An excipient matrix suitable for weakly acidic mucous membrane environment, preparation method and application

Abstract

This invention discloses an excipient matrix suitable for weakly acidic mucosal environments, its preparation method, and its application, relating to the field of pharmaceutical excipient technology. The matrix includes polycarbophen, carbomer, a dynamic site polymer containing benzo[a]oxoborazole or boron-oxygen heterocyclic groups, a competing diol blocking agent, a diol donor polymer, and a buffer system. The pH of the excipient matrix is ​​4.0–4.4. After contact with the weakly acidic mucosal fluid, the dynamic site polymer, the diol donor polymer, and the mucosal glycan diol sites form a dynamic reversible crosslinking network. The ratio of the total molar amount of diol hydroxyl groups in the competing diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer is 1.2:1–3.5:1. This invention maintains the structural stability of the matrix by reversibly blocking dynamic sites under storage conditions using a competing diol blocking agent.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical excipients technology, and in particular to an excipient matrix, preparation method and application suitable for weakly acidic mucosal environments. Background Technology

[0002] Mucosal drug delivery systems are widely used in clinical fields such as gynecology, proctology, and urology due to their advantages of convenient local administration, prolonged drug action time, and reduced systemic adverse reactions. They are particularly suitable for administration to mucosal sites such as the vagina, rectum, and urogenital tract. For prostate-related diseases, local or adjunctive drug delivery is also frequently administered through urological routes. Therefore, excipient matrices suitable for weakly acidic mucosal environments have high practical application value in gynecology, proctology, and urology, especially in prostate-related drug delivery applications. In the present technology, commonly used mucosal drug delivery excipient matrices mainly include high molecular weight polymers such as carbomer and cellulose derivatives. These materials usually form a gel structure through physical entanglement or hydrogen bonding between molecular chains, thereby forming a coating layer on the mucosal surface to improve the adhesion of the formulation and the drug retention time.

[0003] However, existing excipient matrices often suffer from insufficient stability in weakly acidic environments, and are prone to structural relaxation during storage, leading to a decrease in system viscosity and a decline in rheological properties. At the same time, after contact with mucous membranes, they are difficult to form a stable dynamic cross-linking network quickly, affecting the in-situ gelling performance, mucous membrane adhesion performance, and consistency of use of the formulation. Especially in the weakly acidic physiological environment of pH 4.0 to 4.4, traditional borate ester dynamic chemical systems usually lack effective site blocking mechanisms, making it difficult to balance structural stability during storage and cross-linking efficiency during application. Summary of the Invention

[0004] In view of this, this application provides an excipient matrix suitable for weakly acidic mucosal environments, its preparation method, and its application.

[0005] According to one aspect of this disclosure, an excipient matrix suitable for weakly acidic mucosal environments is provided, comprising polycarbophen, carbomer, a dynamic site polymer containing benzo[a]oxoborazole or boron-oxygen heterocyclic groups, a competing diol blocking agent, a diol donor polymer, and a buffer system; the pH value of the excipient matrix is ​​4.0 to 4.4; under storage conditions, the competing diol blocking agent forms a reversible binding state with the dynamic sites in the dynamic site polymer; after the excipient matrix comes into contact with the weakly acidic mucosal liquid, the dynamic site polymer forms a dynamic reversible crosslinking network with the diol donor polymer and the mucosal glycan diol sites; the ratio of the total molar amount of diol hydroxyl groups in the competing diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer is 1.2:1 to 3.5:1.

[0006] According to another aspect of this disclosure, a method for preparing an excipient matrix suitable for weakly acidic mucosal environments is provided, comprising: Step 1: dispersing polycarbophen in purified water and performing a swelling treatment to obtain a skeleton dispersion; Step 2: adding pre-dispersed carbomer to the skeleton dispersion and adjusting the shear rate to ensure uniform distribution of carbomer; Step 3: mixing the dynamic site polymer with the diol donor polymer, adding the competing diol blocking agent, and pre-reacting at a temperature of 10°C to 25°C for 30 to 60 minutes to form a blocked prepolymer; the amount of the competing diol blocking agent added is such that at least 80% of the dynamic sites in the dynamic site polymer are in a blocked state; Step 4: adding the blocked prepolymer to the skeleton dispersion for mixing; Step 5: adding the buffer system to adjust the pH to 4.0 to 4.4, degassing, and filling.

