Method for detecting in-vitro release rate of osmotic pressure drug-loaded microneedle patch device

Abstract

The invention discloses a method for detecting the in-vitro release rate of an osmotic pressure drug-loaded microneedle patch device, and belongs to the field of detection and evaluation of biomedical materials and medical instruments. A liquid collecting pipe sleeving the periphery of the hollow microneedle array is mounted on the microneedle patch device, one end of the liquid collecting pipe is sealed with the shell, and the other end of the liquid collecting pipe is open; liquid medicine is driven to flow through osmotic pressure difference, the device adopts an inverted mode to eliminate the gravity influence, and the osmotic pressure effect is specially investigated; the key physical environment of subcutaneous administration is simulated by dynamically regulating and controlling the equivalent hydraulic column, liquid medicine flowing out of the liquid collecting pipe is siphoned at a fixed time interval, the liquid level is kept at the needle point height of the hollow microneedle, and the average release rate and the instantaneous release rate are calculated according to recorded data. The problems that according to an existing traditional Franz diffusion cell method, real contribution of osmotic pressure driving cannot be accurately distinguished and quantified, the key physical environment of subcutaneous administration is difficult to simulate, and the liquid outlet amount in the injection process cannot be accurately captured and metered are solved.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and medical device testing and evaluation, and particularly relates to a method for detecting the in vitro release rate of an osmotically loaded drug microneedle patch device. Background Technology

[0002] With the rapid development of biomedical technology, microneedle drug delivery systems, as an innovative drug delivery method, have received widespread research and attention due to their advantages such as being painless or low-pain, requiring no syringes, and improving drug bioavailability and therapeutic effects.

[0003] However, based on existing technology, although microneedle devices can reduce the pain of traditional injections, their structure requires electric means to drive the solution flow, resulting in high overall complexity and making them difficult to replace and maintain. Furthermore, their drug release rate may not be precise enough and is easily affected by environmental factors. This patent previously provided an osmotic pressure-loaded drug-eluting microneedle patch device that drives the drug solution flow through osmotic pressure difference, eliminating the need for complex electric drives. This makes the entire device more compact and lightweight, reducing the possibility of malfunctions and maintenance difficulty. It further reduces pressure and discomfort on the skin. The overall structure is relatively simple, and it adopts a detachable and replaceable design, allowing users and caregivers to easily clean, maintain, and replace the device, avoiding complex maintenance operations and thus facilitating its use.

[0004] Existing in vitro release detection methods based on the Franz diffusion cell system have fundamental limitations in evaluating patches with microneedle puncture capabilities. These limitations primarily manifest in their inability to accurately distinguish and quantify the true contribution of osmotic pressure drive, their difficulty in simulating the key physical environment of subcutaneous drug delivery, and their inability to precisely capture and measure the volume of fluid output during the simulated injection process. Specifically, traditional methods require the sample to be upright (microneedle array face down), resulting in the measured drug output being essentially a superposition of the osmotic pressure drive effect and the gravity drainage effect. This makes it impossible to separate the contribution of the osmotic pressure drive force alone, distorting the assessment of the product's core performance osmotic pressure drive efficiency. Furthermore, existing technologies severely lack the ability to simulate the dynamic environment of real subcutaneous injection: as the drug is continuously injected into the simulated subcutaneous tissue through the microneedles, a dynamically increasing reverse pressure (back pressure) inevitably arises within the tissue due to fluid accumulation and tissue compliance. This pressure significantly inhibits the subsequent output rate and total volume of the drug solution, and is a key in vivo environmental factor determining the actual infusion rate and final dose. Current standard devices with static or slow-flow receiving cells cannot generate or regulate this dynamically increasing tissue back pressure that accumulates with the injected volume. Furthermore, simulating subcutaneous injection and accurately measuring the actual output volume in an in vitro environment presents significant challenges: direct release of the drug into the receiving medium (such as a liquid or simulated gel) results in rapid diffusion and dilution, making it difficult to completely and losslessly capture and recover all the delivered drug. Coupled with the lack of efficient separation and direct quantification methods, accurately quantifying the actual "volume of drug injected into subcutaneous tissue" (i.e., output volume) becomes extremely difficult and prone to significant errors. Therefore, traditional techniques cannot meet the comprehensive requirements of eliminating gravity interference under controllable conditions, simulating dynamic tissue back pressure, and simultaneously achieving high-precision output volume measurement, severely restricting the accurate and reliable evaluation of the in vitro release behavior of osmotic microneedle patches.

