Slow-release hydrogel for preventing premature delivery as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines for obstetrics and gynecology, and particularly relates to slow-release hydrogel for preventing premature delivery as well as a preparation method and application of the slow-release hydrogel. The sustained-release hydrogel for vaginal administration comprises a uterine contraction inhibitor, a medicinal gel matrix, polycarbophil, glycerol, liquid paraffin and sorbic acid. According to the sustained-release hydrogel, through local administration, the first-pass elimination effect is avoided, the biocompatibility is good, trauma is avoided, sustained release of the medicine can be achieved, repeated administration is avoided, and the compliance of a patient is improved. Meanwhile, the bioavailability is improved, the curative effect of the medicine is enhanced, the dosage can be reduced, the economic cost can be reduced, and safety and high efficiency are achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of obstetrics and gynecology drugs, and particularly relates to a sustained-release hydrogel for preventing premature birth, a preparation method thereof, and an application thereof. Background Art

[0002] Premature birth is childbirth before 37 weeks of gestation. Currently, about 15 million pregnant women give birth prematurely every year globally, and the number is continuously increasing. Premature birth is the main cause of high morbidity and mortality of newborns, accounting for 35% of the total number of neonatal deaths. This is mainly because premature birth is associated with many adverse pregnancy outcomes. For example, premature infants are usually physiologically and metabolically immature and are prone to cerebral palsy, chronic lung disease, intracranial hemorrhage, sepsis, cardiovascular disease, chronic kidney disease in later life, neurodevelopmental disorders, and are also prone to problems such as gastrointestinal tract, immunity, vision, and hearing.

[0003] To prevent premature birth in pregnant women, cervical cerclage and cervical pessary surgeries are clinically used. However, this technology is not applicable to all pregnant women; moreover, these surgical interventions may cause serious side effects to pregnant women, such as bleeding and an increased risk of infection. In addition to surgical interventions, Makena is the only drug approved by the US Food and Drug Administration for preventing premature birth. However, due to efficacy and safety issues of this drug, the Center for Drug Evaluation and Research of the US Food and Drug Administration has recommended revoking its approval. In addition, some studies have shown that some small molecule drugs, such as progestogens, oxytocin antagonists, calcium channel blockers, beta-mimetic agonists, and non-steroidal anti-inflammatory drugs, etc., can play a role in improving fetal maturity to varying degrees in some pregnant women. The above small molecule drugs mainly delay premature birth by blocking or slowing down uterine contractions, but currently, they are mainly administered orally and intravenously, resulting in different problems. For example, nifedipine has obvious first-pass elimination after oral administration and has a poor effect on patients with acute onset; injection administration (such as Atosiban acetate, an oxytocin receptor antagonist with fewer side effects and contraindications) will cause certain trauma, which may damage tissues, cause pain and the possibility of infection, and adverse reactions can appear rapidly; moreover, the continuous treatment time of a course of treatment with Atosiban acetate injection in clinical use is up to 45h - 48h at most, the treatment time is relatively long, the compliance of patients is poor, and long-term medication causes redness and lumps at the injection site, causing inconvenience to the lives of patients.

[0004] Therefore, it is very necessary to develop a preparation that can avoid the first-pass elimination effect, has high patient compliance, is safe and reliable, and can inhibit uterine contractions to relieve or treat related pregnancy diseases. Summary of the Invention

[0005] In view of the above problems, the object of the present invention is to provide a sustained-release hydrogel for preventing premature birth. The sustained-release hydrogel mainly forms a mucoadhesive gel by the interaction between a medicinal gel matrix and polycarbophil, and can deliver a uterine contraction inhibitor to the uterus through vaginal administration to prevent premature birth. The sustained-release hydrogel is administered locally, avoiding the first-pass elimination effect, having good biocompatibility and being non-invasive, and can achieve the sustained release of the drug, avoiding multiple administrations and improving the compliance of patients.

[0006] In order to achieve the above object, the present invention can adopt the following technical solutions:

[0007] On the one hand, the present invention provides a sustained-release hydrogel for preventing premature birth, comprising a uterine contraction inhibitor, a medicinal gel matrix, polycarbophil, glycerol, liquid paraffin and sorbic acid.

[0008] On the other hand, the present invention also provides a sustained-release hydrogel for preventing premature birth, comprising a uterine contraction inhibitor, a medicinal gel matrix, polycarbophil, glycerol, liquid paraffin, sorbic acid and a stabilizer.

[0009] On the other hand, the present invention provides a preparation method of the above-mentioned sustained-release hydrogel for preventing premature birth, which comprises: (1) dissolving sorbic acid in water to obtain an aqueous solution of sorbic acid; (2) sequentially adding a medicinal gel matrix and polycarbophil to the aqueous solution of sorbic acid, fully dissolving and swelling, and adjusting the pH to 4.0 - 5.0 to obtain a composite gel matrix; (3) mixing a uterine contraction inhibitor and / or a stabilizer with the composite gel matrix and stirring evenly to obtain a drug-containing composite gel matrix; (4) mixing glycerol and liquid paraffin in batches with the drug-containing composite gel matrix and emulsifying to obtain a sustained-release hydrogel for preventing premature birth.

[0010] On the other hand, the present invention provides an application of the above-mentioned sustained-release hydrogel for preventing premature birth in the preparation of a drug for preventing premature birth.

[0011] The beneficial effects of the present invention at least include:

[0012] (1) The sustained-release hydrogel is administered locally, avoiding the first-pass elimination effect, having good biocompatibility and being non-invasive, and can also achieve the sustained release of the drug, avoiding multiple administrations and improving the compliance of patients.

[0013] (2) The sustained-release hydrogel provided by the present invention can expand on the surface of the vaginal mucosa and adhere tightly to the mucosa, having strong adhesiveness, and can remain in the vagina for more than 12 hours, prolonging the drug action time, reducing the number of administrations, and achieving good therapeutic effects.

[0014] (3) The sustained-release hydrogel provided by the present invention has good temperature change stability and centrifugal stability. It is placed overnight in a 4°C refrigerator or a 55°C incubator, and centrifuged under different centrifugal conditions (3000 r / min, 5000 r / min, or 8000 r / min), and there is no obvious change in the appearance of the sustained-release hydrogel.

