CN115919742A - Tinidazole suppository composition and preparation method and application thereof - Google Patents
Tinidazole suppository composition and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, relates to a suppository for vaginal administration, and particularly relates to a tinidazole suppository composition, and a preparation method and application thereof. Each tinidazole suppository comprises the following components and weight, 0.4-0.8 g of nano tinidazole, 1-1.5 g of mixed fatty glyceride, 0.05-0.1 g of clindamycin hydrochloride, 0.1-0.2 g of fluconazole, 0.05-0.1 g of surface functionalized nano zinc oxide, 0.1-0.2 g of nano chitosan, 0.1-0.2 g of poly dimethyl diallyl ammonium chloride, 0.1-0.2 g of boric acid and 0.05-0.07 g of microcrystalline cellulose. The tinidazole suppository prepared by the invention has stable and reliable quality and high cure rate for trichomonas vaginitis infection and bacterial infection.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a suppository for vaginal administration, and particularly relates to a tinidazole suppository composition, and a preparation method and application thereof.
Background
Vaginal infections are among the most common problem infections in gynaecology, due to infectious diseases caused by different types of microorganisms, which if severe can lead to chronic pain, infertility, inflammatory pelvic diseases, vulvar pruritus, burns, stinging, dysuria, dyspareunia and vaginal malodor.
If a woman is infected with vaginal infection during pregnancy, it may cause serious problems such as abortion, premature birth, ectopic pregnancy, etc. Therefore, early prevention, diagnosis or treatment is required.
Microorganisms are often found during vaginal infections, which cause mixed vaginal infections. Vulvovaginitis, vulvitis and vaginitis are terms commonly associated with swelling of the vagina or vulva, usually caused by fungi, bacteria and parasites. By vulvovaginitis, we understand the abnormal and irritating flow of secretions, whether malodorous or not, which produce local discomfort (itching or burning sensations) and may be accompanied by dysuria and/or dyspareunia. Trichomonas vaginitis is the most common vaginitis, resulting from trichomonas vaginalis infection. Typical symptoms of trichomonas vaginitis are pruritus, burning pain and dyspareunia of the vaginal orifice and the pudendum, and leucorrhea is increased, thin foam, yellow green and smelly. Trichomonas vaginalis also invades urethra or periurethral gland, even bladder and renal pelvis, and if combined with urethral infection, there are frequent, urgent and painful urination, sometimes hematuria. The susceptibility factor is related to the low cell immunity of the organism, and the application of immunosuppressant, broad-spectrum antibiotics, adrenocortical hormone, antitumor drugs and the like for a long time can cause the dysbacteriosis in vivo, change the mutual inhibition relationship among microorganisms in the vagina and cause the reproduction of the flora to cause infection. In addition, pregnant women, diabetics, patients receiving estrogen treatment, serious infectious diseases, consumptive diseases, lack of B vitamins and the like also become susceptible people and good factors of the disease. At present, the market has fewer medicines for treating trichomonas vaginitis, mainly takes local wiping and oral medicines, and has the defects of slow effect and low cure rate.
At present, the preparation forms of the variety are sold on the market abroad, such as solution, cream, vaginal ointment, vaginal suppository and the like. The suppository is widely used for rectal and vaginal administration, the matrix of the suppository has important influence on the suppository forming and the active ingredient release, and the matrix comprises two types, namely oil-soluble matrix and water-soluble matrix. The pessary requires that the matrix has proper hardness at room temperature, and can not deform or break when inserted into the cavity. Is easy to soften and melt at body temperature, and can be mixed with or dissolved in body fluid; has moistening ability, high water value, and is suitable for pH environment of vagina; the suppository forming is not influenced by the transformation of the crystal form; is suitable for preparing suppository by cold pressing method and hot melting method, and is easy to demould. Most importantly, the stability of suppositories is also of particular concern, with tinidazole suppositories being no exception.
Therefore, it is highly desirable to provide a suppository, particularly a tinidazole suppository, which has excellent stability and high cure rate.
Disclosure of Invention
The invention aims to provide a tinidazole suppository composition with excellent stability and high cure rate, wherein each tinidazole suppository comprises the following components and weight, 0.4-0.8 g of nano tinidazole, 1-1.5 g of mixed fatty glyceride, 0.05-0.1 g of clindamycin hydrochloride, 0.1-0.2 g of fluconazole, 0.05-0.1 g of nano zinc oxide with functionalized surface, 0.1-0.2 g of nano chitosan, 0.1-0.2 g of poly-dimethyl diallyl ammonium chloride, 0.1-0.2 g of boric acid and 0.05-0.07 g of microcrystalline cellulose.
Preferably, the preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2-5 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
Preferably, the specific surface area of the surface functionalized nano zinc oxide particles is 10-200 m 2 /g。
Preferably, the particle size of the surface functionalized nano zinc oxide particles is 20-25 nm.
Preferably, the particle size of the nano tinidazole is 10-20 nm.
Preferably, the nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1-2.
Preferably, the polydimethyldiallyl ammonium chloride is polydimethyldiallyl ammonium chloride containing octadecyl hydrophobic group.
Preferably, the mixed fatty acid glyceride is 36 type.
