CN106619685B - Oral solid preparation containing ivermectin medicine - Google Patents

Abstract

The invention provides an oral solid preparation containing ivermectin medicaments, which is prepared by combining the ivermectin medicaments with a selected nonionic surfactant and other auxiliary agents. The invention mainly solves the technical problems of improving the dissolution rate of ivermectin medicines in the preparation in water and overcoming the defect that the ivermectin medicines are easy to hydrolyze under an acidic condition so as to achieve the purposes of improving the dissolution rate of the medicines in vivo and protecting the medicines from being damaged or less damaged in acidic gastric juice; and secondly, the problems of acid/alkali catalytic degradation and oxidative degradation of active ingredients during the storage of the preparation are overcome, so that the degradation of the effective components of the preparation is less. The combination of polyoxyethylene hydrogenated castor oil condensate with benzyl benzoate or azone or caprylic/capric triglyceride or isopropyl myristate is particularly preferred in the present invention to prepare oral solid formulations containing ivermectin drugs more resistant to acid/base catalyzed degradation.

Description

Oral solid preparation containing ivermectin medicine

Technical Field

The invention belongs to a preparation technology of veterinary drug preparations, and particularly relates to a preparation technology of an oral solid preparation of ivermectin drugs.

Background

Ivermectin is a high-efficiency broad-spectrum antiparasitic drug, has strong repelling and killing effects on nematodes and ectoparasites parasitizing in animals, and is widely used for preventing and treating animal parasitic diseases. The commercially available veterinary products include injection, oral liquid, pour-on, paste, granule, sustained-release pellet, tablet, powder, premix and the like. The premix is mainly used for preventing and treating the parasitic diseases of pigs and horses. At the present stage of China, the commercially available products comprise imported 0.6% ivermectin premix (such as pest control), domestic ivermectin/albendazole compound premix and powder, domestic albendazole oxide/ivermectin compound premix, and the commercially available single preparations of the domestic powder or premix are not available.

The poor solubility and acid sensitivity of the drug are important factors affecting the bioavailability of oral drugs. The test and data show that: (1) ivermectin drugs are hardly soluble in water. For example, only 6-9 micrograms of ivermectin can be dissolved in 1 liter of water. Therefore, in the preparation of oral solid preparations containing ivermectin, in order to ensure that the medicines can be absorbed more, the problem of improving the water solubility of the medicines is a technical link to be considered. (2) The molecular structure of the ivermectin drug has 2 glycosidic bonds, and the ivermectin drug is easy to hydrolyze under the catalysis of acid to lose sugar residues. For example, ivermectin is susceptible to acid catalyzed waterHydrolyzed and converted into monosaccharide ivermectin B with low activity₁a(MS H₂B₁a) And H₂B₁a aglycone (see table 1). The gastric juice of animals such as pig and chicken is mostly acidic, and the highest acidity can reach about pH 1 (about equivalent to the acidity of 0.1M hydrochloric acid). This suggests us: the acid resistance of the preparation is improved to reduce the hydrolysis of the acidic gastric juice on the ivermectin medicaments, so that the possibility that the oral preparation of the medicaments can be absorbed more is provided. The results of the tests on products sold in China show that the imported 0.6% ivermectin premix (pest control) has high drug dissolution rate and can resist acid-catalyzed hydrolysis (see table 2). And the dissolution rate of ivermectin in almost all domestic compound powder and premix is zero. Clinical application shows that the imported product has definite curative effect and small volatility on the effect of killing the pig sarcoptidosis and the pig sucking lice. According to related research, the oral ivermectin preparation for pigs has the bioavailability of only about 41 percent. The dissolution rate of ivermectin in water and the strength of the acid-catalyzed hydrolysis resistance in the preparation are considered to be important factors influencing the oral bioavailability of the ivermectin. Therefore, the dissolution rate and the acid catalysis hydrolysis rate of the product are used as quality indexes for measuring the quality of the medicine, so that the quality of the medicine can be further monitored and reflected from the other side, and the quality control of the medicine can be more scientific, accurate and comprehensive.

Experiments show that the C2 position in the molecular structure of the ivermectin drug is easy to epimerize under the alkaline condition and is converted into the 2-epimer H₂B₁a(2-epimer H₂B₁a) Its anthelmintic activity is only H₂B₁a activity is about 1%; c₃＝C₄The double bond at the position is easily displaced and converted into a less reactive delta^2，3H₂B₁a (see table 3); the lactone bond in the molecular structure of ivermectin is also easily changed by OH^-The attack is destroyed. In fact, the degradation of ivermectin drugs during storage presents problems of acid/base catalyzed degradation in addition to oxidative degradation. The published data shows that the ivermectin drugs are in partialMore stable under acidic conditions, preferably with a pH in the range of 4-6. Our experiments with the formulation containing ivermectin showed that the greater the impurities generated during shelf life was 2-dissimilatory ivermectin B when the pH of the carrier material comprising the formulation was greater than 6.2₁a; when the pH of the carrier material is less than 4.3, the more impurities produced during shelf life are the monosaccharide ivermectin B₁a. Tests have shown that oral formulations containing ivermectin drugs prepared with the selected nonionic surfactants of the present invention exhibit better stability (relative percentage of the 2-epimer ivermectin and MS H/H as shelf life is increased) at pH 4.8 to 5.3 of the carrier material₂B₁The relative percentage content of a is used as an inspection index).

