WO2023125763A1 - Povidone iodine-containing temperature-sensitive gelling preparation - Google Patents
Povidone iodine-containing temperature-sensitive gelling preparation Download PDFInfo
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- WO2023125763A1 WO2023125763A1 PCT/CN2022/143220 CN2022143220W WO2023125763A1 WO 2023125763 A1 WO2023125763 A1 WO 2023125763A1 CN 2022143220 W CN2022143220 W CN 2022143220W WO 2023125763 A1 WO2023125763 A1 WO 2023125763A1
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
- A61K31/79—Polymers of vinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
Definitions
- Povidone iodine can directly denature and precipitate proteins in bacteria to cause the death of pathogenic microorganisms for efficient disinfection and sterilization, whereby viruses, bacteria, spores, fungi, protozoa, etc. can be killed, and the toxicity is low.
- the aqueous solution of povidone iodin shows a strong pharmacological activity against Staphylococcus aureus, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Treponema pallidum, hepatitis B virus, human immunodeficiency virus, Trichomonas vaginalisis, etc.
- the povidone iodine can continuously release free iodine, such that the skin and mucous membranes maintain certain effective iodine concentration to inhibit and kill bacteria.
- the povidone iodine is against gynecological vaginal infections.
- the povidone iodine is inter-miscible with vaginal secretions to kill pathogenic microorganisms in the secretions, block the spread and invasion of sexually transmitted diseases, and treat vaginal diseases induced by other bacterial infections.
- the present invention has unexpectedly overcome such shortcomings.
- the present invention provides a temperature-sensitive gelling preparation which contains povidone iodine, a temperature-sensitive gel matrix, an oxidant, a pH regulator, and purified water.
- a gelling preparation is unexpectedly effective in treating a gynecological vaginal infection or a vaginal disease induced by gynecological vaginal infection in a subject in need thereof.
- gelling preparation means that the preparation would undergo the process to form a gel, typically by phase transformation, from the liquid state to a non-chemical cross-linked semi-solid gel state
- the gelling preparation of this invention After being administered in a liquid state at room temperature, the gelling preparation of this invention can undergo phase transformation, from the liquid state to a non-chemical cross-linked semi-solid gel state, at the site of administration along with temperature rise in a body cavity, and the gel thus formed is attached and fixed to a lesion of the body cavity, thereby providing sustained release of the iodine compound and exerting in a targeted fashion a long lasting therapeutic effect.
- the temperature-sensitive in-situ gelling preparation of this invention when administered vaginally, exhibited unexpected characteristics such as good spreadability, large coverage, long residence time, good efficacy, little side effects, and convenient medication for patients.
- povidone iodine accounts for 0.1%-15%(weight/weight) of the gelling preparation
- the temperature-sensitive gel matrix accounts for 0.1%-35%(weight/weight) of the gelling preparation
- the oxidant accounts for 0.01%-10%(weight/weight) of the gelling preparation
- the osmotic pressure regulator accounts for 0.01%-10%(weight/weight) of the gelling preparation
- the pH regulator accounts for 0.01%-5%(weight/weight) of the gelling preparation.
- the balance of the gelling preparation can be purified water.
- the temperature-sensitive gel matrix is natural and modified polymers, a poly (N-isopropyl phthalein) polymer, a polyoxyethylene-polyoxypropylene copolymer, a crosslinked PLGA block copolymer, or any combination thereof.
- the temperature-sensitive gel matrix is a poloxamer or chitosan.
- a poloxamer is a surprising choice matrix material for the preparation as a poloxamer has been found to have serious chemical incompatibility with povidone iodine by readily reacting with each other, resulting in povidone iodine degrading rapidly from reddish brown to colorless solution.
- a stable temperature-sensitive gelling preparation of this invention can ben prepared with a poloxamer with povidone iodine also in the preparation since it is particularly important to solve the problem of incompatibility between povidone iodine and poloxamer, so as to further prepare a povidone iodine-and poloxamer-containing temperature- sensitive gelling preparation with characteristics such as good spreadability, large coverage, long residence time, good efficacy, little side effects, and convenient medication for patients.
- the temperature-sensitive gelling preparation of this invention includes an osmotic pressure regulator.
- the osmotic pressure regulator can be included in the gelling preparation, e.g., at a concentration of 0.01%-10% (weight/weight) .
