CN117442545A - Intravaginal drug delivery system based on maltodextrin and application thereof in treating vaginitis - Google Patents
Intravaginal drug delivery system based on maltodextrin and application thereof in treating vaginitis Download PDFInfo
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- CN117442545A CN117442545A CN202311472859.8A CN202311472859A CN117442545A CN 117442545 A CN117442545 A CN 117442545A CN 202311472859 A CN202311472859 A CN 202311472859A CN 117442545 A CN117442545 A CN 117442545A
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- CN
- China
- Prior art keywords
- maltodextrin
- use according
- vaginitis
- delivery system
- tablet
- Prior art date
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- 201000008100 Vaginitis Diseases 0.000 title claims abstract description 25
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- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 229940032147 starch Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention provides an intravaginal drug delivery system based on maltodextrin and application thereof in treating vaginitis. The maltodextrin-based intravaginal drug delivery system comprises maltodextrin. The invention provides a drug release system capable of prolonging the time of drug stagnancy in vagina, enhancing the treatment effect of the existing drug, improving the life quality of colpitis patients and being beneficial to the physical and mental health of patients.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an intravaginal drug delivery system based on maltodextrin and application thereof in treating vaginitis.
Background
Abnormal vaginal secretions, malodor, vaginal itching, burning, and even pain, collectively referred to as vaginitis. Associated with microbial infections, mainly bacteria, fungi (candida) and trichomonas. Vaginal dysbacteriosis, reduced hormone levels, pregnancy, diabetes, unclean custom, immune damage, etc. are susceptibility factors that induce vaginitis. Vaginitis caused by bacterial infection is called bacterial vaginitis (BV for short), and vaginitis caused by fungal infection is called mycotic vaginitis. Foreign data indicate that women have developed vaginitis at least once in their lifetime. Because of high incidence rate and serious clinical symptoms, the physical and mental health, daily work and life of women are seriously affected.
There are various dosage forms of current drugs for the treatment of vaginitis. After the oral preparation is taken, the active ingredients are absorbed by gastrointestinal tracts and enter blood, and then are transported to vagina infection parts through blood circulation, so that the medicine has long transportation path in vivo, is easily metabolized by liver and kidney or degraded by digestive juice, and is damaged, and the treatment dosage is required to be increased. During the transport process, the drug may also be absorbed by other organs and tissues, resulting in toxic side effects and drug interactions. Oral medications have a relatively long period of time to eliminate and may also adversely affect recovery of the vaginal microbial flora. In addition, patients with gestational vaginitis cannot be orally administered. The ideal treatment mode is vaginal administration, the medicine is in direct contact with pathogenic bacteria, the medicine is killed by contact, the medicine does not enter or rarely enters blood, the systemic system is not influenced or is less influenced, and the toxic and side effects are low.
However, most of the existing pharmaceutical compositions for vaginal topical administration are immediate release formulations, such as clotrimazole ointment, miconazole ointment, clotrimazole pessary, miconazole pessary, terconazole pessary, nystatin pessaries, etc., for treating candidal vaginitis. And other medicines such as nifuratel vaginal tablet, dequalinium chloride vaginal tablet, metronidazole vaginal effervescent tablet, metronidazole gel, etc. for treating bacterial vaginitis. The medicines, in particular to semisolid preparations such as ointment, gel and the like, have short stagnancy time in vagina and are frequently leaked, so that the dosage of the medicines is insufficient and the treatment course is prolonged. The medicine is placed in the deep vaginal cavity, and has poor patient compliance and influences the curative effect.
The voriconazole is used for preparing pessaries in China patent (CN 102525883), and although the anti-candida efficacy of the voriconazole is improved compared with that of miconazole, clotrimazole and the like, the problem of short stagnancy time of the medicine in the vagina is not mentioned. Also, neither chinese patent (CN 105796477) nor WO2022091016 relates to the problem of slow run time or slow release. CN103391764 suggests that the drug lag time can be prolonged with pH sensitive in situ gel, but no application effect is reported.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an intravaginal drug delivery system based on maltodextrin and application thereof in treating vaginitis.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect the present invention provides a maltodextrin-based intravaginal drug delivery system comprising maltodextrin.
Further, the intravaginal drug delivery system further comprises one or more of chitosan, modified chitosan, acacia, xanthan gum, tragacanth gum, guar gum, povidone, carboxymethylcellulose, hydroxypropyl methylcellulose, poloxamer, carbomer, polycarbophil and pharmaceutically acceptable salts thereof.
Further, in the intravaginal delivery system, the maltodextrin content is 3% -100%.
