CN113230229A - Nifuratel nystatin soft capsule and preparation method thereof - Google Patents
Nifuratel nystatin soft capsule and preparation method thereof Download PDFInfo
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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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
- A61K31/41—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
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61K9/4825—Proteins, e.g. gelatin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/4833—Encapsulating processes; Filling of capsules
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- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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Abstract
The invention relates to a soft capsule of nifuratel nystatin and a preparation method thereof, wherein the content of the soft capsule comprises nifuratel, nystatin, olive oil and medicinal vaseline; the soft capsule shell comprises the following components: gelatin, glycerol, water and epsilon-polylysine. According to the invention, the formula of the nifuratel nystatin soft capsule is optimized, the olive oil is used for replacing the conventional medicinal soybean oil, and the epsilon-polylysine is used as a preservative, so that the stimulation of the nifuratel nystatin soft capsule to the vagina is reduced.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a nifuratel nystatin soft capsule and a preparation method thereof.
Background
Nifuratel (Nifuratel) is a broad-spectrum antibacterial drug belonging to furazolidone (this class of drugs also includes furacilin, furidadin, furazolidone). Nifuratel is researched and marketed in 60 s by Poli Industrial Chimica S.p.A company in Italy, is marketed in more than 20 countries in the world, has been marketed for over thirty years so far, and has a strong and effective killing effect on bacteria, trichomonas, mold and the like causing female reproductive system infection, but rarely produces any acute and chronic side effect. Due to its multi-aspect therapeutic action, it has obvious curative effect for various vaginitis caused by bacteria, trichomonas or mould infection.
Nystatin, also known as nystatin, is yellow or brownish yellow powder, has a grain-like smell, has strong hygroscopicity, is unstable to light, air, acids and alkalis, and is extremely unstable in aqueous solution, and 50% of the effect can be lost when the nystatin is stored at 37 ℃ for one week. The product is polyene antifungal, has broad-spectrum antifungal effect, is membrane permeability enhancer, and is most sensitive to Candida. Sensitive to Aspergillus, Trichophyton trichomonad, Staphyloccocus, Epidermophyton and Microsporum. It also has antibacterial activity against coccidioidomycosis and histoplasma bacteria. It also has effect in inhibiting trichomonas. The mechanism of action is the combination with specific sterol on the fungal cell membrane, which results in the destruction of the plasma membrane and the change in permeability, so that important cell contents leak out and die, thereby killing the fungus.
Nifuratel + nystatin pessary is sold in China under the registration card numbers X970408 and X20010224, with the trade name of "Compound Mai Mino" in 1997 and the trade name of Mi Mino "being changed to Mi kang Paa later. The medicine has more than 30 years of clinical use experience, comprises a major sample clinical test retrospective study and is mostly seen in a professional journal in Europe, and shows that the medicine has a special position in the treatment field of gynecological diseases although the time of marketing is early, so that the medicine still receives close attention of the medical and academic circles until now, and has no sign of exiting the market.
At present, nifuratel nysfungin vaginal soft capsules are mainly used clinically, and indications are bacterial vaginosis, trichomonas vaginitis, monilial vulvovaginitis and vaginal mixed infection. The existing nifuratel nysfungin vaginal soft capsules on the market contain 500mg of nifuratel and 20 ten thousand units of nysfungin. The auxiliary materials are as follows: the content comprises vaseline, soybean oil, ethylparaben, gelatin contained in capsule shell, glycerol, water, sunset yellow and titanium pigment.
Chinese patent application CN111557897A discloses a pharmaceutical composition containing nifuratel and a preparation method thereof, wherein the pharmaceutical composition is prepared from the following components in parts by weight: 1 part of nifuratel, 0.07 part of nystatin, 0.2 to 0.4 part of gelatin for capsules, 25 to 1.8 parts of dimethicone AK 10001.6 and 0.26 to 0.36 part of purified water. The pharmaceutical composition containing nifuratel provided by the invention overcomes the phenomenon that nifuratel nystatin vaginal soft capsules in the prior art cannot disperse during melting time limit detection. The experimental results show that: when the nifuratel-containing pharmaceutical composition is subjected to melting time limit detection, the sustained dispersion hydrophilicity is better, and the melting time limit is obviously superior to other similar products.
