Iron ion transdermal delivery base with high conversion rate and preparation method thereof

Abstract

The application discloses an iron ion transdermal delivery matrix with high conversion rate and a preparation method thereof. The matrix formula comprises ferric pyrophosphate, low molecular weight hyaluronic acid, 3-O-ethyl ascorbic acid and sodium citrate, the solid weight ratio of which is 3-8:2-6:0.2-2, and the addition amount of sodium citrate is 0.1-1.5 times the weight of ferric pyrophosphate. The application adopts the process steps of "high-temperature chelation combined with low-temperature post addition", first chelates ferric pyrophosphate with sodium citrate at 70 DEG C, and then post adds 3-O-ethyl ascorbic acid and hyaluronic acid in a low-temperature ice bath state. By introducing sodium citrate, the dispersion of ferric pyrophosphate is significantly improved, and a significant synergistic catalytic effect is produced with 3-O-ethyl ascorbic acid in the research of local iron ion transmission or the scene of nutritional care of the skin, so that Fe 3+ The conversion rate of Fe 2+ to Fe is more than 60% at 60 minutes. The application effectively solves the defect that the reducing agent is easy to degrade and discolor in the preparation of traditional microneedles, and ensures the uniformity of microneedle forming and the stability of long-term storage.

Description

Technical Field

[0001] This invention belongs to the technical field of transdermal delivery system (TDS), and specifically relates to a soluble microneedle patch matrix formulation for research on local iron ion transport in the skin or for nutritional care, as well as a specific low-temperature preparation method for the matrix. Background Technology

[0002] Currently, oral iron supplements are commonly used in clinical practice and daily life to address iron deficiency. However, oral iron supplements can easily cause side effects such as gastrointestinal irritation, nausea, and constipation, and their absorption rate is severely limited by the human gut system.

[0003] In traditional transdermal iron transport techniques, if nano-ferrous sulfate nanoparticles are used, although their ferrous iron (Fe2+) can be reduced... 2+ While readily absorbed in its ferric form, it is highly susceptible to oxidation and deterioration, and poses significant skin irritation and regulatory risks. If a safer form, ferric pyrophosphate (FPP), is used, it is a ferric iron (Fe3+) form... 3+ The molecules are relatively large and highly charged, resulting in extremely low penetration and bioavailability.

[0004] To facilitate the reduction of ferric iron to easily absorbed ferrous iron, existing transdermal technologies often incorporate ascorbic acid (vitamin C). However, traditional ascorbic acid is highly susceptible to degradation and inactivation during the high-humidity, high-temperature microneedle casting process, resulting in poor stability, short shelf life, and easy discoloration of the final microneedle product.

[0005] The information disclosed in this background section is intended only to enhance the understanding of the overall background of the invention and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention

[0006] The purpose of this invention is to provide a transdermal iron ion delivery matrix with high conversion rate and its preparation method, so as to solve the technical defects of existing transdermal iron delivery preparations such as poor stability, low conversion rate, easy degradation and discoloration.

[0007] To achieve the above objectives, the present invention provides a transdermal iron ion delivery matrix with high conversion efficiency, the formulation of which contains the following components in the following weight ratios: 3-8 parts ferric pyrophosphate, 2-6 parts hyaluronic acid (low molecular weight HA, -10kDa), 0.2-2 parts 3-O-ethyl ascorbic acid, and sodium citrate at 0.1 to 1.5 times the weight of ferric pyrophosphate.

[0008] Preferably, the ratio of ferric pyrophosphate, hyaluronic acid and EAA is 5:4:1, and the amount of sodium citrate added is 0.5-1.0 times the weight of ferric pyrophosphate.

[0009] This invention, by introducing sodium citrate, not only significantly improves the dispersibility and solubility of ferric pyrophosphate in a polymer matrix, but also produces a significant synergistic effect with 3-O-ethyl ascorbic acid in studies of local iron ion transport in the skin or in nutritional care settings, thereby enhancing the dispersibility and solubility of ferric pyrophosphate. 3+ To Fe 2+ The conversion rate reaches over 60% within 60 minutes (specifically up to 65.0%).

