Antibody pharmaceutical preparation for inhalation treatment of lung cancer
阅读说明：本技术 用于吸入治疗肺癌的抗体类药物制剂 (Antibody pharmaceutical preparation for inhalation treatment of lung cancer ) 是由 黄才古 张海龙 贺宁 于 2020-07-29 设计创作，主要内容包括：本发明涉及通过软雾吸入器或雾化器施用治疗性抗体药物以治疗肺癌(特别是非小细胞肺癌)的制剂和药物施用方法。(The present invention relates to formulations and methods of drug administration for the administration of therapeutic antibody drugs for the treatment of lung cancer, particularly non-small cell lung cancer, by soft mist inhaler or nebulizer.)
1. A liquid, propellant-free pharmaceutical formulation comprising: (a) an active substance; (b) a solvent; (c) pharmacologically acceptable excipients.
2. The pharmaceutical formulation of claim 1, wherein: the active substance is selected from the group consisting of alemtuzumab, nivolumab, pembrolizumab, dulatumab, bevacizumab, and combinations thereof.
3. The pharmaceutical formulation of claim 1, wherein: the active substance is present in an amount of about 1mg/ml to about 100 mg/ml.
4. The pharmaceutical formulation of claim 1, characterized by: the pharmaceutically acceptable excipients are selected from the group consisting of L-histidine, L-histidine hydrochloride monohydrate, sodium citrate dihydrate, polysorbate 80, polysorbate 20, sodium chloride, sodium phosphate, mannitol, pentetic acid, anhydro α, α -trehalose, sucrose, and combinations thereof.
5. The pharmaceutical formulation of claim 1, wherein: comprising about 1mg/ml to about 25mg/ml pembrolizumab, about 1mM to about 10mM L-histidine, about 50mM to about 200mM sucrose, and about 0.05mM to about 0.15mM polysorbate 80, said pharmaceutical formulation having a pH of about 5.5 to about 5.7 and being stable for at least 12 months when stored under refrigerated conditions of 2 ℃ to 8 ℃.
6. The pharmaceutical formulation of claim 1, wherein: comprising about 10mg/ml to about 65 mg/ml of attrituximab, about 50mM to about 450 mM of L-histidine, about 500 mM to about 2450 mM of sucrose and about 1mM to about 10mM of polysorbate 20, and about 60mM to about 300mM of anhydrous acetic acid, the pharmaceutical formulation having a pH of about 5.8 to about 6 and being stable for at least 12 months when stored under refrigerated conditions of 2 ℃ to 8 ℃.
7. The pharmaceutical formulation of claim 1, wherein: comprising about 5mg/ml to 10mg/ml of nivolumab, about 0.05mM to about 200mM of polysorbate 80, about 10mM to about 30 mM of sodium citrate dihydrate, about 20mM to about 60mM of sodium chloride, about 50mM to about 200mM of mannitol, and about 0.005 mM to about 0.025 mM of pentetic acid, said pharmaceutical formulation having a pH of about 6 and being stable for at least 12 months when stored under refrigerated conditions of 2 ℃ to 8 ℃.
8. Pharmaceutical formulation according to claim 1, characterized in that: comprising about 10mg/ml to 55mg/ml of dulvacizumab, about 1mM to about 15mM of L-histidine, about 0.03mM to about 0.2mM polysorbate 80, about 1mM to about 15mM of L-histidine hydrochloride monohydrate, and about 50mM to about 300mM trehalose dihydrate, said pharmaceutical formulation having a pH of about 6 and being stable for at least 12 months when stored under refrigerated conditions of 2 ℃ to 8 ℃.
9. The pharmaceutical formulation of claim 1, wherein: comprising about 10mg/ml to 25mg/ml bevacizumab, about 0.15mM to about 0.35mM polysorbate 20, about 15mM to about 55 sodium phosphate monohydrate, about 1mM to about 10mM disodium phosphate dihydrate and about 50mM to about 200mM trehalose dehydrate, said pharmaceutical formulation having a pH of about 6 and being stable for at least 12 months when stored under refrigerated conditions of 2 ℃ to 8 ℃.