In summary, it can be seen that in the preparation of formulations containing ivermectin, the problem of water insolubility of the drug and the problem of acid/base catalyzed degradation of the drug need to be solved. Because ivermectin drugs also have double bonds that can be oxidized, the problem of oxidative degradation of the ivermectin drug must be considered in preparing formulations containing the same.

The surfactant is used as a solubilizer or cosolvent, so that the water solubility of some hydrophobic drugs can be improved, and the existence of the specific surfactant can enhance the stability of some formulations containing easily hydrolyzed drugs in an acidic or alkaline environment ' because the surfactant can form micelles in a solution, namely a barrier ' is formed ', and the ' micelle barrier ' coated with the drugs prevents H from being blocked⁺、OH^-Attack of easily hydrolyzed drugs. However, if the surfactant is not properly selected, the drug is more susceptible to acid/base catalyzed degradation. For example sodium dodecyl sulfate (abbreviated as SDS), which has a significant enhancing effect on the acid-catalyzed hydrolysis of ivermectin (see table 5). Therefore, by increasing the dissolution (dissolution) rate or the amount of a poorly soluble drug in water by a method using a surfactant while requiring a preparation having resistance to catalytic hydrolysis by an acid and improved stability of the preparation during storage (including resistance to acid or base destruction and oxidative degradation), the selection of the type of surfactant and the establishment of the method of use are undoubtedly the crucial technical circlesAnd (4) saving.

Disclosure of Invention

The invention mainly solves the technical problems of improving the dissolution rate of the ivermectin medicaments in the solid preparation in water and overcoming the defect that the ivermectin medicaments are easy to hydrolyze under an acidic condition so as to achieve the purposes that the medicaments can be dissolved out in gastric juice and cannot be damaged by the acidic gastric juice or are damaged less; secondly, the problems of acid/base catalytic degradation and oxidative degradation of active ingredients of the preparation during storage are overcome, so that the active ingredients of the preparation are degraded less. The present invention more preferably achieves the objects of the invention by using a surfactant in combination with a selected hydrophobic solvent (benzyl benzoate or caprylic/capric triglyceride or isopropyl myristate or azone) to produce an oral solid formulation that is more resistant to acid/base catalyzed degradation.

The preparation comprises the following components:

(1) active ingredients, the content of which in each kilogram of preparation is 0.1 to 20 grams; the active ingredient comprises one of abamectin, ivermectin, doramectin, moxidectin, acetamido abamectin and selamectin. They are both macrolide antiparasitic agents.

(2) A nonionic surfactant having a hydrophilic-lipophilic balance (HLB) value of 12 or more, which is present in the formulation in a maximum amount of 20%, preferably 3 to 20 times the weight of the antiparasitic agent, more preferably 6 to 14 times the weight of the antiparasitic agent. The surfactant can be tween, ceresin, benezin, peregal, polyoxyethylene hydrogenated castor oil condensate, and polyethylene glycol vegetable oil condensate. Further selected surfactants include one or more of polyoxyethylene (35) hydrogenated castor oil (HEL-35), polyoxyethylene (40) hydrogenated castor oil (HEL-40), polyoxyethylene (50) hydrogenated castor oil (HEL-50), polyoxyethylene (60) hydrogenated castor oil (HEL-60), polyethylene glycol (40) palm kernel oil, polyethylene glycol (60) corn oil glyceride, polyethylene glycol (60) almond oil, polyethylene glycol (50) castor oil, polyoxyethylene cetyl alcohol ether having a hydrophilic-lipophilic balance (HLB) value greater than 12, and benzyl zer-35; HEL-35, HEL-40 or HEL-60 is even more preferred for use in the preparation of the formulations of the present invention.

(3) Carrier material, added up to 1 kg. The carrier material comprises one or more of corncob powder, zeolite powder, stone powder, diatomite, gypsum powder, starch, fish meal, beef powder, chicken powder, pork liver powder and chicken liver powder. 4 g of the support material are soaked in 20-40 ml of water for 10-30 minutes and the pH of the support material is measured by an acidimeter and is in the range 4.4-5.7, preferably 4.7-5.3.

A hydrophobic solvent (medium) can be added into the preparation, and the hydrophobic solvent comprises one or more of benzyl benzoate, caprylic/capric triglyceride, isopropyl myristate, ethyl oleate, azone, dipropylene glycol dibenzoate and diethylene glycol benzoate; the content of hydrophobic solvent in each kilogram of preparation is 10-110% of the weight of the surfactant. The hydrophobic solvent has the common characteristics of better solvent capability for ivermectin medicaments and strong affinity with a preferred surfactant. This is that they can form a tight "micellar barrier" to block H⁺、OH^-And the main chemical basis of oxygen for drug attack.