[0015] (4) The sustained-release hydrogel provided by the present invention has a relatively low cost, which is lower than the existing cost of preventing premature birth. Description of the Drawings

[0016] Figure 1 It is a microscopic gel state diagram of the sustained-release hydrogel sample A;

[0017] Figure 2 It is a microscopic gel state diagram of the sustained-release hydrogel sample B;

[0018] Figure 3 It is a microscopic gel state diagram of the sustained-release hydrogel sample C;

[0019] Figure 4 It is a microscopic gel state diagram of the sustained-release hydrogel sample D;

[0020] Figure 5 It is a microscopic gel state diagram of the sustained-release hydrogel sample E;

[0021] Figure 6 It is the sweep frequency analysis result of the sustained-release hydrogel sample A in the oscillation mode;

[0022] Figure 7 It is the sweep frequency analysis result of the sustained-release hydrogel sample B in the oscillation mode;

[0023] Figure 8 It is the sweep frequency analysis result of the sustained-release hydrogel sample C in the oscillation mode;

[0024] Figure 9 It is the sweep frequency analysis result of the sustained-release hydrogel sample D in the oscillation mode;

[0025] Figure 10 It is the sweep frequency analysis result of the sustained-release hydrogel sample E in the oscillation mode;

[0026] Figure 11 It is the dynamic viscosity result of the sustained-release hydrogel sample A in the shear mode;

[0027] Figure 12 It is the dynamic viscosity result of the sustained-release hydrogel sample B in the shear mode;

[0028] Figure 13 It is the dynamic viscosity result of the sustained-release hydrogel sample C in the shear mode;

[0029] Figure 14For the dynamic viscosity results of the sustained-release hydrogel sample D in shear mode;

[0030] Figure 15 For the dynamic viscosity results of the sustained-release hydrogel sample E in shear mode;

[0031] Figure 16 For the in vitro drug release of the sustained-release hydrogel samples A, B, C, D and E;

[0032] Figure 17 For the static appearance diagrams of the sustained-release hydrogel samples A, B, C, D and E;

[0033] Figure 18 For the temperature change resistance stability and centrifugal stability of the sustained-release hydrogel sample A;

[0034] Figure 19 For the temperature change resistance stability and centrifugal stability of the sustained-release hydrogel sample B;

[0035] Figure 20 For the temperature change resistance stability and centrifugal stability of the sustained-release hydrogel sample D;

[0036] Figure 21 For the temperature change resistance stability and centrifugal stability of the sustained-release hydrogel sample E;

[0037] Figure 22 For the confocal images of the effect of atosiban (at different concentrations) released in vitro from the sustained-release hydrogel sample D on the intracellular Ca 2+ expression (i.e., cell contraction), where the scale bar is 100 μm;

[0038] Figure 23 For the statistical chart of the first pregnancy and delivery time of SD rats, n = 10;

[0039] Figure 24 For the statistical chart of the second pregnancy and delivery time of SD rats, n = 10;

[0040] Figure 25 For the statistical chart of the delivery time of SD rats, n = 20;

[0041] Figure 26 For the delivery time diagram of pregnant rats with ICR preterm birth model after treatment in different groups, n = 4;

[0042] Figure 27 For the statistical chart of the body weight of the offspring of the first pregnancy and delivery of SD rats, n = 10;

[0043] Figure 28 For the statistical chart of the body weight of the offspring of the second pregnancy and delivery of SD rats, n = 10;

[0044] Figure 29 Statistical graph of the body weights of the offspring delivered by SD rats, n = 20;

[0045] Figure 30 Graph showing the monitoring results of the uterine muscle tension contraction in vivo of pregnant rats with ICR premature birth model after treatment in the normal group;

[0046] Figure 31 Graph showing the monitoring results of the uterine muscle tension contraction in vivo of pregnant rats with ICR premature birth model after treatment in the model group (1 μg / g LPS);

[0047] Figure 32 Graph showing the monitoring results of the uterine muscle tension contraction in vivo of pregnant rats with ICR premature birth model after treatment in the Atosiban group (0.62 mg / 100 g);

[0048] Figure 33 Graph showing the monitoring results of the uterine muscle tension contraction in vivo of pregnant rats with ICR premature birth model after treatment in the A-gel-1 / 2 dose group (0.31 mg / 100 g);

[0049] Figure 34 Graph showing the monitoring results of the uterine muscle tension contraction in vivo of pregnant rats with ICR premature birth model after treatment in the A-gel dose group (0.62 mg / 100 g);

[0050] Figure 35 Statistical graph of the uterine contraction frequency of pregnant rats in each group collected by RM6240 multi-channel physiological signal, n = 6;

[0051] Figure 36 Statistical graph of the maximum value of uterine tension of pregnant rats in each group collected by RM6240 multi-channel physiological signal, n = 6;

[0052] Figure 37 Statistical graph of the area under the curve of the uterine tension contraction graph of pregnant rats in each group collected by RM6240 multi-channel physiological signal, n = 6;

[0053] Figure 38 Graph of blood drug concentration-time in rats in vivo. Detailed implementation manners

[0054] The examples given are for better illustration of the present invention, but the content of the present invention is not limited only to the examples given. Therefore, those skilled in the art who make non-essential improvements and adjustments to the implementation manners based on the above invention content still fall within the protection scope of the present invention.

[0055] The terms used in this document are only for describing specific embodiments and are not intended to limit the present disclosure. Unless otherwise clearly different in the context, singular expressions include plural expressions. As used herein, it should be understood that terms such as "including", "having", "containing", etc. are intended to indicate the existence of features, numbers, operations, materials or combinations. The terms of the present invention are disclosed in the specification, and it is not intended to exclude the possibility that one or more other features, numbers, operations, materials or combinations may exist or can be added. As used herein, depending on the circumstances, " / " can be interpreted as "and" or "or".

[0056] An embodiment of the present invention provides a sustained-release hydrogel for preventing premature birth, comprising a uterine contraction inhibitor, a medicinal gel matrix, polycarbophil, glycerin, liquid paraffin, and sorbic acid.

[0057] It should be noted that the vaginal administration method is a drug administration method with good patient compliance. It places the preparation (such as effervescent tablets, suppositories or gels) in the vagina, and the drug is absorbed through the vaginal mucosa. The drug is directly delivered from the vagina to the uterus and enters the body to produce a therapeutic effect. It is one of the important drug administration routes for preventing and treating female reproductive system diseases. Moreover, vaginal administration is an effective strategy for local treatment, with advantages such as a large specific surface area, rich blood supply, and avoidance of the first-pass effect of the liver. In addition, compared with other drug administration methods, the drug absorbed through the vagina can play a role locally or systemically, with high bioavailability. In addition, vaginal administration can also achieve the sustained release of the drug, avoiding repeated administration and not showing peak-valley phenomena multiple times during the administration process, and the drug effect is stable. Currently, there is no vaginal administration preparation of uterine contraction inhibitors.

[0058] In addition, the existing gel preparations for vaginal administration (other drugs) mainly use carbomer as the matrix, and their functions are relatively limited. Most gels only form a gel protective film on the vaginal wall to play a role in physically isolating from external bacteria. Due to the self-cleaning effect of the vagina and the existence of gravity, ordinary gynecological gels cannot stay in the vagina for a long time (the retention time does not exceed 2h), and often cannot reach a high drug concentration, and the therapeutic effect is limited. In the present invention, in combination with the performance of the uterine contraction inhibitor and on the basis of the carbomer gynecological gel, the medicinal gel matrix and polycarbophil interact to form a mucoadhesive material to prepare a sustained-release hydrogel. The sustained-release hydrogel with mucoadhesiveness has excellent adhesion performance and the ability to resist physiological clearance in the body, can stay at the drug administration site for a long time (the longest retention time can reach more than 12 hours) to play a role, extend the drug circulation time in the body, and improve the bioavailability.