[0007] The beneficial effects of this invention are as follows: by competing diol blocking agents to reversibly block dynamic sites in the storage state, the stability of the matrix structure is maintained; after contact with weak acid mucosal liquid, the dynamic site polymer, the diol donor polymer and the mucosal glycan diol sites rapidly form a dynamic reversible cross-linking network, achieving a synergistic effect of high viscosity maintenance and rapid in-situ film formation, significantly improving the mucosal adhesion ability and film toughness. Attached Figure Description

[0008] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0009] Figure 1 A schematic diagram of the pH-dependent viscosity curve of a weakly acidic mucosal excipient matrix.

[0010] Figure 2 This is a schematic diagram showing the relationship between the amount of sealing agent and the film retention performance. Detailed Implementation

[0011] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this disclosure.

[0012] In a first aspect, the present invention aims to construct an excipient matrix suitable for weakly acidic mucosal environments. In embodiments of this application, the excipient matrix suitable for weakly acidic mucosal environments includes: polycarbophen, carbomer, a dynamic site polymer containing benzo[a]oxoborazole or boron-oxygen heterocyclic groups, a competing diol blocking agent, a diol donor polymer, and a buffer system; the pH value of the excipient matrix is ​​4.0–4.4; under storage conditions, the competing diol blocking agent forms a reversible binding state with the dynamic sites in the dynamic site polymer; after the excipient matrix comes into contact with the weakly acidic mucosal liquid, the dynamic site polymer, the diol donor polymer, and the mucosal glycan diol sites form a dynamic reversible crosslinking network; the ratio of the total molar amount of diol hydroxyl groups in the competing diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer is 1.2:1 to 3.5:1.

[0013] In some embodiments of this application, in the dynamic site polymer containing benzo[a]oxorbazole or boro[a]oxorbazole groups, the benzo[a]oxorbazole groups are grafted onto the water-soluble polymer backbone via linking arms. The water-soluble polymer backbone is selected from at least one of polyvinyl alcohol, polyethylene glycol, hyaluronic acid derivatives, or chitosan derivatives; The benzene ring of the benzo[a]oxorbazole group is substituted with an electron-withdrawing group, wherein the electron-withdrawing group is selected from at least one of fluorine atom, nitro or trifluoromethyl; The apparent dissociation constant pKa of the benzo[a]oxorbazole group is 5.0 to 6.5.

[0014] In some embodiments of this application, the competing diol blocking agent is selected from at least one of ortho-diol compounds having a five-membered or six-membered ring structure and aliphatic diol derivatives having steric hindrance. The competitive diol blocking agent contains at least one hydrophobic side chain with a volume larger than that of a methyl group in its molecular structure. In the storage state, the binding affinity of the competing diol blocker to the dynamic sites in the dynamic site polymer is higher than that of the competing diol blocker to the mucosal glycan diol sites. In a weakly acidic simulated body fluid diluted more than 5 times, the dissociation time between the competing diol blocking agent and the dynamic site in the dynamic site polymer is less than 30 seconds.

[0015] In some embodiments of this application, the diol donor polymer is a polyhydroxy polymer; The molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer is 1.5:1 to 5:1. The molecular weight range of the diol donor polymer is 10 kDa to 500 kDa.

[0016] In some embodiments of this application, the polycarboxyphene contains 0.5% to 3.0% by mass in the excipient matrix; The carbomer content in the auxiliary matrix is ​​0.05% to 0.5% by mass; The mass ratio of the carbomer to the polycarboferrite is 1:10 to 1:6; The carbomer is a hydrophobically modified carbomer, and the hydrophobic group of the hydrophobically modified carbomer is selected from C10-C30 alkyl chains; The degree of hydrophobic modification of the hydrophobic modified carbomer is 1.5% to 4.0%; The carbomer, as a rheology modifier, provides film toughness, surface feel, and mucosal retention assistance through hydrophobic association.

[0017] In some embodiments of this application, the buffer system is a buffer pair composed of lactic acid and sodium lactate, or a buffer pair composed of citric acid and sodium citrate; The ionic strength of the buffer system is 0.05 mol / L to 0.15 mol / L.