The invention also provides a process for preparing the tinidazole suppository, which comprises the following steps:
(1) Weighing the components in the formula according to the weight of each component;
(2) Adding boric acid, nano chitosan, nano zinc oxide with functionalized surface, poly dimethyl diallyl ammonium chloride, nano tinidazole, clindamycin hydrochloride and fluconazole into a batching tank, mixing for 2-3 h at 70-80 ℃, then reducing the temperature to 40-50 ℃, sequentially adding mixed fatty glyceride and microcrystalline cellulose, and mixing for 10-30 mm;
(3) And (3) after the step (2) is finished, injecting the mixture into a PVC plug die, quickly cooling, edging and thermally sealing, and packaging to obtain the PVC pipe.
In addition, the present invention also provides a composition of the tinidazole suppository for treating an infection selected from a bacterial infection, a trichomonas infection, a viral infection, a mixed infection or a urinary tract infection.
Compared with the prior art, the invention has the beneficial effects that:
(1) When the tinidazole suppository is actually used for treating vaginitis, the tinidazole suppository is not only related to the weight of tinidazole suppository components, but also has a great relationship with the particle sizes of tinidazole, zinc oxide and chitosan particles. When the particle sizes of tinidazole, zinc oxide and chitosan particles are all in nanometer level, the nanoparticles have higher surface activity and larger specific surface area, so that the contact area of tinidazole suppository and harmful germs is greatly increased, the harmful germs can be fully prevented from being attached to vaginal epithelial cells, glycoprotein in the harmful germs cannot be in contact with receptors of glycoprotein of host cells, and the living environment of the harmful germs is damaged, so that the nano tinidazole, the surface functionalized nano zinc oxide and the nano chitosan have certain particle size dependence on the elimination of the harmful germs, and research and development of research and development personnel find that particularly the specific surface area of the surface functionalized nano zinc oxide particles is 10-200 m 2 The grain diameter is 20-25 nm, the grain diameter of the nano tinidazole grains is 10-20 nm, and the grain diameters of the nano carboxymethyl chitosan and the nano polyethylene glycol chitosan grains are both 20-30 nm, which is favorable for enhancing the drug effect of the suppository for treating the vaginitis, and particularly, the cure rate of the suppository for treating the trichomonas vaginitis can reach more than 90.9 percent and even up to 96.7 percent。
(2) The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, and nano zinc oxide is subjected to surface functionalization to enable the surfaces of the nano carboxymethyl chitosan and the nano pegylated chitosan to be easily exposed with more amino groups. On the other hand, the surface functionalized nano zinc oxide particles induce the cell walls of pathogenic bacteria to generate hydroxyl radicals, and because the poly dimethyl diallyl ammonium chloride is a water-soluble cationic polyquaternary ammonium salt, in particular to poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic groups, wherein the octadecyl hydrophobic groups are hydrophobic structural units, the poly dimethyl diallyl ammonium chloride containing the octadecyl hydrophobic groups can be tightly combined with the hydroxyl radicals of pathogenic bacteria cells in vivo, so that the proliferation capacity of the pathogenic bacteria cells is damaged, the pathogenic bacteria are killed finally, and the effect of sterilizing and inhibiting the pathogenic bacteria is greatly improved. Therefore, the combination of the nano zinc oxide, the nano carboxymethyl chitosan, the nano polyethylene glycol chitosan and the poly dimethyl diallyl ammonium chloride is effective and shows synergistic interaction, so that on one hand, the vaginal microenvironment for the growth of pathogenic bacteria is destroyed from the external environment, the pathogenic bacteria cannot survive, and on the other hand, the proliferation capacity of pathogenic bacteria cells is destroyed from the internal cause, and the radical cure of vaginitis is realized. In addition, a large number of experiments prove that the poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic group also contributes to the stable quality of the tinidazole suppository.
(3) A large number of experimental studies show that 10nm tinidazole, clindamycin hydrochloride and fluconazole are all favorable for delaying the release speed of a tinidazole suppository composition, can be continuously released for about 75min, have an obvious slow-release effect, prolong the acting time of the tinidazole suppository on the vagina, prolong the curative effect of the tinidazole suppository, reduce the medicine taking frequency, facilitate the medicine taking of patients, and solve the problems that the traditional vaginal suppository is quickly discharged from the body, so that the retention time of the medicine at the acting part is short, and the therapeutic effect of the medicine cannot be achieved.
(4) When the tinidazole suppository is used for treating bacterial vaginitis, the treatment effect of the tinidazole suppository prepared by the invention is related to the particle size of tinidazole, when the particle size of nano tinidazole in the tinidazole suppository composition is 10nm, the effect of treating the bacterial vaginitis is particularly remarkable, and if the tinidazole in the tinidazole suppository composition is not in a nano level, the effect of treating the bacterial vaginitis is poor.
(5) The composition of the nano carboxymethyl chitosan and the nano polyethylene glycol chitosan has the functions of moisturizing and healing promotion on wounds.
(6) The microcrystalline cellulose added in the tinidazole suppository can meet the standard requirements of the compressibility and the fluidity of the tinidazole suppository, has the appearance compliance, is free from spots, improves the content uniformity and improves the dissolution rate.
