CN115212115A

CN115212115A - Nasal feeding administration of zebritinib

Info

Publication number: CN115212115A
Application number: CN202111137657.9A
Authority: CN
Inventors: 仇罡
Original assignee: Baiji Shenzhou Suzhou Biotechnology Co ltd
Current assignee: Baiji Shenzhou Suzhou Biotechnology Co ltd
Priority date: 2021-09-27
Filing date: 2021-09-27
Publication date: 2022-10-21

Abstract

The present invention relates to nasal feeding administration of zerewitinoib, and provides a method of delivering a composition comprising zerewitinoib to an individual in need thereof, comprising: providing a drug delivery device to the nasal cavity of the subject; and providing a feeding unit for delivering the composition comprising zetinib nasally to the stomach by the drug delivery device. The invention provides an acceptable administration mode for patients with dysphagia of the zetinib capsule; and this mode of administration can be achieved by existing formulation products without the need for modification or adaptation thereof.

Description

Nasal feeding administration of zebritinib

Technical Field

The present invention relates to the nasal feeding administration of zetinib, in particular to a method and a nasal feeding administration system for the intranasal administration of zetinib to the stomach in combination with a medical device.

Background

International application WO2014173289A discloses a novel Bruton' S Tyrosine Kinase (BTK), more specifically (S) -7- [4- (1-acryloylpiperidine) ] -2- (4-phenoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide (generic name zebrafenib), having the chemical structure:

zertinib belongs to a second generation BTK inhibitor that irreversibly inactivates the enzyme by covalently binding to tyrosine kinase. It can be used for treating B lymphocyte tumor by single drug or in combination with other drugs, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle Cell Lymphoma (MCL), waldenstrom's Macroglobulinemia (WM), follicular Lymphoma (FL), non-germinal center subtype diffuse large B cell lymphoma (non-GCB DLBCL), etc.

The bulk drug (API) of zertinib is slightly hygroscopic. DSC results show that the compound has a definite endothermic peak when being melted, the initial temperature and the peak temperature are 139 ℃ and 144 ℃ respectively, and the sticking phenomenon is easy to occur. The prior art has improved the problems of high stickiness, poor flowability, etc. of the zetidine powder by selecting suitable excipients and provided tablets and capsules of zetidine.

However, for dysphagia patients (e.g., covid19 critically ill patients), the tablets and capsules of zetinib do not meet their requirements. Thus, there remains a need for new modes of administration of zerewitinoid to meet the needs of specific patients.

Disclosure of Invention

To address compliance of dysphagia patients, the present invention provides a method of delivering a composition comprising zerewitinib to an individual in need thereof. The method comprises the following steps: providing a drug delivery device to an individual via the nasal cavity; and providing a delivery unit for delivering the composition comprising zetinib nasally to the stomach by the drug delivery device.

In some embodiments, the method further comprises: providing an airflow through the delivery device into the nasal cavity during delivery of the composition comprising zerewitinoib.

In some embodiments, the method further comprises: after delivery of the composition comprising zerewitinonib, water for injection or coca-cola is delivered.

In some embodiments, the delivery device is selected from a nasogastric tube or a feeding tube. The nasogastric or feeding tube has a diameter in the range of about 2mm to about 6 mm. In preferred embodiments, the nasogastric or feeding tube comprises a length adjustment mechanism. In a preferred embodiment, the nasogastric or feeding tube comprises a fixation mechanism. In some embodiments, the securing mechanism comprises an adhesive.

In some embodiments, the supply unit is a medical injector.

In some embodiments, the individual is a human.

In some embodiments, the composition comprises zerewitinib, a filler, a disintegrant, a wetting agent, a glidant, and a lubricant.

In some embodiments, the zerewitinib may be in any solid form thereof, such as a crystalline form (e.g., form a disclosed in WO 2018033853A) or amorphous form or a mixture of crystalline form and amorphous form, preferably, the zerewitinib is crystalline form a, amorphous form, or a mixture of crystalline form a and amorphous form. The particle size of the zertinib is less than or equal to 40 mu m, and the mass percentage of the zertinib is 20-70%, preferably 20-50%, relative to the total mass of the composition.

In some embodiments, the filler is selected from the group consisting of starch, sucrose, microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof, and is present in an amount of 20% to 90%, preferably 30% to 80%, by mass relative to the total mass of the composition. The average particle diameter of the filler is preferably 100 to 200 μm. More preferably, the average particle size of the filler is the same as the average particle size of the drug substance.

More preferably, the filler is microcrystalline cellulose or a mixture of microcrystalline cellulose and colloidal silicon dioxide, or anhydrous calcium hydrogen phosphate is further added. Further preferably, the filler is microcrystalline cellulose, and the mass percentage of the microcrystalline cellulose with respect to the total mass of the composition for oral capsules is 30% to 80%.