Chinese patent application CN108853003A discloses a nifuratel-nysfungin soft capsule suppository and a preparation method thereof, wherein nifuratel-nysfungin sol in the nifuratel-nysfungin soft capsule suppository comprises the following components in parts by weight: 40-60 parts of nifuratel, 3-5 parts of nysfungin, 2-3 parts of carbomer, 1-2 parts of ethylparaben, 50-70 parts of glycerol, 70-100 parts of ethanol, 20-30 parts of pH buffer solution and 800 parts of medicinal pure water. The preparation method comprises the following steps: s1 preparing raw materials; s2 preparing liquid medicine: mixing nifuratel and nysfungin uniformly in a sterile environment, performing sterile filtration by using a sterile filtration system, and performing microporous filtration to obtain a liquid medicine for later use; s3 preparing a gel matrix; s4, preparing nifuratel-nysfungin sol; s5 pressing the capsule; s6 making soft capsule suppository. The preparation method has the advantages of no influence on body hormone secretion, good bactericidal effect and simple preparation method.
Nifuratel nysfungin soft capsule is generally applied by vaginal administration once every night after vulva is cleaned before sleep, and the product is placed at the fornix of the back for 6 days. The medicine can locally stimulate vagina, and may have burning sensation, vaginal dryness, or gastrointestinal nausea and other adverse reactions. For those skilled in the art, there is a need to optimize the formulation of nifuratel nystatin soft capsules to reduce irritation to the vagina and improve patient compliance. The present invention was made based on this object and as a result of its research.
Disclosure of Invention
Based on the background technology, the invention aims to provide a nifuratel nystatin soft capsule and a preparation method thereof. In order to realize the purpose of the invention, the following technical scheme is adopted:
the invention relates to a nifuratel nystatin soft capsule, the content of which comprises nifuratel, nystatin, olive oil and medicinal vaseline; the soft capsule shell comprises the following components: gelatin, glycerol, water and epsilon-polylysine.
In a preferred embodiment of the present invention, the soft capsule shell composition further comprises sunset yellow and titanium dioxide.
In a preferred embodiment of the present invention, the content components are: 600 parts of nifuratel 400-; the soft capsule shell comprises the following components: 450 parts of gelatin, 220 parts of glycerol 150, 500 parts of water 300, 0.5-2 parts of sunset yellow, 1-3 parts of titanium dioxide and 6-10 parts of epsilon-polylysine.
In a preferred embodiment of the invention, each soft capsule of nifuratel nystatin contains 500mg of nifuratel and 20 ten thousand IU of nystatin.
The invention also relates to a preparation method of the nifuratel nystatin soft capsule, which comprises the following steps:
(1) pretreating raw materials, namely sieving nifuratel and nystatin by a 120-mesh sieve, and weighing the formula for later use;
(2) sequentially adding medicinal vaseline, nifuratel and nystatin with the prescription amount into a stirring and heat-preserving barrel filled with olive oil, wherein the temperature is 35-45 ℃, and the stirring speed is 800-1500rpm until the mixture is uniform for later use;
(3) preparing a soft capsule shell material, namely adding epsilon-polylysine, sunset yellow and titanium dioxide in the formula amount into a proper amount of water, homogenizing and grinding by using a colloid mill, flushing the colloid mill by using water until the colloid mill is clean, and collecting grinding fluid and cleaning fluid for later use; adding the glycerol with the prescription amount and the residual water into a sol pot, stirring for 10-15 minutes, pouring all the liquid in the step I into the sol pot, and stirring for 10-15 minutes; thirdly, adding the gelatin with the prescription amount into a gelatin dissolving tank, setting the temperature to be 90 ℃, starting stirring, and boiling the gelatin for 1-2 hours; fourthly, vacuumizing: stopping stirring, starting a vacuum pump, stopping the vacuum pump after keeping a vacuum state for a certain time, closing a vacuum valve, and starting an air release valve to enable the air pressure to return to zero; fifthly, discharging glue solution: a 100-mesh stainless steel screen is sleeved at the glue solution outlet, compressed air is started to transfer all glue solution into a heat-preservation tank, and the glue solution is stored at 50-60 ℃ for later use;
(4) pressing soft capsules, mounting an elliptical pressing die, adjusting gaps, mounting a glue applying pipeline, setting the temperature of a left glue box and a right glue box to be 40-50 ℃, starting an air box to refrigerate, pressing a rubber sheet with the thickness of 0.85-1.00mm, adding contents into a feeding box after the soft capsules pass, setting the heat preservation temperature of the feeding box to be 30-35 ℃ and the temperature of a spraying body to be 30-40 ℃, and pressing after the soft capsules pass;
(5) shaping, drying, placing the soft capsule in drying cage, and opening cold air at 10-15 deg.C for shaping and drying;
(6) washing the soft capsule, namely washing the surface of the soft capsule by using 85% -95% ethanol solution;
(7) airing the pills, namely flatly paving the washed soft capsules in a tray placed with gauze, pushing the soft capsules into a pill airing room for airing, wherein the temperature is 30-35 ℃, the humidity is less than or equal to 25%, and regularly turning the tray to prevent adhesion;
(8) lamp inspection and pill picking, namely placing the aired soft capsules on a lamp inspection table, and removing the soft capsules with unqualified appearance;
(9) packaging the soft capsules qualified by inspection by adopting aluminum-plastic or aluminum-aluminum bubble caps;
(10) and (5) packaging and storing, namely filling the semi-finished products qualified by full inspection into a small box with a label, and storing.