[0059] In addition, the above-mentioned sustained-release hydrogel has a sustained-release effect, enabling the drug to be released continuously and steadily, with a long-lasting and stable drug effect, which can reduce the frequency and dosage of drug use by patients and improve the drug compliance of patients. In addition, the pharmaceutical gel matrix and polycarbophil are inert materials, which do not react with the drug and other excipients, do not affect the stability of the drug, and do not affect the drug content. In addition to the above advantages, the materials of the sustained-release hydrogel in the present invention can have good compatibility with hydrophilic uterine contraction inhibitors, and similarly, can be well mixed with lipophilic uterine contraction inhibitors; and are non-toxic and non-irritating, and can be biodegradable; the price is appropriate and it is easy to obtain.

[0060] It should also be noted that the polycarbophil in the above-mentioned sustained-release hydrogel is similar to biomimetic negatively charged mucin, has good bioadhesion and biocompatibility, is a water-insoluble polymer, can adhere to vaginal epithelial cells, and has good swelling properties. And, polycarbophil is weakly acidic and has good buffering capacity to maintain the acidic environment of the vagina and physically isolate the vaginal wall from external bacteria.

[0061] It should also be noted that before the present invention, the existing progesterone sustained-release gel formulation was investigated. It used hydrogenated palm oil glyceride as the emulsifying oil phase, and this oil phase needed to be in a molten state at 60°C to 80°C. The emulsification preparation process needed to be kept at a temperature above 60°C, which was inconvenient for operation; and it was found during the preparation process that when the preparation returned to room temperature, the hydrogenated palm oil glyceride would precipitate out, resulting in the separation of the water phase and oil phase of the hydrogel, with a relatively large particle size and uneven drug loading, affecting drug release. In the present invention, considering the different solubilities of uterine contraction inhibitors (such as atosiban acetate) and progesterone, the present invention has explored and found that on the basis of the progesterone sustained-release gel, the use of hydrogenated palm oil glyceride is removed, and only liquid paraffin and glycerol are used as the oil phase for homogenization. While reducing the operation difficulty, it can improve the drug content and stability of the sustained-release hydrogel.

[0062] It should also be noted that the glycerol and liquid paraffin in the above-mentioned sustained-release hydrogel are common lubricants and wetting agents for vaginal gels, with relatively high safety and low price and easy availability. In addition, it should be understood that in addition to the above components in the above-mentioned sustained-release hydrogel, water should also be included, and the content of water is the balance of the percentage of the above-mentioned materials.

[0063] In some specific embodiments, the mass percentages of the above-mentioned uterine contraction inhibitor, pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid may also include: uterine contraction inhibitor 0.75% to 1.5%, pharmaceutical gel matrix 0.1% to 40%, polycarbophil 0.2% to 4%, glycerol 5% to 15%, liquid paraffin 2.5% to 10%, and sorbic acid 0.08% to 0.16%.

[0064] It should be noted that the proportion of each raw material of the above-mentioned sustained-release hydrogel affects the prepared sustained-release hydrogel. Preferably, the mass percentages of the uterine contraction inhibitor, pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid can be: uterine contraction inhibitor 0.75% - 1.5%, pharmaceutical gel matrix 0.1% - 40%, polycarbophil 0.2% - 4%, glycerol 5% - 15%, liquid paraffin 2.5% - 10%, and sorbic acid 0.08% - 0.16%. More preferably, the mass percentages of the uterine contraction inhibitor, pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid can be: uterine contraction inhibitor 0.75%, pharmaceutical gel matrix 1%, polycarbophil 2%, glycerol 10%, liquid paraffin 5%, and sorbic acid 0.08%; or more preferably, uterine contraction inhibitor 0.75%, pharmaceutical gel matrix 1.5%, polycarbophil 3%, glycerol 5%, liquid paraffin 2.5%, and sorbic acid 0.08%. The stability and drug content of the above two preferred sustained-release hydrogels are better than those of other ratios.

[0065] It should also be noted that the sustained-release hydrogel in the present invention uses a pharmaceutical gel matrix to uniformly encapsulate the uterine contraction inhibitor in the pore structure of the hydrogel through an emulsification method. The amounts of polycarbophil and the oil phase (glycerol and liquid paraffin) are the main factors affecting the appearance, viscosity, and release rate of the sustained-release gel. Therefore, changes in their concentrations affect the properties of the preparation. During the screening of the ratios, the effects of changes in different excipients on the appearance, particle size, viscosity, drug content, in vitro release, and other related properties of the gel were investigated, and finally the sustained-release hydrogel with the above ratios was obtained.

[0066] In some specific embodiments, the above-mentioned pharmaceutical gel matrix may include one or more of carbomer, poloxamer, chitosan, sodium carboxymethylcellulose, sodium alginate, or tragacanth gum. It should be noted that there are differences in the adhesion degree to the vaginal mucosa of the sustained-release hydrogels prepared by different pharmaceutical gel matrices interacting with polycarbophil to form mucoadhesive materials. In the present invention, one or more of carbomer, poloxamer, chitosan, sodium carboxymethylcellulose, sodium alginate, or tragacanth gum are preferred. Specifically, there is a weak cross-linking effect between the carbomer or (poloxamer, chitosan, sodium carboxymethylcellulose, sodium alginate, tragacanth gum) and the polycarbophil to form a bioadhesive polymer. The physical entanglement and chemical bonds between the high-molecular polymers in the mucoadhesive hydrogel will absorb water and swell when contacting water, making its aqueous solution form a gel state, expand on the mucosal surface, and adhere tightly to the mucosa, and can remain in the vagina for more than 12 hours at most, prolonging the in vivo circulation time.

[0067] In addition, in the present invention, poloxamer is selected as the gel matrix to prepare a thermogel, which undergoes a solution-gel transition when the temperature rises to a specific gelling temperature (37 °C), and the anti-shear and dilution properties of the gel enhance its retention in the vaginal cavity.

[0068] In some specific embodiments, any one of the carbomers known in the art is selected as the above-mentioned carbomer, such as carbomer 974P, carbomer 934P, carbomer 934 or carbomer 940; similarly, poloxamer is also known in the art, such as poloxamer P407 or poloxamer P188.

[0069] In some specific embodiments, the above uterine contraction inhibitor can be selected from one or more combinations of atosiban acetate, nifedipine, ritodrine, magnesium sulfate or indomethacin. It should be noted that the uterine contraction inhibitor in the present invention is a substance known in the art with the function of inhibiting uterine contractions, and the efficacy of the sustained-release hydrogel in the present invention also depends on the selection of the uterine contraction inhibitor. The selection of the uterine contraction inhibitor can be made according to specific clinical needs.