In some embodiments, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof; and the mass percent of the disintegrating agent is 0.5-5%, preferably 1-3% relative to the total mass of the composition. More preferably, the disintegrant is croscarmellose sodium.

In some embodiments, the wetting agent is sodium lauryl sulfate, and the mass percentage of sodium lauryl sulfate relative to the total mass of the composition is 0% to 5%, preferably 0.5% to 1.0%.

In some embodiments, the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc, and any combination thereof, and is present in an amount from 0.1% to 20%, preferably from 0.1% to 0.5% by mass relative to the total mass of the composition. More preferably, the glidant is colloidal silicon dioxide.

In some embodiments, the lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium fumarate stearate and any combination thereof, and is present in a mass percentage of 0.1% to 2%, preferably 0.3% to 1%, relative to the total mass of the composition. More preferably, the lubricant is magnesium stearate.

In some embodiments, the composition comprising zerewitinib of the present invention is not particularly limited as long as it is a dosage form capable of transmucosal absorption, and may be, for example, a powder, a solution, a suspension, an emulsion, a paste, a gel, a paste, or the like. Preferably, the composition comprising zerewitinoib is delivered as a liquid. In some embodiments, the osmolality of the formulation is adjusted by an isotonic agent. The isotonic agent is not particularly limited as long as it is a substance that normally acts as an isotonic agent, and it may be contained in 1 or 2 or more kinds in a solution, suspension or emulsion, and examples thereof include sodium chloride, potassium chloride, magnesium chloride, fructose, citric acid, sodium citrate, glycerin, physiological saline, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like.

In some embodiments, as the concentration of the liquid formulation, there is no particular limitation as long as it is a concentration suitable for nasal feeding administration, and the upper limit may be 1000mg/ml, preferably 600mg/ml, preferably 400mg/ml, preferably 300mg/ml, preferably 250mg/ml, and the lower limit may be 10mg/ml, preferably 25mg/ml, preferably 50mg/ml, preferably 100mg/ml, preferably 125mg/ml, preferably 150mg/ml, in terms of zebertinib. As the amount of liquid to be administered per nasal feeding delivery, the upper limit may be 200ml, preferably 180ml, preferably 150ml, preferably 120ml, preferably 100ml, preferably 80ml, preferably 50ml, and the lower limit may be 5ml, preferably 10ml, preferably 20ml, preferably 30ml, preferably 40ml.

In some embodiments, the administration may be 1 or 2 or more times per day as a number of nasal feeding delivery administrations per day. The number of times can be selected as appropriate. When the preparation of the present invention is administered by nasal feeding, the administration may be performed from one nostril or from both nostrils for 1 administration in a desired amount.

In some embodiments, the composition comprising zertinib is formulated as a suspension using water for injection or coca-cola. In some embodiments, a powder or a zetidine tablet in a commercially available zetidine capsule is suspended or mixed with an amount of water for injection or coca-cola to obtain the desired zetidine suspension or solution.

In some embodiments, the method of preparing a zerewitinoib suspension or solution comprises the steps of: i) Premixing zerewitinoib, a disintegrant, a wetting agent, and a portion of a filler to obtain a premix, and then sieving to obtain a 1 st mixture; ii) sieving the glidant and the rest of the filler, and adding the sieved glidant and the rest of the filler to the 1 st mixture obtained in the step i) for mixing to obtain a 2 nd mixture; iii) Sieving and adding the lubricant to the 2 nd mixture obtained in step ii), followed by mixing to obtain a final mixture; and iv) dissolving the final mixture using a solvent to obtain the zebrafenib suspension or solution. In some embodiments, the pre-mixing in step i) is performed at a speed of 10rpm to 25rpm for 2 minutes to 10 minutes, and the mesh size of the mesh used for the sieving is 1.0mm to 2.5mm. In some embodiments, the mixing in step ii) is performed at a speed of 10 to 20rmp for 3 to 5 minutes. In some embodiments, the sieving in step ii) is performed at a rotational speed of 550rmp to 650rmp, and the sieve used for sieving has a mesh size of 1.0mm to 2.5mm. In some embodiments, the mixing in step iii) is performed at a speed of 10rpm to 15rpm for 3 minutes to 6 minutes, and the mesh size of the screen used for the sieving is 35mm to 45mm. In some embodiments, the solvent used in step iv) is water for injection or coca-cola.

According to another aspect of the present invention, there is provided a method of modulating a condition in a human subject using a composition comprising zerewitinib. The method comprises the following steps: providing a drug delivery device to the human subject nasally; and providing a delivery unit for delivering the composition comprising zetinib nasally to the stomach by the drug delivery device.

