration of the aqueous solution is 0.5% (W/V), the inlet temperature is 70 ℃, the outlet temperature is 42 ℃, the sample flow rate is 200mL/h, and the atomization pressure is 0.3MPa;
in step S03, the gas stream mixture was fed at a pressure of 6bar, wherein the comminution discharge pressure was 1bar.
Example 5
The vardenafil and dapoxetine compound dry powder inhalation preparation of the embodiment comprises the following raw materials: a first active agent, a second active agent, and a carrier;
wherein the first active pharmaceutical ingredient is vardenafil, accounting for 5% of the total mass; the second active medicine component is dapoxetine, which accounts for 15% of the total mass, the carrier is lactose, and the total mass is 80%.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, carrying out spray drying on the first active medicine to obtain a first component, wherein the particle size D90 is 4.6um;
s02, carrying out spray drying on the second active medicine to obtain a second component, wherein the particle size D90 is 4.3um;
s03, mixing the first component with a carrier to obtain a first mixture;
s04, mixing the first mixture and the second component to obtain a uniform mixture, and selecting a capsule type deviceDevice) was dispensed 20mg.
Wherein, the spray drying conditions in step S01 are: the concentration of the aqueous solution is 0.5% (W/V), the inlet temperature is 120 ℃, the outlet temperature is 83 ℃, the sample flow rate is 200mL/h, and the atomization pressure is 0.3MPa;
the spray drying conditions in step S02 are: the concentration of the aqueous solution is 0.5% (W/V), the inlet temperature is 70 ℃, the outlet temperature is 42 ℃, the sample flow rate is 200mL/h, and the atomization pressure is 0.3MPa;
the mixing in steps S03 and S04 was carried out by air-flow mixing at a feed pressure of 6bar and a discharge pressure of 1bar.
Comparative example 1
This comparative example is basically the same as example 1, except that: the carrier lactose is removed.
The preparation method comprises the following raw materials: a first active agent and a second active agent;
wherein the first active pharmaceutical ingredient is vardenafil, accounting for 30 mass percent of the total amount, and the particle diameter D90 is 5um;
the second active medicine component is dapoxetine, accounting for 70 percent of the total mass, and the particle diameter D90 is 5um.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component to obtain a uniform mixture, and selecting a bubble cap type deviceDevice) was dispensed 20mg.
Wherein the feed pressure of the jet milling in S01 is 8bar, and wherein the discharge pressure of the jet milling is 8bar;
the mixing mode in S02 is air flow mixing, the feeding pressure of air flow mixing is 6bar, and the discharging pressure of crushing is 1bar.
Comparative example 2
This comparative example is basically the same as example 2, except that: the carrier lactose is removed.
The preparation method comprises the following raw materials: a first active agent and a second active agent;
wherein the first active pharmaceutical ingredient is vardenafil, accounting for 20 mass percent of the total amount, and the particle diameter D90 is 5um;
the second active medicine component is dapoxetine, which accounts for 80 mass percent of the total amount, and the particle diameter D90 is 5um.
The preparation method of the vardenafil and dapoxetine compound dry powder inhalation preparation is as follows:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with the carrier to obtain a uniform mixture, and selecting a capsule type deviceDevice) was dispensed 20mg.
Wherein the feed pressure of the jet milling in S01 is 8bar, and wherein the discharge pressure of the jet milling is 8bar; the mixing mode in S02 is high shear mixing, the mixing speed is 600rpm, and the mixing time is 30min.
Test example 1
The dry powder inhalants prepared in examples 1-5 and comparative examples 1-2 were subjected to a fog distribution test and stability investigation.
And (3) fog particle distribution test: mist distribution testing was performed using a New Generation Impactor (NGI). NGI consists of seven stages, and can be calibrated at flow rates of 30, 60 and 100 LPM. In contrast to ACI, the impactor stages of ACI are stacked, with the stages of NGI all in one plane. The collection cup is used to collect particles below each stage of NGI. See U.S. patent No.8,614,255, the entire contents of which are incorporated herein by reference. Unless otherwise stated, the characterization of the present disclosure of NGI is obtained as required with a 4kPa pressure drop (USP <601 >).