In a second aspect, the present invention provides the use of an intravaginal delivery system as described above for the preparation of a topical vaginal formulation for the treatment of vaginitis, the topical vaginal formulation further comprising an active ingredient for the treatment of vaginitis.
Further, the vaginitis is selected from one or more of fungal vaginitis, bacterial vaginitis and trichomonas vaginalis.
Further, the effective active ingredient is selected from one or more of Lei Fukang azole, isaconazole, efonazole, clotrimazole, voriconazole, posaconazole, itraconazole, fluconazole, ciclopirox olamine, octenidine and secnidazole.
Further, the dosage form of the vaginal topical administration preparation is suppository, tablet, soft capsule, cream, gel, cream or spray.
Further, the suppository further comprises a matrix.
Further, the matrix includes an oil-soluble matrix and/or a water-soluble matrix; the oil-soluble matrix is preferably selected from one or more of cocoa butter, hydrogenated neutral fat, mixed fatty acid glyceride, propylene glycol stearate; the water-soluble matrix is preferably one or more selected from glycerogelatin, polyethylene glycol, poloxamer, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate.
Further, the suppository further comprises a plasticizer, and the plasticizer is preferably one or more selected from polysorbate, fatty acid glyceride and castor oil.
Further, the tablet further comprises a binder and a lubricant.
Further, the binder is one or more selected from acacia, starch, povidone, hydroxypropyl cellulose and hydroxyethyl cellulose, preferably including povidone and starch.
Further, the lubricant is one or more selected from stearate, talcum powder, silica gel micropowder, hydrogenated vegetable oil, polyethylene glycol and sodium dodecyl sulfate, preferably one or more selected from magnesium stearate, talcum powder and silica gel micropowder.
Further, the tablet may further contain a filler, if necessary, and the filler is preferably one or more selected from starch, modified starch, microcrystalline cellulose, and mannitol.
Further, the spray preparation further comprises a solvent, and the solvent is preferably one or more selected from water, ethylene glycol, propylene glycol, glycerin, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, polyethylene glycol and polyethylene glycol modified substances.
Compared with the prior art, the invention has the following technical effects:
the invention provides a drug release system capable of prolonging the time of drug stagnancy in vagina, which can enhance the treatment effect of the existing drug, improve the life quality of patients with colpitis and is beneficial to the physical and mental health of patients.
Drawings
FIG. 1 shows the cumulative elution amounts of 4 samples at different time points in an embodiment of the present invention.
Detailed Description
The present invention will be described in detail and specifically by way of the following specific examples and drawings to provide a better understanding of the present invention, but the following examples do not limit the scope of the present invention.
The method in the examples adopts a conventional method without special description, and the used auxiliary materials adopt conventional commercial auxiliary materials or medicinal auxiliary material mixtures prepared according to the conventional method without special description.
Example 1
This example demonstrates the adhesive slow release effect of maltodextrin, with the following specific steps and results:
1. preparation of vaginal tablet
According to the formulation of Table 1, lei Fukang azole, corn starch, maltodextrin or cyclodextrin were mixed in a wet granulator with stirring, polyethylene glycol 6000 was dissolved in 15ml of water, sprayed into the granulator, and the shear granulation was started and dried. Finishing, mixing with talcum powder and magnesium stearate, and making into round tablet with diameter of 10mm (for measuring adhesion), and average tablet weight of 330mg.
Table 1 Lei Fukang azole vaginal tablet formulation
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | |
| Lei Fukang Azole | 200 | 200 | 200 | 200 |
| Corn starch | 75 | 70 | 65 | 65 |
| Polyethylene glycol 6000 | 15 | 15 | 15 | 15 |
| Maltodextrin | 0 | 5 | 10 | 0 |
| Cyclodextrin | 0 | 0 | 0 | 10 |
| Talc powder | 30 | 30 | 30 | 30 |
| Magnesium stearate | 10 | 10 | 10 | 10 |
| Totals to | 330 | 330 | 330 | 330 |
2. Hardness measurement
5 tablets of each sample were taken and subjected to hardness measurement on a day-to-day YD-35 intelligent tablet hardness tester, and the statistical average results are shown in Table 2. As can be seen from Table 2, both maltodextrin and cyclodextrin increased the hardness of the tablets, but the maltodextrin increased by a greater amount.