The preparation per kilogram also comprises 10-220 grams of solid dispersion medium (also called as curing agent), the solid dispersion medium is a pharmaceutical adjuvant with a melting point of more than 45 ℃ and less than 100 ℃, and the preferable solid dispersion medium comprises one or more of glyceryl monostearate, glyceryl tristearate, solid polyethylene glycol, stearic acid, solid fatty alcohol, animal wax, carnauba wax, hydrogenated castor oil, behenic acid or glyceryl behenate. The solid dispersion medium added in the preparation can dissolve the surfactant and the antiparasitic drug in liquid state into the solid dispersion medium and fix the surfactant and the antiparasitic drug in the solid dispersion medium, so that the attack (oxidative degradation) of the drug by oxygen in the air can be blocked more effectively. Tests show that when the content of the solid dispersion medium in the preparation exceeds 10 times of the content of the medicine, the preparation is still stable even if the antioxidant is not added, the shelf life can reach more than 2 years, and the shelf life is longer when the content of the solid dispersion medium is more.

The preparation per kilogram also comprises 10 to 120 grams of Arabic gum or polyvinylpyrrolidone.

The preparation per kilogram also comprises 0.2-5 g of antioxidant, and the antioxidant comprises one or more of dibutyl hydroxy toluene, tert-butyl-4-hydroxy anisole and propyl gallate. The addition of antioxidants can further reduce the likelihood of degradation of the formulation due to oxidation.

10-100 g of other antiparasitic drug can be added into the preparation per kilogram, and the other antiparasitic drug comprises one of albendazole, albendazole oxide, fenbendazole, oxfendazole and insect growth regulator.

The solid preparation can be prepared by one of the following methods:

mixing ivermectin medicines or a solution containing the ivermectin medicines dissolved by a solvent with the nonionic surfactant, adding or not adding 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, and stirring at 70-85 ℃ to completely dissolve the medicines to obtain liquid containing the ivermectin medicines; adding the carrier material into the liquid at 70-85 ℃, fully stirring, uniformly mixing, cooling the material to room temperature, removing the solvent, and sieving with a 24-mesh sieve to obtain the solid preparation; the solvent is ethanol or ethyl acetate or a combination thereof.

Mixing the ivermectin medicine or the solution containing the ivermectin medicine dissolved by the solvent with the nonionic surfactant, adding or not adding 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, stirring at 70-85 ℃ to completely dissolve the medicine, adding the solid dispersion medium, continuously stirring to melt and uniformly mix the solid dispersion medium, adding the carrier material at 70-85 ℃, fully stirring, uniformly mixing, cooling the material to room temperature, removing the solvent after the material is completely solidified or dried, and sieving by a 24-mesh sieve to obtain the undersize product, namely the solid preparation; the solvent is ethanol or ethyl acetate or a combination thereof.

Mixing the ivermectin medicaments, the nonionic surfactant and the 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, stirring at 70-85 ℃ to completely dissolve the medicaments, cooling to 30-45 ℃, adding water with the weight 5-70 times that of the ivermectin medicaments under the stirring condition, and preparing into emulsion; then mixing the carrier material and the emulsion with the same amount to 5 times of the weight of the emulsion, fully stirring, uniformly mixing, and then drying to obtain the solid preparation;

mixing the ivermectin medicaments, the nonionic surfactant and the 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, stirring at 70-85 ℃ to completely dissolve the medicaments, cooling to 30-45 ℃, adding water with the weight 5-70 times that of the ivermectin medicaments under the stirring condition, and preparing into emulsion; then mixing the carrier material with 5 times of the emulsion in an amount equal to the weight of the emulsion with the emulsion, fully stirring, uniformly mixing, and drying to obtain medicine-carrying particles; melting the solid dispersion medium at 70-95 ℃, adding the prepared drug-loaded particles at the temperature, fully stirring, uniformly mixing, cooling to room temperature, solidifying, and sieving with a 24-mesh sieve to obtain the solid preparation.

The method e, mixing the ivermectin medicaments, the nonionic surfactant and the 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, stirring at 70-85 ℃ to completely dissolve the medicaments, cooling to 30-45 ℃, adding the aqueous solution containing polyvinylpyrrolidone or Arabic gum under stirring, fully mixing uniformly, and preparing viscous emulsion; then mixing the corncob powder with 5 times of the emulsion by weight, stirring and mixing evenly, and drying to obtain the solid preparation.

Mixing the ivermectin drug, the nonionic surfactant and the 1, 2-propylene glycol, adding or not adding the hydrophobic solvent, stirring at 70-85 ℃ to completely dissolve the drug, cooling to 30-45 ℃, adding an aqueous solution or an ethanol solution containing polyvinylpyrrolidone or an aqueous solution containing Arabic gum under stirring, and fully and uniformly mixing to prepare a slightly viscous emulsion or solution; then mixing the carrier material with the emulsion or the solution, stirring and mixing evenly, and drying to obtain medicine-carrying particles, wherein the carrier material is equal to or 5 times the weight of the emulsion or the solution; melting the solid dispersion medium at 70-95 deg.C, adding the obtained drug-loaded particles at the temperature, stirring, cooling to room temperature, solidifying, and sieving to obtain the solid preparation.