10. A method of administering a pharmaceutical formulation according to claim 1, wherein: comprising atomizing said pharmaceutical formulation in an inhaler as shown in figure 1.
11. A method of treating lung cancer in a patient comprising administering to the patient the pharmaceutical formulation of claim 1.
12. The method of claim 11, further comprising aerosolizing the pharmaceutical formulation in an inhaler.
13. The pharmaceutical formulation according to claim 1, comprising a combination of pembrolizumab and bevacizumab as active ingredients.
14. The pharmaceutical formulation of claim 1, comprising a combination of alt-rubizumab and bevacizumab as active ingredients.
15. The pharmaceutical formulation of claim 1, comprising a combination of dolvacizumab and bevacizumab as active ingredients.
16. The pharmaceutical formulation of claim 1, comprising a combination of nivolumab and bevacizumab as active ingredients.
17. A method of administering a pharmaceutical formulation according to claim 5, comprising generating an aerosol of the pharmaceutical formulation using a nebulizer or soft mist inhaler.
18. A method of administering a pharmaceutical formulation according to claim 6, comprising generating an aerosol of the pharmaceutical formulation using a nebulizer or soft mist inhaler.
19. A method of administering a pharmaceutical formulation according to claim 7, comprising generating an aerosol of the pharmaceutical formulation using a nebulizer or soft mist inhaler.
20. A method of administering a pharmaceutical formulation according to claim 8, comprising generating an aerosol of the pharmaceutical formulation using a nebulizer or soft mist inhaler.
21. A method of administering a pharmaceutical formulation according to claim 9, comprising generating an aerosol of the pharmaceutical formulation using a nebulizer or soft mist inhaler.
22. The method of administering a drug according to claim 10, wherein: the aerosolization process provides aerosol particles having an average size of less than about 10 μm.
23. The method of administering a drug according to claim 10, wherein: the aerosolization process provides aerosol particles having an average size of less than about 5 μm.
Technical Field
The present invention relates to formulations and methods of drug administration for the administration of therapeutic antibody drugs for the treatment of lung cancer, particularly non-small cell lung cancer, by soft mist inhaler or nebulizer.
Background
Therapeutic monoclonal antibodies and antibody-based therapies (modalities) are now being developed at any time more than ever. Faster, more accurate drug discovery processes will ensure that the number of drug candidates entering the biopharmaceutical channel will increase in the future.
Cancer is one of the leading causes of death worldwide. In particular, lung cancer is one of the three most common cancers with very low survival rates. According to the SEER (surveillance, epidemiological and end-result database) stage of disease progression, the five-year relative survival rate for the long-term lung cancer (distant stage) is 6%, the regional stage 35%, the localized stage 61%, and the five-year combined survival rate for the entire SEER stage 24%. Although there are many cancer drugs available, it is difficult, and in some cancer types, it is almost impossible to improve the cure rate or survival rate. The lack of success has many reasons, but one of them is the inability to deliver sufficient amounts of drug to the tumor without causing debilitating and life-threatening toxicities to the patient. In fact, most chemotherapeutic drugs used to treat cancer have high toxicity to normal and tumor tissues.
Over the past two decades, significant advances have been made in the treatment of non-small cell lung cancer (NSCLC), including deeper understanding of disease biology and tumor progression mechanisms, as well as advances in early diagnosis and multi-modal therapy. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival gains in selected patients. However, the overall cure rate and survival rate of NSCLC remains low, particularly in metastatic disease. The medicament may be administered in a variety of ways, for example by swallowing, inhalation, absorption through the skin or by intravenous injection. Each method has its advantages and disadvantages, and not all methods can be used for each drug. Improving current methods of administration or designing new methods of administration can enhance the efficacy and utility of existing drugs to expand their clinical benefit to a broader patient population and improve the efficacy of NSCLC.
