Adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control

Abstract

The invention belongs to the technical field of biological medicine, and relates to an adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control, which comprises the following steps: placing a preset complete drug delivery device into a vagina, and enabling a soluble osmotic active substance in a peripheral structure to be in contact with vaginal body fluid to form a local high-concentration salt solution area; generating a continuously inward body fluid permeate flow; forming a medicine-containing mixed solution; establishing a directional driving force for conveying the medicine-containing mixed solution to the vaginal mucosa; the intensity of body fluid permeation flow is adjusted, and the moving speed of the medicine to the mucosa interface is controlled; when the drug release is completed or the preset treatment duration is reached, the complete drug delivery device is removed from the vagina; through directional pushing force, directional enrichment of the medicine-containing mixed solution on the vagina mucosa surface layer is achieved, and a medicine enrichment zone is formed. The problem that a dosage form or a device cannot realize real-time regulation and control of the release rate is solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to an adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control. Background Art

[0002] Existing vaginal drug delivery technologies face the core challenge of low drug delivery efficiency. The complex anatomical structure and dynamic physiological environment of the vagina mean that traditional dosage forms such as suppositories, gels, or tablets are easily diluted and washed away by body fluids after administration, making it difficult for the drug to be effectively concentrated in the targeted mucosal area. Furthermore, the physical barrier formed by the folds of the vaginal mucosa hinders the uniform distribution of the drug. A large amount of active ingredients are excreted with secretions or diffuse into deeper tissues before they can exert their therapeutic effects, resulting in a significant reduction in bioavailability and the potential risk of systemic toxicity.

[0003] Traditional solutions primarily rely on optimizing the physical form of the dosage form or passive diffusion mechanisms. Adhesive hydrogels are used to extend drug retention. However, these approaches are unable to actively overcome the flushing force of body fluids and can only delay, not prevent, drug loss. While sustained-release rings provide sustained release, drug migration still relies on passive diffusion driven by a concentration gradient, making it difficult to form a high-concentration drug reservoir on the mucosal surface. Furthermore, the release rate cannot be dynamically adjusted and cannot respond to changes in the physiological environment.

[0004] Based on the above problems, the dosage form or device cannot achieve real-time regulation of the release rate, and can neither adapt to individual differences nor cope with physiological changes such as increased secretions during ovulation. Summary of the Invention

[0005] In order to solve the above problems, the present invention provides an adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control.

[0006] The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control comprises the following steps:

[0007] S1. The pre-set complete drug delivery device is placed into the vagina, so that the soluble osmotic active substance in the peripheral structure contacts the vaginal fluid, forming a local high-concentration salt solution area;

[0008] S2. utilizing the osmotic pressure difference between the local high-concentration salt solution area and the vaginal body fluid environment to drive the vaginal body fluid to flow into the interior of the complete drug delivery device, thereby generating a continuous inward body fluid osmotic flow;

[0009] S3, guiding the continuous inward permeation flow of body fluid to mix with the absorbent carrier and drug in the inner layer of the complete drug delivery device to form a drug-containing mixed solution;

[0010] S4, establishing a directional driving force for transporting the drug-containing mixed solution to the vaginal mucosa by utilizing the continuous inward osmotic flow of body fluids and the squeezing effect caused by the water absorption and expansion of the water-absorbing carrier;

[0011] S5. By changing the surface area of ​​soluble substances in the peripheral structure exposed to body fluids, the intensity of the body fluid osmotic flow is adjusted, thereby controlling the rate of drug migration to the mucosal interface;

[0012] S6. When drug release is complete or the preset treatment duration is reached, remove the complete drug delivery device from the vagina;

[0013] S7. Through directional driving force, the drug-containing mixed solution is directional enriched on the surface of the vaginal mucosa to form a drug enrichment zone.

[0014] A further embodiment of the present invention forms a local high concentration salt solution area, comprising the following steps:

[0015] Assembling the replaceable drug core into the central slot of the adjustable osmotic pressure regulating ring to form a complete drug delivery device;

[0016] The complete drug delivery device is placed into the vaginal vault, so that the soluble osmotic active substance filled in the cavity of the osmotic pressure regulating ring contacts the body fluid secreted by the surface of the vaginal mucosa;

[0017] Through the microporous channels preset on the wall of the osmotic pressure regulating ring, body fluids penetrate into the cavity to dissolve soluble osmotic active substances, forming a local high-concentration salt solution area.

[0018] A further embodiment of the present invention generates a continuous inward osmotic flow of body fluids, comprising the following steps:

[0019] Based on the osmotic pressure difference between the local high-concentration salt solution area and the vaginal body fluid environment, the body fluid is driven to continuously flow into the osmotic pressure regulating ring cavity through the microporous channel;

[0020] By rotating the rotatable outer shell of the osmotic pressure regulating ring, the effective exposed area of ​​the microporous channel can be changed to adjust the flow rate of the body fluid osmotic flow;

[0021] Maintain the osmotic pressure difference not lower than the vaginal fluid osmotic pressure, generating a continuous inward osmotic flow of body fluids.