Dissolution tests show that after the solid preparation prepared by the method is mixed with water, the medicine is dissolved out by shaking and exists in the system in the form of emulsion droplets. This suggests that the preparation can spontaneously form emulsion under the body temperature condition when meeting body fluid, and therefore, the preparation is considered to be a self-emulsifying drug delivery system (jiawei, high language distance master edition, qiu mingfeng auxiliary master edition, new drug controlled release formulation, chemical industry press, 4.2005, 1 st edition, pages 71-83), i.e. the preparation is a self-emulsifying solid preparation.

Tests show that the oral solid preparation containing ivermectin prepared by the formula and the method is preserved for 3 hours at the temperature of 36-37 ℃ in a solution with the hydrochloric acid concentration of 0.09-0.11M, and is detected by HPLC, and particularly, the monosaccharide ivermectin B of the preparation is preferred₁Chromatographic peak area of a and ivermectin B₁The ratio of chromatographic peak areas of a is less than 2% (example 2 to example 4). The ratio of the imported products was more than 5% (see tables 12 and 15), and the area ratio of the samples (M-102-1, M-105-1 in example 3) prepared according to the technique disclosed in the related patent was also more than 5%. This demonstrates that the present formulation has a stronger repression of the catalytic degradation of acids. The preparation also has stronger inhibition effect on the catalytic degradation of alkali (see tables 16 and 17).

The essential features and advantages of the invention will appear more clearly from the foregoing description.

Among the screened surfactants, some were abandoned because they showed a significant promoting effect on the acid-catalyzed degradation of ivermectin type drugs. Such as sodium lauryl sulfate, which has a good solubilizing/emulsifying effect on ivermectin drugs, it is not suitable for preparing the formulation of the present invention because it also has a strong acid-catalyzed hydrolysis promoting effect on ivermectin (see tables 4 and 5). Similarly, solid dispersions of ivermectin and sodium lauryl sulfate, while highly water soluble, are more easily destroyed by acidic gastric juices in the preparation of oral formulations.

Still other surfactants, while having very good solubilization/emulsification of ivermectin and inhibition of acid catalyzed hydrolysis, are not meant to be suitable for use in the preparation of the formulations of the present invention. Acid-catalyzed degradation tests of surfactants such as poloxamer 188 and polyethylene glycol (12) stearate, and emulsions or microemulsions prepared with these surfactants and ivermectin show that these surfactants have good solubilizing/emulsifying properties for ivermectin and inhibit the catalytic hydrolysis of acid. However, the solid preparation containing the ivermectin prepared by combining the ivermectin and the carrier material adopted by the invention has the dissolution rate of the ivermectin in water of less than 20 percent even if the content of the surfactant in the preparation is 10 to 33 times of that of the ivermectin. Thus, such surfactants are also not suitable for use in the preparation of the formulations of the present invention.

From the above, it can be seen that the present preparation technology is based on the insight of the physicochemical properties of ivermectin and the knowledge of the problems associated with the commercial products. Therefore, the technical features of the present invention will be more clearly described. It is necessary to describe the main fundamental tests closely related to the present invention.

1. Hydrolysis test of ivermectin in hydrochloric acid solutions of different concentrations (methanol/water as solvent). The test method comprises the following steps: the sample is kept at the temperature of 36-37 ℃ for 0-3 hours. Determination of MS H in the reaction solution by HPLC₂B₁a and H₂B₁a, degree of hydrolysis as MS H₂B₁The peak area of a is 0 h for ivermectin B₁a(H₂B₁a) The peak area (%) of (A) represents. The test results are shown in Table 1.

TABLE 1 hydrolysis of ivermectin in hydrochloric acid solutions of different concentrations (methanol/water as solvent)

2. The hydrolysis degree and dissolution rate of ivermectin in hydrochloric acid/water solution with different concentrations are measured for the imported product. The test method comprises the following steps: 1 g of the inlet sample was placed in 20 ml of hydrochloric acid/water solution at 36-37 ℃ for 3 hours. Measured by HPLC method, as MS H₂B₁Peak area of a and H₂B₁The ratio (%) of the peak area values of a measures the degree of hydrolysis of ivermectin. Assay at 0 hours: 1 g of the sample was placed in 20 ml of water at 36-37 ℃ for 3 hours; thereafter, the operation is the same as above. The test results are shown in Table 2.

TABLE 2 hydrolysis degree and dissolution rate of ivermectin in hydrochloric acid/water solution with different concentrations for imported product

3. Degradation of ivermectin in 0.1M NaOH solution (methanol/water 1: 1): 10 ml of a solution containing 0.6% ivermectin in methanol was mixed with 10 ml of a 0.2M sodium hydroxide solution, and the mixture was left at 21 to 24 ℃ for 0 to 930 minutes. Determination of 2-epimer H in reaction solution by HPLC method₂B₁a、Δ²，³H₂B₁a and H₂B₁a, calculating 2-epimer H₂B₁a and H₂B₁a ratio (%) of peak area, Delta²，³H₂B₁a and H₂B₁a ratio (%) of peak area values, H₂B₁a and 0 min H₂B₁a ratio (%) of peak area values. The test results are shown in Table 3.

