CN115137700B

CN115137700B - Dexmedetomidine aqueous solution preparation for reducing water loss rate

Info

Publication number: CN115137700B
Application number: CN202210310562.0A
Authority: CN
Inventors: 石新玥; 李扬强; 王万; 王震宇; 侯曙光
Original assignee: Sichuan Pu Et Pharmaceutical Co ltd
Current assignee: Sichuan Pu Et Pharmaceutical Co ltd
Priority date: 2021-03-29
Filing date: 2022-03-28
Publication date: 2024-07-26
Anticipated expiration: 2042-03-28
Also published as: CN115137700A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides a dexmedetomidine aqueous solution preparation for reducing water loss rate and a dexmedetomidine nasal spray for reducing water loss rate. The product provided by the invention remarkably reduces the water loss rate by optimizing the prescription composition into dexmedetomidine hydrochloride, glycerin, benzalkonium chloride, edetate disodium and water, stabilizes the content change of key components of the product by controlling the water loss rate, and improves the quality of the product.

Description

Dexmedetomidine aqueous solution preparation for reducing water loss rate

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dexmedetomidine aqueous solution preparation for reducing water loss rate.

Background

Dexmedetomidine, dexmedetomidine, (+) -4- [ (S) -1- (2, 3-dimethylphenyl) ethyl ] -1H-imidazole, is a non-narcotic alpha-2 adrenergic receptor agonist with sympatholytic, sedative and analgesic properties developed by the company Orion Pharma and Abbott.

The dexmedetomidine is used in the form of aqueous solutions, whether in the form of injection solutions which are already on the market or in the form of solution nasal sprays which are still under development. The Chinese drug administration, the guidelines of the chemical drug (bulk drug and formulation) stability research technology, states that "the potential water loss of aqueous formulations packaged in semi-permeable containers should also be assessed. "," formulation packaged in semi-permeable container, is left for 3 months at 40 ℃ and no more than 25% RH, and the water loss is 5% from the initial value, i.e. it is considered to have significant variation. However, for small volumes (1 mL or less) or single dose packaged formulations, a water loss of 5% or more is acceptable when left for 3 months at 40℃ and no more than 25% RH. "semi-permeable container" refers to a container that prevents the loss of solute, but allows the passage of solvent, particularly water. Including plastic flexible and semi-rigid plastic bags, low Density Polyethylene (LDPE) high volume parenteral formulation bags (LVPs), and low density polyethylene ampoules, bottles, vials and the like. "including the aforementioned guidelines", studies on inhibition of water loss of an aqueous solution preparation are generally focused on packing materials and structural sealability, and studies on the relationship between the prescription composition of an aqueous solution preparation and water loss are rare. The first technical problem faced by the invention is the relationship between the prescription composition and the water loss of the system in the dexmedetomidine aqueous solution preparation.

In the solution type dexmedetomidine nasal spray, the package material is mainly composed of a metering pump and a container, the container is usually made of non-permeable borosilicate glass, and according to the guidelines, the non-permeable container can prevent water from passing through, and water loss research is not needed. However, as a multi-dose, semi-open preparation, dexmedetomidine nasal spray requires the presence of an airway in communication with the outside for compression of the spray due to inherent characteristics, and loss of solvent from the preparation may volatilize from the tiny airways of the metering pump, rather than through the walls of the container, based on which the improved technology of prior art partial nasal spray devices is directed to reducing the loss of liquid drug from the nasal spray by improving the structural sealing properties of the device. However, since the liquid medicine is always communicated with the outside through the tiny air passage of the metering pump, the water loss rate of the nasal spray is difficult to accurately and stably control to a reasonable range by simply relying on the sealing performance of devices such as a sealing ring and the structure. Since water loss = 100% of water loss value/loading, for low-loading (referring to a loading volume of less than 5mL, for example, a loading volume of 2mL for dexmedetomidine nasal spray), a trace amount of water loss may lead to a higher water loss rate, while too high a water loss rate may cause significant changes in product quality attributes such as press times, content, etc. Therefore, the invention is next to the technical problem that the water loss rate of the low-loading, multi-dose and semi-open preparation of the dexmedetomidine nasal spray is difficult to control.