[0022] A further embodiment of the present invention forms a mixed solution containing medicine, comprising the following steps:

[0023] The body fluid continues to flow inward through the preset diversion mesh and enters the absorbent carrier receiving area, which is the replaceable drug core receiving area;

[0024] The pre-set diversion mesh allows body fluid to pass through but blocks the entry of soluble osmotic active substance particles;

[0025] The continuous inward osmotic flow of body fluid mixes with the cross-linked sodium alginate carrier and the drug to generate a drug-containing mixed solution with a preset viscosity.

[0026] A further embodiment of the present invention is to establish a directional driving mechanism for delivering the drug-containing mixed solution to the vaginal mucosa, comprising the following steps:

[0027] The directional water flow power of the body fluid osmotic flow and the radial pressure generated by the expansion of cross-linked sodium alginate generate a directional driving force superimposed in the same direction;

[0028] Drive the drug-containing mixed solution to migrate through the preset microporous diffusion layer on the outer surface of the drug core to the vaginal mucosa interface;

[0029] The microporous diffusion layer is used to limit the leakage of gel macromolecules, forming a directional drug delivery channel.

[0030] A further embodiment of the present invention regulates the intensity of the body fluid osmotic flow, comprising the following steps:

[0031] Rotating the rotatable housing of the adjustable osmotic pressure regulating ring changes the effective exposed area of ​​the microporous channel to dynamically adjust the intensity of the body fluid osmotic flow;

[0032] The rotatable housing is provided with a spiral convex track structure, and the change in the rotation angle corresponds to the proportional adjustment of the exposed area of ​​the micropores.

[0033] A further embodiment of the present invention, wherein the intensity of the body fluid osmotic flow is adjusted, further comprises the following steps:

[0034] An environmental response barrier is set in the adjustable osmotic pressure regulating ring. When the pH value of the vaginal environment changes, the effective exposed area of ​​the micropores is automatically adjusted to maintain the stable intensity of the body fluid osmotic flow;

[0035] Among them, the environmentally responsive barrier is composed of pH-sensitive hydrogel, whose swelling behavior adaptively shrinks or expands as the pH value changes.

[0036] A further embodiment of the present invention is to remove the complete drug delivery device from the vagina, comprising the following steps:

[0037] At the end of the treatment cycle, the gel-like substance dehydrates and shrinks due to the loss of continuous replenishment of body fluid osmotic flow, and adheres to the surface of the replaceable drug core, forming a device ready for removal;

[0038] The microporous diffusion layer blocks the gel-state substance from falling off during the removal process, and the drug delivery device in the state of the device to be removed is completely removed;

[0039] The syneresis shrinkage property of the gel-state substance is combined with the physical barrier function of the microporous diffusion layer.

[0040] A further embodiment of the present invention forms a drug-enriched zone, comprising the following steps:

[0041] The radial expansion pressure in the directional driving force is used to embed the drug-containing mixed solution into the surface microfolds of the vaginal mucosa;

[0042] And the continuous replenishment mechanism formed by the directional drug delivery flow is used to counteract the flushing effect of vaginal secretions;

[0043] The drug-containing mixed solution is embedded in the surface microfolds of the vaginal mucosa, and the synergistic effect of the formed continuous replenishment mechanism achieves the directional enrichment and long-term retention of the drug in the surface layer of the vaginal mucosa, thereby forming a drug enrichment zone.

[0044] In summary, the present invention has the following beneficial technical effects:

[0045] 1. Through the synergistic effect of directional fluid permeation driven by osmotic pressure differential and the mechanical pressure generated by the gel carrier's water absorption and expansion, drug molecules are actively pushed and embedded into the micro-folds of the vaginal mucosa, forming a high-concentration drug-enriched zone at a depth of 0-200 microns on the mucosal surface. This mechanism not only effectively prevents drug loss caused by vaginal secretions, but also enables local drug concentrations to reach more than five times that of vaginal fluid and maintain effective therapeutic concentrations for over six hours.

[0046] 2. Leveraging the mechanical control structure of the adjustable osmotic pressure regulating ring and the intelligent feedback mechanism of the environmentally responsive barrier, the user can manually adjust or the system can automatically sense changes in the vaginal environment and dynamically adjust the fluid osmotic flow intensity. This allows the drug migration rate to the mucosal interface to be continuously controlled within a range of 0.05 to 0.25 mg / cm2 / min. This not only meets individualized treatment needs, but also automatically enhances osmotic flow to maintain stable drug concentration during periods of increased secretion, such as ovulation.