The active components vardenafil and dapoxetine are measured by adopting a high performance liquid ultraviolet chromatography method, and the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; the gradient elution procedure was 0-2min20% A,2-7min B phase gradient up to 30%,7-8min B phase gradient up to 40%,8-10min B phase gradient up to 60%,12-14min B phase gradient down to 40% and 14-15min B phase gradient down to 20% with 0.05% formic acid aqueous solution (A)/acetonitrile (B). The detection wavelength is 230nm; the flow rate is 1.0ml/min; the sample volume was 5. Mu.l.
The specific test results of the fog particle distribution are shown in table 1.
Table 10 day fog particle distribution data
The dry powder formulations of examples 1-5 and comparative examples 1-2 were subjected to stability test examination under 40 ℃ C./75% RH, and specific test results of specific accelerated 3-month fog particle distribution are shown in Table 2.
Table 2 accelerated 3 month fog particle distribution data
As can be seen from the data in tables 1 and 2, in examples 1-3 of the present invention, there was no significant difference in FPF value, and after 3 months of acceleration, there was no tendency of drop in the fog particle distribution of examples 1-3, whereas in examples 4-5 and comparative examples 1-2, FPF values below 0 day were found, and in examples 4 and comparative examples 1-2, since lactose was not used as a carrier, the raw materials were easily agglomerated, making the formulation unstable. Example 5 has some hygroscopicity because a certain amount of amorphous compound is produced during the spray drying process.
Test example two
The dry powder inhalants of examples 1-5 were subjected to the rat Pk experiment with a commercially available oral drug.
The testing method comprises the following steps: the test was performed using the rat tracheal intubation method and reference was made to Tonnis W F, bagerman M, weij M, et al A novel aerosol generator for homogenous distribution of powder over the lungs after pulmonary administration to small laboratory animals [ J ]. European Journal of Pharmaceutics & biopharmaceuticals, 2014,88 (3): 1056-1063. Test methods:
rats were selected for in vivo Pk assay
The male and female halves were randomly divided into three groups (one group for blank control group) of 10
Animal feeding is carried out at 25+/-3 ℃ and relative humidity of 60% -75%, day and night light and shade alternation time is 12 hours, free feeding and drinking are carried out, and the animal is used for experiments after being fed for one week in an adaptive mode.
The animals were then tested for Pk, as shown in tables 3 and 4.
TABLE 3 90% CI for dapoxetine Pk data in rats
TABLE 4 in vivo vardenafil Pk data 90% CI in rats
As can be seen from the results in tables 3 and 4, the concentrations of dapoxetine and vardenafil in the plasma in examples 1 to 5 reached a peak within a few minutes, whereas the peak was reached after 1 hour for all oral medicines on the market.
The vardenafil and dapoxetine compound dry powder inhalation preparation prepared in examples 1-3 shows rapid drug absorption and can effectively improve the bioavailability of active ingredients.
As shown in fig. 1 to 5, in steps S01 and S02, the first active drug, the second active drug are micronized by a pulverizing and mixing device, and then the first component, the second component, and the carrier are mixed by the pulverizing and mixing device;
the crushing and mixing device comprises a shell 1, wherein a crushing box 2 is arranged in the shell 1, two bilaterally symmetrical supporting columns 18 are fixedly arranged at the lower end of the shell 1, the crushing box 2 is in sliding connection with the inner walls of the left side and the right side of the shell 1, two bilaterally symmetrical feeding pipes 4 are arranged on the crushing box 2, the feeding pipes 4 extend upwards out of the crushing box 2, the feeding pipes 4 are in sliding connection with the extending positions of the crushing box 2, a driving motor 7 is fixedly arranged at the upper end of the shell 1, the lower output end of the driving motor 7 is fixedly connected with a rotating rod 11, the rotating rod 11 downwards penetrates through the shell 1 and extends into the crushing box 2, the rotating rod 11 is in rotating connection with the extending positions of the shell 1, a reciprocating screw 10 is fixedly arranged at the extending positions of the rotating rod 11 and the crushing box 2, a filter screen 13 is arranged at the lower end of the crushing box 2, the rotating rod 11 is in rotating connection with the filter screen 13, and a plurality of cutters 3 are fixedly arranged on the rotating rod 11;
still install circulation air pump 6 on the casing 1, two bilateral symmetry's outlet duct 5 are installed to circulation air pump 6 downside, outlet duct 5 downwardly extending is gone into in casing 1, and outlet duct 5 and casing 1 extend position fixed connection, fixedly be equipped with inlet box 8 on the casing 1 upside inner wall, inlet box 8 and outlet duct 5 link up the connection, dwang 11 passes inlet box 8 downwards, and dwang 11 passes the position with inlet box 8 and rotates to be connected, be equipped with a plurality of through-holes in inlet box 8, dwang 11 sets up to the cavity, a plurality of through-holes are installed on dwang 11, smash and be equipped with a plurality of fumaroles 12 in the case 2, a plurality of fumaroles 12 are installed on dwang 11.