Drawings
FIG. 1 is a graph showing the results of a release test of the compositions of examples 1, 4 and 8 and comparative examples 1, 11, 12 and 14.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.4g, mixed fatty glyceride type 36 1g, clindamycin hydrochloride 0.05g, fluconazole 0.1g, and surface-functionalized nano-zinc oxide 20nm in particle size, and has specific surface area of 200m 2 0.1g of nano chitosan, 0.1g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain the surface functionalized nano zinc oxide, wherein the weight part ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
A process for preparing a tinidazole suppository comprises the following steps:
(1) Weighing the components in the formula according to the weight of each component;
(2) Adding boric acid, nano chitosan, nano zinc oxide with functionalized surface, poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic group, nano tinidazole, clindamycin hydrochloride and fluconazole into a material preparing tank, mixing for 2h at 70 ℃, then reducing the temperature to 40 ℃, sequentially adding 36 type mixed fatty glyceride and microcrystalline cellulose, and mixing for 30 mm;
(3) And (3) after the step (2) is finished, injecting the mixture into a PVC suppository mold, quickly cooling, edging and thermally sealing, and packaging to obtain the tinidazole suppository 1.
The release test for the composition of example 1 is shown in figure 1.
Example 2
A tinidazole suppository composition comprises (by weight) tinidazole 20nm 0.4g, mixed fatty glyceride 36 1g, clindamycin hydrochloride 0.05g, fluconazole 0.1g, surface-functionalized nano-zinc oxide 20nm 0.05g, and surface-functionalized nano-zinc oxide particles with specific surface area of 200m 2 0.1g of nano chitosan, 0.1g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 2 was prepared by the same process as that of the tinidazole suppository of example 1, and finally tinidazole suppository 2 was prepared.
Example 3
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.4g, mixed fatty glyceride 36 1g, clindamycin hydrochloride 0.05g, fluconazole 0.1g, surface-functionalized nano-zinc oxide 25nm 0.05g, and surface-functionalized nano-zinc oxide particles with specific surface area of 200m 2 0.1g of nano chitosan, 0.1g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 3 was prepared by the same process as that of example 1, and tinidazole suppository 3 was finally prepared.
Example 4
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.4g, mixed fatty glyceride type 36 1g, clindamycin hydrochloride 0.05g, fluconazole 0.1g, surface-functionalized nano zinc oxide 20nm in particle size, and surface-functionalized zinc oxideThe specific surface area of the functionalized nano zinc oxide particles is 200m 2 0.1g of nano chitosan, 0.1g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 4 was prepared by the same process as that of example 1, and tinidazole suppository 4 was finally prepared.
The release test of the composition of example 4 is shown in figure 1.
Example 5
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.4g, mixed fatty glyceride 36 1g, clindamycin hydrochloride 0.05g, fluconazole 0.1g, surface-functionalized nano-zinc oxide 20nm in particle size 0.05g, and surface-functionalized nano-zinc oxide particles with specific surface area of 10m 2 0.1g of nano chitosan, 0.1g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 5 was prepared by the same process as that of example 1, and tinidazole suppository 5 was finally prepared.
Example 6
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.6g, mixed fatty glyceride type 36 1.3g, clindamycin hydrochloride 0.08g, fluconazole 0.15g, surface-functionalized nano-zinc oxide 20nm 0.08g, and surface-functionalized nano-zinc oxide particles with specific surface area of 200m 2 Per gram, 0.15 gram of nano chitosan, 0.15 gram of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.15 gram of boric acid and 0.06 gram of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain the surface functionalized nano zinc oxide, wherein the weight part ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 6 was prepared by the same process as that of example 1, and tinidazole suppository 6 was finally prepared.
Example 7
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.8g, mixed fatty glyceride type 36 1.5g, clindamycin hydrochloride 0.1g, fluconazole 0.2g, surface-functionalized nano-zinc oxide 20nm 0.1g, and surface-functionalized nano-zinc oxide particles with specific surface areaIs 200m 2 0.2g of nano chitosan, 0.2g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.2g of boric acid and 0.07g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The tinidazole suppository of example 7 was prepared by the same process as that of example 1, and tinidazole suppository 7 was finally prepared.
Example 8
A tinidazole suppository composition comprises (by weight) tinidazole 15nm 0.5g, mixed fatty glyceride type 36 1.2g, clindamycin hydrochloride 0.06g, fluconazole 0.1g, and surface-functionalized nano-zinc oxide 23nm 0.08g, and the surface-functionalized nano-zinc oxide has specific surface area of 100m 2 0.2g of nano chitosan, 0.2g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.1g of boric acid and 0.05g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 4 hours to obtain the surface functionalized nano zinc oxide, wherein the weight part ratio of the rosin to the nano zinc oxide particles is 1.1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 2.
A process for preparing a tinidazole suppository comprises the following steps:
(1) Weighing the components in the formula according to the weight of each component;
(2) Adding boric acid, nano chitosan, nano zinc oxide with functionalized surface, poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic group, nano tinidazole, clindamycin hydrochloride and fluconazole into a material preparing tank, mixing for 3h at 80 ℃, then reducing the temperature to 50 ℃, sequentially adding 36 type mixed fatty glyceride and microcrystalline cellulose, and mixing for 10 mm;
(3) And (3) after the step (2) is finished, injecting the mixture into a PVC (polyvinyl chloride) bolt die, quickly cooling, edging and thermally sealing, and packaging to obtain the tinidazole bolt 8.
The release test of the composition of example 8 is shown in figure 1.
Comparative example 1
Comparative example 1 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that 10nm tinidazole is changed to tinidazole, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of the comparative example 1 is completely the same as that of the tinidazole suppository composition of the example 1, and finally the tinidazole suppository 9 is prepared.
The release test for the composition of comparative example 1 is shown in figure 1.