TABLE 3 degradation of ivermectin in 0.1M NaOH solution (methanol/water 1: 1)

In conclusion, the invention has the following key points and benefits: (1) the preparation prepared by the technology has the property of forming a 'micelle barrier' due to the selected surfactant/benzyl benzoate or azone, so that the ivermectin medicaments contained in the preparation are difficult to be easily subjected to H⁺Attack, which reduces to some extent the extent or probability of hydrolysis of the drug by acidic gastric juices, thereby reducing the tendency for the absorption of the drug to decrease due to the action of gastric acid. (2) The oral solid preparation prepared by the technology of the invention has stronger barrier H⁺、OH^-Performance of the attack. Therefore, the invention better solves the problem of acid/base catalytic degradation of the ivermectin solid preparation, so that the active ingredients of the preparation are less degraded during the storage period, and the product quality and the market competitiveness are improved.

Detailed Description

Example 1 surfactant screening Using Ivermectin as an example

When the surfactant is screened, in addition to the examination of the emulsification/solubilization effect of the surfactant on the ivermectin, the acid-catalyzed degradation rate of the ivermectin is determined as a screening index, and an acid-catalyzed hydrolysis reaction test is carried out on the emulsion prepared by the surfactant. The primary screening is to combine the screened surfactant with ivermectin to prepare micro-emulsion or sub-micro-emulsion, and determine the emulsification/solubilization effect according to the dosage of the surfactant, so as to obtain the acid catalytic degradation rate (using Ms H) in 0.1M hydrochloric acid aqueous solution₂B₁a and H₂B₁The peak area ratio of a) measures how strong the surfactant is against the acid-catalyzed degradation of ivermectin. Specific tests and results are as follows.

Taking 1 ml of the emulsion in Table 4, mixing with 19 ml of 0.1M hydrochloric acid aqueous solution, reacting at 36-37 ℃ for 1 hour, and measuring MS H in the reaction solution by HPLC₂B₁a、H₂B₁a, recording peak area, calculating MS H₂B₁a chromatographic peak area and H₂B₁a ratio (%) of chromatographic peak areas, and the test results are shown in Table 4.

The results of further testing the microemulsion of ivermectin containing SDS, the microemulsion containing polyoxyethylene (40) hydrogenated castor oil and the test article containing poloxamer 188 in Table 4 on the acid degradation rate and dissolution rate are shown in tables 5 and 6.

The data reported in table 5 were obtained by the following test methods: (a) preparation of SDS-containing microemulsion and acid-catalyzed hydrolysis reaction: taking 0.7g of SDS, 1 ml of 1, 2-propylene glycol and 0.75 ml of ethyl acetate solution containing 0.15 g of ivermectin, stirring and uniformly mixing, adding water to 25 ml, and fully stirring to obtain clear and transparent microemulsion; 1 ml of microemulsion is added with 19 ml of 0.01M hydrochloric acid/water solution and reacted for 3 hours at the temperature of 36-37 ℃. (b) Control preparation and acid catalyzed hydrolysis reaction: 0.5 ml of ethyl acetate solution containing 6 mg of ivermectin is mixed with 9.5 ml of methanol uniformly, 10 ml of hydrochloric acid/water solution with the concentration of 0.02M is added, and the mixture is mixed uniformly and reacts for 3 hours at the temperature of 36-37 ℃. Determination of MS H in the reaction solution by HPLC₂B₁a、H₂B₁a AG、H₂B₁a, recording peak area, calculating H₂B₁a degradation Rate (%), MS H₂B₁a and H₂B₁a peak area ratio (%), H₂B₁aAG(H₂B₁a aglycone) with H₂B₁a ratio (%) of peak areas of a.

TABLE 4 acid catalyzed hydrolysis test and results for ivermectin emulsions with different surfactants

Surface active agent	MS H2B1a/H2B1a％	H2B1a degradation rate%
			Polyoxyethylene (40) castor oil	3.7-4.1 (interference, inaccuracy)	3.3-4.3
Polyoxyethylene (90) castor oil	5-6 (interference, inaccuracy)	4.5-7.2
			Nonylphenol polyoxyethylene ether (OP-10)	2.3-2.6	2.1-2.8
Polyoxyethylene (23) laureth (beneze 35)	2.9-3.8	3.1-3.6
			Polyoxyethylene (20) cetyl alcohol ether (beneze 58)	2.2-2.8	2.3-3.2
Polyethylene glycol stearate SG-40	2.8-3.5	4.9-5.3
			Polyethylene glycol stearate SG-100	3.1-3.3	4.6-5.3
Polyoxyethylene (9) laurate LAE-9	3.3-3.5	4.2-4.8
			Polyethylene glycol 400 monolaurate	1.4-1.6	2.7-3.1
Polyethylene glycol (50) Castor oil	1.5-1.9	1.0-1.4
			Tween-80	1.7-2.1 (with interference)	1.9-2.4
Polyoxyethylene (35) hydrogenated castor oil HEL-35	1.4-1.7	2.8-3.3
			Polyoxyethylene (40) hydrogenated castor oil HEL-40	1.4-1.7	2.7-3.1
Polyoxyethylene (50) hydrogenated castor oil HEL-50	1.4-1.7	2.9-3.4
			Polyoxyethylene (60) hydrogenated castor oil HEL-60	2.0-2.2	3.6-3.9
Sodium dodecyl sulfate	79.66	96.07