Preferably, a receiving box 27 is installed at the lower end of the crushing box 2, the receiving box 27 is in through connection with the crushing box 2, a filter screen 13 is arranged at the through position of the receiving box 27 and the crushing box 2, a powder outlet pipe 25 is installed on the left side and the right side of the receiving box 27 in a through manner, an auxiliary box 15 is connected with the other end of the powder outlet pipe 25 in a through manner, the auxiliary box 15 is fixedly arranged on the inner walls of the left side and the right side of the shell 1, a bag type filter screen 14 is installed in the auxiliary box 15, the bag type filter screen 14 is in sliding connection with the inner wall of the auxiliary box 15, a driving rod 31 is fixedly arranged on one side wall of the auxiliary box 15, which is mutually close, a through groove is formed in one side wall of the auxiliary box 15, the driving rod 31 penetrates through the through groove to extend out of the auxiliary box 15, the driving rod 31 is in sliding connection with the through groove, and a sealing gasket is arranged on the through groove and used for sealing the through groove when the driving rod 31 moves;
grooves are formed in the left side wall and the right side wall of the crushing box 2, an air pipe 9 is connected to the upper side of the auxiliary box 15 in a penetrating manner, the air pipe 9 upwards penetrates through the grooves to extend out of the shell 1, the air pipe 9 is fixedly connected with the extending position of the shell 1, and the other end of the air pipe 9 is connected to the circulating air pump 6 in a penetrating manner;
the rotating rod 11 is also fixedly provided with a first bevel gear 28, the left side and the right side of the first bevel gear 28 are connected with a second bevel gear 29 in a meshed manner, one far away side of the second bevel gear 29 is fixedly connected with a rotating shaft 26, the rotating shaft 26 is rotationally connected with the auxiliary box 15, the rotating shaft 26 is fixedly provided with a cam 32, and the cam 32 is in contact fit with the driving rod 31.
Preferably, an opening is formed in the inner wall of the lower side of the shell 1, a mixing box 17 is mounted at the opening, carrier pipes 16 are connected to the left side and the right side of the mixing box 17 in a penetrating manner, the carrier pipes 16 extend out of the shell 1, the carrier pipes 16 are fixedly connected with the extending position of the shell 1, component pipes 24 are further arranged on the left side and the right side of the mixing box 17 in a penetrating manner, the component pipes 24 are connected with the lower surface of the auxiliary box 15 in a penetrating manner, a rotating rod 11 extends downwards into the mixing box 17, the rotating rod 11 is connected with the extending position of the mixing box 17 in a rotating manner, two stirring rods 19 which are symmetrical left and right are fixedly arranged at the lower end of the rotating rod 11, scraping plates 22 are fixedly arranged at the ends of the stirring rods 19 which are far away from each other, and the scraping plates 22 are abutted against the inner wall of the mixing box 17;
the fixed dead lever 23 that is equipped with a plurality of evenly distributed on the inboard wall of mixing box 17, dead lever 23 lower extreme is fixed to be equipped with fixed circle shell 21, has seted up a plurality of first mixed grooves 30 on the fixed circle shell 21, still is equipped with rotatory circle shell 20 in the mixing box 17, is equipped with a plurality of blades 34 on the rotatory circle shell 20 inner wall fixedly, and the other end of a plurality of blades 34 is fixed to be equipped with ring 33, and ring 33 fixed mounting is on dwang 11, still is equipped with a plurality of second mixed grooves 35 on the rotatory circle shell 20, and rotatory circle shell 20 cooperatees with fixed circle shell 21.