[0018] In some embodiments of this application, the static viscosity of the excipient matrix at a shear rate of 0.1 sec-1 under storage conditions of 25°C is 5000 mPa·s to 50000 mPa·s. After the excipient matrix is ​​diluted with simulated mucosal solution and allowed to stand for 60 seconds to recover, the in-situ viscosity at a shear rate of 0.1 sec-1 is more than 5 times the static viscosity. The time required for the viscosity of the auxiliary matrix to recover to 90% of its initial value after 100% strain shear failure is less than or equal to 120 seconds.

[0019] In some embodiments of this application, the auxiliary material matrix does not contain free strong alkaline neutralizing agents; The dosage form of the excipient matrix is ​​a gynecological mucosal gel, anorectal gel, or mucosal film-forming dressing.

[0020] Secondly, this application embodiment also provides a method for preparing an excipient matrix suitable for weakly acidic mucosal environments, including step 1: dispersing polycarboxyphene in purified water, and performing swelling treatment to obtain a skeleton dispersion; Step 2: Add the pre-dispersed carbomer to the skeleton dispersion and adjust the shear rate to ensure uniform distribution of carbomer; Step 3: Mix the dynamic site polymer with the diol donor polymer, add the competing diol blocking agent, and pre-react at a temperature of 10℃~25℃ for 30 minutes~60 minutes to form a blocked prepolymer liquid; The amount of the competing diol blocking agent added is such that at least 80% of the dynamic sites in the dynamic site polymer are in a blocked state. Step 4: Add the closed-state prepolymer to the skeleton dispersion and mix. Step 5: Add the buffer system to adjust the pH value to 4.0-4.4, degas, and fill.

[0021] This invention provides the application of the excipient matrix suitable for weakly acidic mucosal environments in the preparation of gynecological gel formulations, anorectal gel formulations, and mucosal film-forming dressings.

[0022] Example 1: The components were formulated in the following mass percentages: 2.0% polycarbophen, 0.25% carbomer, 1.5% dynamic site polymer containing benzo[a]oxorubicin group, 0.8% sorbitol derivative (competitive diol blocking agent), and 2.0% hyaluronic acid derivative (diol donor polymer). The buffer system consisted of lactic acid and sodium lactate, and the pH was adjusted to 4.2. In preparation, polycarbophen was first dispersed in purified water to swell and obtain a framework dispersion. Then, carbomer was pre-dispersed and the shear rate was adjusted to ensure uniform distribution. Separately, the dynamic site polymer and the diol donor polymer were mixed, and the competitive diol blocking agent was added. The mixture was pre-reacted at 15°C for 45 minutes to form a blocked prepolymer, at which point 85% of the dynamic sites in the dynamic site polymer were blocked. The blocked prepolymer was added to the framework dispersion and mixed. The pH was adjusted to 4.2 using a buffer system, and the mixture was degassed before filling. The ratio of the total molar amount of diol hydroxyl groups in the competing diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer is 1.8:1, the ratio of the molar equivalent of hydroxyl groups in the diol donor polymer to the molar equivalent of boron atoms in the dynamic site polymer is 2.5:1, the mass ratio of carbomer to polycarboferrite is 1:8, and the degree of hydrophobic modification of the hydrophobic modified carbomer is 2.5%.

[0023] The difference between Example 2 and Example 1 is as follows: the amount of polycarbophen is adjusted to 1.5%, the amount of carbomer is 0.2%, the amount of dynamic site polymer is 1.2%, the competing diol blocking agent is 0.65% mannitol derivative, the diol donor polymer is 1.8% polyethylene glycol derivative, the buffer system is changed to citric acid and sodium citrate, and the pH value is adjusted to 4.1. The pre-reaction temperature is set to 12°C, the pre-reaction time is 40 minutes, and the dynamic site blocking rate is 82%. The molar ratio of the total amount of diol hydroxyl groups in the competing diol blocking agent to the total amount of boron atoms in the dynamic site polymer is 1.5:1, the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer is 2.0:1, the mass ratio of carbomer to polycarbophen is 1:7.5, and the degree of hydrophobic modification of the hydrophobically modified carbomer is 2.0%.