[0070] Another embodiment of the present invention provides a method for preparing the above-mentioned sustained-release hydrogel for preventing premature birth, which includes: (1) dissolving sorbic acid in water to obtain a sorbic acid aqueous solution; (2) sequentially adding a medicinal gel matrix and polycarbophil to the sorbic acid aqueous solution, fully dissolving and swelling, and adjusting the pH to 4.0-5.0 to obtain a composite gel matrix; (3) mixing the uterine contraction inhibitor with the composite gel matrix and stirring evenly to obtain a drug-containing composite gel matrix; (4) batchwise mixing glycerol and liquid paraffin with the drug-containing composite gel matrix and emulsifying to obtain a sustained-release hydrogel for preventing premature birth.

[0071] It should be noted that in the present invention, corresponding studies have been carried out on the addition method of the uterine contraction inhibitor, emulsifying equipment, hydration time, hydration rotation speed, emulsification time, emulsification rotation speed and pH adjustment time, and the appearance properties, particle size, viscosity, etc. of the gels prepared under different conditions have been investigated, and the best preparation process has been screened out. Using the screened proportion range and preparation process, the prepared sustained-release hydrogels are all delicate and uniform, no particles larger than 180 μm are detected, the particle size morphology meets the requirements, and they have good centrifugal stability and heat and low temperature stability; their viscosity decreases with the increase of the shear rate, has viscoelasticity and conforms to the shear thinning characteristics of the gel. This shear thinning rheological property is beneficial to the filling and drug loading in the gel preparation process; the in vitro cumulative release rate of the sustained-release hydrogel reaches 34.2% in 24 hours, indicating that the prepared sustained-release hydrogel has a sustained-release effect, enables the drug to be released continuously and steadily, can reduce the number of drug administrations and the dosage of the patient, is beneficial to improving the medication compliance of the patient, and is convenient for clinical use.

[0072] In some specific embodiments, in step (3), in order to prevent uneven dispersion of the uterine contraction inhibitor and the composite gel matrix during mixing, batch mixing can be selected, that is, part of the uterine contraction inhibitor is added and stirred, and then another part is added and stirred until all the uterine contraction inhibitor is added.

[0073] In some specific embodiments, in the above step (1), water and sorbic acid can be heated in a water bath at 70°C to 85°C, which can improve the dissolution rate. If the temperature is too low, the dissolution is slow, and if the temperature is too high, sorbic acid may denature, so 70°C to 85°C is selected.

[0074] In some specific embodiments, in the above step (2), swelling can be selected to fully swell for 1h to 12h or be placed at 4°C overnight to fully swell; in addition, stirring can be carried out during swelling, and the stirring rate can be 500rpm to 2000rpm, preferably 1000rpm. At this rate, full swelling can be achieved in the shortest time; in addition, sodium hydroxide or hydrochloric acid can be used as the pH regulator for pH adjustment.

[0075] In some specific embodiments, in the above step (3), the stirring rate can be 200rpm to 400rpm, preferably 300rpm. At this rate, the uterine contraction inhibitor can be fully mixed with the swollen composite gel matrix in batches on the basis of the shortest time and the most energy-saving.

[0076] In some specific embodiments, in the above step (4), the emulsification time can be 0.5h to 2h. If the emulsification time is too short, the emulsification is not sufficient. When the emulsification time is about 2h, it is already sufficient. Continuing emulsification cannot make it more sufficient, so 0.5h to 2h is selected in the present invention.

[0077] It should also be noted that in the above preparation method, if the pharmaceutical gel matrix is selected as poloxamer, the involved preparation steps are carried out at a low temperature (4°C). It should be noted that poloxamer can produce gelation by forming hydrogen bonds between molecules. It has two critical temperatures, namely the low solution-gel transition temperature and the high gel-solution transition temperature (UCST). An aqueous solution of a higher concentration of poloxamer forms a hydrogel between these two temperatures. This gel can be formed by refrigerating its aqueous solution at 0 to 10°C and then transferring it to room temperature environment naturally, so as to be used as a thermosensitive gel matrix.

[0078] Another embodiment of the present invention also provides a sustained-release hydrogel containing a stabilizer, that is, the sustained-release hydrogel includes: a uterine contraction inhibitor, a pharmaceutical gel matrix, polycarbophil, glycerin, liquid paraffin, sorbic acid, and a stabilizer. It should be noted that the stabilizer in the present invention can further improve the stability of the sustained-release hydrogel. In addition, the stabilizer is well known in the art, preferably β-cyclodextrin or disodium ethylenediaminetetraacetate (EDTA-2Na), more preferably β-cyclodextrin. The drug content and stability of the sustained-release hydrogel prepared by selecting β-cyclodextrin are better than those of other stabilizers.

[0079] It should be noted that the mass percentage of the stabilizer will affect the stability of the prepared sustained-release hydrogel. In the present invention, 0.04% to 0.06% can be selected. For example, in some specific embodiments, the mass percentages of the above-mentioned uterine contraction inhibitor, pharmaceutical gel matrix, polycarbophil, glycerin, liquid paraffin, sorbic acid, and β-cyclodextrin can preferably include: uterine contraction inhibitor 0.75% to 1.5%, pharmaceutical gel matrix 0.1% to 40%, polycarbophil 0.2% to 4%, glycerin 5% to 15%, liquid paraffin 2.5% to 10%, sorbic acid 0.08% to 0.16%, and β-cyclodextrin 0.04% to 0.06%; in some specific embodiments, the mass percentages of the above-mentioned uterine contraction inhibitor, pharmaceutical gel matrix, polycarbophil, glycerin, liquid paraffin, sorbic acid, and β-cyclodextrin can be more preferably include: uterine contraction inhibitor 0.75%, pharmaceutical gel matrix 1%, polycarbophil 2%, glycerin 10%, liquid paraffin 5%, sorbic acid 0.08%, and β-cyclodextrin 0.05%; or uterine contraction inhibitor 0.75%, pharmaceutical gel matrix 1.5%, polycarbophil 3%, glycerin 5%, liquid paraffin 2.5%, sorbic acid 0.08%, and β-cyclodextrin 0.05%. The stability of the sustained-release hydrogel at this mass percentage is far better than that of the sustained-release hydrogel prepared by other ratios.

[0080] Another embodiment of the present invention provides a preparation method of the above-mentioned sustained-release hydrogel containing a stabilizer, which includes: (1) dissolving sorbic acid in water to obtain a sorbic acid aqueous solution; (2) sequentially adding a pharmaceutical gel matrix and polycarbophil to the sorbic acid aqueous solution, fully dissolving and swelling, and adjusting the pH to 4.0 to 5.0 to obtain a composite gel matrix; (3) mixing the uterine contraction inhibitor, the stabilizer with the composite gel matrix, and stirring evenly to obtain a drug-containing composite gel matrix; (4) mixing glycerin and liquid paraffin in batches with the drug-containing composite gel matrix, and emulsifying to obtain a sustained-release hydrogel for preventing premature birth.