- Examples of an osmotic pressure regulator suitable for the present invention include sodium chloride, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, and any combination thereof.
- the pH regulator includes boric acid, sodium borate, a phosphate buffer, tromethamine, a tromethamine hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, or any mixture thereof.
- the temperature-sensitive gelling preparation of the present invention includes povidone iodine at a concentration of 0.1%-5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
- the temperature-sensitive gelling preparation of the present invention includes povidone iodine at a concentration of 0.1%-2% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
- the temperature-sensitive gelling preparation of the present invention contains povidone iodine at a concentration of 2%, 2.5%or 5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 35% (weight/weight) , and the oxidant at a concentration of 0.01%-1.0% (weight/weight) .
- the 35%(weight/weight) temperature-sensitive gel matrix includes 15%of poloxamer 407 (weight/weight) and 20%of poloxamer 188 (weight/weight) , based on the weight of the gelling preparation.
- the present invention takes the povidone iodine as the main drug, the poloxamer as the temperature-sensitive gel matrix, and the hydrogen peroxide as the oxidant, an osmotic pressure regulator, and a pH regulator to prepare the povidone iodine-containing temperature-sensitive gelling preparation.
- the poloxamer used in the present invention is a pharmaceutical-grade excipient, which is for an injection use, a topical use, an ophthalmic use and other medical uses, and is safe to use.
- the poloxamer is a block copolymer consisting of polyethylene oxide and polypropylene oxide (PEO PEO PEO) , and pertains to a nonionic surfactant, with a unique reverse thermogel property. Its 20%-30%aqueous solution has the characteristics of being a liquid-state gel at 5°C to room temperature, and changing to a solid-state gel when the temperature is up to 35°C-37°C it becomes a solid gel.
- poloxamer suitable for the present invention includes poloxamer 407, poloxamer 188, poloxamer 124, poloxamer 237, poloxamer 338, and any combination thereof.
- the aqueous solution of poloxamer 407 has the nature of temperature-sensitive in-situ gel, its gel surface is smooth and soft without obvious foreign body sensation, non-toxic and non-irritating, and has good biocompatibility.
- the present invention takes a combination of the poloxamer 407 and the poloxamer 188 as a preferred temperature-sensitive gel matrix.
- An oxidant suitable for the preparations of the present invention can be an inorganic oxidant or an organic oxidant.
- a specific example of a suitable oxidant for the present invention is hydrogen peroxide, which is an acidic strong oxidant.
- the inventors have surprisingly found that the povidone iodine can become compatible with the poloxamer by adding an oxidant to allow the oxidant to react with the reducing agent in the poloxamer in advance so as to completely consume the reducing agent, then mixing the povidone iodine with the poloxamer, and the content of povidone iodine no longer decreases.
- the temperature-sensitive gel properties of the poloxamer were not changed.
- An osmotic pressure regulator suitable for the preparations of the present invention includes sodium chloride, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, or any combination thereof.
- a pH regulator suitable for the preparations of the present invention include boric acid, sodium borate, a phosphate buffer, tromethamine, a tromethamine hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, or any combination thereof.
- the present invention successfully solves the technical problem of the incompatibility between povidone iodine and poloxamer, and provides a new povidone iodine-containing temperature-sensitive gelling preparation.
- the temperature-sensitive gelling preparation containing the povidone iodine and poloxamer according to the present invention effectively makes up for the defects of current clinically related preparations for diseases related to gynecological vaginal infections.
- the temperature-sensitive gelling preparation of the present invention can rapidly form a semi-solid gel after application to a luminal tract, showing strong retention and sustained release effects, such that the bioavailability is increased.
- the semi-solid gel formed can reside at the site of administration without loss, and can gradually release povidone iodine to kill various infectious microorganisms at the site of application.
- another aspect of the present invention provides a method for treating a gynecological vaginal infection or a vaginal disease induced by gynecological vaginal infection in a subject in need thereof with a therapeutically effective amount of a temperature-sensitive gelling preparation described above.
- the present invention has the following unexpected advantages: good spreadability, large coverage, long residence time, good efficacy, little side effects, convenient medication for patients, etc.
- FIG. 1 shows the results of a test of a pharmaceutical preparation of this inventio against the fungus Candida parapsilosis.