[0024] Example 3: The components were formulated in the following mass percentages: 2.5% polycarbophen, 0.3% carbomer, 1.8% dynamic site polymer containing benzo[a]oxorubicin group, 0.95% fructose derivative (competitive diol blocking agent), and 2.5% chitosan derivative (diol donor polymer). The buffer system consisted of lactic acid and sodium lactate, with a pH of 4.3. During preparation, the dynamic site polymer and diol donor polymer were mixed, and then the competitive diol blocking agent was added. The mixture was pre-reacted at 18°C ​​for 50 minutes, achieving a dynamic site blocking rate of 88%. The molar ratio of the total diol hydroxyl groups in the competitive diol blocking agent to the total boron atoms in the dynamic site polymer was 2.2:1; the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer was 3.0:1; the mass ratio of carbomer to polycarbophen was 1:8.3; and the degree of hydrophobic modification of the hydrophobically modified carbomer was 3.0%.

[0025] Example 4 is a low-viscosity formulation, with the following mass percentage proportions of components: 1.2% polycarbophen, 0.18% carbomer, 1.1% dynamic site polymer containing benzo[a]borazole group, 0.6% xylitol derivative (competitive diol blocking agent), and 1.6% polyvinyl alcohol derivative (diol donor polymer). The buffer system uses lactic acid and sodium lactate, with a pH of 4.0. The pre-reaction was carried out at 10°C for 35 minutes, achieving a dynamic site blocking rate of 82%. The molar ratio of the total number of diol hydroxyl groups in the competitive diol blocking agent to the total number of boron atoms in the dynamic site polymer was 1.3:1; the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer was 1.8:1; the mass ratio of carbomer to polycarbophen was 1:6.7; and the degree of hydrophobic modification of the hydrophobically modified carbomer was 1.8%.

[0026] Example 5 is a high-viscosity formulation, with the following mass percentage proportions of each component: 3.0% polycarbophen, 0.4% carbomer, 2.0% dynamic site polymer containing benzo[a]oxorubicin group, 1.1% competitive diol blocking agent (galactose derivative), 3.0% diol donor polymer (hyaluronic acid derivative), and a buffer system of citric acid and sodium citrate with a pH of 4.4. The pre-reaction temperature was 20°C, the pre-reaction time was 55 minutes, and the dynamic site blocking rate was 90%. The molar ratio of the total number of diol hydroxyl groups in the competitive diol blocking agent to the total number of boron atoms in the dynamic site polymer was 2.8:1, the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer was 4.0:1, the mass ratio of carbomer to polycarbophen was 1:7.5, and the degree of hydrophobic modification of the hydrophobically modified carbomer was 3.5%.

[0027] Example 6: The components were formulated as follows by mass percentage: 2.2% polycarbophen, 0.28% carbomer, 1.6% dynamic site polymer containing benzo[a]oxorubicin group, 0.85% glucose derivative (competitive diol blocking agent), and 2.2% polyethylene glycol derivative (diol donor polymer). The buffer system consisted of lactic acid and sodium lactate at pH 4.2. The pre-reaction conditions were 16°C for 45 minutes, resulting in a dynamic site blocking rate of 86%. The molar ratio of the total number of hydroxyl groups in the competitive diol blocking agent to the total number of boron atoms in the dynamic site polymer was 2.0:1; the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer was 2.8:1; the mass ratio of carbomer to polycarbophen was 1:7.9; and the degree of hydrophobic modification of the hydrophobically modified carbomer was 2.8%.

[0028] Example 7 uses a sucrose derivative as a competing diol blocking agent. The components are formulated in the following mass percentages: 1.8% polycarbophen, 0.22% carbomer, 1.4% dynamic site polymer containing benzo[a]borazole group, 0.75% sucrose derivative (competing diol blocking agent), and 1.9% chitosan derivative (diol donor polymer). The buffer system is lactic acid and sodium lactate, with a pH of 4.1. The pre-reaction temperature is 14°C, the pre-reaction time is 42 minutes, and the dynamic site blocking rate is 84%. The molar ratio of the total number of diol hydroxyl groups in the competing diol blocking agent to the total number of boron atoms in the dynamic site polymer is 1.6:1, the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer is 2.2:1, the mass ratio of carbomer to polycarbophen is 1:8.2, and the degree of hydrophobic modification of the hydrophobically modified carbomer is 2.2%.