[0005] Therefore, developing an in vitro detection method that can eliminate gravitational interference, accurately simulate the subcutaneous dynamic back pressure environment, and simultaneously achieve high-precision direct measurement of fluid output during simulated injection is an indispensable core technological foundation for overcoming current bottlenecks in the development of osmotic pressure microneedle patches, improving the controllability of manufacturing processes and the reliability of product quality, establishing a highly predictive IVIVC model, and ultimately ensuring the safe and effective clinical application of products. The successful development and application of this method will have a profound and positive impact on the technological advancement, product development efficiency, and regulatory science level of osmotic pressure microneedle patches. Summary of the Invention

[0006] To achieve the aforementioned objectives, this invention aims to provide a method for detecting the in vitro release rate of an osmotically loaded drug-eluting microneedle patch device, enabling more accurate evaluation of the drug release performance of the osmotically loaded drug-eluting microneedle patch in practical applications. This provides reliable technical support for the quality control, formulation optimization, and in vitro release consistency evaluation of infusion patch products.

[0007] The technical solution adopted in this invention is as follows: The present invention provides a method for detecting the in vitro release rate of an osmotically loaded drug microneedle patch device. The osmotically loaded drug microneedle patch device includes a shell, and an upper liquid storage chamber and a lower drug loading chamber separated by a semi-permeable membrane inside the shell. The top of the shell is provided with an injection port communicating with the liquid storage chamber, and the bottom of the shell is provided with a hollow microneedle communicating with the drug loading chamber. It also includes a liquid collection tube fitted around the hollow microneedle array, with one end of the liquid collection tube sealed to the shell and the other end open; The detection method includes the following steps: Step 1): Inject solvent into the storage chamber through the injection port until droplets seep out from the tip of the hollow microneedle; Step 2): When the droplets in Step 1) seep out, it is considered that the experiment has started. The osmotic pressure drug microneedle patch device is inverted with the injection port facing down and immersed in a container containing the same solvent, and the timer is activated simultaneously. Step 3): Since the drug-loaded chamber is filled with solvent, the pre-loaded drug dissolves to form a saturated solution with a high osmotic pressure environment. This creates a positive osmotic pressure difference from the outside to the inside between the drug-loaded chamber and the solvent in the reservoir. This pressure difference drives the solvent in the reservoir to continuously permeate into the drug-loaded chamber through the semi-permeable membrane. At the same time, the permeation causes the volume of the drug-loaded chamber to expand, pushing the drug solution in the drug-loaded chamber into the collection tube through the hollow microneedles. The drug solution in the collection tube forms an equivalent hydraulic column to simulate the dynamic environment of real subcutaneous injection. Step 4): Record the time when the liquid reaches the tip height of the hollow microneedle, dynamically adjust the equivalent hydraulic column height, and collect the outflowing liquid in the sampling tube at fixed time intervals Δt to ensure that the remaining liquid level is maintained at the tip height of the hollow microneedle. Step 5): Calculate the average release rate based on the cumulative discharge time T and the cumulative discharge volume ΣV, and calculate the instantaneous release rate based on the discharge volume ΔV / Δt per unit time.

[0008] Furthermore, the osmotic pressure drug-loaded microneedle patch device also includes a top cover, fasteners, and a base. The top cover has an installation groove for mounting a filter membrane on its inner side, and the filter membrane is fixed by the fasteners. The base has a stepped groove on its inner side, and the top of the stepped groove is connected to the installation groove. A semi-permeable membrane is located on the stepped platform of the stepped groove, dividing the stepped groove into an upper liquid storage chamber and a lower drug loading chamber. The semi-permeable membrane is fixed by an elastic sealing ring, and the base is threadedly connected to the top cover.