Comparative example 2
Comparative example 2 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: the surface functionalized nano zinc oxide 0.05g is changed into nano zinc oxide 0.05g, the nano zinc oxide in the comparative example 2 is not subjected to surface functionalization operation, meanwhile, the preparation method of the surface functionalized nano zinc oxide in the example 1 is removed, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of the comparative example 2 is completely the same as that of the tinidazole suppository composition of the example 1, and finally the tinidazole suppository 10 is prepared.
Comparative example 3
Comparative example 3 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that the 20nm surface functionalized nano-zinc oxide is changed to 30nm surface functionalized nano-zinc oxide, and the other components and the weight are kept unchanged.
The preparation process of the tinidazole suppository composition of the comparative example 3 is completely the same as that of the tinidazole suppository composition of the example 1, and finally the tinidazole suppository 11 is prepared.
Comparative example 4
Comparative example 4 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that 10nm of tinidazole is changed to 30nm of tinidazole, and the other components and weights are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 4 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 12 is prepared.
Comparative example 5
Comparative example 5 the composition of the tinidazole suppositories is essentially the same as the composition of example 1, except that: the nano chitosan is only nano carboxymethyl chitosan, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 5 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 13 is prepared.
Comparative example 6
Comparative example 6 the composition of the tinidazole suppository is essentially the same as the composition of example 1, except that: the nano chitosan is only nano polyethylene glycol chitosan, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 6 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 14 is prepared.
Comparative example 7
Comparative example 7 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: the preparation method is characterized in that 20nm nano chitosan is changed into 50nm nano chitosan, the nano chitosan is a mixture of nano carboxymethyl chitosan and nano polyethylene glycol chitosan, the weight ratio of the nano carboxymethyl chitosan to the nano polyethylene glycol chitosan is 1, and the particle diameters of the nano carboxymethyl chitosan and the nano polyethylene glycol chitosan are both 50nm. The other components and weights were kept constant.
The preparation process of the tinidazole suppository composition of comparative example 7 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 15 is prepared.
Comparative example 8
Comparative example 8 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: 0.1g of poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic group is removed, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 8 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 16 is prepared.
Comparative example 9
Comparative example 9 the composition of the tinidazole suppository was substantially the same as the composition of example 1, except that: the octadecyl hydrophobic group-containing poly-dimethyl diallyl ammonium chloride is changed into dodecyl hydrophobic group-containing poly-dimethyl diallyl ammonium chloride, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 9 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 17 is prepared.
Comparative example 10
Comparative example 10 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: the boric acid 0.1g was removed and the other components and weights were kept constant.
The preparation process of the tinidazole suppository composition of comparative example 10 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 18 is prepared.
Comparative example 11
Comparative example 11 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: 0.05g of clindamycin hydrochloride is removed, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 11 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 19 is prepared.
The release test for the composition of comparative example 11 is shown in figure 1.
Comparative example 12
Comparative example 12 the composition of the tinidazole suppository was essentially the same as the components and weight of example 1, except that: 0.1g of fluconazole is removed, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 12 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 20 is prepared.
The release test for the comparative example 12 composition is shown in figure 1.
Comparative example 13
Comparative example 13 the composition of the tinidazole suppository is substantially the same as the composition of example 1, except that: 1g of 36-type mixed fatty glyceride is changed into 1g of 38-type mixed fatty glyceride, and other components and weight are kept unchanged.
The preparation process of the tinidazole suppository composition of comparative example 13 is completely the same as that of the tinidazole suppository composition of example 1, and finally the tinidazole suppository 21 is prepared.
Comparative example 14
A tinidazole suppository composition comprises (by weight) tinidazole 10nm 0.3g, mixed fatty glyceride type 36 2g, clindamycin hydrochloride 0.2g, fluconazole 0.3g, surface-functionalized nano-zinc oxide 20nm 0.3g, and surface-functionalized nano-zinc oxide particles with specific surface area of 200m 2 0.4g of nano chitosan, 0.5g of octadecyl hydrophobic group-containing polydimethyldiallyl ammonium chloride, 0.4g of boric acid and 0.08g of microcrystalline cellulose.
The preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1.
The nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight part ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1.
The process for preparing the tinidazole suppository composition of comparative example 14 is identical to the process for preparing the tinidazole suppository composition of example 1, and finally the tinidazole suppository 22 is prepared.
The release test for the comparative example 14 composition is shown in figure 1.
Performance study of tinidazole suppositories
Test example 1: suppository quality test investigation
According to the quality requirements of tinidazole suppositories which are clinically and conventionally required at present, the suppositories prepared in the embodiments 1 to 8 and the comparative examples 1 to 14 are inspected, and the inspection methods and results are as follows:
taking the tinidazole suppositories prepared in the embodiments 1-8 and the comparative examples 1-14, taking 2 tinidazole suppositories in each embodiment and comparative example, putting the tinidazole suppositories in a 100ml triangular flask, adding 50ml of water, heating in a water bath, uniformly mixing, putting the mixture in a refrigerator at 5 ℃ for layering, standing the mixture to room temperature, filtering, taking subsequent filtrate, and determining according to a method (appendix of 2020 version of Chinese pharmacopoeia), wherein the pH value is 5.0-7.0.
As a result: the pH values of all the suppositories of examples 1 to 8 of the present invention were in the range of 5.2 to 6.5, whereas those of the suppositories prepared in comparative examples 1 to 14 were unstable and had pH values in the range of 4.0 to 8.0. Therefore, the tinidazole suppository prepared by the method has stable and reliable quality.