As part of the bio-agent price competition and innovation act (BPCIA), among other things, if the data show that a biopharmaceutical (produced in vivo or derived from an organism) is "highly similar" to an approved biological product, it can be proven to be a "biosimilar". The biosimilar product should retain at least the biological function and therapeutic efficacy of the biological product approved by the U.S. food and drug administration. However, the composition of the biosimilar drug may be different from the approved biological product. Different formulations may improve the stability and shelf life of the biopharmaceutical and may also improve the efficacy of the treatment of a particular disease or disorder. Different formulations may also improve other aspects of administration, including reducing discomfort or other unwanted effects that a patient may experience when using an approved biologic. Antibody molecules can be produced as biosimilar and reconstituted accordingly. There remains a need in the art for high quality antibody formulations, and methods of administration and use thereof.
Currently, systemic intravenous administration of lung cancer drugs can only deliver about 9-10% of the drug to the site of the lung tumor, and therefore requires administration of high doses of anti-cancer drugs. The intravenous route of the drug exposes the entire body to the drug. Although doses were chosen to kill tumor cells, these doses also kill normal cells. Thus, patients often experience severe toxic side effects. For example, severe myelosuppression may lead to a decrease in the patient's ability to resist infection and allow the tumor to spread. Antineoplastic drugs can also elicit other life-threatening effects such as hepatotoxicity, nephrotoxicity, pulmonary toxicity, cardiotoxicity, neurotoxicity and gastrointestinal toxicity. In addition, a large amount of drug remains in the blood circulation system, causing serious side effects and adverse reactions. Furthermore, it is noteworthy that these toxicities are associated to varying degrees with all antineoplastic drugs, but all due to systemic administration of the drugs.
The difference of action mechanism and pharmacokinetic property of different anti-cancer drugs on different types of tumors leads to different biological behaviors, and the curative effect of the anti-cancer drugs is determined to a certain extent.
The concept of local drug delivery has been proposed as a method for delivering high concentrations of drugs to a target while preventing vital organs from being exposed to toxic high concentrations of drugs through systemic circulation. In this way, systemic side effects are minimized. The respiratory system has large surface area, thin alveolar epithelium, fast absorption, lack of first-pass metabolism and high bioavailability, and can absorb a large amount of drugs, thereby being an ideal administration route (Labiris and Dolovich 2003).
In order to achieve pulmonary topical administration of active substances, it is clinically advantageous to administer liquid formulations of the active substance using a suitable inhaler. Furthermore, it is important to increase the pulmonary deposition of inhaled drugs using soft mist inhalation or nebulization inhalation. Therefore, there is a need to improve the drug delivery of potent anticancer drugs by increasing the pulmonary deposition of anticancer drugs. Soft mist inhalation devices or other nebulizing devices can significantly increase pulmonary deposition of liquid drug formulations.
U.S.6471943b1 shows that highly toxic, blistering and previously unknown non-blistering anti-tumor drugs can be effectively delivered by inhalation to patients in need of treatment for tumors or cancers. This approach is particularly effective for treating tumors or cancers of the pulmonary system because the highly toxic drug is delivered directly to the site of need, providing a local dose far in excess of that achievable by conventional intravenous injection.
Konstantinos et al have recently studied three immunotherapeutic drugs, nivolumab (nivolumab), ipilimumab (ipilimumab) and pembrolizumab (pembrolizumab), which can produce aerosols from their current state in water as a solvent using a jet nebulizer and a residual cup (residual cup). (Sapalidis, Zarogoulidis et al 2018).
The main objective in formulating a therapeutic monoclonal antibody solution for treatment of NSCLC using an inhaler is to increase the efficacy of the therapeutic monoclonal antibody and to reduce the dose of IV infusion and the resulting side effects. The general disadvantages of IV infusion of therapeutic monoclonal antibodies are the route of administration, high dosage and stability. Once the infusion solution is formulated, it must be administered by intravenous injection as soon as possible, since it can be stored only for 24 hours in a refrigerator at 2 ℃ to 8 ℃, or for 8 hours at room temperature.