[0047] 3. The device utilizes a modular design with replaceable drug cores and adjustable components, streamlining operation and reducing long-term treatment costs. At the end of the treatment cycle, the syneresis properties of the gel carrier and the physical barrier of the microporous diffusion layer work together to ensure that no gel or drug remains in the vaginal cavity upon device removal. This feature not only reduces the risk of secondary infection but also enhances the convenience and safety of clinical operation through ergonomic design features such as anti-slip bumps, providing a patient-friendly treatment experience. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. The drawings are used to provide a further understanding of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0049] Figure 1 A schematic diagram of the flow chart in the embodiment of the present application is disclosed.

[0050] Figure 2 The present invention discloses a schematic structural diagram in an embodiment of the present application. DETAILED DESCRIPTION

[0051] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0052] The following is combined with Figure 1-Figure 2 The preferred embodiments of the present invention are described in detail.

[0053] Refer to the attached Figure 1 The present invention proposes an adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control, comprising the following steps:

[0054] S1. The pre-set complete drug delivery device is placed into the vagina, so that the soluble osmotic active substance in the peripheral structure contacts the vaginal fluid, forming a local high-concentration salt solution area;

[0055] S2. utilizing the osmotic pressure difference between the local high-concentration salt solution area and the vaginal body fluid environment to drive the vaginal body fluid to flow into the interior of the complete drug delivery device, thereby generating a continuous inward body fluid osmotic flow;

[0056] S3, guiding the continuous inward permeation flow of body fluid to mix with the absorbent carrier and drug in the inner layer of the complete drug delivery device to form a drug-containing mixed solution;

[0057] S4, establishing a directional driving force for transporting the drug-containing mixed solution to the vaginal mucosa by utilizing the continuous inward osmotic flow of body fluids and the squeezing effect caused by the water absorption and expansion of the water-absorbing carrier;

[0058] S5. By changing the surface area of ​​soluble substances in the peripheral structure exposed to body fluids, the intensity of the body fluid osmotic flow is adjusted, thereby controlling the rate of drug migration to the mucosal interface;

[0059] S6. When drug release is complete or the preset treatment duration is reached, remove the complete drug delivery device from the vagina;

[0060] S7. Through directional driving force, the drug-containing mixed solution is directional enriched on the surface of the vaginal mucosa to form a drug enrichment zone.

[0061] In one embodiment of the present invention, step S1 includes the following steps:

[0062] The peripheral structure containing a high concentration of soluble osmotically active substances contacts the intravaginal environment.

[0063] The replaceable drug core and adjustable osmotic pressure regulating ring are assembled into a complete drug delivery device, which is then inserted into the vaginal vault. Assembly of the replaceable drug core and adjustable osmotic pressure regulating ring involves physically inserting the cylindrical drug core, loaded with the drug and a hydrophilic carrier, into the central slot of the replaceable drug core and adjustable osmotic pressure regulating ring. This ensures that the peripheral structure containing a high concentration of soluble osmotic active substances is in full contact with the body fluids secreted from the vaginal mucosal surface. The peripheral structure containing a high concentration of soluble osmotic active substances consists of compacted sodium chloride crystal particles filled within the annular cavity of the osmotic pressure regulating ring. The crystal particle size is controlled between 150 and 300 μm to balance dissolution rate and structural stability, and the filling concentration ranges from 40% to 60% of the total cavity volume.

[0064] The peripheral structure containing high-concentration soluble osmotic active substances specifically refers to the sodium chloride or glucose crystal material layer loaded in the osmotic pressure regulating ring. Experiments on in vitro pig vaginal mucosa have confirmed that when the osmotic pressure of the salt solution reaches three times the osmotic pressure of the vaginal body fluid (about 280-320mOsm / L), a stable flow force in the body fluid can be generated.

[0065] After the complete drug delivery device fully contacts the body fluids secreted from the surface of the vaginal mucosa, the body fluids penetrate into the annular cavity through the preset microporous channels on the surface of the adjustment ring, causing the surface of the crystal particles to dissolve and forming a local high-concentration salt solution area on the outside of the complete drug delivery device. The osmotic pressure of the local high-concentration salt solution area needs to be preset to more than 3 times the osmotic pressure of the vaginal body fluids, that is, ≥900mOsm / L. The osmotic pressure difference between the high-concentration salt solution and the vaginal body fluids drives the directional flow of body fluids in subsequent steps. The microporous channels are an array of through holes with a diameter of 50-100μm formed by laser drilling on the wall of the adjustment ring. The total opening area accounts for 5%-15% of the ring surface area.