- Example 1 Preparation and investigation of poloxamer-containing temperature-sensitive gel.
- the formula of the poloxamer-containing temperature-sensitive gel included: 15 g of poloxamer (407) , 20 g of poloxamer (188) , and 65 g of purified water.
- a preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker, putting the beaker in an ice bath, placing a stirrer in the beaker and stirring the purified water; and (2) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 1.
- Table 1 show that the poloxamer possess strong temperature-sensitive gel characteristics under the established type and dosage conditions. It was in a liquid state at room temperature, and quickly changed to a semi-solid state in an environment at 35 °C, showing its potential function of slow release.
- Example 2 Preparation and investigation of povidone iodine-containing temperature-sensitive gel.
- the formula of a 2%povidone iodine-containing temperature-sensitive gel included: 2 g of povidone iodine, 15 g of poloxamer (407) , 20 g of poloxamer (188) , and the balance of purified water added to a total of 100 g.
- a preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker, putting the beaker in an ice bath, placing a stirrer in the beaker and stirring the purified water; (2) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (3) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 2.
- Example 2 The sample of Example 2 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results are shown in Table 3.
- Example 3 Preparation and investigation of 2%povidone iodine-containing (hydrogen peroxide-containing) temperature-sensitive gel.
- Example 3 included 2 g of povidone iodine, to which 15 g/10 g/5 g/2 g/1 g of 6%hydrogen peroxide, 15 g of poloxamer (407) , and 20 g of poloxamer (188) were added, and purified water was added to reach 100 g.
- a total of 5 formula samples were prepared, namely, Sample 1 of Example 3, Sample 2 of Example 3, Sample 3 of Example 3, Sample 4 of Example 3, and Sample 5 of Example 3.
- a preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding in each case a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain in each case the Sample 1 of Example 3, Sample 2 of Example 3, Sample 3 of Example 3, Sample 4 of Example 3, or Sample 5 of Example 3.
- Example 3 The five samples prepared in Example 3 were titrated with 0.01 mol/L sodium thiosulfate respectively to measure the effective iodine content. The results were shown in Table 5.
- Example 4 Preparation and investigation of temperature-sensitive gel containing 2%povidone iodine, 0.25%hydrogen peroxide, temperature-sensitive gel matrix and purified water.
- This preparation included 2 g of povidone iodine, 0.25 g of 6%hydrogen peroxide, 15 g of poloxamer (407) , 20 g of poloxamer (188) , and the balance of purified water added to a total of 100 g.
- a preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 4.
- the temperature-sensitive gel of the sample of Example 4 was investigated, with the results shown in Table 6.
- Example 4 The sample of Example 4 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results were shown in Table 7.
- Example 5 Preparation and investigation of temperature-sensitive gel containing 5%povidone iodine, 0.62% (6%) hydrogen peroxide, temperature-sensitive gel matrix and purified water.
- a preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 5.
- the temperature-sensitive gel of the sample of Example 5 was investigated, with the results shown in Table 8.
- Example 5 The sample of Example 5 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results were shown in Table 9.
- the gelling preparation contains 2% (weight/weight) , 15%of poloxamer 407 (weight/weight) , 20%of poloxamer 188 (weight/weight) , At the end of the indicated time, 1 mL of the inoculums was removed and mixed with 9 mL of phosphate buffer saline (PBS) contained 0.5%sodium thiosulfate to inactivate the remaining pharmaceutical preparation/solution (dilution factor 1: 10) .
- PBS phosphate buffer saline
- Plate method -100 ⁇ L of the inactivated inoculums was removed in duplicate and plated separately on the fungal medium plate (2%MEA) .
- a control was performed under the same condition as described above except the pharmaceutical preparation of this invention was replaced with PBS.
- FIG. 1 shows the results of this test, illustrating that the gelling preparation of this invention not only effectively eliminated the fungus Candida parapsilosis, but also inhibited its growth.
Abstract
Provided herein is a povidone iodine-containing temperature-sensitive gelling preparation for the treatment of luminal tract diseases induced by infections. The preparation is prepared from povidone iodine, a temperature-sensitive gel matrix, an oxidant, an osmotic pressure regulator, a pH regulator, and purified water. It solves the problem of chemical incompatibility between the povidone iodine and the temperature-sensitive gel matrix to successfully prepare the povidone iodine-containing temperature-sensitive gelling preparation.