Disclosure of Invention
The present invention relates to a novel therapeutic strategy for the treatment of metastatic NSCLC by means of a soft mist inhaler or nebulizer. Therapeutic monoclonal antibodies for metastatic NSCLC are formulated to form an aerosol using a soft mist inhaler. Aerosolized therapeutic monoclonal antibodies are delivered locally to lung tumors by inhalation. Local delivery of therapeutic monoclonal antibodies is intended to improve the efficacy of treatment of metastatic NSCLC by increasing lung deposition. This therapeutic strategy reduces the side effects of the drug, as very low concentrations of antibody are absorbed through the alveoli and into the blood circulation. Local delivery of therapeutic monoclonal antibodies by inhalation reduces the dose of therapeutic antibody, and thus toxicity, compared to systemic intravenous injection.
Drawings
FIG. 1 shows a longitudinal cross-sectional view of an atomizer in a pressurized state;
fig. 2 shows a counter element of the nebulizer;
the use of the same or similar reference symbols in different drawings indicates the same or similar features.
Detailed Description
Technical and non-technical terms used herein are used to describe specific embodiments only and are not used to limit the present invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. As used herein, the singular forms "a", "an" and "the" are intended to include the plural as well as the singular, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
In this context, the respiratory tract includes the oral and nasopharyngeal cavities, the tracheobronchial and pulmonary regions. The pulmonary region includes the upper and lower bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli.
In describing the present invention, it should be understood that a number of formulations and steps are disclosed. Each of these techniques has individual advantages, and each can also be used in combination with one or more, or in some cases all, of the other disclosed techniques. Thus, for the sake of clarity, the description will avoid repeating every possible combination of the various steps in an unnecessary fashion. However, it is to be understood that such combinations are entirely within the scope of the invention and the claims when read.
The disclosure of the present invention is to be considered as an example of the invention and is not intended to limit the invention to the particular embodiments shown by the following drawings or description.
The invention describes a pharmaceutical preparation of an active therapeutic monoclonal antibody and other auxiliary materials which can be used for treating NSCLC by soft mist inhalation or nebulizer inhalation. The soft mist inhaler formulations of the present invention should meet standard quality guidelines. It is therefore an object of the present invention to provide a stable formulation containing a functional form of a therapeutic monoclonal antibody and an inactive ingredient in solution that meets the standard delivery dose requirements required to achieve optimal aerosolization of the solution using a soft mist inhaler. It is of utmost importance to formulate the pharmaceutically active formulation as the most stable solution to maintain the functionality of the active ingredient at the labeled dose. Another aspect is to provide a propellant-free suspension containing a therapeutic monoclonal antibody and an adjuvant, which is nebulized under pressure using a soft mist or nebulizing inhalation device. The amount of the composition delivered by the aerosol can be reproducibly produced within a specified range.
The invention relates to an inhalable therapeutic monoclonal antibody preparation for NSCLC, which comprises an anti-cancer monoclonal antibody as a main active molecule, wherein the main active molecule is dispersed in a mixture of sodium chloride, sodium citrate dihydrate, mannitol, glutaric acid and polysorbate 80 as inactive ingredients. Preferably, the mixture is administered as an aerosol formed by a soft mist inhaler or nebulizer. The pharmaceutical formulations disclosed herein are particularly suitable for soft mist or aerosol inhalation, with significantly better lung deposition, typically up to 55-60%, compared to intravenous injection. Furthermore, liquid inhalation formulations of therapeutic monoclonal antibodies have other advantages over therapeutic monoclonal antibodies administered by intravenous infusion, particularly for the treatment of NSCLC.