[0066] Exemplarily, medical-grade sodium chloride crystals are ground and sieved to obtain particles with a particle size of 200 μm, which are loaded into the adjustable osmotic pressure regulating ring cavity of polylactic acid material at a volume filling rate of 55%. The adjustable osmotic pressure regulating ring has an outer diameter of 45 mm, and 80 micropores with a diameter of 80 μm are evenly distributed on the wall. After the regulating ring is assembled with a mixed drug core containing clotrimazole / sodium alginate, it is placed in an environment simulating the body fluid secreted from the surface of the vaginal mucosa (osmotic pressure 305 mOsm / L). Within 10 seconds, body fluid can be seen penetrating into the cavity through the micropores. At 60 seconds, the salt solution concentration outside the cavity is detected to be 28%, corresponding to an osmotic pressure value of 952 mOsm / L, forming a stable osmotic pressure difference with the body fluid secreted from the surface of the vaginal mucosa.

[0067] In one embodiment of the present invention, step S2 includes the following steps:

[0068] The outside of the complete drug delivery device forms a continuous inward permeation flow of body fluid.

[0069] Specifically, the device utilizes a localized high-concentration saline solution zone on the periphery of the complete drug delivery device. The osmotic pressure differential established between this zone and the vaginal fluid environment drives vaginal fluid through the microporous channels of the adjustable osmotic pressure regulating ring and continuously flows into the annular cavity. The direction of vaginal fluid osmotic flow is from the vaginal environment toward the interior of the complete drug delivery device.

[0070] Continuous inward osmotic flow of body fluids refers specifically to the unidirectional migration of body fluids due to an osmotic pressure differential. The flow direction is determined by the location of the high-concentration saline solution zone established in step S1. When the ratio of the saline solution osmotic pressure to the vaginal fluid osmotic pressure is ≥2.5, in vitro porcine vaginal mucosa experiments have shown that the body fluid flow rate can reach over 0.15 ml / min, meeting the requirement for continuous drug carrier infiltration. The flow rate is controlled by both the real-time osmotic pressure intensity of the high-concentration saline solution zone and the open area of ​​the microporous channel. The open area of ​​the microporous channel is adjusted by rotating the adjustment ring to change the effective exposure ratio of the through-holes. Each 30-degree increase in the rotation angle increases the effective open area by 20%. This mechanical adjustment method ensures repeatable flow control. The high-concentration saline solution zone maintains the osmotic pressure differential through the continuous dissolution of sodium chloride crystal particles. The dissolution rate is determined by the specific surface area of ​​the crystal particles and the fluid exchange rate, ensuring that the osmotic pressure value is no less than 2.5 times the vaginal fluid osmotic pressure during the preset dosing cycle, thereby maintaining effective body fluid osmotic flow.

[0071] Illustratively, step S1 has established a 952 mOsm / L high-concentration salt solution area to simulate the vaginal body fluid environment and continuously monitor the body fluid flow direction.

[0072] Using dyed saline as a tracer, fluid flowed directionally into the adjustment ring through 80 80μm-diameter micropores, with a cumulative inflow of 0.32mL within 2 minutes. Rotating the adjustment ring to increase the effective exposed area of ​​the micropores by 40% increased inflow to 0.51mL over the same period. The osmotic pressure in the high-concentration saline solution region remained within the 780-920mOsm / L range for 60 minutes, consistently maintaining an osmotic pressure differential of ≥2.56 times that of vaginal fluid, resulting in a stable osmotic flow.

[0073] In one embodiment of the present invention, step S3 includes the following steps:

[0074] Guide the body fluid flowing into the vagina to mix with the absorbent carrier and drug on the inner layer of the complete drug delivery device.

[0075] Specifically, after the continuous inward osmotic flow generated in step S2 enters the annular cavity of the adjustable osmotic pressure regulating ring, the vaginal fluid passes through the pre-set diversion mesh at the bottom of the annular cavity of the adjustable osmotic pressure regulating ring and enters the storage area of ​​the replaceable drug core, where it comes into contact and infiltrates with the absorbent carrier and drug molecules in the inner layer of the replaceable drug core. The diversion mesh refers to a nylon mesh structure with a pore size of 100-200 μm set at the bottom of the osmotic pressure regulating ring cavity. Its function is to allow the osmotic flow of the body fluid to pass through while blocking sodium chloride crystal particles from entering the drug core area.

[0076] The water-absorbing carrier is composed of a uniform mixture of cross-linked sodium alginate powder and the drug clotrimazole in a mass ratio of 3:1. The water-absorbing carrier specifically refers to cross-linked sodium alginate powder with a three-dimensional network structure, with a particle size distribution of 80-150μm. The cross-linking degree is controlled by calcium ion concentration in the range of 0.5%-1.2%. This parameter setting is based on the results of in vitro pig vaginal mucosal adhesion test. When the cross-linking degree is 0.8%, the adhesion of the carrier to the mucosa after expansion reaches 0.32N / cm 2 .