3. Determination of adhesion
Adhesion is a measure of the ability of a drug to adhere to the vaginal mucosa. The greater the adhesion, the greater the ability of the drug to adhere to the vaginal mucosa, the less prone to shedding. One side of the test tablet was adhered to the push-pull rod of the handlepi push-pull meter, and the other side was placed on a glass plate after being wetted with water for 30 seconds and pressed for 2 minutes, followed by slow stretching by the push-pull meter until the tablet was peeled off from the contact surface. The force required for stripping is the adhesive force of the preparation. The test was carried out on 5 tablets each of the above samples, and the average value was taken as the adhesion of each tablet, and the results are shown in table 2. As can be seen from Table 2, both maltodextrin and cyclodextrin increased the tablet adhesion, but the maltodextrin increased by a greater amount.
Table 2 results of hardness and adhesion measurements for each of the formulations
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | |
| Hardness (N) | 6.72 | 8.81 | 10.63 | 8.84 |
| Adhesive force (N) | 4.72 | 6.32 | 8.16 | 7.42 |
4. Drug release rate
Drug release rate is a core indicator in consideration of a slow release drug delivery system.
The sample medicines were taken and subjected to dissolution measurement (section 0931 of the fourth edition of Chinese pharmacopoeia 2020), the rotation speed of the first method (blue method) was 60 rotations per minute, and the medium was a buffer solution having a pH of 4.0. At each time point in Table 3, samples were taken, and the cumulative elution amount (average value of 6 particles) was measured, and the results are shown in Table 3 and FIG. 1.
TABLE 3 results of elution test of samples 1 to 4
| 0 | 1h | 2h | 4h | 6h | 8h | 10h | |
| Sample 1 | 0 | 52.89 | 88.94 | 99.36 | 99.28 | 99.53 | 99.69 |
| Sample 2 | 0 | 35.06 | 44.03 | 63.85 | 81.63 | 96.22 | 99.28 |
| Sample 3 | 0 | 15.81 | 32.1 | 48.03 | 65.74 | 81.68 | 96.85 |
| Sample 4 | 0 | 34.51 | 64.88 | 81.90 | 96.91 | 99.89 | 99.67 |
As can be seen from Table 3 and FIG. 1, maltodextrin has an obvious effect of prolonging the drug release, but cyclodextrin has an insignificant effect of prolonging the drug release.
Example 2
In the embodiment, an animal in-vivo model is adopted to verify that the maltodextrin system improves the drug effect, and specific experimental steps and results are as follows:
1. sample preparation
Samples 5-6 were prepared according to the formulation of table 4 below.
Table 4 preparation of samples 5-6 formulation (1000) granules
Mixing the efucaconazole, the mixed fatty glyceride, the maltodextrin or the cyclodextrin and the lactic acid, heating and melting, putting into a mould, and cooling and forming. Making into suppository with weight of 40 mg.
2. Pharmacological test
Five week old mice (18 g in weight) were randomized into three groups of 5 in the same cage. Food and water were provided ad libitum.
Mice were subcutaneously injected with 0.5mg of estradiol valerate three days before infection and 4, 11 and 18 days after challenge, with false oestrus maintained throughout the experiment. On the day of infection, ketamine hydrochloride (80 mg/kg) was administered intraperitoneally for anesthesia and 20 μl 2×10 of clinically isolated candida albicans was inoculated intravaginally 8 Colony Forming Units (CFU)/ml. The next day after inoculation, the swab smear was performed on the vagina of each mouse (prior to treatment), ensuring that all animals were infected. Thereafter, vaginal test samples were taken every 12 hours, and potassium hydroxide smear examination was performed to evaluate the therapeutic efficacy and recovery of vaginal microbial flora. The dosing was started the next day after infection, with the first and second groups being the treatment group given sample 5 and sample 6, respectively, and the third group being the negative control group given matrix-mixed fatty acid glycerides only, all samples placed in the posterior fornix. The negative transfer times for each group of animal test smears are shown in Table 5.
TABLE 5 time to negative for each group of animal test strip smears
| Animal number | 1 | 2 | 3 | 4 | 5 | Average of |
| First group of | 36 | 48 | 48 | 60 | 60 | 50.4 |
| Second group of | 48 | 48 | 60 | 60 | 72 | 57.6 |
| Third group of | 72 | / | / | / | / |
All animal test smears of the first group and the second group can turn negative, which shows that the sample 5 and the sample 6 have curative effects on vaginal candida infection, but the time for turning negative of the first group is obviously shorter than that of the second group, which shows that maltodextrin helps to improve the curative effects of the medicine.
Example 3
This example provides a maltodextrin-based octenidine vaginal tablet for the treatment of vaginitis, the formulation of which is shown in Table 6.