Test example 2: investigation of the persistent stability of tinidazole suppositories
The tinidazole suppositories prepared in examples 1 to 8 and comparative examples 1 to 14 of the present invention were taken, 1 tinidazole suppository in each example and comparative example was placed at a high temperature of 40 ℃ and a relative humidity of 75% +/-5%, and the time points in table 1 below were used for accelerated test investigation. For each suppository batch, the tinidazole content was determined using the HPLC method of the present invention.
Chromatographic conditions are as follows: adopts lichrosorbC 18 Chromatography column (5 μm,46 mm. Times.200 mm); using 0.05mol/L potassium dihydrogen phosphate solution (pH value is adjusted to 3.5 by phosphoric acid) -methanol (80); the detection wavelength is 310nm; the flow rate is: 0.9mL/min; sample injection volume: 20 μ L. The system requires: the number of theoretical plates is not less than 2000 calculated according to the tinidazole peak, and the separation degree of the tinidazole peak and the adjacent impurity peak is in accordance with the requirement.
Sample solutions of tinidazole suppositories prepared in the examples and comparative examples of the present invention were prepared: taking the tinidazole suppositories prepared in the embodiments 1 to 8 and the comparative examples 1 to 14, taking 1 particle in each embodiment and comparative example, accurately weighing, cutting into powder, precisely weighing 120mg of tinidazole, placing in a 100ml measuring flask, adding a proper amount of mobile phase, heating in a water bath, shaking constantly to dissolve the tinidazole, cooling, adding the mobile phase to dilute to a scale, and shaking uniformly. Cooling in ice bath for 1 hr, taking out, filtering rapidly, cooling to room temperature, precisely measuring the filtrate to 5ml, placing in 50ml measuring flask, adding mobile phase to dilute to scale, shaking, precisely measuring 20 μ l, injecting into liquid chromatograph, and recording chromatogram.
Control solution: taking a proper amount of tinidazole reference substance, precisely weighing, adding mobile phase for dissolving, quantitatively diluting to obtain a solution containing about 120 μ g of tinidazole in each 1ml, measuring by the same method, and recording chromatogram.
And (3) the retention time of the main peak of the sample solution is consistent with that of the main peak of the reference solution, and the sample solution is obtained by calculating the peak area according to an external standard method.
TABLE 1 Tinidazole suppository content determination
From the results in table 1, it is known that the content of the tinidazole suppository prepared in the embodiments 1 to 8 of the present invention is within 100 to 105% of the theoretical feeding amount, and the tinidazole suppository is kept at about 100% and is relatively stable; the content of the tinidazole suppositories prepared in the comparative examples 1 to 14 is within 90 to 97 percent of the theoretical feeding amount, and is about 92 percent, and the stability is relatively poor.
Test example 3: fusion time limit investigation
The melting time limit is an important index of the physical stability of the suppository, and particularly, the suppository can experience various temperature changes during storage-transportation, and the temperature changes can have great influence on the melting property of the suppository.
The tinidazole suppositories prepared in the embodiments 1 to 8 of the present invention and the comparative examples 1 to 14 are taken, and the time (the time for the water-soluble matrix to be completely dissolved) for 3 granules of each suppository batch to reach the 'complete melting, softening or no hard core under touch pressure' is respectively measured by referring to the melting time limit inspection method of the appendix of the second part of the China pharmacopoeia 2020 edition, the time is called melting time, and the time is measured at 0 time and is marked as T0. Next, each suppository batch was allowed to stand at 5. + -. 2 ℃ for 2 weeks, then at 35. + -. 2 ℃ for 2 weeks, and then cycled 3 times at this low-high temperature for 6 weeks, and the melting time of each suppository batch after 6 weeks of this treatment, measured at 6 months, was measured and can be labeled T6.
Percent (%) change in time to fusion at 6 weeks was calculated: percent change in fusion time (%) = [ | (T6-T0) | ÷ T0 ]. Times 100%
The closer the percent (%) change of the melting time is to 0, the fact that the melting time is basically unchanged after 6 weeks of low-temperature-high-temperature cyclic treatment indicates that the physical stability of the suppository is good; the greater the percent (%) change in melting time, the greater the change in melting time after 6 weeks of low-temperature-high temperature cycling, indicating poor physical stability of the suppository. The percent (%) change in fusion time for tinidazole suppositories prepared in inventive examples 1 to 8 and comparative examples 1 to 14 is shown in table 2 below.
TABLE 2 percent Change in fusion time for tinidazole suppositories (%)
From the above table 2, it can be seen that the tinidazole suppositories prepared in the embodiments 1 to 8 of the present invention have the melting time change percentage (%) ranging from 9 to 10%, the change range is small, and the melting time limit is stable; the tinidazole suppositories prepared in comparative examples 1 to 14 have melting time change percentage (%) in the range of 22 to 29% and relatively large change amplitude, and the melting time change percentage (%) of the tinidazole suppositories prepared in inventive examples 1 to 8 is closer to 0, which indicates that the tinidazole suppositories prepared in inventive examples 1 to 8 have good physical stability, while comparative example 9 in the comparative example has the largest change amplitude and the worst melting time limit stability. This is because comparative example 9 is based on that dodecyl-containing hydrophobic poly-dimethyl-diallyl-ammonium chloride is not octadecyl-containing hydrophobic poly-dimethyl-diallyl-ammonium chloride, which shows that octadecyl-containing hydrophobic poly-dimethyl-diallyl-ammonium chloride contributes to the quality stabilization of tinidazole suppository. The tinidazole suppository prepared by the method has stable and reliable product quality, stable property in the storage process in the valid period, and can meet the requirement of quality standard.