Disclosure of Invention

In order to solve the problems in the prior art, the invention aims to provide a novel dexmedetomidine aqueous solution preparation and a dexmedetomidine nasal spray containing the same, which realizes reasonable control of the water loss rate of the preparation through the optimization of prescription composition unexpectedly.

The invention surprisingly found that in the aqueous dexmedetomidine formulation, inhibition of the water loss rate of the formulation can be achieved by a combination of glycerol and benzalkonium chloride at specific concentrations. Based on the above, the invention provides the following technical scheme:

An aqueous dexmedetomidine solution formulation comprising dexmedetomidine or a salt thereof, glycerin as an osmotic pressure regulator and benzalkonium chloride as a preservative. According to a specific embodiment of the present invention, the concentration of glycerin may be selected to be 0.1% -5.0% or 2.5% -2.8% by mass. The mass percentage concentration of the benzalkonium chloride can be selected to be 0.002% -0.02%. Compared with the scheme that the osmotic pressure regulator is NaCl, the glycerol and benzalkonium chloride are used in combination, so that the water loss in the dexmedetomidine aqueous solution preparation system can be obviously inhibited.

In order to reduce the influence of the preparation on the nasal mucosa injury, the mass percentage concentration of benzalkonium chloride in the dexmedetomidine aqueous solution preparation can be reduced to 0.005% -0.0085%. The unstable antiseptic antibacterial effect brought by lowering the concentration of benzalkonium chloride, especially the unstable antibacterial effect for escherichia coli, can be solved by adding a small amount of edetic acid or salt thereof, so that the preparation can meet the antibacterial effect standard required by pharmacopoeia again, and can effectively inhibit the growth of bacteria or fungi such as escherichia coli, and the like, wherein the mass percent concentration of the addition of the small amount of edetic acid or salt thereof is 0.005-0.015%, especially 0.005-0.01% of disodium edetate. In view of reducing damage to nasal mucosa and satisfactory bacteriostatic efficacy, aqueous formulations of dexmedetomidine may be provided without more irritating preservative than benzalkonium chloride, or even without any preservative other than benzalkonium chloride, and it should be stated that "glycerin, edetate disodium, dexmedetomidine and dexmedetomidine hydrochloride" as referred to in the formulation prescription of the present invention are not included in "other preservative" herein.

The aqueous dexmedetomidine formulations provided herein may contain a therapeutically effective amount of dexmedetomidine having a concentration of 0.005% to 1.3%, 0.0125% to 0.7% or 0.006% to 0.108% by mass, based on dexmedetomidine as disclosed in the art, and optionally 0.01%, 0.015%, 0.02%, 0.03% or 0.05% by mass of dexmedetomidine, according to embodiments of the present invention, which may preferably be provided as the hydrochloride salt.

According to the specific embodiment provided by the invention, the dexmedetomidine aqueous solution preparation consists of 0.005-1.3% of dexmedetomidine, 2.5-2.8% of glycerin, 0.005-0.0095% of benzalkonium chloride, 0.005-0.0095% of edetate disodium and the balance of water.

The invention also provides a dexmedetomidine nasal spray, which comprises a nasal spray device and the dexmedetomidine aqueous solution preparation provided by the invention, wherein the dexmedetomidine aqueous solution preparation is loaded in a container of the nasal spray device.

The nasal spray device includes a metering pump and a container in combination, and according to embodiments of the present invention, the container may be a borosilicate glass container having a volume of no more than 5mL, and the metering pump may be an upper vent metering pump. The combination mode of the metering pump and the container can be bayonet, screw or clamping.