The working principle and the beneficial effects of the technical scheme are as follows: the method comprises the steps that a first active medicine enters a crushing box 2 through a feed pipe 4, a driving motor 7 and a circulating air pump 6 are started, the driving motor 7 drives a rotating rod 11 to rotate, the rotating rod 11 drives a cutting knife 3 to cut the first active medicine, meanwhile, gas generated by the circulating air pump 6 enters the rotating rod 11 through an air outlet pipe 5 and an air inlet box 8, then enters the crushing box 2 from an air jet hole 12, the first active medicine is cut through high-speed air flow, after passing through the cutting knife 3 and the gas cutting, the first active medicine is micronized to form a first component, and particles smaller than a filter hole of a filter screen 13 enter a receiving box 27;
then under the action of gas, the first component enters the auxiliary box 15 through the powder outlet pipe 25, and as the circulating air pump 6 enters from the air pipe 9 and exits from the air outlet pipe 5, smaller particles are adsorbed on the bag type filter screen 14, and larger particles fall into the mixing box 17 through the component pipe 24; when the rotating rod 11 rotates, the rotating rod 11 drives the reciprocating screw rod 10 to rotate, so that the crushing box 2 moves up and down, the active medicine in the crushing box 2 is cut at a higher speed, the practicability is effectively improved, and in the process of moving the crushing box 2 up and down, the crushing box 2 drives the feeding pipe 4 to move up and down together, so that a worker can conveniently observe whether the whole device is still working;
meanwhile, in the process of rotating the rotating rod 11, the rotating rod 11 can drive the first bevel gear 28 to rotate, the first bevel gear 28 drives the second bevel gear 29 to rotate, the second bevel gear 29 drives the rotating shaft 26 to rotate, the rotating shaft 26 drives the cam 32 to rotate, the cam 32 drives the driving rod 31 to slowly rise and then quickly fall down, the vibration effect on the bag type filter screen 14 is achieved, too many tiny particles are prevented, the bag type filter screen 14 is prevented from being blocked, and accordingly gas circulation is not smooth (in the process of moving the driving rod 31 up and down, gas in the auxiliary tank 15 can be prevented from leaking as much as possible through sealing of a sealing gasket on a through groove, even if a small amount of leakage occurs, the adsorption force of the circulating gas pump 6 on the air in the auxiliary tank 15 is enough to enable small particles to be adsorbed on the filter screen 14, and accordingly the gas outlet pipe 5, the gas pipe 9 and the circulating gas pump 6 form a finished gas circulation);
meanwhile, after micronization is finished, the powder on the bag filter screen 14 can be collected by a person skilled in the art, so that raw materials are saved; then the second active medicine enters the crushing box 2 through the feeding pipe 4, and the steps are repeated; after the first component and the second component are put into the mixing box 17, the carrier is put into the mixing box 17 through the carrier pipe 16, at this time, due to the rotation of the rotating rod 11, the rotating rod 11 drives the circular ring 33 to rotate together with the rotary circular shell 20, the first component, the second component and the carrier are subjected to the comprehensive effects of strong mechanical extrusion and the like of the first mixing tank 30 and the second mixing tank 35, the first component and the second component are rapidly and uniformly distributed on the carrier, the first component, the second component and the carrier are effectively mixed, the rotating rod 11 drives the stirring rod 19 to rotate while the rotating rod 11 rotates, the stirring rod 19 drives the scraping plate 22 to rotate, the inner wall of the mixing box 17 is scraped, and after a period of stirring, the third component is discharged from the lower end of the mixing box 17;
in the structure, the rotating rod 11 is driven to rotate only by arranging the driving motor 7, the rotating rod 11 rotates, the functions of rotary cutting, vibrating the bag type filter screen 14, mixing the first component with the second component and the like can be completed, the structure innovation is strong, only one power source is needed, the energy is effectively saved, secondly, the active medicine in the crushing box 2 can be sheared by airflow through arranging the circulating air pump 6, micronization is realized, meanwhile, small particle components entering the auxiliary box 15 can be sucked onto the bag type filter screen 14, raw materials are additionally collected, the raw materials are saved, and then the air is circulated into the circulating air pump 6 through the air pipe 9, so that a complete air circulation channel is formed; the steps S01 and S02 can be completed only by arranging the crushing and mixing device, and the practicability and the functionality of the device are effectively improved.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. The vardenafil and dapoxetine compound dry powder inhalation preparation is characterized by comprising a first active drug, a second active drug and an optional carrier.