Soft mist inhalers nebulize small amounts of liquid formulations containing the required dose of therapeutic monoclonal antibodies into aerosols suitable for therapeutic inhalation within a few seconds. Soft mist inhalers are particularly suitable for use with the liquid formulations disclosed herein. An aerosol parameter indicative of aerosol mass is the so-called respirable ratio, which is defined herein as the proportion of droplets whose Measured Median Aerodynamic Diameter (MMAD) is less than about 10 μm. The respirable fraction can be measured using an "Andersen impact sampler". For good protein absorption, it is important not only to achieve aerosolization with substantially no loss of activity, but also to generate an aerosol with a good respirable fraction. Aerosols with MMAD less than about 10 μm are more suitable for reaching the alveoli with a greater probability of being absorbed. Soft mist inhaler
The effectiveness of the (SMI) device may also be tested in vivo. As an example of an in vivo test system, a mist containing proteins can be administered to a dog through an endotracheal tube. Blood samples are taken at appropriate time intervals and the protein levels in the plasma are then measured immunologically or biologically.
The invention also relates to aerosol formulations in the form of aqueous solutions containing biologically active macromolecules, in particular therapeutic antibodies, as active substance in an amount of between about 1mg/ml and about 100mg/ml, preferably between about 10mg/ml and about 100 mg/ml.
Preferably, the therapeutic monoclonal antibody for treating metastatic NSCLC of the present invention is nivolumab, ipilimumab, attrituzumab (Atezolizumab), pembrolizumab, Durvalumab (Durvalumab), bevacizumab (Avastin), or a combination thereof.
The pharmaceutical formulations of the present invention may be formulated using one or more physiologically acceptable carriers comprising adjuvants and adjuvants known in the art. Preferably, the adjuvants and adjuvants are selected from L-histidineAcid (molecular formula is C)6H9N3O2The molecular weight is: 155.15g/mol, IUPAC name (2S) -2-amino-3- (1H-imidazol-5-yl) propionic acid); dehydrated sodium citrate (molecular formula C)6H9Na3O9Molecular weight of 294.098g/mol, IUPAC name is dehydrated sodium 2-hydroxypropane-1, 2, 3-tricarboxylate); sodium chloride (molecular weight 58.44g/mol, IUPAC name sodium chloride); mannitol (molecular formula C)6H14O6Molecular weight 182.172g/mol, IUPAC name (2R,3R,4R,5R) -hexane-1, 2,3,4,5, 6-hexanol); pentetic acid (molecular formula is C)14H23N3O10Molecular weight of 393.349g/mol, IUPAC name 2- [ bis [2- [ bis (carboxymethyl) amino group]Ethyl radical]Amino group]Acetic acid); polysorbate 80 (molecular formula is C)32H60O10Molecular weight 604.822g/mol, IUPAC name 2- [2- [3, 5-bis (2-hydroxyethoxy) furyl-2-yl]-2- (2-hydroxyethoxy) ethoxy]Ethyl (E) -octadec-9-enoic acid ester); anhydrous alpha, alpha-trehalose (molecular formula C)12H26O13Molecular weight 378.33g/mol, IUPAC name (2R,3S,4S,5R,6R) -2- (hydroxymethyl) -6- [ (2R,3R,4S,5S,6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) pyran-2-yl]Oxapyran-3, 4, 5-triol; dehydrate); sucrose (molecular formula is C)12H22O11Molecular weight 342.3g/mol, IUPAC name (2R,3R,4S,5S,6R) -2- [ (2S,3S,4S,5R) -3, 4-dihydroxy-2, 5-bis (hydroxymethyl) pyran-2-yl]Oxo-6- (hydroxymethyl) pyran-3, 4, 5-triol).
The formulations of the present invention may include chelating agents, preservatives, antioxidants, processing aids, and other additives.
To prepare the propellant-free aerosol of the present invention, the antibody-containing pharmaceutical formulation is preferably administered using a soft mist inhalation device.
Typical devices for propellant-free administration of a given amount of a liquid pharmaceutical composition for soft mist inhalers are described in detail in, for example, US20190030268 "inhalation nebulizer containing a blocking function and a counter".
The drug solution in the nebulizer is converted into an aerosol that acts on the lungs. The drug solution is ejected by the nebulizer in a high pressure manner.
The inhalation device can be carried anywhere by the patient because of its convenient size in cylindrical shape and less than 8cm to 18cm long and 2.5cm to 5cm wide. Nebulizers eject a volume of a drug formulation under high pressure through a small nozzle to produce an inhalable aerosol.