[0081] It should be noted that the preparation method of the sustained-release hydrogel containing a stabilizer is basically the same as that of the sustained-release hydrogel without a stabilizer. The only difference is that in step (3), the uterine contraction inhibitor, the stabilizer and the composite gel matrix are mixed together.

[0082] Another embodiment of the present invention provides an application of the above-mentioned sustained-release hydrogel for preventing preterm birth in the preparation of a drug for preventing preterm birth. It should be noted that the above-mentioned sustained-release hydrogel for preventing preterm birth can prevent preterm birth by inhibiting uterine contractions.

[0083] To better understand the present invention, the content of the present invention will be further clarified below with specific examples, but the content of the present invention is not limited to the following examples.

[0084] I. Preparation of Sustained-Release Gel and Performance Testing

[0085] In the following examples, the HPLC detection chromatographic conditions for the drug content in the sustained-release hydrogel are as follows: Octadecylsilane-bonded silica gel (Shimadzu) is used as the filler; 0.05 mol / L phosphate buffer solution (take 6.8 g of potassium dihydrogen phosphate, add 1000 mL of water, adjust the pH value to 2.3 with phosphoric acid, and then add 120 μL of triethylamine to obtain) is used as mobile phase A, and acetonitrile is used as mobile phase B for linear gradient elution (the gradient elution program is shown in Table 1 below); the flow rate is 1.0 mL / min; the detection wavelength is 215 nm (source: "Chinese Pharmacopoeia (2020 Edition)").

[0086] Table 1 Gradient Elution Program for HPLC Detection of Drug Content

[0087] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 80 20 28 73 27 44 60 40 49 60 40 50 80 20 60 80 20

[0088] In the following examples, the preparation method of the sustained-release hydrogel (without stabilizer) is carried out according to the following steps: Take atosiban acetate, carbomer 974P, polycarbophil, glycerol, liquid paraffin, sorbic acid and water respectively and set aside; Heat and dissolve water and sorbic acid in a water bath at 75 °C, and cool to room temperature; Sequentially add the prescribed amount of carbomer 974P and polycarbophil, stir at 500 rpm, and fully swell for 4 h, adjust the pH to 4.0 to obtain a swollen composite gel matrix; Then add atosiban acetate in batches (using a 1 mL syringe, add atosiban acetate drop by drop under stirring conditions, the purpose is to fully mix the drug and the gel matrix) to the swollen composite gel matrix, and stir evenly; Add glycerol and liquid paraffin in batches, and emulsify at 200 rpm for 0.5 h to obtain the sustained-release hydrogel product (without stabilizer).

[0089] In the following examples, the preparation method of the sustained-release hydrogel (containing stabilizer) is carried out according to the following steps: Take atosiban acetate, carbomer 974P, polycarbophil, glycerol, liquid paraffin, sorbic acid, β-cyclodextrin and water respectively, and set aside; Heat and dissolve water and sorbic acid in a water bath at 75 °C, and cool to room temperature; Add the prescribed amounts of carbomer 974P and polycarbophil in sequence, stir at 500 rpm, and fully swell for 4 h. Adjust the pH to 4.0 to obtain a swollen composite gel matrix; Then add atosiban acetate and β-cyclodextrin in batches (using a 1 mL syringe, add atosiban acetate drop by drop under stirring conditions, aiming to fully mix the drug and the gel matrix) to the swollen composite gel matrix, and stir evenly; Add glycerol and liquid paraffin in batches, and emulsify at 200 rpm for 0.5 h to obtain the sustained-release hydrogel product (containing stabilizer).

[0090] Example 1 Screening of Medicinal Gel Matrix

[0091] In the following examples, the vaginal tissue distribution experiment is carried out according to the following steps: Female SD rats weighing 200 g - 220 g are fasted for 24 hours and then randomly grouped. At 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration, 5 rats are decapitated and sacrificed at each time point, and the vaginal tissue is dissected. Wash with normal saline, blot dry with filter paper, and weigh. Then add 4 times the amount of normal saline, homogenize with an electric homogenizer, centrifuge at 3000×g for 10 min, precisely pipette 0.1 mL of the tissue homogenate into a 1.5 mL EP tube, add 0.2 mL of methanol, vortex for 10 min, centrifuge at 8000×g for 15 min, take 20 μL of the supernatant for injection, and determine the drug content in the vaginal tissue by HPLC (the HPLC detection conditions are in accordance with the above-mentioned detection chromatographic conditions for drug content) until the drug content cannot be detected, which is the retention time.

[0092] By mass fraction, take 0.75% of atosiban acetate, 1% of medicinal gel matrix, 2% of polycarbophil, 10% of glycerol, 5% of liquid paraffin, 0.08% of sorbic acid and the balance of water respectively, and set aside; Heat and dissolve water and sorbic acid in a water bath at 75 °C, and cool to room temperature; Add the prescribed amounts of carbomer 974P and polycarbophil in sequence, stir at 500 rpm, and fully swell for 4 h. Adjust the pH to 4.0 to obtain a swollen composite gel matrix; Then add atosiban acetate in batches (using a 1 mL syringe, add atosiban acetate drop by drop under stirring conditions, aiming to fully mix the drug and the gel matrix) to the swollen composite gel matrix, and stir evenly; Add glycerol and liquid paraffin in batches, and emulsify at 200 rpm for 0.5 h to obtain the sustained-release hydrogel.

[0093] The above-mentioned pharmaceutical gel matrix is set as Carbomer 974P, chitosan, poloxamer, sodium alginate, sodium carboxymethyl cellulose, and tragacanth gum to prepare different sustained-release hydrogels, and the vaginal tissue distribution experiments described above are used to test their residence time in the vaginal environment. The results are shown in Table 2 below.

[0094] Table 2 Vaginal Residence Time of Sustained-Release Hydrogels Prepared with Different Pharmaceutical Gel Matrices

[0095] Pharmaceutical Gel Matrix Retention Time (h) Carbomer 974P 12 Chitosan 6 Poloxamer 8 Sodium Alginate 6 Sodium Carboxymethylcellulose 4 Tragacanth Gum 4

[0096] Example 2 Preparation of Sustained-Release Hydrogel

[0097] In the examples of the present invention, according to the components shown in Table 3 below, the preparation method of the above-mentioned sustained-release hydrogel is used to prepare different sustained-release hydrogel samples (Sample A, Sample B, Sample C, Sample D, and Sample E), and performance tests are carried out on different samples respectively.

[0098] Table 3 Samples Prepared with Different Components and Proportions

[0099]

[0100]

[0101] Observe the morphology of the different sustained-release hydrogels prepared in Table 3 above under a microscope. The results are as Figures 1 to 5 shown. Among them, the particle diameters from Figure 1 , Figure 2 , Figure 4 and Figure 5 are not greater than 180 μm, and the hydrogel is delicate and uniform, and the particle size morphology meets the requirements; Figure 3 has some particle diameters greater than 180 μm, and the dispersion is uneven, and the particle size morphology does not meet the requirements.