TABLE 5 promotion of acid-catalyzed hydrolysis of ivermectin by Sodium Dodecyl Sulfate (SDS)

TABLE 6 acid catalyzed degradation test of HEL-40 containing ivermectin microemulsions

As can be seen by comparing table 4 with table 1, among the surfactants listed in table 4, other surfactants, except SDS, all inhibited the acid-catalyzed degradation of ivermectin to varying degrees; tables 4 and 5 show that the SDS-containing ivermectin microemulsions were reacted in 0.1M hydrochloric acid solution for 1 hour H₂B₁a degradation rate reaches 96.07 percent, and the reaction is carried out in 0.01M hydrochloric acid solution for 3 hours H₂B₁The degradation rate of a reaches 99.81 percent. Therefore, SDS has very obvious promotion effect on catalytic degradation of ivermectin acid, and is not suitable for being used as an emulsifying/solubilizing agent of an oral ivermectin preparation. Tables 4 and 6 show that HEL-40 and its homologues (HEL-35, HEL-50, HEL-60) have a significant inhibitory effect on the acid-catalyzed degradation of ivermectin, which is stronger than that of other surfactants.

EXAMPLE 2 screening test for hydrophobic Medium (oil phase)

The self-emulsifying drug delivery system contains an oil phase component and a co-emulsifier besides a surfactant. Suitable oil phases have the effect of stabilizing the emulsion droplets. Therefore, in the formulation screening process, hydrophobic media which can become oil phases are screened, and the influence on the acid catalytic degradation rate of ivermectin when different hydrophobic media are added or the hydrophobic media are not added is mainly examined. The test article composition containing the hydrophobic medium comprises: 0.6% ivermectin, 10% HEL-40, 16% 1, 2-propanediol, hydrophobic medium were added in the amounts shown in Table 7, isopropanol to 100%.

The screening test method comprises the following steps: 1 ml of the emulsion containing the hydrophobic medium shown in Table 7 was mixed with 19 ml of 0.1M aqueous hydrochloric acid solution, reacted at 36 to 37 ℃ for 2 hours, and MS H in the reaction solution was measured by HPLC₂B₁a、H₂B₁a, recording peak area value, and calculating MS H₂B₁a and H₂B₁a peak area ratio (%) and the test results are shown in Table 7.

TABLE 7 Effect of hydrophobic Medium on acid catalyzed hydrolysis of ivermectin

Hydrophobic medium and content	MSH2B1a peak area value/H2B1a peak area value%
		2 percent of castor oil	3.1-4.4
3 percent of soybean oil	3.1-4.1
		Sucrose stearate 2%	4.3-4.5 (with interference)
Stearic acid monoglyceride 3.3%	3.5-4.2
		3.3 percent of glyceryl triacetate	2.9-3.5
9 percent of ethyl oleate	1.6-2.1
		Isopropyl myristate 9%	1.7-2.4
10 percent of caprylic/capric triglyceride	1.4-1.8
		5.5 percent of azone	1.3-1.8
Span-603%	1.6-2.1
		Span-803%	2.8-3.1
Benzyl benzoate 3.3%	1.1-1.6
		Dipropylene glycol dibenzoate 4.5%	1.2-1.6
3.3 percent of ethyl acetate	3.5-4.2
		Cetyl alcohol 5%	2.5-3.1
Without addition of hydrophobic medium	3.5-4.2

TABLE 8 Effect of hydrophobic Agents on acid catalyzed hydrolysis of Ivermectin (repeats)

Formulation number	NO.35	NO.43	NO.44	NO.131	NO.12-2	NO.342
							Ivermectin g	0.134	0.132	0.13	0.13	0.13	0.13
HEL-40g	1.2	1.2	1.2	1.55	1.20	1.63
							Monoglyceride g	1.2	1.2	1.2	-	-	-
Caprylic/capric acid triglyceride g	-	0.81	-	-	-	-
							Isopropyl myristate g	-	-	0.9	-	-	-
Oleic acid Ethyl ester g	0.99	-	-	-	-	-
							Azone g	-	-	-	0.78	-	-
Benzyl benzoate g	-	-	-	-	0.56	-
							Dipropylene glycol dibenzoate g	-	-	-	-	-	0.92
1, 2-propanediol g	0.2	0.3	0.3	0.39	0.2
							Corncob meal g	16.28	16.36	16.35	16.67	18	17.76
MS H2B1a/H2B1a％	1.45	1.39	1.73	1.39	1.12	1.21

As can be seen from Table 7, benzyl benzoate, dipropylene glycol dibenzoate, azone, in combination with HEL-40, gave the strongest inhibition of acid-catalyzed degradation of ivermectin, followed by caprylic/capric triglyceride, isopropyl myristate, and ethyl oleate. Repeated experiments show (see table 8) that the test sample reacts in 0.1M hydrochloric acid solution (1 g of test sample: 20 ml of acid solution) for 2 hours, and the acid-catalyzed degradation inhibition effect of benzyl benzoate, dipropylene glycol dibenzoate and azone on ivermectin is strong.