Description
Cross-Reference to Related Application
The present application claim priority to Chinese Application No. 202111643943.2, filed on December 29, 2021, the contents of which are incorporated herein by reference in their entirety.
Povidone iodine can directly denature and precipitate proteins in bacteria to cause the death of pathogenic microorganisms for efficient disinfection and sterilization, whereby viruses, bacteria, spores, fungi, protozoa, etc. can be killed, and the toxicity is low. The aqueous solution of povidone iodin shows a strong pharmacological activity against Staphylococcus aureus, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Treponema pallidum, hepatitis B virus, human immunodeficiency virus, Trichomonas vaginalisis, etc. The povidone iodine can continuously release free iodine, such that the skin and mucous membranes maintain certain effective iodine concentration to inhibit and kill bacteria.
One of the main uses of the povidone iodine is against gynecological vaginal infections. The povidone iodine is inter-miscible with vaginal secretions to kill pathogenic microorganisms in the secretions, block the spread and invasion of sexually transmitted diseases, and treat vaginal diseases induced by other bacterial infections.
At present, there are many povidone iodine-related preparations, including irrigants, gels, ordinary suppositories, etc., against diseases related to gynecological vaginal infections. However, during clinical application, these preparations all shown some defects or shortcomings. For example, the irrigants run off too fast with short contact time; the ordinary suppositories easily flow out after melting in the vagina, with poor efficacy; and the gelling preparations show poor spreadability with small coverage in the vagina. As a result, the above dosage forms still cannot fully meet the clinical needs.
The present invention has unexpectedly overcome such shortcomings.
Brief Summary of the Invention
In one aspect, the present invention provides a temperature-sensitive gelling preparation which contains povidone iodine, a temperature-sensitive gel matrix, an oxidant, a pH regulator, and purified water. Such a gelling preparation is unexpectedly effective in treating a gynecological vaginal infection or a vaginal disease induced by gynecological vaginal infection in a subject in need thereof.
As used herein, the term “gelling preparation” means that the preparation would undergo the process to form a gel, typically by phase transformation, from the liquid state to a non-chemical cross-linked semi-solid gel state
After being administered in a liquid state at room temperature, the gelling preparation of this invention can undergo phase transformation, from the liquid state to a non-chemical cross-linked semi-solid gel state, at the site of administration along with temperature rise in a body cavity, and the gel thus formed is attached and fixed to a lesion of the body cavity, thereby providing sustained release of the iodine compound and exerting in a targeted fashion a long lasting therapeutic effect. The temperature-sensitive in-situ gelling preparation of this invention, when administered vaginally, exhibited unexpected characteristics such as good spreadability, large coverage, long residence time, good efficacy, little side effects, and convenient medication for patients.
In some embodiments of this invention, povidone iodine accounts for 0.1%-15%(weight/weight) of the gelling preparation, the temperature-sensitive gel matrix accounts for 0.1%-35%(weight/weight) of the gelling preparation , the oxidant accounts for 0.01%-10%(weight/weight) of the gelling preparation , the osmotic pressure regulator accounts for 0.01%-10%(weight/weight) of the gelling preparation , and the pH regulator accounts for 0.01%-5%(weight/weight) of the gelling preparation. The balance of the gelling preparation can be purified water.
In some embodiments, the temperature-sensitive gel matrix is natural and modified polymers, a poly (N-isopropyl phthalein) polymer, a polyoxyethylene-polyoxypropylene copolymer, a crosslinked PLGA block copolymer, or any combination thereof.
In some other embodiments, the temperature-sensitive gel matrix is a poloxamer or chitosan.
A poloxamer is a surprising choice matrix material for the preparation as a poloxamer has been found to have serious chemical incompatibility with povidone iodine by readily reacting with each other, resulting in povidone iodine degrading rapidly from reddish brown to colorless solution. As such, it is totally unexpected or surprising that a stable temperature-sensitive gelling preparation of this invention can ben prepared with a poloxamer with povidone iodine also in the preparation since it is particularly important to solve the problem of incompatibility between povidone iodine and poloxamer, so as to further prepare a povidone iodine-and poloxamer-containing temperature- sensitive gelling preparation with characteristics such as good spreadability, large coverage, long residence time, good efficacy, little side effects, and convenient medication for patients.