The preferred nebulizer comprises nebulizer 1, liquid 2, container 3, liquid compartment 4, pressure generator 5, holder 6, drive spring 7, delivery tube 9, check valve 10, pressure chamber 11, nozzle 12, mouthpiece 13, aerosol 14, air inlet 15, upper housing 16 and inner part 17.
A nebulizer 1 for ejecting a medicinal liquid 2 having the above-described blocking function and counter is shown in fig. 1 in a pressurized state. The nebulizer 1 comprising the above-described blocking function and counter is preferably a portable inhaler and does not require propellant gas.
FIG. 1 shows a longitudinal cross-sectional view of an atomizer in a pressurized state;
for a typical nebulizer 1 comprising the above-mentioned blocking function and counter, an aerosol 14 to be inhaled by a patient can be generated by nebulizing a liquid 2, which liquid 2 is preferably formulated as a pharmaceutical liquid. The medicament is generally administered at least once a day, more specifically multiple times a day, preferably at predetermined time intervals, depending on the severity of the disease affecting the patient.
A preferred nebulizer 1 comprising the above-described blocking function and counter has a replaceable and insertable container 3 containing a medicament liquid 2. Thus, a container for containing the liquid 2 is formed in the container 3. In particular, the liquid 2 is located in a liquid compartment 4 formed by a collapsible bag in the container 3.
The amount of liquid 2 in the container 3 of the inhalation nebulizer 1 comprising the above-described blocking function and counter is preferably sufficient to provide up to 200 doses. A typical container 3 has a volume of about 2 to about 10 ml. The pressure generator 5 in the nebulizer 1 is used to deliver and nebulize the liquid 2, in particular in a predetermined dose. Thus, the liquid 2 can be released and ejected preferably in a single dose of about 5 to about 30 microliters.
A typical nebulizer 1 comprising the above-described blocking function and counter preferably has a pressure generator 5 and a holder 6, a drive spring 7, a delivery tube 9, a check valve 10, a pressure chamber 11 and a nozzle 12 in a mouthpiece 13. The container 3 is locked in the nebulizer 1 by the holder 6, so that the delivery tube 9 is inserted into the container 3. The container 3 can be separated from the nebulizer 1 for replacement.
The nebulizer 1, which contains the blocking function and the counter described above, will move the delivery tube 9 and the container 3 and the holder 6 downwards when the drive spring 7 is compressed in the axial direction. The liquid 2 will then be sucked into the pressure chamber 11 through the delivery pipe 9 and the non-return valve 10.
With the above described inhalation nebulizer 1 comprising a blocking function and a counter, the pressure is relieved after the holder 6 is released. During this process, the delivery tube 9 and the closed non-return valve 10 are moved back up to the home position by releasing the drive spring 7. Causing the liquid 2 to be pressurized in the pressure chamber 11. The liquid 2 is then pushed through the nozzle 12 and atomised under pressure into an aerosol 14. When air is drawn into the mouthpiece 13 through the air inlet 15, the patient can inhale the aerosol 14 through the mouthpiece 13.
The above described inhalation nebulizer 1 comprising the blocking function and the counter has an upper housing 16 and an inner part 17, which inner part 17 is rotatable relative to the upper housing 16. The lower housing 18 is manually operable to be attached to the inner member 17. The lower housing 18 can be separated from the atomiser 1 so that the container 3 can be replaced and inserted.
The above-described inhalation nebulizer 1 comprising the blocking function and the counter preferably has a lower housing 18 which carries an inner part 17 which is rotatable relative to the upper housing 16. As a result of the rotation and engagement between the upper part 17 and the carriage 6, the carriage 6 moves axially through the gear 20, the counter and the drive spring 7 is compressed.
In the compressed state, the container 3 moves downwards and reaches a final position, as shown in fig. 1. The drive spring 7 is compressed in this final position and the holder 6 is clamped. Thus, the container 3 and the delivery tube 9 are prevented from moving upwards, thus avoiding the drive spring 7 from being loosened.