In some embodiments, the condition is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer.

In some embodiments, the condition is a B cell proliferative disease selected from chronic lymphocytic lymphoma, non-hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma, and full blood lymphocytic leukemia.

In some embodiments, the method further comprises: providing an airflow through the drug delivery device into the nasal cavity during delivery of the composition comprising zerewitinoib.

In some embodiments, the method further comprises: after delivery of the composition comprising zertinib, water for injection or coca cola is delivered.

In some embodiments, the drug delivery device is selected from a nasogastric or feeding tube. The nasogastric or feeding tube has a diameter in the range of about 2mm to about 6 mm.

In some embodiments, the supply unit is a syringe.

In some embodiments, the composition comprising zerewitinib is delivered as a liquid, wherein the solvent is water for injection or coca-cola.

According to yet another aspect of the present invention, there is provided a nasal feeding drug delivery system comprising: a medical syringe filled with a composition comprising zerewitinoib and a drug delivery device in fluid communication with the medical syringe. In some embodiments, the drug delivery device is selected from a nasogastric or feeding tube.

The invention has the beneficial effects that: i) Provides an acceptable administration mode for patients with difficulty in swallowing zerewitinib capsules or tablets (such as severe Covid19 patients), namely, solves the compliance of the patients;

ii) this mode of administration can be achieved by existing formulation products without the need for modification or adaptation thereof;

iii) The water for injection or the coca cola is selected, and the good dispersibility of the existing zetinib preparation can be realized by simple shaking; for example, when 320mg drug loading is dispersed with 50mL water for injection or Coca Cola, good dispersion can be achieved by shaking manually for 5 seconds, and no precipitate is found in the solution by visual inspection;

iv) because the composition comprising zerewitinoib is capable of being rapidly dispersed in, for example, water and coca-cola, larger doses can be achieved using less solvent; and

v) compared to the zerewitinoside capsules or tablets, the suspension formulations of the present invention have good therapeutic effect and absorption and fast onset of action.

Detailed Description

Technical terms

Unless defined otherwise, 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.

As used herein, the terms "comprises," "comprising," or any other variation thereof, mean that the compositions and methods described, etc., include the recited elements and do not exclude others.

All ranges cited herein are inclusive unless expressly stated to the contrary; that is, the range includes the values of the upper and lower limits of the range, as well as all values in between. For example, temperature ranges, percentages, equivalent ranges, and the like, as described herein, include the upper and lower limits of the ranges, and any value for the continuum between them.

The compositions of the present invention comprise a mixture of the active ingredient with other chemical ingredients.

Examples

The following examples may assist those skilled in the art in a more complete understanding of the present invention, but are not intended to limit the invention in any way. The auxiliary materials are all available on the market.

Example 1

The formulation of the composition comprising zerewitinoib (total 320 mg) was as follows: zebritinib (form a): 80.00mg; microcrystalline cellulose: 263.80mg; croscarmellose sodium: 10.80mg; colloidal silica: 1.8mg; sodium lauryl sulfate: 1.8mg; and magnesium stearate: 1.8mg.

The preparation method of the composition comprising zerewitinoib is as follows:

(1) Adding zetinib, sodium lauryl sulfate, croscarmellose sodium and 60.28% microcrystalline cellulose into a mixing hopper, and then mixing at a speed of 20rpm for 3 minutes; the pre-mixed material was sieved by a cone-type sieving machine with a mesh size of 1.5mm and a granulator speed of 600rpm, the sieved material was transferred back to the mixing hopper and then mixed at 20rpm for 20 minutes.

(2) Sieving the rest part of microcrystalline cellulose and colloidal silicon dioxide together, wherein the aperture of the used sieve is 1.5mm, and the rotating speed of the granulator is 600rpm; the sieved material was transferred to a mixing hopper and then mixed for 5 minutes at 20 rpm.

(3) And (3) sieving magnesium stearate with a 40-mesh sieve, adding into a mixing hopper, and mixing at the rotating speed of 20rpm for 5 minutes to obtain mixed powder.

Preparation of the suspension:

320mg of the above composition containing zetidine was poured into a medical reagent bottle containing 50mL of water for injection and shaken by hand for 5-10 seconds to obtain the desired formulation. After allowing the formulation to stand for 10 minutes, no precipitate was observed by visual inspection.

The delivery test of the formulation was as follows:

test equipment: emulsion tube (made by Watson Marlow, silica gel) with diameter of 3.2mm and medical injection (commercially available conventional medical disposable syringe, matching with emulsion tube diameter) with volume of 100ml

The test method comprises the following steps:

the formulation of example 1 was withdrawn using the medical injection;

delivering the formulation via an emulsion tube; and

using the medical injection, 50mL of additional water for injection was withdrawn and the syringe and emulsion tube were flushed.