The invention also relates to application of the nifuratel nystatin soft capsule in preparing a medicament for treating vaginitis.
In a preferred embodiment of the invention, the vaginitis is bacterial vaginitis, trichomonas vaginitis, candidal vulvovaginitis, mixed infection vaginitis.
In a preferred embodiment of the invention, the medicament is for reducing irritation of the vagina.
Advantageous effects
According to the invention, the formula of the nifuratel nystatin soft capsule is optimized, the olive oil is used for replacing the conventional medicinal soybean oil, and the epsilon-polylysine is used as a preservative, so that the stimulation of the nifuratel nystatin soft capsule to the vagina is reduced.
Detailed Description
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1: preparation of pharmaceutical preparations
The contents comprise the following components in percentage by weight of 1000 granules: 500g of nifuratel, 33.4g of nysfungin, 900g of olive oil and 100g of medicinal vaseline. The soft capsule shell comprises the following components: 380g of gelatin, 182.4g of glycerol, 380g of water, 1g of sunset yellow, 2g of titanium dioxide and 8g of epsilon-polylysine.
According to the formula, the operation process is as follows:
(1) pretreating raw materials, namely sieving nifuratel and nystatin by a 120-mesh sieve, and weighing the formula for later use;
(2) sequentially adding medicinal vaseline, nifuratel and nystatin with the prescription amount into a stirring and heat-insulating barrel filled with olive oil, wherein the temperature is 40 ℃, the stirring speed is 800-1500rpm, and the mixture is uniform for later use;
(3) preparing a soft capsule shell material, namely adding epsilon-polylysine, sunset yellow and titanium dioxide in the formula amount into a proper amount of water, homogenizing and grinding by using a colloid mill, flushing the colloid mill by using water until the colloid mill is clean, and collecting grinding fluid and cleaning fluid for later use; adding the glycerol with the prescription amount and the residual water into a sol pot, stirring for 10-15 minutes, pouring all the liquid in the step I into the sol pot, and stirring for 10-15 minutes; thirdly, adding the gelatin with the prescription amount into a gelatin dissolving tank, setting the temperature to be 90 ℃, starting stirring, and boiling the gelatin for 1-2 hours; fourthly, vacuumizing: stopping stirring, starting a vacuum pump, stopping the vacuum pump after keeping a vacuum state for a certain time, closing a vacuum valve, and starting an air release valve to enable the air pressure to return to zero; fifthly, discharging glue solution: a 100-mesh stainless steel screen is sleeved at the glue solution outlet, compressed air is started to transfer all glue solution into a heat-preservation tank, and the glue solution is stored at 50-60 ℃ for later use;
(4) pressing soft capsules, mounting an elliptical pressing die, adjusting gaps, mounting a glue applying pipeline, setting the temperature of a left glue box and a right glue box to be 40-50 ℃, starting a wind box to refrigerate, pressing a rubber sheet with the thickness of 0.85-1.00mm, adding contents into a feeding box after the rubber sheet is qualified, setting the heat preservation temperature of the feeding box to be 30-35 ℃ and the spraying temperature to be 30-40 ℃, pressing after the rubber sheet is qualified, regularly checking the loading capacity of the soft capsules according to process rules, and conforming to the loading control limit (plus or minus 5%);
(5) shaping, drying, placing the soft capsule in drying cage, and starting cold air (10-15 deg.C) to shape and dry; (6) washing the soft capsule, namely washing the surface of the soft capsule by using 85% -95% ethanol solution;
(7) airing the pills, namely flatly paving the washed soft capsules in a tray placed with gauze, pushing the soft capsules into a pill airing room for airing, wherein the temperature is 30-35 ℃, the humidity is less than or equal to 25%, and regularly turning the tray to prevent adhesion;
(8) performing light inspection and pill picking, placing the aired soft capsules on a light inspection table, and removing the soft capsules with unqualified appearance (such as suppressed pills, leaked pills, asymmetric pills and the like);
(9) packaging the soft capsules qualified by inspection by adopting aluminum-plastic or aluminum-aluminum bubble caps;
(10) and (4) outer packaging and storing, namely putting the semi-finished products (the aluminum plastic plates and the aluminum plates) which are completely qualified in inspection into a small box with a label, and storing.