Test example 4: clinical trial of trichomonas vaginitis
1. Research method
The research scheme is made according to the content of ' clinical verification of local medicine application of gynecological genital tract inflammation ' related to the new medicine clinical guiding principle of Ministry of health of the people's republic of China.
(II) diagnostic criteria
1. Symptoms are: trichomonas vaginitis, pruritus, burning pain and sexual intercourse pain of the vaginal orifice and the pudendum, and leucorrhea increase, which is in thin foam, yellow green and smelly;
2. gynecological examination: trichomonas vaginitis and inflammation of vaginal mucosa are bright red, are covered with spot-shaped false membranes, are often accompanied with foam-like secretion, are consciously itchy in different degrees, and are few with burning sensation, increased leucorrhea, yellowish green and slightly odorous.
3. Laboratory examination: the trichomonas vaginitis finds trichomonas in vaginal secretion, is beneficial to a normal saline suspension drip method, and the trichomonas moving in a wave shape and increased leucocytes are pushed and removed under a microscope.
(III) test case criteria
Medical record standard inclusion: married women 18-50 years old and eligible for bacterial diagnosis.
(IV) methods of treatment
1. Treatment groups: the tinidazole suppositories prepared in examples 1 to 8 are used for treatment, one granule per day, and a treatment course is 7 days.
2. Control group: the tinidazole suppositories prepared in comparative examples 1 to 14 are used for treatment, one granule per day, and a treatment course is 7 days.
(V) therapeutic efficacy judgment criteria
1. And (3) healing: disappearance of symptoms, normal gynecological examination and laboratory examination;
2. the effect is shown: the symptoms are obviously relieved, and gynecological examination and laboratory examination are obviously improved;
3. the method has the following advantages: the symptoms are relieved, and gynecological examination and laboratory examination are improved;
4. and (4) invalidation: there was no change or significant change after treatment compared to before treatment.
(VI) therapeutic results
The therapeutic effect of trichomonas vaginitis was compared between the treatment group and the control group in Table 3
As can be seen from the data in Table 3, as a whole, compared with comparative examples 1 to 14, the tinidazole suppositories provided in examples 1 to 8 of the present invention have a cure rate of 90.9% or more, even 96.7%, and a higher cure rate for trichomonas vaginitis. While the cure rates of comparative examples 1 to 14 were all below 85%. Specifically, the cure rate of comparative example 14 was the lowest, only 60%. Comparative example 14 weight of composition components of tinidazole suppository outside the range of composition components of tinidazole suppository of the present invention resulted in poor therapeutic effect and drop-to-dropThe cure rate of the insect vaginitis is the lowest. The effect of the tinidazole suppository in actual use is greatly related to the weight of the tinidazole suppository components, and when the tinidazole suppository components are used, the tinidazole suppository has a remarkable curative effect on treating trichomonas vaginitis. Secondly, the effective rates of the comparative examples 1, 3, 4 and 7 are low because the particle diameters of the tinidazole, the zinc oxide and the chitosan particles used in the comparative examples 1, 3, 4 and 7 are not within the range of the particle diameters of the tinidazole, the zinc oxide and the chitosan particles used in the present invention, and in the tinidazole suppository compositions provided in the examples 1 to 8, when the particle diameters of the tinidazole, the zinc oxide and the chitosan particles are all in the nanometer grade of the present invention, specifically, the specific surface area of the nano zinc oxide particles with functionalized surfaces is 10 to 200m 2 The grain diameter is 20-25 nm, the grain diameter of the nano tinidazole grains is 10-20 nm, and the grain diameters of the nano carboxymethyl chitosan and the nano polyethylene glycol chitosan grains are both 20-30 nm, which is beneficial to enhancing the treatment effect on trichomonas vaginitis. Specifically, it is known from examples 1 to 4 that the smaller the particle size of the nano tinidazole, the surface functionalized nano zinc oxide and the nano chitosan particles is, the higher the cure rate of the trichomonas vaginitis is; from examples 1 and 5, it is known that the larger the specific surface area of the surface-functionalized nano zinc oxide particles is, the more significant the cure rate for trichomonas vaginitis is. If the particle size of 10nm nanometer tinidazole is changed into tinidazole (comparative example 1) or 30nm nanometer tinidazole (comparative example 4) or the particle size of nanometer zinc oxide is changed into 30nm (comparative example 3) or the particle size of nanometer chitosan is 50nm (comparative example 7), the nanometer tinidazole, the surface functionalized nanometer zinc oxide and the nanometer chitosan show certain particle size dependence on harmful bacteria elimination, and research of research and development personnel finds that the specific surface area of the nanometer zinc oxide particles with surface functionalization is 10-200 m 2 The particle size of the nano tinidazole particles is 20-25 nm, the particle size of the nano tinidazole particles is 10-20 nm, and the particle sizes of the nano carboxymethyl chitosan and the nano pegylated chitosan particles are both 20-30 nm, the effect of killing pathogenic bacteria is obvious, and the cure rate of trichomonas infection is high.
Test example 5: clinical trials of bacterial vaginosis
45 women over 18 years old and not pregnant were selected for pre-treatment and post-treatment vaginal culture. Patients were asked to refrain from intercourse and avoid menstrual periods during vaginal culture. Simple random assignments were made into 3 groups of 15 people each. The tinidazole suppository group prepared in the example 1 of the invention, the commercial product (national standard H20133115) group and the tinidazole suppository group prepared in the comparative example 1 are divided into two groups.