In some other embodiments, the temperature-sensitive gelling preparation of this invention includes an osmotic pressure regulator. The osmotic pressure regulator can be included in the gelling preparation, e.g., at a concentration of 0.01%-10% (weight/weight) , Examples of an osmotic pressure regulator suitable for the present invention include sodium chloride, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, and any combination thereof.
In some other embodiments of the temperature-sensitive gelling preparation of the present invention, the pH regulator includes boric acid, sodium borate, a phosphate buffer, tromethamine, a tromethamine hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, or any mixture thereof.
In some other embodiments, the temperature-sensitive gelling preparation of the present invention includes povidone iodine at a concentration of 0.1%-5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
In some other embodiments, the temperature-sensitive gelling preparation of the present invention includes povidone iodine at a concentration of 0.1%-2% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
In yet some other embodiments, the temperature-sensitive gelling preparation of the present invention contains povidone iodine at a concentration of 2%, 2.5%or 5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 35% (weight/weight) , and the oxidant at a concentration of 0.01%-1.0% (weight/weight) .
In yet some other embodiments of the gelling preparation of this invention, the 35%(weight/weight) temperature-sensitive gel matrix includes 15%of poloxamer 407 (weight/weight) and 20%of poloxamer 188 (weight/weight) , based on the weight of the gelling preparation.
In some other embodiments, the present invention takes the povidone iodine as the main drug, the poloxamer as the temperature-sensitive gel matrix, and the hydrogen peroxide as the oxidant, an osmotic pressure regulator, and a pH regulator to prepare the povidone iodine-containing temperature-sensitive gelling preparation.
The poloxamer used in the present invention is a pharmaceutical-grade excipient, which is for an injection use, a topical use, an ophthalmic use and other medical uses, and is safe to use. The poloxamer is a block copolymer consisting of polyethylene oxide and polypropylene oxide (PEO PEO PEO) , and pertains to a nonionic surfactant, with a unique reverse thermogel property. Its 20%-30%aqueous solution has the characteristics of being a liquid-state gel at 5℃ to room temperature, and changing to a solid-state gel when the temperature is up to 35℃-37℃ it becomes a solid gel.
Examples of poloxamer suitable for the present invention includes poloxamer 407, poloxamer 188, poloxamer 124, poloxamer 237, poloxamer 338, and any combination thereof.
Because the aqueous solution of poloxamer 407 has the nature of temperature-sensitive in-situ gel, its gel surface is smooth and soft without obvious foreign body sensation, non-toxic and non-irritating, and has good biocompatibility. In order to adjust for appropriate gel time and temperature, the present invention takes a combination of the poloxamer 407 and the poloxamer 188 as a preferred temperature-sensitive gel matrix.
An oxidant suitable for the preparations of the present invention can be an inorganic oxidant or an organic oxidant. A specific example of a suitable oxidant for the present invention is hydrogen peroxide, which is an acidic strong oxidant. Through tests, it was surprised to find that hydrogen peroxide effectively solved the problem of incompatibility between povidone iodine and poloxamer. Specifically, through analysis, the inventors have found that the reason why the povidone iodine is incompatible with the poloxamer lies in that a redox reaction occurs between a reducing agent present in the poloxamer and the povidone iodine to rapidly degrade the povidone iodine. The inventors have surprisingly found that the povidone iodine can become compatible with the poloxamer by adding an oxidant to allow the oxidant to react with the reducing agent in the poloxamer in advance so as to completely consume the reducing agent, then mixing the povidone iodine with the poloxamer, and the content of povidone iodine no longer decreases. Through tests, we have found that, even after all the reducing agent in the poloxamer was consumed, the temperature-sensitive gel properties of the poloxamer were not changed.
An osmotic pressure regulator suitable for the preparations of the present invention includes sodium chloride, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, propylene glycol, or any combination thereof.
A pH regulator suitable for the preparations of the present invention include boric acid, sodium borate, a phosphate buffer, tromethamine, a tromethamine hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, or any combination thereof.
The present invention successfully solves the technical problem of the incompatibility between povidone iodine and poloxamer, and provides a new povidone iodine-containing temperature-sensitive gelling preparation.