Further studies with water loss of dexmedetomidine nasal spray have found that an excessively high water loss rate unexpectedly has a significant adverse effect on the stability of API and preservative of dexmedetomidine nasal spray. Thus, the dexmedetomidine nasal spray should preferably have a water loss rate of less than 12.03% during its shelf life, and more preferably a water loss rate of less than 10% during its shelf life, and most preferably less than 8.82% as demonstrated by embodiments of the present invention. The term expiration date is usually chosen to be within 2 years. In particular, the water loss rate in the inversion jump still meets the requirement in the effective period. According to the verification of the specific embodiment of the invention, the provided dexmedetomidine nasal spray preferably has a water loss rate of less than 12.03%, especially less than 10%, especially less than 8.82% within 24 months under intermediate conditions of 30 ℃ and 65% RH. It is further preferred that the water loss rate in 6 months is less than 12.03%, especially less than 10%, especially less than 8.82% under acceleration conditions of 40 ℃, 25% rh. The dexmedetomidine nasal spray obtained by optimizing the prescription can conveniently control the water loss rate of the preparation so as to achieve the control standard of the water loss rate, and further realize good control on the product quality, particularly the stability of the API and the preservative.

Detailed Description

In the present invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by the industry.

In the present invention, the reagents and instruments mentioned are obtained by ordinary commercial purchase unless otherwise specified.

In the invention, the conversion coefficient of the dexmedetomidine hydrochloride and the dexmedetomidine is approximately converted by 1.182.

In the present invention, "%" as used herein refers to "mass percent", unless otherwise specified.

In the present invention, the water content in the dexmedetomidine nasal spray formulation is the vast majority, so the density is approximately calculated as the density of water of 1 g/mL. 10mL of the aqueous solution containing 1mgBKC examples of the dexmedetomidine nasal spray had a mass (g) volume (mL) concentration of BKC expressed as 0.01% (W/V) and a mass percentage concentration of BKC expressed as 0.01% (W/W).

In the invention, BKC is English shorthand of benzalkonium chloride. EDTA-2Na is disodium edentate, also known as disodium edetate.

The invention will be further illustrated with reference to specific examples.

Example 1: water loss test of dexmedetomidine aqueous solution formulation

1. Test prescription

TABLE 1

Note that: [1] the conversion coefficient of the dexmedetomidine hydrochloride and the dexmedetomidine is 1.182 based on the dexmedetomidine, and the dexmedetomidine hydrochloride are dried and pure; [2] benzalkonium chloride is calculated as the sum of the total amounts of n-C ₁₂H₂₅ and n-C ₁₄H₂₉ homologs, on a dry basis.

2. Preparation method

Preparing sample solution according to the above table, filling the sample with a filling amount of 1.0-2.0 ml, and assembling the rolling cover in different combination modes of a metering pump (upper exhaust metering pump is selected in the test) and a container (borosilicate glass is selected in the test) to prepare a plurality of dexmedetomidine nasal sprays of various types.

3. Water loss investigation test

After the initial weight of 0d is weighed and recorded, the sample is placed under the stability condition (acceleration and middle), the recorded weight is weighed and recorded at different time nodes, the sample is placed until the stability condition is inspected and recorded, and the stability inspection is finished.

4. Test results

The water loss rate was calculated as water loss rate (%) = (0 d weight-time point of investigation weight)/loading 100%. The average water loss rate of the dexmedetomidine nasal spray of the same device combination at each time node was calculated and the test results of the acceleration conditions and intermediate conditions are listed in the following table. In the table, "d" is simply written as "day" and represents the number of days; "m" is abbreviated "monta" and represents the number of months.

TABLE 2

Note that: [1] "/" represents undetected; [2] the calculation formula of the 6m predicted value is as follows: the measured water loss rate at the longest investigation time point of the formulation/the measured longest investigation time is the predicted time.

TABLE 3 Table 3

Note that: [1] "/" represents undetected; [2] the 24m predicted value calculation formula is: the measured water loss rate at the longest investigation time point of the formulation/the measured longest investigation time is the predicted time.