Comparative example 1:
the same formulation as in example 1 was used except that medicinal soybean oil was used instead of olive oil.
Comparative example 2:
the same formulation as in example 1 was used except that 4g of ethylparaben was used instead of 8g of epsilon-polylysine.
Example 2: irritation test of vaginal administration to rabbits
(one) Experimental groups
Selecting 24 female experimental rabbits qualified for quarantine, and dividing the experimental rabbits into two groups by a completely random method according to the body weight, wherein each group comprises 6 rabbits.
Each group is respectively
(1) Placebo group (given 0.5g saline);
(2) experimental group (given 0.5g of example 1 soft capsules);
(3) control 1 (given 0.5g of comparative example 1 soft capsules);
(4) control 2 (giving 0.5g of comparative example 2 Soft capsules)
(II) administration method
The administration mode of the test is vaginal administration of test rabbits. Each experimental rabbit was bound and fixed on a fixator for its hind limb, and the animal tail was lifted to expose the vaginal opening, 0.5g gel per time, and administered for 6 days continuously. It should be noted that the examples and comparative examples were prepared based on the specification of administration to human body, and the specification of soft capsules for animal experiments was smaller than that of administration to human body.
Vaginal orifice and perineal discharge, erythema and edema status were recorded 24 h after initial exposure and before each trial run. Taking 6 experimental rabbits 24 h after the last administration for CO implementation2Euthanasia, comparing the test sample with the matrix group, longitudinally cutting after completely cutting the vagina, checking the stimulation, damage and necrosis of the epithelial tissue layer, placing the removed vaginal tissue into a fixing agent for fixation, and performing histological examination and evaluation.
(III) Observation index and evaluation method
And (4) visual observation and evaluation, namely comparing the vaginal tissue of the experimental rabbit with the vaginal tissue of the control rabbit through visual observation and recording.
Histological evaluation vaginal tissue was scored according to the classification system specified in tables 1 and 2.
Table 1: microscopic observation and scoring standard for vaginal tissue reaction
Table 2: evaluation criteria for vaginal irritation index
The animal microscopic evaluation scores of the administration groups are added and divided by the total number of observations to obtain the average score of the administration groups, and the maximum score is 16. The control group is calculated by the same method. Microscopic evaluation of the total score of greater than 9 in the control animals indicates possible damage to the experimental procedure. The mean score of the control group was subtracted from the mean score of the administration group to obtain the stimulation index. The results of the experiment are shown in table 3.
TABLE 3 evaluation results of drugs for vaginal irritation
The results prove that: the average score of the test group corresponding to stimulation is closest to that of the placebo group, and compared with the control group 1 and the control group 2, the medicine of the test group can obviously reduce the stimulation to the vagina. Although the reason for this is still under study, it is presumed that olive oil contains more antioxidant components than soybean oil for medical use and epsilon-polylysine has better compatibility with human tissues, thereby helping to relieve vaginal irritation caused by drugs.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (8)
1. A soft capsule containing nifuratel nystatin comprises nifuratel, nystatin, oleum Olivarum, and medicinal vaseline; the soft capsule shell comprises the following components: gelatin, glycerol, water and epsilon-polylysine.
2. The nifuratel nystatin soft capsule according to claim 1, further comprising sunset yellow and titanium dioxide.
3. The nifuratel nystatin soft capsule according to claim 1, the contents of which are: 600 parts of nifuratel 400-; the soft capsule shell comprises the following components: 450 parts of gelatin, 220 parts of glycerol 150, 500 parts of water 300, 0.5-2 parts of sunset yellow, 1-3 parts of titanium dioxide and 6-10 parts of epsilon-polylysine.
4. The nifuratel nystatin soft capsule according to claim 1, each containing 500mg of nifuratel and 20 ten thousand IU of nystatin.