[0009] Preferably, in step 1), the solvent is deionized water or physiological buffer solution.

[0010] Preferably, in step 2), the height of the solvent in the container is not higher than the tip height of the hollow microneedle.

[0011] As a preferred embodiment of the present invention, in step 4), the time interval Δt is less than 10% of the expected release cycle.

[0012] Specifically, the expected release period is obtained through a preliminary experiment. During the preliminary experiment, the drug solution in the collection tube is removed in real time to ensure that there is no outflow pressure, and the continuous outflow time is the expected release period.

[0013] Preferably, the solvent type and ambient temperature remain constant throughout the detection process.

[0014] As a preferred embodiment of the present invention, before the tip of the hollow microneedle leaks out droplets, there is no drug solution in the collection tube, and there is no back pressure. The drug solution in the drug-carrying chamber diffuses spontaneously, simulating the initial penetration of the subcutaneous space. As the amount of drug solution injected into the collection tube accumulates, the equivalent hydraulic column will generate an increasing back pressure, simulating the increase of tissue resistance in the body. The drug solution is drawn out from the collection tube by siphoning at fixed time intervals Δt, simulating local tissue absorption.

[0015] As a preferred embodiment of the present invention, the experiment was repeated, and a cumulative release curve was plotted based on the cumulative discharge time T and the cumulative discharge volume ΣV.

[0016] As a preferred embodiment of the present invention, the outer wall of the liquid collection tube is finely machined or printed with a series of continuous measurement scale marks along its length.

[0017] The beneficial effects of this invention are: This invention overcomes the shortcomings of traditional detection methods, which require the microneedle patch to be upright (microneedle array facing down), resulting in measurement results that are mixed with the dual effects of osmotic pressure driving and gravity drainage, making it impossible to accurately quantify the independent contribution of osmotic pressure. This invention innovatively uses an inverted testing method (microneedle array facing up), completely eliminating the interference of gravity on drug flow. This ensures that the output collected by the sampling tube purely reflects the effectiveness of the osmotic pressure driving force, thereby achieving a high-precision, unbiased quantitative assessment of the osmotic pressure driving effect.

[0018] This invention dynamically controls the height of the equivalent hydraulic column: before droplets seep from the tip of the hollow microneedle, there is no drug solution in the collection tube, and no back pressure. The drug solution in the drug-carrying chamber diffuses spontaneously, simulating the initial infiltration of the subcutaneous space. As the amount of drug injected into the collection tube accumulates, the equivalent hydraulic column generates an increasing back pressure, accurately simulating the increase in tissue resistance in the body. The drug solution is then siphoned out of the collection tube, simulating local tissue absorption, forming a dynamic fluid dissipation cycle similar to that of a biological organism. This real-time pressure feedback mechanism achieves accurate simulation of the in vivo infusion resistance environment, ensuring that the measured drug delivery curve truly reflects the actual effectiveness of the osmotic pressure driving force in clinical applications.

[0019] This invention integrates a high-precision graduated liquid sampling tube to form a metering tool, which tracks changes in liquid level displacement in real time: the operator directly observes the scale on the tube wall, and the continuous liquid level change ΔL is recorded through a preset tube diameter parameter (ΔV = πr). 2 ΔL) is dynamically converted into instantaneous liquid volume, enabling zero-delay, lossless closed-loop monitoring of the entire process from drug release from the microneedle array to the sampling tube. This design simultaneously eliminates transfer errors, evaporation interference, and manual reading errors. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the microneedle patch device for osmotic ballast loading in Example 1.

[0021] Figure 2 This is a schematic diagram illustrating the usage of the osmotic ballast drug microneedle patch device in Example 1.

[0022] Figure 3 This is a diagram showing the in vitro release results of the osmotically loaded drug microneedle patch device in Example 1.