The influence of the content ratio of benzyl benzoate, azone and ethyl oleate on the acid catalytic degradation rate of ivermectin is further discussed by taking benzyl benzoate, azone and ethyl oleate as hydrophobic media. The test methods and results are as follows:

the test article containing benzyl benzoate comprises the following components: the contents of 1% ivermectin, 16% 1, 2-propanediol, benzyl benzoate and HEL-40 were calculated as the weight ratio of ivermectin (see Table 9), with isopropanol added to 100%.

Acid catalyzed hydrolysis test: mixing 0.3 ml of the sample in Table 9 with 4.7 ml of 0.1M hydrochloric acid aqueous solution, reacting at 36.5-37.5 ℃ for 2 hours, adding about 230 microliters of 10% sodium hydroxide solution, mixing uniformly, adding methanol to reach a constant volume of 10 ml, filtering, and detecting Ms H in the reaction solution by HPLC₂B₁a、H₂B₁a, recording peak area, calculating H₂B₁a hydrolysis rate as Ms H₂B₁a and H₂B₁The ratio (%) of the peak area of a measures the degree of hydrolysis. The test results are shown in Table 9.

TABLE 9 acid catalyzed hydrolysis test of different ratios of ivermectin/benzyl benzoate/HEL-40 formulations

Formulation number	Weight ratio of ivermectin/benzyl benzoate/HEL-40	MS H2B1a/H2B1a％
			Test article 1	1∶1∶6	2.23
Sample 2	1∶2∶6	1.94
			Test article 3	1∶3∶6	1.67
Test article 4	1∶4∶6	1.29
			Test article 5	1∶3∶9	2.01
Test article 6	1∶4.5∶9	1.58
			Test article 7	1∶2∶9	2.31
Reference substance-1	Ethyl acetate instead of benzyl benzoate in the ratio of 1: 3: 9	4.27
			Reference substance-2	Ethyl acetate instead of benzyl benzoate in the ratio of 1: 4: 6	4.22

As can be seen from Table 9, MS H was determined for a 1 to 1.5 weight ratio of benzyl benzoate/HEL-40 (test sample 4)₂B₁a and H₂B₁The ratio of a is minimal. The ratio of MS H2B1a to H2B1a was greatest when benzyl benzoate was replaced with ethyl acetate.

The test sample comprises the following components: the contents of 1% ivermectin, 3% 1, 2-propanediol, azone and HEL-40 were calculated as the weight ratio of ivermectin (see Table 10), and isopropanol was added to 100%.

Acid catalyzed hydrolysis test: the test procedure was the same as the acid catalyzed hydrolysis test of the test sample containing benzyl benzoate. The test results are shown in Table 10.

TABLE 10 acid catalyzed hydrolysis test for different ratios of ivermectin/azone/HEL-40 samples

Formulation number	Weight ratio of ivermectin/azone/HEL-40	MS H2B1a/H2B1a％
			Sample 8	1∶1∶6	2.86
Test article 9	1∶2∶6	1.99
			Test article 10	1∶3∶6	1.72
Test article 11	1∶4∶6	1.46
			Sample 12	1∶3∶9	2.20
Test article 13	1∶6∶9	1.62
			Sample 14	1∶4.5∶9	1.85
Reference substance-3	Ethyl acetate instead of azone in a ratio of 1: 3: 9	4.23

As can be seen from Table 10, MS H was calculated when the weight ratio of azone/HEL-40 was 1 to 1.5 (test article 11)₂B₁a and H₂B₁The ratio of a is minimal. Replacement of Azone by Ethyl acetate MS H₂B₁a and H₂B₁The ratio of a is the largest.

The test sample containing ethyl oleate comprises the following components: the contents of 0.6% ivermectin, 1.8% 1, 2-propanediol, ethyl oleate and HEL-40 are shown in Table 11, with isopropanol added to 100%.

Acid catalyzed hydrolysis test: mixing 0.3 ml of sample with 4.7 ml of 0.1M hydrochloric acid aqueous solution, reacting at 36.5-37.5 ℃ for 1 hour, adding about 230 microliters of 10% sodium hydroxide solution, mixing uniformly, adding 5 ml of methanol, filtering, and then

Detection of MS H in reaction solution by HPLC method₂B₁a、H₂B₁a, recording peak area, calculating H₂B₁a hydrolysis rate in MS H₂B₁a and H₂B₁The ratio (%) of the peak area values of a measures the magnitude of the hydrolysis rate. The test results are shown in Table 11.