[0102] Under the 25° oscillation mode, a constant pressure of 15 Pa is applied, and a frequency sweep analysis is carried out in the range of 0.1 - 10 Hz. The results are as Figures 6 to 10 shown. The results show that the storage modulus (G') > loss modulus (G"), indicating that the sustained-release hydrogels prepared according to different prescriptions all have viscoelasticity.

[0103] Under the 25° shear mode, the shear rate is increased from 0.01 to 100 s -1 , and the dynamic viscosity at different shear rates is recorded. The results are as Figures 11 to 15As shown, the results indicate that the viscosity of the hydrogel decreases with the increase of the shear rate, which conforms to the characteristics of gel shear thinning (the characteristics of gel shear thinning indicate that under the action of external force, the gel can become a fluid-like material, with good injectability and without affecting the properties of the gel itself. When the external force is removed, the gel can quickly restore its original mechanical properties, with self-healing function, facilitating the use of the gel).

[0104] The drug content in the sustained-release hydrogel was detected by HPLC (the HPLC detection conditions were in accordance with the above-mentioned detection chromatographic conditions for drug content). The drug contents in Sample B and Sample C were low and did not meet the requirements, as shown in Table 4 specifically.

[0105] Table 4 Drug content of different sustained-release hydrogel samples

[0106] Sample Content (%) Sample A 91.23 Sample B 53.88 Sample C 83.19 Sample D 95.59 Sample E 95.36

[0107] Furthermore, using a Franz diffusion cell with a 0.22 μm filter membrane, with the cumulative permeation amount as the detection index, the in vitro release of the above-prepared sustained-release hydrogel samples was investigated by HPLC method. Specifically, it included: fixing the filter membrane at one end of the release cell of the Franz diffusion cell, with the rough surface facing the release cell, and the release area being 0.6 cm 2 ; taking about 100 mg of different sustained-release hydrogels and evenly coating them on the filter membrane, injecting an appropriate amount of water into the thermostatic water tank of the transdermal tester, starting the water pump and heating, adjusting the temperature to 37°C ± 0.1°C, waiting for the temperature to reach the set temperature and stabilizing for 5 min, putting the magnetic stirrer into the receiving cell, turning on the magnetic stirring, and adjusting the rotation speed to 100 r / min; fixing the release cell on the receiving cell, adding 25 mL of release medium as the receiving solution into the receiving cell, making the other side of the filter membrane contact with the receiving solution; sampling 1 mL at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h respectively, and adding an equal amount of receiving solution at the same temperature at the same time; after filtering the sampled receiving solution, taking 20 μL and injecting it into the high-performance liquid chromatograph for detection (the chromatographic conditions were the same as the HPLC detection chromatographic conditions for drug content). The results are as Figure 16 shown. The cumulative release rates of Sample B and Sample C were low and did not meet the medication requirements. The hydrogels of Sample A, Sample D, and Sample E had good sustained-release effects, which were beneficial for clinical use.

[0108] II. Performance verification

[0109] (1) Stability experiment

[0110] Taking the different sustained-release hydrogels prepared in Example 2 and placing them at room temperature, after placing for a period of time, observing the states of the 5 different sustained-release hydrogels, as Figure 17As shown, sample A is delicate and meets the requirements; sample B is thinner, with water seeping out and poor stability; sample C has stratified and is unstable; sample D is delicate and meets the requirements; sample E is delicate and meets the requirements; from the above, it can be seen that sample C is unstable, and subsequently, further temperature resistance and centrifugal stability tests are carried out on sample A, sample B, sample D and sample E.

[0111] Take 2.0 g of sample A, sample B, sample D and sample E respectively and place them in centrifuge tubes, and leave them overnight in a 4°C refrigerator and a 55°C incubator to observe changes in the appearance of the samples; in addition, take 2.0 g respectively and place them in centrifuge tubes, centrifuge at 3000 r / min, 5000 r / min, 8000 r / min for 30 min and then let stand to observe whether there are changes in the appearance of the samples; the states of sample A, sample B, sample D and sample E at different temperatures and different centrifugal speeds are respectively as Figure 18 , Figure 19 , Figure 20 and Figure 21 shown. The results show that after sample A is placed overnight at 4°C and 55°C, the gel state basically does not change, and the gel state after centrifugation at different centrifugal speeds basically does not change either, indicating that sample A has good temperature change resistance and centrifugal stability (see Figure 18 ); after sample B is placed overnight at 4°C and 55°C, the gel state does not change significantly, but after centrifugation at different centrifugal speeds, obvious stratification occurs, indicating that sample B has poor centrifugal stability (see Figure 19 ); after sample D is placed overnight at 4°C and 55°C, the gel state basically does not change, and the gel state after centrifugation at different centrifugal speeds basically does not change either, indicating that sample D has good temperature change resistance and centrifugal stability (see Figure 20 ); after sample D is placed overnight at 4°C and 55°C, the gel state basically does not change, and the gel state after centrifugation at different centrifugal speeds basically does not change either, indicating that sample E has good temperature change resistance and centrifugal stability (see Figure 21 ).

[0112] (2) Stability of drug content

[0113] Take the sustained-release hydrogel sample A prepared in Example 2 and test the drug content after being placed for 1 month, 3 months and 6 months. The results are shown in Table 5.

[0114] Table 5 Stability of drug content of sample A

[0115]

[0116] It can be seen from Table 5 above that the drug content of the sustained-release hydrogel prepared in the present invention basically does not change after being placed for 6 months, indicating that sample A has good stability.

[0117] The drug content of the sustained-release hydrogel sample D prepared in Example 2 was tested after being placed for 1 month, 3 months, and 6 months, and the results are shown in Table 6.

[0118] Table 6 Stability of the drug content of sample D

[0119]

[0120] As can be seen from Table 6 above, the drug content of the sustained-release hydrogel prepared in the present invention basically does not change after being placed for 6 months, indicating that sample D has good stability.

[0121] The drug content of the sustained-release hydrogel sample E prepared in Example 2 was tested after being placed for 1 month, 3 months, and 6 months, and the results are shown in Table 7.

[0122] Table 7 Stability of the drug content of sample E

[0123]

[0124]

[0125] As can be seen from Table 7 above, the drug content of the sustained-release hydrogel prepared in the present invention basically does not change after being placed for 6 months, indicating that hydrogel sample E has good stability.

[0126] III. Cell experiments

[0127] It should be noted that the purpose of the cell experiment in the embodiment of the present invention is to verify the in vitro efficacy of the sustained-release hydrogel. Different sustained-release hydrogels will all show efficacy. Therefore, in the embodiment of the present invention, only sample D was selected for the cell experiment.