[0023] In the diagram, 1 is the top cover, 2 is the fastener, 3 is the base, 4 is the hollow microneedle, 5 is the liquid collection tube, 6 is the liquid injection port, 7 is the liquid storage chamber, and 8 is the drug loading chamber. Detailed Implementation

[0024] The present invention will be further described and illustrated below with reference to specific embodiments. The embodiments described are merely examples of the content of this disclosure and do not limit the scope of the invention. The technical features of each embodiment in the present invention can be combined accordingly, provided that there is no mutual conflict.

[0025] The present invention aims to provide a method for detecting the in vitro release rate of a microneedle patch based on a osmotically loaded drug delivery device, so as to more accurately evaluate the drug release performance of the microneedle patch in practical applications.

[0026] like Figure 1 The osmotic pressure-based drug-loaded microneedle patch device provided by the present invention includes an upper cover 1, a fastener 2, a base 3, several hollow microneedles 4, a liquid collection tube 5, a liquid injection port 6, a liquid storage chamber 7, and a drug loading chamber 8.

[0027] The upper cover 1 has an inner mounting groove for installing a filter membrane, which is fixed by fasteners 2. The outer side of the upper cover 1 has a liquid injection port 6 connecting to the top of the mounting groove. The base 3 is threaded to the upper cover 1. The inner side of the base 3 has a stepped groove, the top of which connects to the mounting groove. A semi-permeable membrane is installed on the stepped surface of the stepped groove. The semi-permeable membrane is fixed by an elastic sealing ring, dividing the stepped groove into an upper liquid storage chamber 7 and a lower drug-carrying chamber 8. The drug-carrying chamber 8 stores drugs, preferably in a semi-solid or centrally hollow form, to facilitate thorough mixing of the solvent and drug to trigger drug activity. Hollow microneedles 4 are installed at the bottom of the base 3 and can be arranged in an array, connecting to the drug-carrying chamber 8. The liquid collection tube 5 is a long, thin tube made of a transparent polymer material (e.g., polycarbonate, PET). One end of the liquid collection tube 5 has an opening as a liquid collection port, and the other end connects to the interface of the microneedle array. Along the length of the outer wall of the sampling tube 5, a series of continuous measurement scale marks are finely machined or printed. Users can accurately read and confirm the volume of the collected liquid by referring to the scale on the sampling tube 5 during or after liquid collection.

[0028] The interface structure design of the sampling tube 5 allows for at least two connection modes: The first is an adhesive mode: a biocompatible adhesive layer (e.g., medical-grade epoxy resin, UV-cured adhesive, or pressure-sensitive tape) is pre-applied to the connection surface of the sampling tube 5. During operation, the outer surface of the connection part is precisely aligned with the outlet area of ​​the hollow microneedle 4 array and pressed together. The adhesive layer then cures immediately or after activation (e.g., light exposure), forming a permanent, highly sealed connection that ensures complete leak-proof connection. The second is a snap-fit ​​mode: a specific snap-fit ​​structure is formed at the connection port or its periphery of the sampling tube 5. The snap-fit ​​structure includes designs such as elastic snap-fit ​​arms, flanges, circumferential protrusions, or latches. Correspondingly, complementary snap-fit ​​receiving structures, such as slots, limiting grooves, or socket edges, are provided around or on the side of the outlet port of the hollow microneedle 4 array. The operator applies an axial thrust or a rotational force at a specific angle to the sampling tube 5, causing the snap-fit ​​structure to elastically deform or shift until it is securely snapped into or locked into the receiving structure, accompanied by a "click" sound / auditory feedback. This method forms a detachable, semi-permanent, or locked sealing connection.

[0029] The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device includes the following steps: like Figure 2As shown, solvent is first injected into the reservoir 7 of the osmotic pressure-loaded drug-eluting microneedle patch device through the injection port 6 until droplets seep out from the tip of the hollow microneedle 4. The selected solvent is deionized water or physiological buffer solution. The emergence of droplets is considered the start of the experiment. The osmotic pressure-loaded drug-eluting microneedle patch device is then inverted with the injection port 6 facing downwards and immersed in a container containing the same solvent, and a timer is activated simultaneously. This time recording marks the official start of the osmotic pressure-driven process and serves as the time reference point for the entire release experiment, i.e., time zero. The liquid level of the solvent in the container must be lower than the tip height of the hollow microneedle 4.