[0010] A method for preparing a transdermal iron ion delivery matrix with high conversion rate, which employs a process of "high-temperature chelation followed by low-temperature addition", specifically including:

[0011] (1) Heat deionized water to 70°C, add the specified amount of ferric pyrophosphate and sodium citrate, stir at high speed for 30 minutes and ultrasonically vibrate for 20 minutes to form a uniform and transparent yellow-brown chelated iron solution;

[0012] (2) Place the above solution in a 4°C ice bath and cool for 10 minutes until it reaches room temperature or below.

[0013] (3) Add 3-O-ethyl ascorbic acid powder slowly in batches to the cooling solution and keep stirring at low temperature to prevent premature redox reaction under high iron ion environment;

[0014] (4) Add hyaluronic acid to the solution after stirring in step (3), and let it stand at 4°C in the dark for 12 hours to swell. Centrifuge at 4,000 RPM for 10 minutes to remove bubbles. After the solution is completely degassed, cast the solution into a microneedle mold with a depth of 280–300 μm. After casting, dry and shape to obtain soluble microneedles.

[0015] A soluble microneedle patch with microneedle height of 280-300μm is used for transdermal local iron supplementation.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] 1. Unique Synergistic Catalytic Effect: This invention utilizes highly stable 3-O-ethyl ascorbic acid as a reducing agent and innovatively introduces sodium citrate as a chelating agent and co-solvent. Experiments have confirmed that sodium citrate not only significantly improves the dispersibility and solubility of ferric pyrophosphate, but also exhibits a significant synergistic catalytic effect with 3-O-ethyl ascorbic acid in studies of local iron ion transport in the skin or in nutritional care settings, greatly enhancing the Fe...3+ Reduced to Fe 2+ The efficiency and the release rate of iron ions.

[0018] 2. Locking in activity and improving process stability: The low-temperature process of this invention avoids the premature initiation of the redox reaction of 3-O-ethyl ascorbic acid under high concentration of iron ions and high temperature environment, thus locking in its reducing activity to the end of product use.

[0019] 3. No discoloration or softening during long-term storage: Accelerated stability tests have proven that the matrix of this invention does not turn black or soften under long-term storage at high temperature and humidity, has a high rate of reducing agent retention, and has an extremely long shelf life. Detailed Implementation

[0020] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0021] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0022] Example 1

[0023] In this embodiment, a transdermal iron ion delivery matrix with high conversion rate is formulated with the following weight ratio of each component: 5 parts ferric pyrophosphate, 4 parts hyaluronic acid (low molecular weight HA, -10kDa), 1 part 3-O-ethyl ascorbic acid, and sodium citrate added at 0.5 times the weight of ferric pyrophosphate.

[0024] A soluble microneedle patch prepared based on this matrix has a tip mold depth of 280-300 μm. The specific theoretical loading of the tip components of a single microneedle patch is as follows: ferric pyrophosphate 3.0 mg, hyaluronic acid 2.4 mg, 3-O-ethyl ascorbic acid 0.6 mg, and sodium citrate 1.5 mg. The total solids content of the tip (including co-solvent) is 7.5 mg.

[0025] A method for preparing a transdermal iron ion delivery matrix with high conversion rate, comprising the following steps:

[0026] (1) High temperature dissolution and chelation: Deionized water was heated to 70°C, 3.0 mg of ferric pyrophosphate and 1.5 mg of sodium citrate were added, and the mixture was stirred at high speed for 30 minutes and ultrasonically vibrated for 20 minutes to form a uniform and transparent yellow-brown chelated iron solution.

[0027] (2) Place the above chelated iron solution in an ice bath at 4°C and cool it for about 10 minutes until it reaches below room temperature;

[0028] (3) Then, 0.6 mg of 3-O-ethyl ascorbic acid powder was slowly added to the cooling solution in batches and stirred at a low temperature to prevent premature redox reaction under high iron ion environment;

[0029] (4) Swelling and casting: Add 2.4 mg of hyaluronic acid to the solution obtained in step (3) and let it swell for 12 hours at 4°C in the dark. Centrifuge at 4,000 RPM for 10 minutes to remove bubbles. After the solution is completely degassed, cast the solution into a microneedle mold with a depth of 280–300 μm. After casting, dry and shape to obtain soluble microneedles.