[0029] Example 8 uses a maltose derivative as a competing diol blocking agent. The components are formulated in the following mass percentages: 2.8% polycarbophen, 0.35% carbomer, 1.9% dynamic site polymer containing benzo[a]borazole group, 1.0% maltose derivative (competing diol blocking agent), and 2.8% polyvinyl alcohol derivative (diol donor polymer). The buffer system is citric acid and sodium citrate, with a pH of 4.3. The pre-reaction conditions are 19°C for 52 minutes, resulting in a dynamic site blocking rate of 89%. The molar ratio of the total number of diol hydroxyl groups in the competing diol blocking agent to the total number of boron atoms in the dynamic site polymer is 2.5:1, the molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer is 3.5:1, the mass ratio of carbomer to polycarbophen is 1:8.0, and the degree of hydrophobic modification of the hydrophobically modified carbomer is 3.2%.

[0030] Comparative Example 1 was used to verify the necessity of a competing diol blocking agent. The formulation, by mass percentage, consisted of: 2.0% polycarbophen, 0.25% carbomer, 1.5% dynamic site polymer containing benzo[a]oxorubicin group, and 2.0% diol donor polymer (hyaluronic acid derivative). The buffer system was lactic acid and sodium lactate, with a pH of 4.2. No competing diol blocking agent was added during preparation. The dynamic site polymer and the diol donor polymer were directly mixed and pre-reacted for 45 minutes, resulting in a dynamic site blocking rate of 0%. The molar equivalent ratio of hydroxyl groups in the diol donor polymer to boron atoms in the dynamic site polymer was 2.5:1, the mass ratio of carbomer to polycarbophen was 1:8, and the degree of hydrophobic modification of the hydrophobically modified carbomer was 2.5%.

[0031] Comparative Example 2 was used to verify the lower limit requirement for the amount of competing diol blocking agent. The formulation, by mass percentage, consisted of: 2.0% polycarbophen, 0.25% carbomer, 1.5% dynamic site polymer containing benzo[a]borazole group, 0.35% sorbitol derivative (competing diol blocking agent), and 2.0% hyaluronic acid derivative (diol donor polymer). The buffer system was lactic acid and sodium lactate, with a pH of 4.2. The ratio of the total molar amount of diol hydroxyl groups in the competing diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer was 0.8:1, which is lower than the range specified in this invention, resulting in a dynamic site blocking rate of only 45%. All other parameters remained consistent with Example 1.

[0032] Comparative Example 3 was used to verify the effectiveness of the pH range. The formulation, by mass percentage, consisted of: 2.0% polycarboflufenicol, 0.25% carbomer, 1.5% dynamic site polymer containing benzo[a]oxorubicin group, 0.8% sorbitol derivative (competitive diol blocker), and 2.0% hyaluronic acid derivative (diol donor polymer). The buffer system was lactic acid and sodium lactate, and the pH was adjusted to 5.5. The pH exceeded the 4.0–4.4 range set in this invention, approaching the pKa value of the benzo[a]oxorubicin group, leading to a shift in the dynamic site dissociation equilibrium during storage. The ratio of the total molar amount of diol hydroxyl groups in the competing diol blocker to the total molar amount of boron atoms in the dynamic site polymer was 1.8:1, resulting in a dynamic site blocking rate of 85%. All other parameters remained consistent with Example 1.

[0033] like Figure 1 As shown in the schematic diagram of the pH-dependent viscosity curve of the weak acid mucosal excipient matrix, the viscosity of the excipient matrix changes with pH value. The maximum viscosity is reached in the pH range of 4.0-4.4, which is completely consistent with the pH range set in this invention. When the pH value enters the pKa transition region, i.e., the pH range of 5.0-6.5, the viscosity drops sharply. This is due to the deprotonation of the benzo[a]oxorubazole group, which leads to the dissociation of the dynamic cross-linked network. Figure 1The necessity of controlling the pH value of the excipient matrix within the range of 4.0-4.4 was verified, which can ensure storage stability and also ensure optimal adhesion performance in a weakly acidic mucosa environment, i.e., within the pH range of 4.0-4.5.

[0034] Storage stability test, in-situ viscosity recovery test and mucosal retention time test were conducted on the products of Examples 1 to 8 and the samples of Comparative Examples 1 to 3.