Various tinidazole suppositories are placed in the vagina and administered vaginally, 1 dose is given 1 time per day, mucous membrane is contacted for at least 1 hour each time, and the administration is continuous. The female patients were followed and recorded at weeks 1, 2, 3 and 4 after administration to assess whether the patients had bacterial vaginitis infection in their vaginas and the results of the test are shown in Table 4.
TABLE 4 bacterial vaginosis infection test
As can be seen from table 4 above, in the evaluation at each stage after the treatment, at 1 week of treatment, the women who did not infect bacterial vaginitis for the tinidazole suppository group prepared in example 1 of the present invention were as high as 93%, compared to 20% and 67%, respectively, for the tinidazole suppository group prepared in comparative example 1 and the women who did not infect bacterial vaginitis for the commercial product group; also at 2 weeks of treatment, the tinidazole suppository group prepared according to example 1 of the present invention had up to 87% of women not infected with bacterial vaginitis, compared to 27% and 73% of women not infected with bacterial vaginitis for the tinidazole suppository group and the commercial product group prepared according to comparative example 1; at 3 weeks of treatment, 80% of women were not infected with bacterial vaginitis in the tinidazole suppository group prepared in example 1 of the present invention, compared to 33% and 80% in the tinidazole suppository group prepared in comparative example 1 and the commercially available product group, respectively; at 4 weeks of treatment, 73% of women were not infected with bacterial vaginitis in the tinidazole suppository group prepared in example 1 of the present invention, compared to 27% and 70% of women in the tinidazole suppository group prepared in comparative example 1 and women in the commercial product group, respectively. These data indicate that the therapeutic effect of the tinidazole suppository prepared in the present invention is related to the particle size of tinidazole when treating bacterial vaginitis, when the particle size of nano tinidazole in the tinidazole suppository composition of the present invention is 10nm, the effect of treating bacterial vaginitis is significant, while tinidazole in the tinidazole suppository composition of comparative example 1 is not nano-scale and the effect of treating bacterial vaginitis is poor.
Test example 6: release test
In order to evaluate the release rate of the tinidazole suppository composition, an in vitro release degree test was performed. The measurement method is as follows: taking appropriate amount of the compositions of examples 1, 4 and 8 and comparative examples 1, 11, 12 and 14 (corresponding to 100mg of the main drug), placing in a release tank, and covering a 0.45 micron microporous filter membrane on the release tank for fixation if necessary. The measurement is carried out by adopting a second method device of XD (X release degree measurement) in appendix of the second part of Chinese pharmacopoeia 2005 edition, the release medium is 500ml of phosphate buffer solution, the temperature is 37 ℃ and 0.5 ℃, the rotating speed is 50r/min, sampling is respectively carried out at intervals of 6min, 12min, 25min, 38min, 50min and 75min, the release medium with the same temperature and volume is supplemented, the HPLC method is adopted for measurement, and the cumulative release percentage is calculated.
The results of the release test are shown in figure 1. The results show that the examples 1, 4 and 8 have no burst release phenomenon, stably release the drug, maintain the effective drug concentration, can continuously release the drug for about 75min, have obvious slow release effect, greatly prolong the action time of the tinidazole suppository on the vagina, prolong the curative effect of the tinidazole suppository, reduce the drug use times and facilitate the administration of patients, while the drug composition of the comparative example 1 (tinidazole is not the 10nm tinidazole), the comparative example 11 (without clindamycin hydrochloride), the comparative example 12 (without fluconazole) and the tinidazole suppository has the weight which is not in the range of the composition components of the tinidazole suppository (the comparative example 14) is released within 50 min. The composition of the invention has the advantages that the 10nm nanometer tinidazole, clindamycin hydrochloride and fluconazole in the weight range of the components are beneficial to prolonging the release speed of the tinidazole suppository composition.
Test example 7: test of enrichment Effect on beneficial bacteria
(I) lactic acid bacteria: adding suppository into MRS culture solution of lactobacillus not containing any saccharide, adjusting pH to 5 with PBS buffer solution, inoculating experimental strain into the culture solution according to inoculation amount of 5% by volume, and making the concentration of CO 5% at 37 deg.C 2 The absorbance values (OD values) of the culture solution are read at 600nm before and 24h after inoculation, the bacterium increasing effect of the suppository is measured by the net increase OD value of 0h, and the group without any suppository treatment is used as a blank control.
(II) Bifidobacterium: adding the suppository into MRS culture medium without any saccharide, sterilizing, cooling, inoculating activated Bacillus bifidus BB01 for three times according to the inoculum size of 4%, and performing anaerobic culture at constant temperature of 37 deg.C; the absorbance values (OD values) of the culture solution were read at 600nm before and 24h after inoculation, respectively, and the enrichment effect of the suppository was measured relative to the net OD value of 0h, and the group treated without any suppository was used as a blank control.
The tinidazole suppositories provided in examples 1 to 8 and comparative examples 1 to 14 were tested for their effect on the in vitro proliferation of lactobacilli and bifidobacteria in the human vagina, respectively, according to the methods described above, and the specific data are shown in table 5.