Table 6 rotinidine vaginal tablet formulation table
| Material name | Feeding quantity (mg) |
| Octenidine | 5 |
| Maltodextrin | 10 |
| Lactose and lactose | 39 |
| Microcrystalline cellulose | 44 |
| Starch | 10 |
| Magnesium stearate | 2 |
| Totalizing | 110 |
The preparation process of the vaginal tablet comprises the following steps:
the octenidine, maltodextrin, lactose, microcrystalline cellulose and starch are placed into a wet granulator to be stirred and mixed, a proper amount of water is sprayed into the granulator, and the shearing granulation and the drying are started. Granulating, mixing with magnesium stearate, and making into spindle-shaped tablet with long axis of 8mm, with average tablet weight of 110mg.
Example 4
This example provides a maltodextrin-based secnidazole vaginal suppository for the treatment of vaginitis, the formulation of which is shown in Table 7 below.
Table 7 secnidazole vaginal suppository formulation table
The preparation process of the vaginal suppository comprises the following steps:
mixing secnidazole, PEG6000, povidone, polyoxyl stearate, maltodextrin and hydroxypropyl methylcellulose, heating for melting, putting into mould, cooling and shaping. The average weight of each tablet is 1800 mg.
Example 5
This example provides a maltodextrin-based spray of ciclopirox olamine for treating vaginitis, the formulation of which is shown in table 8 below.
Table 8 table of formulations of ciclopirox olamine spray
| Material name | Feeding quantity (mg) |
| Ciclopirox olamine | 10 |
| Malt pasteEssence | 10 |
| Ethylhexyl glycerol | 20 |
| Water and its preparation method | 960 |
| Totals to | 1000 |
The preparation process of the ciclopirox olamine spray comprises the following steps:
according to the prescription quantity, the cyclic ketoamine, the maltodextrin and the ethylhexyl glycerin are dissolved in water, filtered, and the filtrate is filled into 100ml bottles.
The above description of the specific embodiments of the present invention has been given by way of example only, and the present invention is not limited to the above described specific embodiments. It will be apparent to those skilled in the art that any equivalent modifications and substitutions of the present invention are intended to be within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (15)
1. An intravaginal delivery system based on maltodextrin, comprising maltodextrin.
2. The intravaginal delivery system of claim 1, further comprising one or more of chitosan, modified chitosan, acacia, xanthan gum, tragacanth, guar gum, povidone, carboxymethylcellulose, hydroxypropyl methylcellulose, poloxamers, carbomers, polycarbophil, and pharmaceutically acceptable salts thereof.
3. The intravaginal delivery system of claim 1, wherein the maltodextrin is present in the intravaginal delivery system in an amount of 3% to 100%.
4. Use of an intravaginal delivery system according to any one of claims 1 to 3 for the preparation of a vaginal topical preparation for the treatment of vaginitis, wherein said vaginal topical preparation further comprises an active ingredient for the treatment of vaginitis.
5. The use according to claim 4, wherein the vaginitis is selected from one or more of fungal vaginitis, bacterial vaginitis and trichomonas vaginalis.
6. The use according to claim 4, wherein the active ingredient is selected from one or more of Lei Fukang azole, isaconazole, ifeconazole, clotrimazole, voriconazole, posaconazole, itraconazole, fluconazole, ciclopirox olamine, octenidine, secnidazole.
7. The use according to claim 4, wherein the formulation for vaginal topical administration is in the form of a suppository, tablet, soft capsule, cream, gel, cream or spray.
8. The use of claim 7, wherein the suppository further comprises a base.
9. The use according to claim 8, wherein the matrix comprises an oil-soluble matrix and/or a water-soluble matrix; the oil-soluble matrix is preferably selected from one or more of cocoa butter, hydrogenated neutral fat, mixed fatty acid glyceride, propylene glycol stearate; the water-soluble matrix is preferably selected from one or more of glycerogelatin, polyethylene glycol, poloxamer, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate.
10. The use according to claim 9, wherein the suppository further comprises a plasticizer, preferably selected from one or more of polysorbate, fatty acid glyceride, castor oil.
11. The use of claim 7, wherein the tablet further comprises a binder and a lubricant.
12. Use according to claim 11, wherein the binder is selected from one or more of acacia, starch, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, preferably comprising povidone and starch.
13. Use according to claim 11, wherein the lubricant is selected from one or more of stearates, talc, aerosil, hydrogenated vegetable oil, polyethylene glycol, sodium dodecyl sulphate, preferably from one or more of magnesium stearate, talc and aerosil.
14. The use according to claim 13, wherein the tablet further comprises a filler, preferably one or more selected from starch, modified starch, microcrystalline cellulose, mannitol.
15. The use according to claim 7, wherein the spray formulation further comprises a solvent; the solvent is preferably selected from one or more of water, ethylene glycol, propylene glycol, glycerol, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, polyethylene glycol modification.
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