A typical fogging process occurs after the stent 6 is released. The container 3, the delivery tube 9 and the support 6 are moved back into the starting position by the drive spring 7. This is referred to herein as a large shift. When a large gear shift occurs, the check valve 10 is closed, the liquid 2 is subjected to pressure in the pressure chamber 11, and then the liquid 2 is pushed out and atomized under pressure.
The above described inhalation nebulizer 1 comprising a blocking function and a counter preferably has a clamping function. During clamping, the container 3 is preferably used to perform the squeezing out or withdrawing of the liquid 2 during the atomization. The gear 20 has a sliding surface 21 on the upper housing 16 and/or the carrier 6, which sliding surface 21 allows the carrier 6 to move axially when the carrier 6 is rotated relative to the upper housing 16.
The carrier 6 will not be blocked for too long and large gear shifts can be made. Thus, the liquid 2 is ejected and atomized.
In this clamping function, the sliding surface 21 is disengaged when the bracket 6 is in the clamped position. The gear 20 then releases the carrier 6, allowing it to move axially in the opposite direction.
The nebulizer 1 preferably comprises a counter element as shown in fig. 2. The counter element has a worm 24 and a counting ring 26. The counter ring 26 is preferably annular and has a toothed portion at the bottom. The worm 24 has an upper end gear and a lower end gear. The upper end gear is in contact with the upper housing 16. The upper housing 16 has an internal projection 25. In use of the atomiser 1, the upper housing 16 rotates; when the projection 25 passes through the upper end gear of the worm 24, the worm 24 is driven to rotate. The rotation of the worm 24 drives the counter ring 26 to rotate through the lower gear to produce a counting effect.
The locking mechanism is mainly realized by two protrusions. The protrusion a is located on the outer wall of the lower unit of the inner member. The protrusion B is located on the inner wall of the counter. The lower unit of the inner part is nested in the counting ring. The counting ring rotates relative to the lower unit of the inner part. Due to the rotation of the counting ring, the number displayed on the counting ring changes along with the increase of the driving times and can be observed by a patient. The number displayed on the counting ring changes after each actuation. Once a predetermined number of drives has been reached, the protrusions a and B will come into contact with each other, after which the counter ring will not be able to rotate any further. Therefore, the atomizer is clogged and cannot be used continuously. The number of times the device is driven is counted by a counting loop.
The nebuliser described above is suitable for nebulising an aerosol formulation of the invention to form an aerosol suitable for inhalation. However, the formulations according to the invention may also be nebulized using other inhalers than those described above, for example ultrasonic vibrating mesh nebulizers and compressed air nebulizers.
A typical ultrasonic vibration mesh nebulizer consists of a reservoir with a piezo-electric mesh mounted on one side and a piezo-electric mesh drive circuit board with a battery. The piezoelectric mesh disk is made of a stainless steel plate with thousands of precisely shaped laser drilled holes surrounded by a piezoelectric material. When the piezoelectric material is driven by an analog signal of a specific voltage, frequency and waveform generated by the driving board, the piezoelectric material vibrates at a very high speed. As a result of the rapid vibration, the solution is expelled through the orifice to form uniformly sized droplets that are delivered at a low velocity for direct inhalation into the lungs.
For a typical compressed air nebulizer, the aerosol is generated by an airflow in the nebulizer chamber. This creates a low pressure zone that draws the mist droplets from the solution or drug suspension in the nebulizer chamber through the feed tube, thereby creating a stream of atomized droplets that flow to the mouthpiece. Higher gas flows result in reduced particle size and increased yield. The baffle in the atomizer chamber is impacted by the larger particles, retaining them and returning them to the solution in the atomizer chamber for re-atomization. The performance of the atomizer varies considerably. In addition, the atomizer requires a source of compressed air.
Examples
The preparation comprises the following components:
pembrolizumab, nivolumab, alemtuzumab, dulvacizumab, bevacizumab, L-histidine hydrochloride monohydrate, polysorbate 80, polysorbate 20, sodium chloride, disodium citrate, monosodium phosphate, disodium phosphate, mannitol, pentetic acid, alpha-dihydrate trehalose, and sucrose.