[0030] Fe 3+ →Fe 2+ Conversion rate experiment

[0031] The aim was to evaluate whether 3-O-ethyl ascorbic acid could effectively promote the growth of Fe in the matrix of iron pyrophosphate microneedle patches. 3+ To Fe 2+ The conversion was analyzed, and the effects of sodium citrate on the dispersibility of ferric pyrophosphate, iron release, and subsequent Fe were compared and analyzed. 2+ The impact of conversion efficiency.

[0032] Experimental group design and theoretical loading capacity of single-chip formulation:

[0033] Group A (basal control group, ferric pyrophosphate + hyaluronic acid): ferric pyrophosphate 3.0mg + hyaluronic acid 2.4mg (total solids at the needle tip 5.4mg).

[0034] Group B (3-O-ethyl ascorbic acid efficacy evaluation group, ferric pyrophosphate + hyaluronic acid + 3-O-ethyl ascorbic acid): ferric pyrophosphate 3.0mg + hyaluronic acid 2.4mg + 3-O-ethyl ascorbic acid 0.6mg (total solids at the needle tip 6.0mg, ratio 5:4:1).

[0035] Group C (Example of the present invention): 3.0 mg ferric pyrophosphate + 2.4 mg hyaluronic acid + 0.6 mg 3-O-ethyl ascorbic acid + 1.5 mg sodium citrate (total solids at the needle tip 7.5 mg).

[0036] Group D (positive control group, ferric pyrophosphate + hyaluronic acid + ascorbic acid): ferric pyrophosphate 3.0mg + hyaluronic acid 2.4mg + ascorbic acid 0.6mg (total solids at the needle tip 6.0mg).

[0037] Detection method:

[0038] The ferrozine colorimetric method was used.

[0039] Fe 2+Concentration determination: Ferrozine reagent was added directly, and the absorbance (OD) was measured at a wavelength of 562 nm. 562 ).

[0040] Total Fe concentration determination: The sample is first pretreated with a reducing agent to convert all iron ions into Fe. 2+ Ferrozine reagent was then added and the absorbance (OD) at 562 nm was measured. 562 ).

[0041] Conversion rate calculation formula:

[0042] .

[0043] Experimental steps:

[0044] (1) Each group of microneedle patches was prepared by a two-step casting method, and their appearance, needle tip integrity and weight were recorded;

[0045] (2) Immerse each microneedle patch in 1 mL of phosphate-buffered saline PBS (pH 5.5 or 7.4) and incubate at 25°C under constant shaking and in the dark.

[0046] (3) Samples were taken at the set time intervals (5 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes);

[0047] (4) Divide the sample at each time point into two parallel subsamples, which are used to determine Fe. 2+ Concentration and total iron concentration;

[0048] (5) Establish a FeSO4 standard calibration curve and calculate the exact iron ion concentration and conversion rate accordingly.

[0049] The conversion rate experimental data are shown in Table 1 under the condition of an experimental temperature of 25°C:

[0050] Table 1: Conversion Rate Experimental Data Table

[0051]

[0052] The highest conversion rate range and functional interpretation of each experimental group within 120 minutes are shown in Table 2:

[0053] Table 2: Highest Conversion Rate and Experimental Conclusions

[0054] Group A FPP+HA 9.8-13.7 The natural conversion rate is extremely low, and the iron release and conversion effects are severely inadequate. Group B FPP+HA+EAA 44.7-54.2 <![CDATA[EAA can significantly enhance the formation of Fe 2+ to reach an acceptable conversion level]]> Group C FPP+HA+EAA+Sodium citrate 53.4-65.0 Sodium citrate further improved dispersion and conversion efficiency, fully demonstrating a synergistic catalytic effect. Group D FPP+HA+Ascorbic Acid 68.6-76.0 The positive control group, while exhibiting the strongest reduction effect, is extremely unstable during microneedle fabrication and long-term storage.