[0030] The solvent in the storage chamber 7 permeates into the drug-carrying chamber 8 through the semi-permeable membrane. Since the drug-carrying chamber 8 is filled with solvent, the pre-loaded drug dissolves to form a high osmotic pressure environment of a saturated solution, which generates a positive osmotic pressure difference from the outside to the inside between the solvent in the external storage chamber 7 and the solvent in the external storage chamber 7. This pressure difference drives the solvent in the storage chamber 7 to continuously permeate into the drug-carrying chamber 8 through the semi-permeable membrane. At the same time, the permeation causes the volume of the drug-carrying chamber 8 to expand, which in turn pushes the drug solution in the drug-carrying chamber 8 to continuously enter the liquid collection tube 5 through the hollow microneedle array 4.

[0031] As the drug continues to dissolve, the drug-loaded chamber 8 remains in a saturated solution state, which ensures that a constant osmotic pressure drives the drug solution to flow out through the hollow microneedle array 4.

[0032] The time is recorded when the liquid column first reaches the needle tip. This time recording marks the beginning of the drug flow from the microneedle and the formation of an equivalent hydraulic column. It is a crucial node for simulating the dynamic subcutaneous back pressure environment and accurately measuring the outflow volume. The time difference between this point and the first recording (i.e., the delay from the start of osmosis to the start of outflow) reflects the osmotic pressure driving efficiency during the initial pressureless simulated tissue osmosis. For example, a slower driving rate results in a longer delay. Subsequently, it is necessary to ensure that the pressure generated by the outflowing liquid column gradually increases to simulate the dynamic environment of real subcutaneous injection, and to dynamically adjust the height of the equivalent hydraulic column. Specifically, the outflowing drug in the sampling tube 5 is collected at fixed time intervals Δt to ensure that the remaining liquid level is maintained at the needle tip height of the hollow microneedle 4. During each collection, the liquid level change ΔL is obtained by accurately reading the scale of the sampling tube. The liquid level change ΔL is then processed through a preset tube diameter parameter (ΔV = πr). 2 ΔL) is dynamically converted into instantaneous outflow volume, and the outflow volume V is obtained from the accumulation of instantaneous outflow volume. n And record the corresponding cumulative time T. n (T) n = n × Δt). The release rate is calculated based on the cumulative discharge time T and the cumulative discharge volume ΣV, and the instantaneous release rate is calculated based on the discharge volume per unit time ΔV / Δt.

[0033] like Figure 3As shown, based on the collected time-series data, a cumulative drug release curve is plotted with time T as the x-axis and cumulative output volume ΣV as the y-axis, or an instantaneous release rate curve is plotted with output volume ΔV / Δt per unit time as the y-axis. Throughout the detection process, the solvent type, ambient temperature (typically 25℃ or 37℃), and microneedle immersion depth must be kept constant, and the time interval Δt should be less than 10% of the expected release cycle to ensure data resolution. The expected release cycle is obtained through a preliminary experiment. During the preliminary experiment, the drug solution in the sampling tube 5 is removed in real time to ensure no output pressure; the continuous output time is the expected release cycle.

[0034] To simulate the critical physical environment for subcutaneous drug delivery, this invention introduces a method where the drug solution flowing from an array of hollow microneedles 4 enters a collection tube 5. Initially, the collection tube 5 contains no drug solution and there is no back pressure; the drug solution in the drug-carrying chamber 8 diffuses spontaneously, simulating initial permeation into the subcutaneous space. As the drug solution enters the collection tube 5, a hydraulic column is generated. With the accumulation of drug solution in the collection tube 5, the equivalent hydraulic column generates an increasing back pressure, simulating increased tissue resistance. During the process of the hydraulic column gradually rising and generating increasing back pressure, the drug solution can be siphoned out of the collection tube 5 to simulate local tissue absorption. The entire process forms a dynamic fluid dissipation cycle similar to that of a living organism. This dynamically controlled real-time pressure feedback mechanism achieves accurate simulation of the in vivo infusion back pressure environment, ensuring that the measured drug delivery curve truly reflects the actual effectiveness of the osmotic pressure driving force in clinical applications.