[0128] In the embodiment of the present invention, the effect of atosiban acetate released from the sustained-release hydrogel D prepared in Example 2 on the Ca 2+ of uterine smooth muscle cells (USMC) was tested as follows: USMC were inoculated at a density of 2×10 5 cells / mL in 200 μL in a 24-well plate and incubated overnight. The released atosiban (Atosiban doses were 0.1 μg / mL, 0.2 μg / mL, 0.4 μg / mL) was used to treat the cells. After incubation for 12 h, the medium was replaced with fresh medium containing LPS (1 μg / mL) and incubated for 6 h; the cells were washed with PBS, and incubated with 2.5 μM Fura-2 AM for 30 min; washed 3 times with PBS, fixed with 4% paraformaldehyde at room temperature for 10 min, and the cell nuclei were stained with DAPI for 8 min, and then the fluorescence intensity was observed by CLSM.

[0129] The Ca 2+ fluorescence signal of USMC after different treatments was detected, and the results are asFigure 22 As shown, the Ca fluorescence intensity of the cells in the model group without treatment 2+ was higher than that in the atosiban acetate pretreatment group, indicating that the atosiban acetate sustained-release hydrogel prepared by the present invention can reduce the intracellular Ca 2+ level (the therapeutic effect is positively correlated with the atosiban acetate content), inhibit the release of Ca 2+ in the myometrial cells, and play a role in inhibiting the contraction of uterine smooth muscle cells.

[0130] IV. Animal experiments

[0131] It should be noted that the purpose of the animal experiment in the embodiment of the present invention is to verify the in vivo efficacy of the sustained-release hydrogel. Different sustained-release hydrogels will all show efficacy. Therefore, in the embodiment of the present invention, only sample D was selected for the animal experiment.

[0132] (1) SD female rats in estrus and fertile SD male rats of matching age (2:1) were randomly caged together (caged in the evening and separated the next morning to check for mating). The next morning, a wet cotton swab was used to check whether there was a milky or light yellow vaginal plug near the vaginal orifice of the rats, and the vaginal secretion was smeared. The presence of sperm was regarded as the 0th day of pregnancy; pregnant rats were weighed and numbered on the 0th, 6th, 10th, and 15th days of pregnancy, separately housed in cages, and the body shape and weight of the pregnant rats were observed and recorded to determine again whether the rats were successfully pregnant (in the middle and late pregnancy, the pregnant rats increased moderately, the abdominal circumference increased significantly, and bead-like structures the size of soybeans could be felt in the lower abdomen). The pregnant rats were randomly divided into a normal group (Saline (normal saline), intravenous injection), a model group (LPS + Saline, intravenous injection), an atosiban acetate group (LPS + Atosiban, intravenous injection), and an atosiban acetate hydrogel group (sample D prepared in Example 2) (LPS + A-gel-1 / 2, LPS + A-gel, vaginal administration); ICR mice were caged in a similar manner.

[0133] (2) Rat premature birth model: SD pregnant rats at 15.5 d of pregnancy were anesthetized by inhaling isoflurane, and the abdomen was disinfected with iodophor; a laparotomy was performed to expose the uterus, and 100 μL of lipopolysaccharide (LPS) (0.1 mg / kg) in normal saline was injected between the 1st and 2nd embryos of the right uterine horn; the abdomen was closed layer by layer; 0.5 h after the uterine injection of LPS, drugs were administered to each group: Atosiban group (1.7 mg / 100 g), A-gel-1 / 2 dose group (0.85 mg / 100 g), A-gel dose group (1.7 mg / 100 g); the delivery time was observed. The full-term pregnancy of rats is 21 - 23 days, and rats that gave birth earlier than 21 days of pregnancy were defined as premature births.

[0134] (3) Mouse preterm birth model: ICR pregnant mice at 16.5 days of gestation were anesthetized by inhalation of isoflurane, and the abdomen was disinfected with iodophor; a laparotomy was performed to expose the uterus, and 100 μL of lipopolysaccharide (LPS) (1 μg / g) in normal saline was injected between the 1st and 2nd embryos in the right uterine horn; the abdomen was closed layer by layer; drugs were administered in groups 0.5 h after uterine injection of LPS: Atosiban group (0.62 mg / 100 g), A-gel-1 / 2 dose group (0.31 mg / 100 g), A-gel dose group (0.62 mg / 100 g); the delivery time was observed. Normal full-term delivery of ICR mice is at 19 - 21 days of gestation. If delivery occurs within 48 hours after modeling, it is defined as preterm birth.

[0135] (4) Observation and record of the delivery situation of rats and mice: The day of delivery of fetal rats in each group and the changes in the body weight of the offspring were recorded in detail.

[0136] After modeling the pregnant mice, different doses of drugs were administered by intravenous injection or vaginally, the time from the start of modeling to delivery of the pregnant mice was observed, the delivery times of rats and mice in different groups were observed, and the body weights of the fetal rats at birth in different groups were recorded, as Figures 23 to 29 shown.

[0137] As can be seen from the figure ( Figures 23 to 26 ), with the increase in the concentration of the hydrogel in the treatment group, the delivery times of rats and mice gradually prolonged. The delivery time of the high-dose group was close to that of the control group of rats and mice, and the effect of the high-dose treatment group in inhibiting preterm birth of rats and mice was more obvious than that of the control group of atosiban raw material drug group; the therapeutic effects of the drugs in each group on the first pregnancy delivery and the second pregnancy delivery of preterm rats were similar, with no significant difference.

[0138] According to the statistical chart of the body weights of fetal rats in the offspring, the records of the body weights of the offspring of the first pregnancy delivery of rats, the average body weight of fetal rats in the Model group was 24.84 g, and the average body weights of fetal rats in the Control group, Atosiban group, A-gel-1 / 2 group, and A-gel group were 30.95 g, 31.02 g, 31.32 g, and 32.05 g respectively; the records of the body weights of the offspring of the second pregnancy delivery of rats, the average body weight of fetal rats in the Model group was 26.33 g, and the average body weights of fetal rats in the Control group, Atosiban group, A-gel-1 / 2 group, and A-gel group were 32.88 g, 32.56 g, 32.53 g, and 33.39 g respectively; it was found that the increase in the body weights of fetal rats in the treatment group was more obvious than that in the model group, indicating that the hydrogel can not only treat preterm birth, but also has a positive effect on the healthy growth of the offspring ( Figures 27 to 29 ).