[0077] Under the influence of body fluid osmotic flow, the cross-linked sodium alginate powder absorbs water and swells, with an expansion coefficient reaching 5-8 times its original volume, carrying the drug molecules to form a uniform drug-containing mixed solution. The final viscosity of the drug-containing mixed solution is controlled in the range of 5000-15000 cP (1 cP = 1 mPa·s), ensuring its sustained drug release properties and mucosal adhesion.

[0078] The viscosity control method of the drug-containing mixed solution is: every milligram of cross-linked sodium alginate absorbs 0.25 ml of body fluid, and a homogeneous gel is formed by mechanical stirring. The liquid-to-solid ratio has been confirmed by rheometer testing to maintain the structural strength required for sustained drug release.

[0079] For example, in step S2, 0.51 mL of body fluid flows through a 200 μm pore nylon mesh into the drug core containing a mixture of 450 mg of cross-linked sodium alginate (cross-linking degree 0.8%) and 150 mg of clotrimazole. At a constant temperature of 37°C, the absorbent carrier is completely soaked within 3 minutes and expands to form a semi-solid gel column with a diameter of 12 mm. Using a rotational viscometer, the drug-containing mixed solution is tested at a shear rate of 10 s -1 The viscosity under these conditions is 11.2 Pa·s (equivalent to 11200 cP).

[0080] In one embodiment of the present invention, step S4 includes the following steps:

[0081] Establish a directional driving force for delivering the drug-containing mixed solution to the vaginal mucosa.

[0082] Specifically, after the drug-containing mixed solution formed in step S3 reaches a stable gel state inside the replaceable drug core, the squeezing effect generated by the water absorption and expansion of the gel state is achieved through the volume expansion of the cross-linked sodium alginate three-dimensional network structure after absorbing water. The expansion pressure value is measured by a pressure sensor to be 0.5-1.2 kPa. With the help of the directional water flow power carried by the continuous inward osmotic flow of body fluids and the radial expansion pressure generated by the water absorption and expansion of the cross-linked sodium alginate, the drug-containing mixed solution is jointly pushed through the microporous diffusion layer on the outer surface of the drug core toward the vaginal mucosa contact interface. The directional water flow power specifically refers to the unidirectional flow inertia of the body fluid generated by the osmotic pressure difference in step S2, and the direction is pointed from the adjustment ring to the central axis of the drug core.

[0083] The microporous diffusion layer, composed of a medical silicone film with pores ranging from 10 to 50 μm, allows free water and drug molecules in the drug-containing mixture to pass through while restricting the leakage of large gel molecules, forming a physical channel for directional drug delivery. The strength of the directional driving force is determined by the vector sum of the body fluid osmotic flow rate and the gel expansion pressure. The synergistic effect of these two factors enables drug delivery rates to reach over three times that of passive diffusion mode.

[0084] For example, the drug-containing mixed solution formed in step S3 can be replaced by a core with a 50 μm thick silica gel diffusion layer with 20 μm micropores attached to the outer surface. After applying a simulated directional water flow (flow rate 0.2 mL / min) and initiating gel expansion, fluorescently labeled clotrimazole molecules were used for tracing and showed that the drug molecules migrated 1.8 mm across the diffusion layer within 20 minutes, compared to only 0.6 mm in the control group without directional water flow. The pressure sensor recorded that the gel expansion pressure was stable at 0.82 kPa, forming a co-directional superposition effect with the water flow.

[0085] In one embodiment of the present invention, step S5 includes the following steps:

[0086] The movement rate of the drug-containing mixed solution is controlled by adjusting the intensity of the vaginal fluid permeation flow.

[0087] Specifically, during the operation of the drug delivery system established in steps S1 to S4, the effective exposure ratio of the microporous channels on the wall of the adjustable component is changed by manually rotating the adjustable component, dynamically adjusting the contact surface area between the sodium chloride crystal particles in the peripheral structure and the vaginal fluid. The adjustable component specifically refers to the rotatable outer shell of the adjustable osmotic pressure regulating ring. The inner wall of the adjustable component is equipped with a spiral convex track structure that mates with the fixed base. The rotation angle range is 0-270 degrees, with each 90-degree rotation corresponding to a 35% change in the exposed microporous area.

[0088] When the exposed area of ​​the micropores is increased, the rate at which vaginal fluid penetrates the annular cavity of the adjustable osmotic pressure regulating ring increases, accelerating the dissolution of sodium chloride crystals and increasing the intensity of the fluid osmotic flow in step S2. Conversely, when the exposed area is reduced, the dissolution rate decreases, resulting in a weakened osmotic flow. This adjustment operation simultaneously affects the directional driving force in step S4, causing the drug to move to the vaginal mucosal interface at a rate of 0.05-0.25 mg / cm 2 Continuously controllable within a range of 100 / min. For adjustable osmotic pressure regulating rings equipped with an environmentally responsive barrier, when the vaginal pH rises above 6.0, the pH-sensitive hydrogel barrier automatically expands and contracts, reducing the actual open area of ​​the micropores and achieving adaptive suppression of osmotic flow during periods of increased secretion.