[0035] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

[0036] The above-described embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. Those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for detecting the in vitro release rate of an osmotically loaded drug-eluting microneedle patch device, characterized in that, Includes the following steps: (1) Install a liquid collection tube on the microneedle patch device and sleeve it around the hollow microneedle array. One end of the liquid collection tube is sealed to the shell and the other end is open. (2) Inject solvent into the storage chamber until droplets seep out from the tip of the hollow microneedle. Then invert the device so that the injection port faces down and is immersed in the same solvent, and activate the timer synchronously. (3) The osmotic pressure difference drives the solvent to permeate through the semi-permeable membrane into the drug-carrying chamber, and pushes the drug solution to continuously enter the collection tube through the hollow microneedle. The drug solution in the collection tube forms an equivalent hydraulic column to simulate the dynamic environment of real subcutaneous injection. (4) Siphon the outflowing liquid in the liquid tube at fixed time intervals to maintain the liquid level at the tip height of the hollow microneedle; The average release rate is calculated based on the cumulative discharge time and cumulative discharge volume, and the instantaneous release rate is calculated based on the discharge volume per unit time.

2. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, The osmotic pressure drug-loaded microneedle patch device includes a housing, and an upper liquid storage chamber and a lower drug loading chamber separated by a semi-permeable membrane inside the housing. The top of the housing is provided with an injection port that communicates with the liquid storage chamber, and the bottom of the housing is provided with a hollow microneedle that communicates with the drug loading chamber.

3. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, In step (2), the solvent is deionized water or physiological buffer solution.

4. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, In step (2), the same solvent is contained in a container, and the height of the solvent in the container is not higher than the tip height of the hollow microneedle.

5. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, In step (4), the time is recorded when the liquid medicine first reaches the tip height of the hollow microneedle, and the time interval for collecting the outflowing liquid medicine is less than 10% of the expected release cycle.

6. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 5, characterized in that, The expected release period is obtained through a preliminary experiment. During the preliminary experiment, the liquid in the collection tube is removed in real time to ensure that there is no liquid pressure. The continuous liquid discharge time is the expected release period.

7. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, The solvent type and ambient temperature remained constant throughout the entire testing process.

8. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, When the device is inverted so that the injection port faces downward and is immersed in the same solvent, the drug-loaded chamber is filled with solvent, and the pre-loaded drug dissolves to form a saturated solution with a high osmotic pressure environment. This creates a positive osmotic pressure difference from the outside to the inside between the drug-loaded chamber and the solvent in the storage chamber. This pressure difference drives the solvent in the storage chamber to continuously permeate through the semi-permeable membrane into the drug-loaded chamber. At the same time, the permeation causes the volume of the drug-loaded chamber to expand, pushing the drug solution in the drug-loaded chamber into the hollow microneedles. Before a droplet seeps out from the tip of the hollow microneedle, there is no drug in the collection tube and no back pressure. The drug in the drug-carrying chamber diffuses spontaneously, simulating the initial penetration of the subcutaneous space. As the amount of drug injected into the collection tube accumulates, the equivalent hydraulic column generates increasing back pressure, simulating an increase in tissue resistance in the body; by aspirating the drug from the collection tube at fixed time intervals, local tissue absorption is simulated.

9. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, Repeat the experiment and plot the cumulative release curve based on the cumulative release time and cumulative release volume.

10. The method for detecting the in vitro release rate of the osmotically loaded drug-eluting microneedle patch device according to claim 1, characterized in that, The outer wall of the liquid collection tube is finely machined or printed with a series of continuous measurement scale marks along its length.

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