The temperature-sensitive gelling preparation containing the povidone iodine and poloxamer according to the present invention effectively makes up for the defects of current clinically related preparations for diseases related to gynecological vaginal infections. Specifically, the temperature-sensitive gelling preparation of the present invention can rapidly form a semi-solid gel after application to a luminal tract, showing strong retention and sustained release effects, such that the bioavailability is increased. The semi-solid gel formed can reside at the site of administration without loss, and can gradually release povidone iodine to kill various infectious microorganisms at the site of application.
Accordingly, another aspect of the present invention provides a method for treating a gynecological vaginal infection or a vaginal disease induced by gynecological vaginal infection in a subject in need thereof with a therapeutically effective amount of a temperature-sensitive gelling preparation described above.
Compared with the prior art, the present invention has the following unexpected advantages: good spreadability, large coverage, long residence time, good efficacy, little side effects, convenient medication for patients, etc.
Brief Description of the Drawing
FIG. 1 shows the results of a test of a pharmaceutical preparation of this inventio against the fungus Candida parapsilosis.
The technical solutions of the present invention will be further described below by means of the specific embodiments.
Example 1: Preparation and investigation of poloxamer-containing temperature-sensitive gel.
The formula of the poloxamer-containing temperature-sensitive gel (100 g) included: 15 g of poloxamer (407) , 20 g of poloxamer (188) , and 65 g of purified water.
A preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker, putting the beaker in an ice bath, placing a stirrer in the beaker and stirring the purified water; and (2) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 1.
The temperature-sensitive characteristics of the sample of Example 1 was investigated, with the results shown in Table 1.
Table 1
The results in Table 1 show that the poloxamer possess strong temperature-sensitive gel characteristics under the established type and dosage conditions. It was in a liquid state at room temperature, and quickly changed to a semi-solid state in an environment at 35 ℃, showing its potential function of slow release.
Example 2: Preparation and investigation of povidone iodine-containing temperature-sensitive gel.
The formula of a 2%povidone iodine-containing temperature-sensitive gel included: 2 g of povidone iodine, 15 g of poloxamer (407) , 20 g of poloxamer (188) , and the balance of purified water added to a total of 100 g.
A preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker, putting the beaker in an ice bath, placing a stirrer in the beaker and stirring the purified water; (2) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (3) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 2.
The temperature-sensitive characteristics of the sample of Example 2 was investigated, with the results shown in Table 2.
Table 2
The results in Table 2 show after the povidone iodine was combined with the poloxamer in this example, the povidone iodine did not affect the temperature-sensitive gel characteristics of the poloxamer, which was in a liquid state at room temperature and changed quickly to a semi-solid state in an environment at 35℃.
Measurement of content of povidone iodine in sample of Example 2
The sample of Example 2 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results are shown in Table 3.
Table 3
Sample | Effective iodine content (mg/g) | Theoretical content (mg/g) |
Sample of Example 2 | 1 . 41 | 2 . 13 |
From the results of Table 3, we knew that although the povidone iodine did not affect the temperature-sensitive gel characteristics of the poloxamer, the poloxamer did clearly show an effect on the povidone iodine to result in a significant decrease in the content of povidone iodine, showing the chemical incompatibility between the two.
Example 3: Preparation and investigation of 2%povidone iodine-containing (hydrogen peroxide-containing) temperature-sensitive gel.
This preparation of Example 3 included 2 g of povidone iodine, to which 15 g/10 g/5 g/2 g/1 g of 6%hydrogen peroxide, 15 g of poloxamer (407) , and 20 g of poloxamer (188) were added, and purified water was added to reach 100 g. A total of 5 formula samples were prepared, namely, Sample 1 of Example 3, Sample 2 of Example 3, Sample 3 of Example 3, Sample 4 of Example 3, and Sample 5 of Example 3.
A preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding in each case a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain in each case the Sample 1 of Example 3, Sample 2 of Example 3, Sample 3 of Example 3, Sample 4 of Example 3, or Sample 5 of Example 3.
The temperature-sensitive gel characteristics of the samples of Example 3 were respectively investigated, with the results shown in Table 4.