[0089] Among them, the environmentally responsive interlayer is composed of dimethylaminoethyl methacrylate copolymer, which has a swelling degree of 20% at pH <5.0 and increases to 65% at pH >6.0. The swelling behavior is controlled by UV cross-linking curing. The change in swelling degree can reduce the effective pore size of the micropores by 40%.

[0090] For example, an adjustable osmotic pressure regulating ring with a pH-sensitive barrier was used, and the initial micropore exposure area was set to 30%. Under a simulated normal vaginal environment (pH 4.2), the body fluid osmotic flow rate was measured to be 0.18 mL / min, corresponding to a clotrimazole migration rate of 0.11 mg / (cm 2 After manually rotating the housing 90 degrees to increase the exposed area to 50%, the flow rate increased to 0.26 mL / min, and the drug migration rate simultaneously increased to 0.17 mg / (cm 2 When the environment switches to the ovulation state (pH 7.0), the barrier automatically expands, reducing the effective exposure area to 18%, the flow rate returns to 0.14 mL / min, and the drug migration rate stabilizes at 0.09 mg / (cm 2 ·min) to achieve dynamic balance control.

[0091] In one embodiment of the present invention, step S6 includes the following steps:

[0092] After the release of the mixed solution containing the drug pre-placed in the complete drug delivery device is completed or the treatment time is reached, the complete drug delivery device is removed from the vagina.

[0093] Specifically, once the expansion pressure of the cross-linked sodium alginate carrier within the replaceable drug core drops below 30% of its initial value, or after the preset 6-8 hour treatment duration has been reached, the operator pinches the anti-slip protrusions on the outer edge of the adjustable osmotic pressure regulating ring and gently removes the complete drug delivery device along the vaginal axis. During removal, the drug-containing mixture adheres to the surface of the drug core due to dehydration and contraction of the gel-like substance. The microporous diffusion layer prevents the shedding of large gel molecules, ensuring that no residual material remains in the vaginal cavity.

[0094] Completion of drug release is determined when the cross-linked sodium alginate gel shrinks to less than 50% of its expanded volume, the viscosity of the drug-containing mixed solution rises to above 25,000 cP, and the drug release rate drops to less than 20% of its initial value. The treatment duration is preset based on maintaining an effective antibacterial concentration of clotrimazole in the vaginal mucosa for 6 hours. Release is considered complete when the drug content in the core is less than 10%. The anti-slip projections are three 0.5mm high annular ribs on the outer wall of the adjustment ring, spaced 5mm apart.

[0095] For example, after 8 hours of operation, the complete drug delivery device was removed from an ex vivo porcine vaginal mold. The volume of the cross-linked sodium alginate gel within the drug core shrank to 42% of its initial expansion state, and the residual clotrimazole content was detected to be 7.3%. During the removal process, the device was pulled at a constant speed of 0.5 m / min, and the peak force sensor recorded 3.8 N. After removal, the complete drug delivery device was inspected for structural integrity, with the gel attached to the microporous diffusion layer ≤0.1 mm thick, and no visible residue within the vaginal mold.

[0096] In one embodiment of the present invention, step S7 includes the following steps:

[0097] Achieve targeted enrichment and long-term retention of drug-containing mixed solutions on the surface of the vaginal mucosa, reducing the risk of diffusion into deep tissues and being washed away by body fluids.

[0098] Specifically, a directional pressure gradient is formed by the high-concentration salt solution zone established in step S1 and the continuous inward osmotic flow of body fluids generated in step S2. The directional pressure gradient refers to the physical potential energy difference formed by the difference between the osmotic pressure of the high-concentration salt solution zone (≥900 milliosmoles per liter) and the osmotic pressure of vaginal body fluids (≈300 milliosmoles per liter). This promotes the continuous delivery of the drug-containing mixed solution formed in step S3 through the microporous diffusion layer in step S4 to the vaginal mucosal interface.

[0099] The 0.5-1.2 kPa radial pressure generated by the cross-linked sodium alginate gel's swelling upon absorption of water embeds the drug molecules into the microfolds of the mucosal surface. Simultaneously, the dynamically regulated osmotic flow of body fluids in step S5 creates a continuous replenishment mechanism to counteract the scouring of vaginal secretions. These microfolds, representing the inherent anatomical structures of the vaginal mucosa, are 50-150 microns deep and have been shown by scanning electron microscopy to mechanically capture the gel carrier. Ultimately, a drug-enriched zone is formed within the mucosal epithelium at a depth of 0-200 microns. The drug concentration in this region is over five times higher than that in the vaginal fluid, maintaining an effective antibacterial concentration for over six hours. This continuous replenishment mechanism is achieved by regulating the exposed micropore area in step S5. When environmental secretions increase, the osmotic flow intensity is increased by 15%-30% to maintain a stable interfacial concentration.