[0139] (5) Monitoring of uterine muscle tension contraction in vivo in mice: On the 16.5th day of pregnancy, ICR pregnant mice were anesthetized by inhaling isoflurane, and the abdomen was disinfected with iodophor; a laparotomy was performed to expose the uterus. One end of a surgical suture was fixed between the 1st and 2nd embryos of the right uterine horn, and the other end was fixed on the specimen hook of the RM6240 multi-channel physiological signal acquisition system. Another surgical suture was fixed between the 2nd and 3rd embryos of the right uterine horn at one end, and the other end was connected to a tension transducer. Different treatments were given: model group (1 μg / g LPS), Atosiban group (0.62 mg / 100 g), A-gel-1 / 2 dose group (0.31 mg / 100 g), A-gel dose group (0.62 mg / 100 g), and the curve of uterine contraction activity changes was recorded. The measurement results are as Figures 30 to 37 shown. After the uterus of the mice in the model group was stimulated by LPS, the contraction frequency and amplitude of the pregnant mice increased significantly. After drug treatment, the contraction frequency of the pregnant mice decreased, and the inhibitory effect of the hydrogel treatment group on contraction was more obvious than that of the Atosiban raw material drug group, indicating that the atosiban acetate hydrogel prepared by the present invention has the effect of inhibiting uterine contraction.

[0140] (6) Analysis of blood drug concentration in rats in vivo: Female rats (9 in each group) were administered atosiban hydrogel vaginally at doses of 1.72 mg / 100 g (low), 3.44 mg / 100 g (medium), and 5.16 mg / 100 g (high). There was also an Atosiban injection control group. At 0, 10 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration, about 0.3 mL of blood was taken from the rat orbital cavity. The whole blood was placed in a heparinized EP tube and centrifuged at 3,000×g for 5 min. 0.1 mL of plasma was precisely aspirated and placed in a 1.5 mL EP tube. 0.2 mL of methanol was added, vortexed for 10 min, and centrifuged at 8,000×g for 15 min. 20 μL of the supernatant was injected for analysis, and the content of the drug in the plasma was determined by HPLC (the HPLC detection conditions were in accordance with the above-mentioned detection chromatographic conditions for drug content). The blood drug concentration-time curves of rats in different dose groups after drug administration are as Figure 38 shown. The results show that the blood drug concentration-time curve in rats is consistent with the in vitro release results, indicating that the sustained-release hydrogel prepared in the present invention has a sustained-release effect.

[0141] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A sustained-release hydrogel for preventing premature birth, characterized in that, It includes a uterine contraction inhibitor, a pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid.

2. The sustained-release hydrogel for preventing premature birth according to claim 1, characterized in that, The mass percentages of the uterine contraction inhibitor, the pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid are as follows: the uterine contraction inhibitor is 0.75% - 1.5%, the pharmaceutical gel matrix is 0.1% - 40%, polycarbophil is 0.2% - 4%, glycerol is 5% - 15%, liquid paraffin is 2.5% - 10%, and sorbic acid is 0.08% - 0.16%.

3. The sustained-release hydrogel for preventing preterm birth according to claim 2, wherein The mass percentages of the uterine contraction inhibitor, the pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, and sorbic acid are as follows: the uterine contraction inhibitor is 0.75%, the pharmaceutical gel matrix is 1%, polycarbophil is 2%, glycerol is 10%, liquid paraffin is 5%, and sorbic acid is 0.08%; or the uterine contraction inhibitor is 0.75%, the pharmaceutical gel matrix is 1.5%, polycarbophil is 3%, glycerol is 5%, liquid paraffin is 2.5%, and sorbic acid is 0.08%.

4. The sustained-release hydrogel for preventing premature birth according to any one of claims 1 to 3, characterized in that, The pharmaceutical gel matrix includes one or more of carbomer, poloxamer, chitosan, sodium carboxymethylcellulose, sodium alginate, or tragacanth.

5. The sustained-release hydrogel for preventing preterm birth according to any one of claims 1 to 3, characterized in that The uterine contraction inhibitor is selected from one or more combinations of atosiban acetate, nifedipine, ritodrine, magnesium sulfate, or indomethacin.

6. The sustained-release hydrogel for preventing preterm birth according to any one of claims 1 to 3, wherein It further includes a stabilizer, and the stabilizer is β-cyclodextrin or disodium edetate.

7. The sustained-release hydrogel for preventing preterm birth according to claim 4, characterized in that, It further includes a stabilizer, and the stabilizer is β-cyclodextrin or disodium edetate.

8. The sustained-release hydrogel for preventing premature birth according to claim 6, characterized in that, The mass percentages of the uterine contraction inhibitor, the pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, sorbic acid, and the stabilizer are as follows: the uterine contraction inhibitor is 0.75% - 1.5%, the pharmaceutical gel matrix is 0.1% - 40%, polycarbophil is 0.2% - 4%, glycerol is 5% - 15%, liquid paraffin is 2.5% - 10%, sorbic acid is 0.08% - 0.16%, and the stabilizer is 0.04% - 0.06%.

9. The sustained-release hydrogel for preventing preterm birth according to claim 7 or 8, characterized in that, The mass percentages of the uterine contraction inhibitor, the pharmaceutical gel matrix, polycarbophil, glycerol, liquid paraffin, sorbic acid, and the stabilizer are as follows: the uterine contraction inhibitor is 0.75%, the pharmaceutical gel matrix is 1%, polycarbophil is 2%, glycerol is 10%, liquid paraffin is 5%, sorbic acid is 0.08%, and the stabilizer is 0.05%; or the uterine contraction inhibitor is 0.75%, the pharmaceutical gel matrix is 1.5%, polycarbophil is 3%, glycerol is 5%, liquid paraffin is 2.5%, sorbic acid is 0.08%, and the stabilizer is 0.05%.

10. The preparation method of the sustained-release hydrogel for preventing premature birth according to any one of claims 1 to 5, characterized in that, It includes: (1) Dissolve sorbic acid in water to obtain an aqueous solution of sorbic acid; (2) Sequentially add the pharmaceutical gel matrix and polycarbophil to the aqueous solution of sorbic acid, fully dissolve and swell, and adjust the pH to 4.0 - 5.0 to obtain a composite gel matrix; (3) Mix the uterine contraction inhibitor with the composite gel matrix and stir evenly to obtain a medicated composite gel matrix; (4) Batchwise mix glycerol and liquid paraffin with the medicated composite gel matrix and emulsify to obtain a sustained-release hydrogel for preventing premature birth.

11. A method for preparing a sustained-release hydrogel for preventing preterm birth according to any one of claims 6 to 9, characterized in that, It includes: (1) Dissolve sorbic acid in water to obtain an aqueous solution of sorbic acid; (2) Sequentially add a medicinal gel matrix and polycarbophil into an aqueous solution of sorbic acid, allow the polycarbophil to fully swell, and adjust the pH to 4.0 - 5.0 to obtain a swollen composite gel matrix; (3) Mix a uterine contraction inhibitor, a stabilizer with the swollen composite gel matrix and stir evenly to obtain a medicated swollen composite gel matrix; (4) Batchwise mix glycerol and liquid paraffin with the medicated swollen composite gel matrix and emulsify to obtain a sustained-release hydrogel for preventing premature birth.

12. Use of the sustained-release hydrogel for preventing premature birth according to any one of claims 1 to 9 in the preparation of a drug for preventing premature birth.

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