Table 4
The results in Table 4 show that the addition of hydrogen peroxide did not affect the temperature-sensitive characteristics of poloxamer, which still showed more significant temperature-sensitive characteristics; and 2) from the initial perspective of the characteristics of the sample, compared with the characteristics of the sample of Example 2, the addition of hydrogen peroxide truly solved the technical problem of chemical incompatibility between the povidone iodine and the poloxamer.
Measurement of the contents of povidone iodine in samples of Example 3:
The five samples prepared in Example 3 were titrated with 0.01 mol/L sodium thiosulfate respectively to measure the effective iodine content. The results were shown in Table 5.
Table 5
The results in Table 5 shown that (1) from the quantitative perspective, by the measurement of the content of povidone iodine, the content of povidone iodine was confirmed to be no longer reduced compared with the theoretical value, which truly illustrated that the inventors solved the technical problem of chemical incompatibility between povidone iodine and poloxamer by adding certain amount of hydrogen peroxide; (2) although the technical problem of chemical incompatibility between povidone iodine and poloxamer was solved by adding different amounts of hydrogen peroxide, the hydrogen peroxide itself also consumed the sodium thiosulfate titration solution according to the measurement results, and moreover, the higher the amount of hydrogen peroxide added, the more the sodium thiosulfate titration solution was consumed, resulting in that the measured effective iodine content was not accurate and the specificity was not high; and (3) by the addition of different amounts of hydrogen peroxide and from the results of measured effective iodine content, the inventors needed to further screen out the content of hydrogen peroxide suitable for the 2%povidone iodine-containing temperature-sensitive gelling preparation.
Example 4: Preparation and investigation of temperature-sensitive gel containing 2%povidone iodine, 0.25%hydrogen peroxide, temperature-sensitive gel matrix and purified water.
This preparation included 2 g of povidone iodine, 0.25 g of 6%hydrogen peroxide, 15 g of poloxamer (407) , 20 g of poloxamer (188) , and the balance of purified water added to a total of 100 g.
A preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 4.
The temperature-sensitive gel of the sample of Example 4 was investigated, with the results shown in Table 6.
Table 6
The results in Table 6 show that the addition of 0.25%hydrogen peroxide did not affect the temperature-sensitive gel characteristics from the initial perspective of the characteristics of the sample.
Measurement of the content of povidone iodine in sample of Example 4:
The sample of Example 4 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results were shown in Table 7.
Table 7
The results in Table 7 show that 0.25%hydrogen peroxide was used with respect to the addition of 2%povidone iodine, which exactly neutralized a factor affecting the incompatibility between the 2%povidone iodine and the poloxamer, and the hydrogen peroxide had no effect on the consumption of sodium thiosulfate.
Example 5: Preparation and investigation of temperature-sensitive gel containing 5%povidone iodine, 0.62% (6%) hydrogen peroxide, temperature-sensitive gel matrix and purified water.
The formula included: 5 g of povidone iodine, 0.62 g of 6%hydrogen peroxide, 12.85 g of poloxamer (407) , 17 g of poloxamer (188) , and the balance of purified water added to a total of 100 g.
A preparation method included the steps of (1) weighing out a prescribed amount of the purified water into a beaker; (2) adding a prescribed amount of hydrogen peroxide to the beaker, putting the beaker in an ice bath, placing a stirrer into the beaker and stirring the hydrogen peroxide; (3) weighing out a prescribed amount of the povidone iodine, slowly adding the povidone iodine to the beaker, and stirring until complete dissolution; and (4) weighing out a prescribed amount of the poloxamer (P188, P407) , slowly adding the poloxamer to the beaker, and stirring until complete dissolution, to obtain a sample of Example 5.
The temperature-sensitive gel of the sample of Example 5 was investigated, with the results shown in Table 8.
Table 8
The results in Table 8 show that the addition of 0.62%hydrogen peroxide did not affect the characteristics of the temperature-sensitive gel from the initial perspective of the characteristics of the sample.
Measurement of the content of povidone iodine in sample of Example 5:
The sample of Example 5 was titrated with 0.01 mol/L sodium thiosulfate to measure the effective iodine content. The results were shown in Table 9.
Table 9
From the results in Table 9, we knew that 0.62%hydrogen peroxide was used with respect to the addition of 5%povidone iodine, which exactly neutralized a factor affecting the incompatibility between the 5%povidone iodine and the poloxamer, and the hydrogen peroxide had no effect on the consumption of sodium thiosulfate.