The experimental results in the table above are combined to show that:

the inverted water loss rate of the dexmedetomidine nasal spray is in a trend of quick and slow, water loss is quick in 0-1 month, and then the water loss is gradually slowed down, so that the measured water loss rate in the initial stage of a sample is accelerated for 6 months and 24 months in the middle according to linear calculation prediction, the worst water loss result can be predicted, and the calculation mode is as follows: the measured water loss rate at the longest measurement time point of the preparation/the measured longest measurement time of the preparation is the predicted time (for example, under the acceleration condition, the water loss rate at the measured longest measurement time point of the preparation 1 is 13.60% of 2 months, so that the predicted water loss rate at 6 months is=13.6%/2*6 =40.8%), and the calculated theoretical worst predicted value and measured value can be respectively compared to investigate the influence of the prescription change on the water loss rate of the dexmedetomidine nasal spray sample.

The accelerated water loss inspection test results of the preparation 1-4 show that the sample solution dexmedetomidine nasal spray of the prescription 1 has serious water loss phenomenon under different metering pump and container combination modes no matter whether the dosage form contains a suction pipe or the container has larger or smaller capacity. The degree of sealing is different in the combination mode of different metering pumps and containers, but the three typical combination modes of bayonet type, screw type and clamping type have no obvious influence on the water loss inhibition of the dexmedetomidine nasal spray.

The accelerated condition water loss investigation test result of the preparation 5 shows that after the preparation prescription is optimally adjusted, the water loss rate of the dexmedetomidine nasal spray based on the sample solution of the prescription 2 is obviously reduced, and compared with the preparation 3 prescription in a metering pump and container clamping combination mode, the water loss problem of the sample is obviously improved. In the further formulation 3 and formulation 5 intermediate conditions, formulation 5 included an optimized formulation 2 sample solution with a significantly lower water loss rate than formulation 3 containing the formulation 1 sample solution.

The unexpected discovery reveals and provides a novel means for solving the problem of water loss of the dexmedetomidine aqueous solution preparation and particularly the dexmedetomidine nasal spray inversion through prescription adjustment, and has great significance for the production, storage, product quality control and the like of the dexmedetomidine aqueous solution preparation and the dexmedetomidine nasal spray.

Example 2: influence of water loss rate on the quality of dexmedetomidine nasal spray product

Dexmedetomidine nasal spray samples of different water loss rates were selected for content detection as shown in the following table:

TABLE 4 Table 4

The result shows that the content change of the key components in the sample and the water loss rate are not completely consistent and have a linear relation, but when the water loss rate reaches a certain degree, the content of the key components in the sample is changed drastically, so that the quality of the product is out of control. When the water loss rate is below 8.82%, the API and BKC contents of the sample are not changed significantly, which shows that when the water loss rate is below 8.8%, the influence of water loss on the content of key components is small. When the water loss is increased to 12.03%, the contents of the API and the BKC are obviously increased, the API content + -10% is taken as a control limit, the API content is changed to 8.3% and approaches to the upper limit of the control limit, the BKC content is changed to 5.00%, and the water loss rate is obviously changed, so that the risk of influencing the content change of the key components is higher. Therefore, the water loss rate of the product during the stability period is controlled to be smaller than 12.03 percent of the actually measured water loss rate, the influence on the content of the key components is smaller when the water loss rate is further below 8.82 percent, and the quality control of the product can be realized by controlling the water loss rate.

The aqueous dexmedetomidine formulations and nasal dexmedetomidine sprays provided herein (e.g., as provided in example 1) allow for control of the water loss rate of the product at relatively low levels (e.g., 6m under the accelerated conditions of example 1, 8.02% water loss, 24m under intermediate conditions, 6.67%) by optimizing the formulation, much less than 12.03% water loss that may cause significant changes in the key component content of the product. Therefore, the invention can solve the water loss problem of the preparation by optimizing the dexmedetomidine aqueous solution preparation and the dexmedetomidine nasal spray provided by the prescription, and can also solve the problem of the content change of key components of the product caused by excessive water loss, thereby realizing good control of the product quality. Furthermore, as the intermediate condition and the accelerating condition adopted in the study of the embodiment 1 are the test conditions for water loss investigation in the guidelines, the water loss of the product under low humidity is more obvious compared with the intermediate condition and the accelerating condition. Because the product provided by the invention under the acceleration condition of 25% RH with lower humidity can meet the water loss control requirement, the water loss rate of the product provided by the invention can be far lower than that of the intermediate condition and the acceleration condition under other stability investigation conditions, and the content of key components of the product provided by the invention in the effective period of 2 years can be predicted to be stable and the water loss rate is controlled.