5. A process for the preparation of the nifuratel nystatin soft capsule according to any one of claims 1 to 4, which comprises the following steps:
(1) pretreating raw materials, namely sieving nifuratel and nystatin by a 120-mesh sieve, and weighing the formula for later use;
(2) sequentially adding medicinal vaseline, nifuratel and nystatin with the prescription amount into a stirring and heat-preserving barrel filled with olive oil, wherein the temperature is 35-45 ℃, and the stirring speed is 800-1500rpm until the mixture is uniform for later use;
(3) preparing a soft capsule shell material, namely adding epsilon-polylysine, sunset yellow and titanium dioxide in the formula amount into a proper amount of water, homogenizing and grinding by using a colloid mill, flushing the colloid mill by using water until the colloid mill is clean, and collecting grinding fluid and cleaning fluid for later use; adding the glycerol with the prescription amount and the residual water into a sol pot, stirring for 10-15 minutes, pouring all the liquid in the step I into the sol pot, and stirring for 10-15 minutes; thirdly, adding the gelatin with the prescription amount into a gelatin dissolving tank, setting the temperature to be 90 ℃, starting stirring, and boiling the gelatin for 1-2 hours; fourthly, vacuumizing: stopping stirring, starting a vacuum pump, stopping the vacuum pump after keeping a vacuum state for a certain time, closing a vacuum valve, and starting an air release valve to enable the air pressure to return to zero; fifthly, discharging glue solution: a 100-mesh stainless steel screen is sleeved at the glue solution outlet, compressed air is started to transfer all glue solution into a heat-preservation tank, and the glue solution is stored at 50-60 ℃ for later use;
(4) pressing soft capsules, mounting an elliptical pressing die, adjusting gaps, mounting a glue applying pipeline, setting the temperature of a left glue box and a right glue box to be 40-50 ℃, starting an air box to refrigerate, pressing a rubber sheet with the thickness of 0.85-1.00mm, adding contents into a feeding box after the soft capsules pass, setting the heat preservation temperature of the feeding box to be 30-35 ℃ and the temperature of a spraying body to be 30-40 ℃, and pressing after the soft capsules pass;
(5) shaping, drying, placing the soft capsule in drying cage, and opening cold air at 10-15 deg.C for shaping and drying;
(6) washing the soft capsule, namely washing the surface of the soft capsule by using 85% -95% ethanol solution;
(7) airing the pills, namely flatly paving the washed soft capsules in a tray placed with gauze, pushing the soft capsules into a pill airing room for airing, wherein the temperature is 30-35 ℃, the humidity is less than or equal to 25%, and regularly turning the tray to prevent adhesion;
(8) lamp inspection and pill picking, namely placing the aired soft capsules on a lamp inspection table, and removing the soft capsules with unqualified appearance;
(9) packaging the soft capsules qualified by inspection by adopting aluminum-plastic or aluminum-aluminum bubble caps;
(10) and (5) packaging and storing, namely filling the semi-finished products qualified by full inspection into a small box with a label, and storing.
6. Use of the nifuratel nystatin soft capsule according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of vaginitis.
7. The use according to claim 6, wherein the vaginitis is bacterial vaginitis, trichomonas vaginitis, candidal vulvovaginitis, mixed infection vaginitis.
8. The use according to claim 6, for reducing irritation of the vagina.
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| CN115561412A (en) * | 2022-10-08 | 2023-01-03 | 哈尔滨海涵丰生物科技开发有限公司 | Medicine automatic checkout device |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417562A (en) * | 2013-07-26 | 2013-12-04 | 国药集团川抗制药有限公司 | Nifuratel-nysfungin vaginal soft capsule and preparation method thereof |
| CN104434942A (en) * | 2014-11-19 | 2015-03-25 | 江苏悦兴药业有限公司 | Nifuratel nysfungin vaginal soft capsule and preparation process thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417562A (en) * | 2013-07-26 | 2013-12-04 | 国药集团川抗制药有限公司 | Nifuratel-nysfungin vaginal soft capsule and preparation method thereof |
| CN104434942A (en) * | 2014-11-19 | 2015-03-25 | 江苏悦兴药业有限公司 | Nifuratel nysfungin vaginal soft capsule and preparation process thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115561412A (en) * | 2022-10-08 | 2023-01-03 | 哈尔滨海涵丰生物科技开发有限公司 | Medicine automatic checkout device |
| CN115561412B (en) * | 2022-10-08 | 2023-05-05 | 哈尔滨海涵丰生物科技开发有限公司 | Automatic medicine detection device |
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