TABLE 5 enrichment Effect test of beneficial bacteria
As can be seen from the data in table 5, compared with the blank control group without the suppository and the comparative examples 1 to 14, the tinidazole suppositories in the embodiments 1 to 8 of the present invention can significantly promote the proliferation of lactobacillus and bifidobacterium, so that the net increase OD value of lactobacillus for 24h reaches more than 1.80, and the net increase OD value of bifidobacterium for 24h reaches more than 1.74, which indicates that the tinidazole suppositories provided in the embodiments 1 to 8 have significant promotion effects on the proliferation of beneficial bacteria in vitro, and have significant beneficial bacteria increasing effects. Comparative example 14, in which the weight of the composition components of the tinidazole suppository is out of the range of the composition components of the tinidazole suppository of the present invention, has the worst bacteria-enriching effect, and is followed by comparative example 10 of the tinidazole suppository without boric acid. It is demonstrated that the proliferation effect of lactobacilli and bifidobacteria is not only related to the weight of tinidazole suppository components, but also boric acid. The boric acid captures the amino groups exposed on the surfaces of the nano carboxymethyl chitosan and the nano pegylated chitosan to form a new vaginal microenvironment which is not beneficial to the growth of harmful bacteria inflammation on the one hand, and is beneficial to the growth of lactobacillus and bifidobacterium on the other hand, so that the growth of beneficial bacteria in the vagina is effectively promoted.
The above embodiments are only some examples of the present invention, and the present invention is not limited thereto in any way, and any simple modification, equivalent change and modification to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (10)
1. A tinidazole suppository composition is characterized in that: each tinidazole suppository contains the following components and weight, 0.4-0.8 g of nano tinidazole, 1-1.5 g of mixed fatty glyceride, 0.05-0.1 g of clindamycin hydrochloride, 0.1-0.2 g of fluconazole, 0.05-0.1 g of nano zinc oxide with functionalized surface, 0.1-0.2 g of nano chitosan, 0.1-0.2 g of poly dimethyl diallyl ammonium chloride, 0.1-0.2 g of boric acid and 0.05-0.07 g of microcrystalline cellulose.
2. A tinidazole suppository composition according to claim 1, characterized in that: the preparation method of the surface functionalized nano zinc oxide comprises the following steps: dissolving rosin in isopropanol, stirring uniformly, slowly adding nano zinc oxide particles, and carrying out ultrasonic oscillation mixing for 2-5 hours to obtain surface functionalized nano zinc oxide, wherein the weight ratio of the rosin to the nano zinc oxide particles is 1-1.1.
3. Combination of tinidazole suppositories according to claim 1An article, characterized in that: the specific surface area of the surface functionalized nano zinc oxide particles is 10 to 200m 2 /g。
4. A tinidazole suppository composition according to claim 1, characterized in that: the particle size of the surface functionalized nano zinc oxide particles is 20-25 nm.
5. A tinidazole suppository composition according to claim 1, characterized in that: the particle size of the nano tinidazole is 10-20 nm.
6. A tinidazole suppository composition according to claim 1, characterized in that: the nano chitosan is a mixture of nano carboxymethyl chitosan and nano pegylated chitosan, the weight ratio of the nano carboxymethyl chitosan to the nano pegylated chitosan is 1-2, 1-3, and the particle size of the nano carboxymethyl chitosan to the nano pegylated chitosan particle is 20-30 nm.
7. A tinidazole suppository composition according to claim 1, characterized in that: the poly dimethyl diallyl ammonium chloride is poly dimethyl diallyl ammonium chloride containing octadecyl hydrophobic group.
8. A tinidazole suppository composition according to claim 1, characterized in that: the mixed fatty glyceride is 36 type.
9. A process for preparing the tinidazole suppository of claim 1, characterized in that: the method comprises the following steps:
(1) Weighing the components in the formula according to the weight of each component;
(2) Adding boric acid, nano chitosan, nano zinc oxide with functionalized surface, poly dimethyl diallyl ammonium chloride, nano tinidazole, clindamycin hydrochloride and fluconazole into a batching tank, mixing for 2-3 h at 70-80 ℃, then reducing the temperature to 40-50 ℃, sequentially adding mixed fatty glyceride and microcrystalline cellulose, and mixing for 10-30 mm;
(3) And (3) after the step (2) is finished, injecting the mixture into a PVC plug die, quickly cooling, edging and thermally sealing, and packaging to obtain the PVC pipe.
10. Use of a tinidazole suppository composition according to any one of claims 1 to 8, characterized in that: the composition of the tinidazole suppository is used for treating infection, wherein the infection is selected from bacterial infection, trichomonas infection, viral infection, mixed infection or urinary tract infection.
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| CN103520090A (en) * | 2013-10-11 | 2014-01-22 | 哈尔滨欧替药业有限公司 | Tinidazole expandable vaginal suppository, and preparation method and detection method thereof |
| CN103784948A (en) * | 2012-11-05 | 2014-05-14 | 上海高科联合生物技术研发有限公司 | Effervescent suppository for treating mammal vaginitis |
| CN114306209A (en) * | 2022-01-10 | 2022-04-12 | 江苏远恒药业有限公司 | Tinidazole suppository composition and preparation method and application thereof |
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| CN103784948A (en) * | 2012-11-05 | 2014-05-14 | 上海高科联合生物技术研发有限公司 | Effervescent suppository for treating mammal vaginitis |
| CN103520090A (en) * | 2013-10-11 | 2014-01-22 | 哈尔滨欧替药业有限公司 | Tinidazole expandable vaginal suppository, and preparation method and detection method thereof |
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