[0055] To confirm that this invention can achieve a high conversion rate while solving shelf-life problems such as microneedle degradation, discoloration, and decreased hardness caused by traditional reducing agents, we placed each group of microneedle patches under long-term storage conditions (25°C / 60%RH) and accelerated conditions (40°C / 75%RH), respectively, and examined the appearance color of the microneedle patches, the residual rate of the reducing agent, and the Fe after resolvation at weeks 1, 2, 4, and 8. 2+ Conversion rate (based on the 60-minute evaluation endpoint) and needle tip mechanical hardness. Data are shown in Tables 3 and 4:

[0056] Table 3. Stability data of each experimental group under long-term storage conditions (25°C / 60%RH)

[0057]

[0058] Note: Group A has no reducing agent, so the residual rate is recorded as "-"; the reducing agent measured in Group D is ascorbic acid, and the reducing agent measured in Groups A, B, and C is 3-O-ethyl ascorbic acid; the conversion rate after reconstitution is the test value at each time point after the sample is reconstituted and the in vitro release reaction is simulated for 60 minutes.

[0059] Table 4: Hard core stability data for each experimental group under accelerated conditions (40°C / 75%RH)

[0060]

[0061] This experiment uses the 60-minute time point as the primary evaluation endpoint for comparative analysis.

[0062] As shown in Table 1, group A can only produce a very low proportion of Fe. 2+ (Only 13.0% at 60 minutes, with a maximum of 13.7%), while the conversion rate of Group B, which only added the reducing agent 3-O-ethyl ascorbic acid, was significantly increased to 54.2% at the primary endpoint at 60 minutes.

[0063] Surprisingly, when 1.5 mg of sodium citrate was further added to group B, resulting in group C (an embodiment of the present invention), not only did the total iron concentration shown in Table 1 significantly improve the dispersibility of ferric pyrophosphate and the rate of iron ion release, but it also increased the Fe... 3+ To Fe 2+ The conversion rate reached over 60% at 60 minutes, significantly better than Group B. Based on pre-set evaluation criteria (60%–80% range), the conversion performance of Group C was rated as "good".

[0064] As shown in Tables 3 and 4, Group D, which used traditional ascorbic acid (vitamin C), exhibited "catastrophic degradation failure" during storage. Its appearance darkened significantly by week 4 of the accelerated test, turning charred black by week 8 with severe hygroscopic gelatinization. The needle tip hardness plummeted from an initial 35 HV to 8.5 HV, completely losing its mechanical strength for skin penetration. Group B, which did not contain sodium citrate and used the more stable 3-O-ethyl ascorbic acid, also showed a significant darkening to a deep yellowish-brown under high temperature and humidity conditions in week 8.

[0065] In contrast, the patches in Group C of this invention exhibited extremely strong physical and chemical stability in both long-term stability studies at room temperature and accelerated studies under harsh high-temperature and high-humidity conditions (40°C / 75%RH). After being placed in a harsh environment of 40°C / 75%RH for 8 weeks, the microneedle patches maintained a uniform, transparent light yellowish-brown appearance throughout, without any perceptible browning or blackening, and the needle tip hardness remained firm at above 35.1 HV, fully demonstrating that the matrix of this invention possesses extremely strong resistance to moisture absorption and softening, as well as excellent color stability.

[0066] Quantitative chemical analysis showed that, after accelerated storage to week 8, the residual rate of the reducing agent (EAA) in group C of this invention was as high as 96.8% (up to 98.6% under long-term stable conditions at room temperature). More importantly, after redissolving the group C patch after 8 weeks of storage and testing its reduction-promoting activity, at the 60-minute primary endpoint, its Fe... 3+ →Fe 2+ The conversion rate remained firmly at a high efficiency level of 62.9%, with almost no decline, perfectly meeting the rigid demand for high conversion rates in clinical or nursing settings. In contrast, the reducing agent in group D was almost completely depleted by week 8 (with a residual rate of only 2.4%), and its conversion rate after reconstitution had dropped to 13.2%, equivalent to the blank matrix in group A, which had completely lost its reducing ability.