2. The compound dry powder inhalation formulation according to claim 1, wherein the first active agent is vardenafil;
the second active drug is dapoxetine;
the carrier is at least one of lactose, mannose, chitosan, DPPC and DSPC.
3. The compound dry powder inhalation formulation according to claim 1, wherein the content ratio of the first active drug, the second active drug and the carrier is (5-20): (10-80): (0-80).
4. A method for preparing a compound dry powder inhalation formulation according to any one of claims 1 to 3, comprising the step of adding an active agent to prepare an inhalation powder aerosol comprising the step of preparing inhalation particles after mixing the added active agent with a carrier or without a carrier.
5. The method for preparing the compound dry powder inhalation formulation according to claim 4, wherein the method for preparing inhalation particles comprises the following steps:
s01, respectively micronizing a first active drug and a second active drug to obtain a first component and a second component;
s02, mixing the first component and the second component with a carrier to obtain a third component;
s03, preparing the third component into a dry powder preparation, and loading the dry powder preparation into a corresponding device for standby.
6. The method for preparing the compound dry powder inhalation formulation according to claim 5, wherein in step S01, the micronization process comprises, but is not limited to, jet milling, spray drying, spray freeze drying, recrystallization or ball milling;
in step S02, the mixing process includes, but is not limited to, high shear mixing, air flow mixing, or three-dimensional mixing;
in step S03, the device includes, but is not limited toDevice(s)>Device, all guarantee->Device or->And (3) a device.
7. The method for preparing a compound dry powder inhalation formulation according to claim 5, wherein the particle size D90 of the first active drug and the second active drug is 1-10um; the carrier particle diameter D90 is 3-200um, and the D50 is 0.5-100um.
8. The method for preparing a compound dry powder inhalation formulation according to claim 5, wherein in steps S01 and S02, the first active drug and the second active drug are micronized by a pulverizing and mixing device, and then the first component, the second component and the carrier are mixed by a pulverizing and mixing device;
the crushing mixing device comprises a shell (1), wherein a crushing box (2) is arranged in the shell (1), two support columns (18) which are bilaterally symmetrical are fixedly arranged at the lower end of the shell (1), the crushing box (2) is connected with the inner walls of the left side and the right side of the shell (1) in a sliding manner, two feed pipes (4) which are bilaterally symmetrical are arranged on the crushing box (2), the feed pipes (4) upwards extend out of the crushing box (2), the feed pipes (4) are in sliding connection with the extending positions of the crushing box (2), a driving motor (7) is fixedly arranged at the upper end of the shell (1), a rotating rod (11) is fixedly connected with the lower output end of the driving motor (7), the rotating rod (11) downwards penetrates through the shell (1) and extends into the crushing box (2), the rotating rod (11) is in rotating connection with the extending positions of the shell (1), a reciprocating screw rod (10) is fixedly arranged at the extending positions of the rotating rod (11) and is in threaded connection with the crushing box (2), a filter screen (13) is arranged at the lower end of the crushing box (2), the rotating rod (11) is in rotating connection with the extending positions of the filter screen (13), and a plurality of cutters (3) are fixedly arranged on the rotating rod (11).