[0100] After removal of the complete drug delivery device, the cross-linked sodium alginate gel fragments remaining on the mucosal surface continue to release the remaining drug, prolonging its retention. Spatial localization of the drug-enriched zone is based on ex vivo tissue cryosections, which show that clotrimazole concentrations reach 1.2 mg / g within the first 200 microns of the mucosal surface, decreasing to 0.3 mg / g at a depth of 400 microns.

[0101] For example, after the ex vivo porcine vagina mold ran the complete process for 6 hours, the ex vivo porcine vagina mold tissue was taken out for longitudinal stratification detection. Fluorescently labeled clotrimazole showed: the concentration of the mucosal epithelium (0-50μm) was 1.8mg / g, the concentration of the lamina propria (200μm) was 0.9mg / g, and the concentration of the muscularis (500μm) was 0.2mg / g. 2 hours after removing the complete drug delivery device, the surface drug concentration remained at 1.2mg / g. When there was no osmotic pressure drive in the control group, the surface concentration was only 0.4mg / g after the same time. Histological sections showed that the drug was mainly enriched in the depressions of the mucosal folds, and the spatial distribution of the microfolds was consistent with 93%, confirming the directional enrichment and long-term retention effects.

[0102] See attached Figure 2 The present invention also proposes an adjustable vaginal mucosa targeted delivery system based on bidirectional osmotic pressure difference control, which includes the following modules:

[0103] The vaginal environment contact module is a pre-set complete drug delivery device that is placed into the vagina, allowing the soluble osmotic active substance in the peripheral structure to contact the vaginal fluid, forming a local high-concentration salt solution area;

[0104] The osmotic pressure driving module utilizes the osmotic pressure difference between the local high-concentration salt solution area and the vaginal fluid environment to drive the vaginal fluid to flow into the complete drug delivery device, generating a continuous inward osmotic flow of body fluid;

[0105] The drug core mixing module guides the continuous inward permeation flow of body fluids to mix with the absorbent carrier and drug in the inner layer of the complete drug delivery device to form a drug-containing mixed solution;

[0106] a directional driving force generating module for establishing a directional driving force for transporting the drug-containing mixed solution to the vaginal mucosa by utilizing the continuous inward osmotic flow of body fluids and the squeezing effect caused by the water-absorbing expansion of the water-absorbing carrier;

[0107] The drug delivery control module controls the rate of drug migration to the mucosal interface by changing the surface area of ​​soluble substances in the peripheral structure exposed to the body fluid and adjusting the intensity of the body fluid osmotic flow;

[0108] The mucosal enrichment maintenance module removes the complete drug delivery device from the vagina when drug release is completed or the preset treatment time is reached;

[0109] The removable execution module can achieve directional enrichment of the drug-containing mixed solution on the surface of the vaginal mucosa to form a drug-enriched zone through directional driving force.

[0110] It should be noted that the formulas described above can translate physical quantities of different attributes into unitless standard values ​​or superimposable parameters of the same dimension through the principle of dimensional consistency and mathematical standardization (e.g., normalization, dimensionless parameter conversion, or unit system unification). This eliminates the interference of different dimensions on the operational logic, allowing the formulas to retain the distribution characteristics of the original data while maintaining mathematical rationality and adaptability to objective laws. The above are merely exemplary embodiments of the present invention and are not intended to limit the scope of the present invention.

[0111] The modules can be implemented in whole or in part through software, hardware, or a combination thereof, supporting hardware embedded in or independent of a processor in a computer device, and also supporting software stored in a memory in a computer device, so that the processor can call and execute operations corresponding to the modules.

[0112] It should be noted that the human body information (including but not limited to human device information and personal information, etc.) and data (including but not limited to data used for analysis, stored data and displayed data, etc.) involved in the present invention are all information and data authorized by the human body or fully authorized by all parties. The collection, use and processing of relevant data require relevant legal standards.

[0113] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention, and should all be included in the scope of protection of the present invention.

Claims

1. An adjustable vaginal mucosal targeted delivery method based on bidirectional osmotic pressure difference control, characterized in that: The following steps are involved: S1. The pre-set complete drug delivery device is placed into the vagina, so that the soluble osmotic active substance in the peripheral structure contacts the vaginal fluid, forming a local high-concentration salt solution area; S2. utilizing the osmotic pressure difference between the local high-concentration salt solution area and the vaginal body fluid environment to drive the vaginal body fluid to flow into the interior of the complete drug delivery device, thereby generating a continuous inward body fluid osmotic flow; S3, guiding the continuous inward permeation flow of body fluid to mix with the absorbent carrier and drug in the inner layer of the complete drug delivery device to form a drug-containing mixed solution; S4, establishing a directional driving force for transporting the drug-containing mixed solution to the vaginal mucosa by utilizing the continuous inward osmotic flow of body fluids and the squeezing effect caused by the water absorption and expansion of the water-absorbing carrier; S5. By changing the surface area of ​​soluble substances in the peripheral structure exposed to body fluids, the intensity of the body fluid osmotic flow is adjusted, thereby controlling the rate of drug migration to the mucosal interface; S6. When drug release is complete or the preset treatment duration is reached, remove the complete drug delivery device from the vagina; S7. Through directional driving force, the drug-containing mixed solution is directional enriched on the surface of the vaginal mucosa to form a drug enrichment zone.

2. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Forming a local high-concentration salt solution area includes the following steps: Assembling the replaceable drug core into the central slot of the adjustable osmotic pressure regulating ring to form a complete drug delivery device; The complete drug delivery device is placed into the vaginal vault, so that the soluble osmotic active substance filled in the cavity of the osmotic pressure regulating ring contacts the body fluid secreted by the surface of the vaginal mucosa; Through the microporous channels preset on the wall of the osmotic pressure regulating ring, body fluids penetrate into the cavity to dissolve soluble osmotic active substances, forming a local high-concentration salt solution area.

3. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Generating a continuous inward osmotic flow of body fluids, comprising the following steps: Based on the osmotic pressure difference between the local high-concentration salt solution area and the vaginal body fluid environment, the body fluid is driven to continuously flow into the osmotic pressure regulating ring cavity through the microporous channel; By rotating the rotatable outer shell of the osmotic pressure regulating ring, the effective exposed area of ​​the microporous channel can be changed to adjust the flow rate of the body fluid osmotic flow; Maintain the osmotic pressure difference not lower than the vaginal fluid osmotic pressure, generating a continuous inward osmotic flow of body fluids.

4. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Forming a drug-containing mixed solution comprises the following steps: The body fluid continues to flow inward through the preset diversion mesh and enters the absorbent carrier receiving area, which is the replaceable drug core receiving area; The pre-set diversion mesh allows body fluid to pass through but blocks the entry of soluble osmotic active substance particles; The continuous inward osmotic flow of body fluid mixes with the cross-linked sodium alginate carrier and the drug to generate a drug-containing mixed solution with a preset viscosity.

5. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Establishing a directional push for the drug-containing mixed solution to be delivered to the vaginal mucosa comprises the following steps: The directional water flow power of the body fluid osmotic flow and the radial pressure generated by the expansion of cross-linked sodium alginate generate a directional driving force superimposed in the same direction; Drive the drug-containing mixed solution to migrate through the preset microporous diffusion layer on the outer surface of the drug core to the vaginal mucosa interface; The microporous diffusion layer is used to limit the leakage of gel macromolecules, forming a directional drug delivery channel.

6. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Adjusting the intensity of the body fluid osmotic flow comprises the following steps: Rotating the rotatable housing of the adjustable osmotic pressure regulating ring changes the effective exposed area of ​​the microporous channel to dynamically adjust the intensity of the body fluid osmotic flow; The rotatable housing is provided with a spiral convex track structure, and the change in the rotation angle corresponds to the proportional adjustment of the exposed area of ​​the micropores.

7. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 6, characterized in that: Adjusting the intensity of the body fluid osmotic flow also includes the following steps: An environmental response barrier is set in the adjustable osmotic pressure regulating ring. When the pH value of the vaginal environment changes, the effective exposed area of ​​the micropores is automatically adjusted to maintain the stable intensity of the body fluid osmotic flow; Among them, the environmentally responsive barrier is composed of pH-sensitive hydrogel, whose swelling behavior adaptively shrinks or expands as the pH value changes.

8. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Removal of the complete delivery device from the vagina involves the following steps: At the end of the treatment cycle, the gel-like substance dehydrates and shrinks due to the loss of continuous replenishment of body fluid osmotic flow, and adheres to the surface of the replaceable drug core, forming a device ready for removal; The microporous diffusion layer blocks the gel-state substance from falling off during the removal process, and the drug delivery device in the state of the device to be removed is completely removed; The syneresis shrinkage property of the gel-state substance is combined with the physical barrier function of the microporous diffusion layer.

9. The adjustable vaginal mucosa targeted delivery method based on bidirectional osmotic pressure difference control according to claim 1, characterized in that: Forming a drug-enriched zone comprises the following steps: The radial expansion pressure in the directional driving force is used to embed the drug-containing mixed solution into the surface microfolds of the vaginal mucosa; And the continuous replenishment mechanism formed by the directional drug delivery flow is used to counteract the flushing effect of vaginal secretions; The drug-containing mixed solution is embedded in the surface microfolds of the vaginal mucosa, and the synergistic effect of the formed continuous replenishment mechanism achieves the directional enrichment and long-term retention of the drug in the surface layer of the vaginal mucosa, thereby forming a drug enrichment zone.

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