[0067] The reason why Group C of this invention exhibits far superior physical and chemical stability compared to Groups B and D is that sodium citrate, 3-O-ethyl ascorbic acid (EAA), and low molecular weight hyaluronic acid (HA) form a unique three-dimensional microenvironmental protective effect under a specific "high-temperature chelation followed by low-temperature addition" process.

[0068] First, in process step (1), the polydentate ligand of sodium citrate undergoes pre-high-temperature coordination chelation with ferric pyrophosphate at 70°C, firmly locking the high-valence trivalent iron ions in the chelation center. This step greatly isolates the catalytic active center of the iron ions, cutting off the direct catalytic oxidation pathway of iron ions to hydrophilic reducing agents during subsequent storage, thereby locking in the source of discoloration and degradation at the small molecule level.

[0069] Secondly, the pre-chelation of sodium citrate improves the spatial dispersion of iron salts in the polymer matrix, preventing localized crystallization and aggregation of high-concentration metal ions. Combined with highly hydrophilic and uniformly molecular weight low-molecular-weight hyaluronic acid (-10kDa), a dense, solid, amorphous spatial barrier is formed after the microneedles are cured and dried. This barrier significantly slows down the penetration rate of external moisture (high humidity environment) into the microneedles, thus preventing moisture absorption and softening of the microneedles at 40°C / 75%RH.

[0070] Therefore, by organically combining specific component ratios with specific low-temperature processing technology, this invention has perfectly achieved a major technological breakthrough in achieving "high conversion, rapid release, ultra-stability, and no browning".

[0071] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A transdermal iron ion delivery matrix with high conversion rate, characterized in that, Its formula includes ferric pyrophosphate, hyaluronic acid, 3-O-ethyl ascorbic acid, and sodium citrate.

2. The transdermal iron ion delivery matrix with high conversion rate according to claim 1, characterized in that: The solid weight ratio of the iron pyrophosphate, hyaluronic acid and 3-O-ethyl ascorbic acid is 3-8:2-6:0.2-2.

3. The transdermal iron ion delivery matrix with high conversion rate according to claim 2, characterized in that: Based on the weight of the ferric pyrophosphate, the amount of sodium citrate added is 0.1-1.5 times that weight.

4. The transdermal iron ion delivery matrix with high conversion rate according to claim 3, characterized in that: The hyaluronic acid is a low molecular weight hyaluronic acid with a molecular weight of approximately 10 kDa.

5. The transdermal iron ion delivery matrix with high conversion rate according to any one of claims 4, characterized in that: When the matrix is ​​treated in vitro at 25°C for 60 minutes, its Fe... 3+ Converted to Fe 2+ The conversion rate can reach over 60%, and the Fe within 120 minutes 3+ Converted to Fe 2+ The highest conversion rate range is 53.4%-65.0%.

6. A method for preparing a transdermal iron ion delivery matrix with high conversion rate according to any one of claims 1-4, characterized in that, Includes the following steps: (1) Heat deionized water to 70°C, add the specified amount of ferric pyrophosphate and sodium citrate, and stir at high speed and vibrate with ultrasonic waves to form a uniform and transparent yellow-brown chelated iron solution; (2) Place the above solution in an ice bath at 4°C to cool it to below room temperature; (3) Add 3-O-ethyl ascorbic acid powder slowly in batches to the cooled solution obtained in step (2) while stirring at a low temperature; (4) Add hyaluronic acid to the solution after stirring in step (3), and let it stand in the dark at low temperature to swell; after centrifugation to remove bubbles, cast the solution into a microneedle mold, and dry it to obtain soluble microneedles.

7. A soluble microneedle patch, characterized in that: The microneedle tip is made of the transdermal iron ion delivery matrix with high conversion rate as described in any one of claims 1 to 5; or, the soluble microneedle patch is prepared by the preparation method described in claim 6, wherein the depth of the microneedle mold is 280-300 μm.

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