[0035] Table 1 Comparison of formulation parameters between the examples and comparative examples. Table 2 Summary of Three Core Performance Test Indicators As shown in Table 1, Examples 1 to 8 achieved a dynamic site blocking rate of over 80% and a viscosity retention rate of over 87% after 60 days by adjusting the molar ratio of the competing diol blocking agent to the boron atoms in the dynamic site polymer within the range of 1.2:1 to 3.5:1. Comparative Example 1, without the addition of the competing diol blocking agent, had a blocking rate of 0% and a viscosity retention rate of only 59.3% after 60 days. Comparative Example 2 had a low blocking agent ratio (0.8:1), resulting in a blocking rate of only 45% and a viscosity retention rate of 64.7%. Comparative Example 3, although achieving a blocking rate of 85%, still suffered from storage stability issues due to its pH value deviating from the weakly acidic range (5.5), with a viscosity retention rate of 83.1%, lower than the Example group.

[0036] Table 2 shows that the excipient matrices prepared in Examples 1 to 8 all met the technical standards in four key evaluation indicators: storage stability, in-situ viscosity recovery ability, self-healing efficiency, and mucosal retention performance. The in-situ viscosity recovery factor was 5.0 to 6.0 times, the complete recovery time was 62 to 95 seconds, the mucosal retention time was 158 to 215 minutes, the film integrity score was 4.0 to 4.8, and the residue rate after rinsing was 68% to 85%. The comparative groups, lacking an effective site blocking and release mechanism, showed significantly lower performance in all indicators compared to the example groups. Comparative Example 1 performed the worst, followed by Comparative Example 3 due to its pH value exceeding the range.

[0037] like Figure 2As shown in the diagram, the relationship between the amount of sealing agent and film retention performance further illustrates the influence of the ratio of the total molar amount of glycol hydroxyl groups in the competing glycol sealing agent to the total molar amount of boron atoms in the dynamic site polymer on the film integrity score and the residual rate after rinsing. When the sealing agent / boron molar ratio is in the range of 1.2:1 to 3.5:1, the film integrity score is ≥4.0 and the residual rate after rinsing is ≥65%, forming the optimal performance window. The formulation parameters of Examples 1-8 all fall within this optimal window, which is consistent with the data in Table 2, verifying the rationality of limiting the sealing agent / boron molar ratio to 1.2:1 to 3.5:1, and ensuring that the excipient matrix has stable film toughness and retention performance in a weakly acidic mucous membrane environment.

[0038] The above description is only a specific embodiment of this disclosure, but the protection scope of this disclosure is not limited thereto. The protection scope of this disclosure should be determined by the protection scope of the claims.

Claims

1. An excipient matrix suitable for weakly acidic mucosal environments, characterized in that, include: Polycarbophen, carbomer, dynamic site polymers containing benzo[a]oxoborazole or boro[a]oxoheterocyclic groups, competitive diol blocking agents, diol donor polymers, and buffer systems; The pH value of the auxiliary material matrix is ​​4.0 to 4.4; In the storage state, the competing diol blocking agent forms a reversible binding state with the dynamic sites in the dynamic site polymer; After the excipient matrix comes into contact with the weak acid mucosal liquid, the dynamic site polymer forms a dynamic reversible cross-linking network with the diol donor polymer and the mucosal glycan diol sites; The ratio of the total molar amount of diol hydroxyl groups in the competitive diol blocking agent to the total molar amount of boron atoms in the dynamic site polymer is 1.2:1 to 3.5:

1.

2. The excipient matrix suitable for weakly acidic mucosal environments as described in claim 1, characterized in that: In the dynamic site polymer containing benzo[a]oxorbazole or boro[a]oxorbazole groups, the benzo[a]oxorbazole groups are grafted onto the water-soluble polymer backbone via linking arms. The water-soluble polymer backbone is selected from at least one of polyvinyl alcohol, polyethylene glycol, hyaluronic acid derivatives, or chitosan derivatives; The benzene ring of the benzo[a]oxorbazole group is substituted with an electron-withdrawing group, wherein the electron-withdrawing group is selected from at least one of fluorine atom, nitro or trifluoromethyl; The apparent dissociation constant pKa of the benzo[a]oxorbazole group is 5.0 to 6.