Example 6. Efficacy of Samples against Candida parapsilosis
Three (3) samples containing the fungus Candida parapsilosis were each inoculated with 10 mL gelling preparation of this invention for 15 seconds, 30 seconds, and 1 minute, respectively. The gelling preparation contains 2% (weight/weight) , 15%of poloxamer 407 (weight/weight) , 20%of poloxamer 188 (weight/weight) , At the end of the indicated time, 1 mL of the inoculums was removed and mixed with 9 mL of phosphate buffer saline (PBS) contained 0.5%sodium thiosulfate to inactivate the remaining pharmaceutical preparation/solution (dilution factor 1: 10) .
Plate method -100μL of the inactivated inoculums was removed in duplicate and plated separately on the fungal medium plate (2%MEA) . A control was performed under the same condition as described above except the pharmaceutical preparation of this invention was replaced with PBS.
FIG. 1 shows the results of this test, illustrating that the gelling preparation of this invention not only effectively eliminated the fungus Candida parapsilosis, but also inhibited its growth.
Claims (16)
- A temperature-sensitive gelling preparation comprising povidone iodine, a temperature-sensitive gel matrix, an oxidant, a pH regulator, and purified water.
- The temperature-sensitive gelling preparation of claim 1, comprising povidone iodine at a concentration of 0.1%-15% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 0.1%-35% (weight/weight) , the oxidant at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
- The temperature-sensitive gelling preparation of claim 1 or 2, wherein the temperature-sensitive gel matrix comprises natural and modified polymers, a poly (N-isopropyl phthalein) polymer, a polyoxyethylene-polyoxypropylene copolymer, or a crosslinked PLGA block copolymer.
- The temperature-sensitive gelling preparation of any of claims 1-3, wherein the temperature-sensitive gel matrix is a poloxamer or chitosan.
- The temperature-sensitive gelling preparation of claim 4, wherein the poloxamer comprises poloxamer 407, poloxamer 188, poloxamer 124, poloxamer 237, poloxamer 338, or any mixture thereof.
- The temperature-sensitive gelling preparation of claim 5, wherein the temperature-sensitive gel matrix comprises poloxamer 407 and poloxamer 188.
- The temperature-sensitive gelling preparation of any of claims 1-6, wherein the oxidant comprises hydrogen peroxide or acetic acid.
- The temperature-sensitive gelling preparation of any of claims 1-7, further comprising an osmotic pressure regulator.
- The temperature-sensitive gelling preparation of claim 8, containing the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) ,
- The temperature-sensitive gelling preparation of claim 8 or 9, wherein the osmotic pressure regulator comprise sodium chloride, mannitol, glucose, sorbitol, glycerol, polyethylene glycol, or propylene glycol.
- The temperature-sensitive gelling preparation of any of claims 1-10, wherein the pH regulator comprises boric acid, sodium borate, a phosphate buffer, tromethamine, a tromethamine hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, or any mixture thereof.
- The temperature-sensitive gelling preparation of any of claims 1-11, comprising povidone iodine at a concentration of 0.1%-5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
- The temperature-sensitive gelling preparation of any of claims 1-12, comprising povidone iodine at a concentration of 0.1%-2% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 10%-35% (weight/weight) , the oxidant at a concentration of 0.01%-1.0% (weight/weight) , the osmotic pressure regulator at a concentration of 0.01%-10% (weight/weight) , and the pH regulator at a concentration of 0.01%-5% (weight/weight) .
- The temperature-sensitive gelling preparation of claim 12, comprising povidone iodine at a concentration of 2%, 2.5%, or 5% (weight/weight) , the temperature-sensitive gel matrix at a concentration of 35% (weight/weight) , and the oxidant at a concentration of 0.01%-1.0% (weight/weight) .
- The temperature-sensitive gelling preparation of claim 14, wherein the 35%temperature-sensitive gel matrix includes 15%of poloxamer 407 (weight/weight) and 20%of poloxamer 188 (weight/weight) , based on the weight of the gelling preparation.
- A method for treating a gynecological vaginal infection or a vaginal disease induced by gynecological vaginal infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a temperature-sensitive gelling preparation of any of claims 1-15.
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