The preparation has high fluidity in the whole delivery process, the delivery is rapid, and the walls of the injector and the emulsion tube are transparent after the delivery is finished without medicine residue.

Example 2

A formulation is prepared in a similar manner to example 1, except that 50mL of coca-cola is substituted for 50mL of water for injection in example 1. After the suspension was allowed to stand for 10 minutes, no precipitate was observed by visual inspection.

At the same time, the formulation of example 2 was delivered in a similar manner to example 1, and 50mL of additional coca-cola was withdrawn with the medical injection and the syringe and emulsion tube were flushed.

The suspension liquid has high fluidity in the whole delivery process, the delivery is rapid, and the walls of the injector and the emulsion tube are transparent after the delivery is finished without drug residue.

The invention has been described in detail with respect to the general description, specific embodiments and experiments, and it is intended that modifications or improvements can be made without departing from the spirit of the invention and within the scope of the claims.

Claims

1. A nasal feeding drug delivery system comprising: a medical syringe filled with a composition comprising zerewitinoib and a drug delivery device in fluid communication with the medical syringe.

2. The nasogastric administration system of claim 1, wherein said drug delivery device is selected from nasogastric or feeding tube, preferably said nasogastric or feeding tube having a diameter in the range of about 2mm to about 6 mm.

3. A nasogastric administration system according to claim 1 or 2, wherein the nasogastric tube or feeding tube comprises a length adjusting mechanism and a fixing mechanism.

4. The nasogastric delivery system of claim 3, wherein said securing mechanism is an adhesive.

5. The nasogastric delivery system of any one of claims 1-4, wherein said composition comprises zerewitinoib, a filler, a disintegrant, a wetting agent, a glidant, and a lubricant.

6. The nasogastric delivery system of any one of claims 1-5, wherein said zebritinib is crystalline form A, amorphous, or a mixture of crystalline form A and amorphous.

7. The nasogastric delivery system of any one of claims 5-6, wherein said filler is selected from the group consisting of starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose and any combination thereof.

8. The nasal feeding delivery system according to any one of claims 5-7, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate and any combination thereof.

9. The nasogastric delivery system of any one of claims 5-8, wherein said wetting agent is sodium lauryl sulfate, said sodium lauryl sulfate being present in an amount of 0-5%, preferably 0.5-1.0%, all by mass.

10. The nasogastric delivery system of any one of claims 5-9 wherein said glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc and any combination thereof.

11. The naso-administration system according to any one of claims 5-10, wherein said lubricant is selected from the group consisting of zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium fumarate stearate and any combination thereof.

12. The nasogastric delivery system of any one of claims 1-11, wherein said composition further comprises water for injection or coca-cola, and is in the form of a solution or suspension.

13. A method of delivering a composition comprising zerewitinoib to an individual in need thereof, comprising:

providing a drug delivery device to the nasal cavity of the individual; and

providing a delivery unit for nasally delivering the composition comprising zertinib to the stomach through the drug delivery device.

14. The method of claim 13, further comprising: providing an airflow through the drug delivery device into the nasal cavity during delivery of the composition comprising zerewitinib.

15. The method of claim 13 or 14, further comprising: after delivery of the composition comprising zertinib, water for injection or coca cola is delivered.

16. The method of any one of claims 13-15, wherein the drug delivery device is selected from a nasogastric or feeding tube.

17. The method of any one of claims 13-16, wherein the supply unit is a syringe.

18. The method of any one of claims 13-17, wherein the individual is a human.

19. The method of any one of claims 13-18, wherein the composition comprising zerewitinoib is delivered as a liquid, wherein the solvent is water for injection or coca-cola.

20. A method of modulating a condition in a human subject using a composition comprising zerewitinoib, comprising:

providing a drug delivery device to the human subject nasally; and

21. The method of claim 20, wherein the condition is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer.

22. The method of claim 20, wherein the condition is a B cell proliferative disease selected from chronic lymphocytic lymphoma, non-hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma, and full blood lymphocytic leukemia.

23. The method according to any one of claims 20-22, further comprising: providing an airflow through the drug delivery device into the nasal cavity during delivery of the composition comprising zerewitinib.

24. The method according to any one of claims 20-23, further comprising: after delivery of the composition comprising zertinib, water for injection or coca cola is delivered.

25. The method of any one of claims 20-24, wherein the drug delivery device is selected from a nasogastric or feeding tube.

26. The method of any one of claims 20-25, wherein the supply unit is a syringe.

27. The method of any one of claims 20-26, wherein the composition comprising zerewitinoib is delivered as a liquid, wherein the solvent is water for injection or coca-cola.