The invention is not limited to the alternative embodiments described above, but any person may derive other various forms of products in the light of the present invention. The above detailed description should not be construed as limiting the scope of the invention, which is defined in the claims and the description may be used to interpret the claims.

Claims

1. A dexmedetomidine nasal spray comprising a nasal spray device and an aqueous dexmedetomidine formulation, the aqueous dexmedetomidine formulation being contained in a container of the nasal spray device;

the dexmedetomidine aqueous solution preparation consists of dexmedetomidine, glycerin with the mass percentage concentration of 0.1% -5.0%, benzalkonium chloride with the mass percentage concentration of 0.005% -0.01%, edetate disodium with the mass percentage concentration of 0.005% -0.01% and the balance of water;

The dexmedetomidine exists in the form of dexmedetomidine hydrochloride, and the mass percentage concentration of the dexmedetomidine is 0.005% -0.05% based on the dexmedetomidine.

2. The dexmedetomidine nasal spray of claim 1 wherein the concentration of glycerin is 2.5% -2.8% by mass.

3. Dexmedetomidine nasal spray according to claim 1, characterized in that the concentration of glycerin in mass percentage is 2.7%.

4. The dexmedetomidine nasal spray of claim 1, wherein the concentration of benzalkonium chloride is 0.005% -0.0095% by mass.

5. The dexmedetomidine nasal spray of claim 1, wherein the benzalkonium chloride mass percentage concentration is 0.005% or 0.0075%.

6. The dexmedetomidine nasal spray of claim 1, wherein the concentration of the edetate disodium is 0.005% -0.0095% by mass.

7. The dexmedetomidine nasal spray of claim 1, wherein the concentration of the edetate disodium is 0.005% or 0.0075% by mass.

8. The dexmedetomidine nasal spray of claim 1 wherein the concentration by mass percent thereof is 0.01%, 0.015%, 0.02%, 0.03% or 0.05% based on dexmedetomidine.

9. The dexmedetomidine nasal spray of any one of claims 1-8, wherein the nasal spray device includes a metering pump and a container in combination with one another.

10. The dexmedetomidine nasal spray of claim 9 wherein the metering pump is an upper vent metering pump.

11. The dexmedetomidine nasal spray of claim 9 wherein the container is a borosilicate glass container having a volume of no more than 5 mL.

12. The dexmedetomidine nasal spray of claim 9 wherein the metering pump and container are combined in a bayonet, screw or clip type.

13. Dexmedetomidine nasal spray according to claim 1, characterized in that it has a water loss rate of less than 12.03% during the period of validity.

14. The dexmedetomidine nasal spray of claim 13 wherein the rate of water loss during the period of effectiveness is less than 10%.

15. The dexmedetomidine nasal spray of claim 13 wherein the rate of water loss during the period of effectiveness is less than 8.8%.

16. The dexmedetomidine nasal spray of claim 13 wherein the period of validity is within 2 years; in an inverted condition.

17. The dexmedetomidine nasal spray of claim 1, wherein it has a water loss rate of less than 12.03% over 24 months at 30 ℃, 65% rh in intermediate conditions.

18. The dexmedetomidine nasal spray of claim 17, wherein the rate of water loss over 24 months is less than 10% at intermediate conditions of 30 ℃, 65% rh.

19. The dexmedetomidine nasal spray of claim 17, wherein the water loss rate over 24 months is less than 8.8% at intermediate conditions of 30 ℃ and 65% rh.

20. The dexmedetomidine nasal spray of claim 1, wherein it has a water loss rate of less than 12.03% within 6 months under acceleration conditions of 40 ℃ and 25% rh.

21. The dexmedetomidine nasal spray of claim 20, wherein the rate of water loss is less than 10% within 6 months at 40 ℃ and 25% rh acceleration.

22. The dexmedetomidine nasal spray of claim 20, wherein the rate of water loss over 6 months is less than 8.8% at 40 ℃ and 25% rh acceleration.