5.

3. The excipient matrix suitable for weakly acidic mucosal environments as described in claim 1, characterized in that: The competing diol blocking agent is selected from at least one of ortho-diol compounds having a five-membered or six-membered ring structure and aliphatic diol derivatives with steric hindrance. The competitive diol blocking agent contains at least one hydrophobic side chain with a volume larger than that of a methyl group in its molecular structure. In the storage state, the binding affinity of the competing diol blocker to the dynamic sites in the dynamic site polymer is higher than that of the competing diol blocker to the mucosal glycan diol sites. In a weakly acidic simulated body fluid diluted more than 5 times, the dissociation time between the competing diol blocking agent and the dynamic site in the dynamic site polymer is less than 30 seconds.

4. The excipient matrix suitable for weakly acidic mucosal environments as described in any one of claims 1 to 3, characterized in that: The diol donor polymer is a polyhydroxy polymer; The molar equivalent ratio of hydroxyl groups in the diol donor polymer to the molar equivalent ratio of boron atoms in the dynamic site polymer is 1.5:1 to 5:

1. The molecular weight range of the diol donor polymer is 10 kDa to 500 kDa.

5. The excipient matrix suitable for weakly acidic mucosal environments as described in claim 1, characterized in that: The polycarboxyphene has a mass percentage content of 0.5% to 3.0% in the excipient matrix; The carbomer content in the auxiliary matrix is ​​0.05% to 0.5% by mass; The mass ratio of the carbomer to the polycarboferrite is 1:10 to 1:6; The carbomer is a hydrophobically modified carbomer, and the hydrophobic group of the hydrophobically modified carbomer is selected from C10-C30 alkyl chains; The degree of hydrophobic modification of the hydrophobic modified carbomer is 1.5% to 4.0%; The carbomer, as a rheology modifier, provides film toughness, surface feel, and mucosal retention assistance through hydrophobic association.

6. The excipient matrix suitable for weakly acidic mucosal environments as described in claim 5, characterized in that: The buffer system is a buffer pair composed of lactic acid and sodium lactate, or a buffer pair composed of citric acid and sodium citrate; The ionic strength of the buffer system is 0.05 mol / L to 0.15 mol / L.

7. The excipient matrix suitable for weakly acidic mucosal environments as described in claim 5 or 6, characterized in that: The static viscosity of the auxiliary matrix at a shear rate of 0.1 sec-1 under storage conditions of 25°C is 5000 mPa·s to 50000 mPa·s. After the excipient matrix is ​​diluted with simulated mucosal solution and allowed to stand for 60 seconds to recover, the in-situ viscosity at a shear rate of 0.1 sec-1 is more than 5 times the static viscosity. The time required for the viscosity of the auxiliary matrix to recover to 90% of its initial value after 100% strain shear failure is less than or equal to 120 seconds.

8. The excipient matrix suitable for weakly acidic mucosal environments as described in any one of claims 1 to 7, characterized in that: The auxiliary material matrix does not contain free strong alkaline neutralizing agents; The dosage form of the excipient matrix is ​​a gynecological mucosal gel, anorectal gel, or mucosal film-forming dressing.

9. A method for preparing an excipient matrix suitable for weakly acidic mucosal environments as described in any one of claims 1 to 8, characterized in that, include: Step 1: Disperse polycarboxyphene in purified water and allow it to swell to obtain a skeleton dispersion; Step 2: Add the pre-dispersed carbomer to the skeleton dispersion and adjust the shear rate to ensure uniform distribution of carbomer; Step 3: Mix the dynamic site polymer with the diol donor polymer, add the competing diol blocking agent, and pre-react at a temperature of 10℃~25℃ for 30 minutes~60 minutes to form a blocked prepolymer liquid; The amount of the competing diol blocking agent added is such that at least 80% of the dynamic sites in the dynamic site polymer are in a blocked state. Step 4: Add the closed-state prepolymer to the skeleton dispersion and mix. Step 5: Add the buffer system to adjust the pH value to 4.0-4.4, degas, and fill.

10. The application of the excipient matrix suitable for weakly acidic mucosal environments as described in any one of claims 1 to 8 in the preparation of gynecological gel formulations, anorectal gel formulations and mucosal film-forming dressings.

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