Still install circulation air pump (6) on casing (1), two bilateral symmetry's outlet duct (5) are installed to circulation air pump (6) downside, outlet duct (5) downwardly extending is gone into in casing (1), and outlet duct (5) and casing (1) extended position fixed connection, fixedly on casing (1) upside inner wall be equipped with inlet box (8), inlet box (8) and outlet duct (5) through-connection, inlet box (8) are passed downwards to dwang (11), and dwang (11) pass the position rotation with inlet box (8) and be connected, be equipped with a plurality of through-holes in inlet box (8), dwang (11) set up to the cavity, a plurality of through-holes are installed on dwang (11), be equipped with a plurality of fumars (12) in smashing case (2), a plurality of fumars (12) are installed on dwang (11).
9. The preparation method of the compound dry powder inhalation formulation according to claim 8, wherein a carrying box (27) is arranged at the lower end of the crushing box (2), the carrying box (27) is in through connection with the crushing box (2), a filter screen (13) is arranged at the through position of the carrying box (27) and the crushing box (2), a powder outlet pipe (25) is arranged at the left side and the right side of the carrying box (27) in a through manner, the other end of the powder outlet pipe (25) is connected with an auxiliary box (15) in a through manner, the auxiliary box (15) is fixedly arranged on the inner walls of the left side and the right side of the shell (1), a bag filter screen (14) is arranged in the auxiliary box (15), the bag filter screen (14) is in sliding connection with the inner wall of the auxiliary box (15), a driving rod (31) is fixedly arranged on one side, which is mutually close to the auxiliary box (15), a through groove is formed on one side, the driving rod (31) extends out of the auxiliary box (15) through the through groove, and the driving rod (31) is in sliding connection with the through groove, and a sealing gasket is arranged on the through groove for sealing the through groove when the driving rod (31) moves;
grooves are formed in the left side wall and the right side wall of the crushing box (2), an air pipe (9) is connected to the upper side of the auxiliary box (15) in a penetrating manner, the air pipe (9) upwards penetrates through the grooves to extend out of the shell (1), the air pipe (9) is fixedly connected with the extending position of the shell (1), and the other end of the air pipe (9) is connected with a circulating air pump (6) in a penetrating manner;
the rotating rod (11) is fixedly provided with a first bevel gear (28), the left side and the right side of the first bevel gear (28) are connected with a second bevel gear (29) in a meshed mode, one side, away from each other, of the second bevel gear (29) is fixedly connected with a rotating shaft (26), the rotating shaft (26) is rotationally connected with the auxiliary box (15), the rotating shaft (26) is fixedly provided with a cam (32), and the cam (32) is in contact fit with the driving rod (31).
10. The preparation method of the compound dry powder inhalation preparation according to claim 8, wherein an opening is formed in the inner wall of the lower side of the shell (1), a mixing box (17) is installed at the opening, carrier pipes (16) are connected on the left side and the right side of the mixing box (17) in a penetrating manner, the carrier pipes (16) extend out of the shell (1), the carrier pipes (16) are fixedly connected with the extending position of the shell (1), component pipes (24) are also connected on the left side and the right side of the mixing box (17) in a penetrating manner, the component pipes (24) are connected with the lower surface of the auxiliary box (15) in a penetrating manner, a rotating rod (11) extends downwards into the mixing box (17), two symmetrically-arranged stirring rods (19) are fixedly arranged at the lower end of the rotating rod (11), one ends, far away from each other, of the stirring rods (19) are fixedly provided with scraping plates (22), and the scraping plates (22) are in abutting connection with the inner wall of the mixing box (17);
fixed a plurality of evenly distributed's dead lever (23) on the inboard wall of mixing box (17), dead lever (23) lower extreme is fixed to be equipped with fixed circle shell (21), a plurality of first mixed grooves (30) have been seted up on fixed circle shell (21), still be equipped with rotatory circle shell (20) in mixing box (17), fixed a plurality of blades (34) that are equipped with on rotatory circle shell (20) inboard wall, the other end of a plurality of blades (34) is fixed to be equipped with ring (33), ring (33) fixed mounting is on dwang (11), still be equipped with a plurality of second mixed grooves (35) on rotatory circle shell (20), and rotatory circle shell (20) cooperatees with fixed circle shell (21).
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