Example 1
The preparation method of an aqueous solution containing pembrolizumab as an active ingredient for soft mist inhalation is as follows: according to Table 1, 5ml of pembrolizumab (10mg/ml and 20mg/ml) solution was prepared by dissolving L-histidine, polysorbate 80 and sucrose in 4ml of sterile water, and the solution was adjusted to the target pH with hydrochloric acid. Finally, sterile water was added to a final volume of 5 ml.
Table 1, sample I and sample II formulation component content
Components
Sample I
Sample II
Pembrolizumab
50mg
100mg
L-histidine
3.1mg
6.2mg
Polysorbate 80
0.4mg
0.8mg
Sucrose
140mg
280mg
pH
5.5
5.5
Sterile water
5ml
5ml
Example 2
The process for the preparation of the alt-rubizumab solution for soft mist inhalation was as follows: according to table 2, a 5ml solution of attrituximab (30mg/ml or 60mg/ml) was prepared by adding and dissolving L-histidine, polysorbate 20 and sucrose in water, and the solution was adjusted to the target pH with acetic acid. Finally, sterile water was added to a final volume of 5 ml.
Table 2 formulation component content for sample I and sample II
Components
Sample I
Sample II
Attrit Zhu monoclonal antibody
150mg
300mg
L-histidine
155mg
310mg
Polysorbate 20
20mg
40mg
Sucrose
2054mg
4108mg
Acetic acid anhydride
41.25mg
82.8mg
pH
5.8
5.8
Sterile water
5ml
5ml
Example 3
The preparation method of the aqueous solution preparation containing nivolumab for soft mist inhalation is as follows: according to Table 3, a 5ml solution of nivolumab (5mg/ml or 10mg/ml) was prepared by adding and dissolving mannitol, sodium chloride, polysorbate 80, sodium citrate dihydrate in 4ml sterile water. The solution was adjusted to the target pH with pentetic acid. Finally, sterile water was added to a final volume of 5 ml.
Table 3 formulation component content for sample I and sample II
Components
Sample I
Sample II
Nivolumab
25mg
50mg
Mannitol
75mg
150mg
Sodium chloride
7.3mg
14.6mg
Polysorbate 80
0.5mg
1mg
Citric acid sodium salt dihydrate
14.7mg
29.4mg
Pentetic acid
0.02mg
0.04mg
pH
6
6
Sterile water
5ml
5ml
Example 4
The preparation method of the dolacizumab solution for soft mist inhalation is as follows: a solution of 5ml of DOVALUMAb (25mg/ml or 50mg/ml) was prepared by adding and dissolving L-histidine, L-histidine hydrochloride monohydrate, alpha-trehalose dihydrate and polysorbate 80 in 4ml of sterile water according to Table 4. The solution was then adjusted to the target pH with hydrochloric acid. Finally, sterile water was added to a final volume of 5 ml.
Table 4 formulation component content for sample I and sample II
Example 5
The preparation method of bevacizumab solutions for soft mist inhalation was as follows: according to table 5, a 5ml solution of bevacizumab (15mg/ml or 25mg/ml) was prepared by adding alpha, alpha-trehalose dihydrate, sodium phosphate (monovalent), sodium phosphate (divalent) and polysorbate 80 to 4ml sterile water. The solution was adjusted to the target pH with hydrochloric acid. Finally, sterile water was added to a final volume of 5 ml.
Table 5, sample I and sample II formulation component content
Components
Sample I
Sample II
Bevacizumab (Avastin)
75mg
125mg
Alpha, alpha-trehalose dihydrate
180mg
300mg
Sodium phosphate (monovalent, monohydrate)
17.4mg
29mg
Sodium phosphate (divalent, anhydrous)
3.6mg
6mg
Polysorbate 20
1.2mg
2mg
pH
5.8
5.8
Sterile water
5ml
5ml