TABLE 11 acid catalyzed hydrolysis test for different ratios of ivermectin/Ethyl oleate/HEL-40 test samples

Formulation number	Ethyl oleate/HEL-40	MS H2B1a	H2B1a	MS H2B1a/H2B1a％
					N0.32	1∶0.77	33989	4280211	0.79
NO.30	1∶1	40122	4837012	0.83
					N0.31	1∶1	34998	4029734	0.87
N0.33	1∶1	32735	4268351	0.77
					N0.34	1∶2.4	46420	4057935	1.14

As can be seen from Table 11, MS H was observed when the weight ratio of ethyl oleate/HEL-40 was 1: 0.77-1₂B₁a and H₂B₁The ratio of a is minimal.

Effect of benzyl benzoate addition on acid resistance of test samples prepared with different emulsifiers

The test method comprises the following steps: taking 40 g of a sample, putting into 800 ml of 0.1M hydrochloric acid aqueous solution, reacting for 1-3 hours at the stirring speed of 50r/min and the temperature of 36.5-37.5 ℃, sampling for 5 ml at 1, 2 and 3 hours respectively, adding 10% sodium hydroxide solution about 250 microliter, mixing uniformly, adding methanol to reach the constant volume of 10 ml, filtering, and detecting MSH in the reaction solution by an HPLC method₂B₁a、H₂B₁a, recording peak area, calculating H₂B₁a hydrolysis rate in MS H₂B₁a and H₂B₁The ratio (%) of the peak area values of a measures the magnitude of the hydrolysis rate. The test results are shown in Table 12.

TABLE 12 Effect of benzyl benzoate on acid resistance of ivermectin-containing test samples prepared with different emulsifiers

Note: the peak area ratio of all the test articles Ms H2B1a to H2B1a is 0.31-0.34% in 0 hour; MS/H2B1a represents the peak area ratio (%) of MS H2B1a to H2B1 a. The reference product is imported product.

The test results shown in table 12 further indicate that: the benzyl benzoate and different surfactants are combined for application, and have obvious effect of enhancing the inhibition effect on acid catalytic degradation. It can also be seen from Table 12 that benzyl benzoate, when used in combination with different emulsifiers, is para-H₂B₁a, the influence difference of dissolution is obvious; when HEL-40 or HEL-35 is used as emulsifier, the preparation with or without benzyl benzoate, its H₂B₁a dissolution rates were almost uniform.

Example 3 preparation of solid preparation containing ivermectin 0.6% Using HEL-40

1. The preparation comprises the following components and the preparation method: the active ingredients of the preparation are ivermectin, and the content of the ivermectin in the preparation is 0.66-0.68 g; other ingredients in the formulation are shown in table 13; corncob meal with a particle size of 140 and 420 microns was added to the final weight of the formulation (100 grams). Formulations No.12-2, N0.12-2-1 and No.13-1 were prepared as described in paragraph [ 0018 ] above, and formulations M-102 to M-109 were prepared as described in paragraph [ 0019 ] above.

2. Acid-catalyzed degradation test: taking 1.00 g of sample, putting the sample into a 25 ml test tube with a plug, adding 18 ml of water, oscillating for 5 minutes, then adding 2 ml of 1M hydrochloric acid solution, mixing uniformly, keeping the temperature at 36-37 ℃ for sampling time, sucking 4 ml of reaction solution, adding about 0.2 ml of 10% sodium hydroxide solution, mixing uniformly, adding 4 ml of methanol, mixing uniformly, filtering by using a 0.45um membrane, detecting the filtrate by HPLC (sample injection of 20 microliter), recording a chromatogram, calculating MS H (Mass Spectrometry) H₂B₁a peak area and H₂B₁a ratio (%) of peak areas. The test results are shown in Table 14.

Table 13.0.6% ivermectin solid formulation ingredients and contents

TABLE 14 acid catalyzed degradation test results for formulations

"control-1" in table 14 is imported product (0.6% ivermectin premix); the preparation method of the reference substance-2 comprises the following steps: adding 5.0 g of reference substance-1 into a 50 ml beaker, adding 0.2 ml of benzyl benzoate, transferring into a water bath at 85 ℃, fully stirring, uniformly mixing, then removing from the water bath, and cooling to room temperature to obtain the reference substance-2; preparation of reference-3 and acid-catalyzed hydrolysis test method: 1.00 g of control-1 was placed in a 25 ml stoppered tube, 37. mu.l of benzyl benzoate was added, 18 ml of water was added, and after sufficient shaking for 5 minutes, 2 ml of 1M hydrochloric acid solution was added, followed by the same procedure as described above for the test of acid-catalyzed degradation.

Comparing table 14 with table 1, it is evident that, using HEL-40 as a solubilizer, not only allows ivermectin in the formulation to have a higher dissolution rate in water, but also HEL-40 has a significant inhibitory effect on acid-catalyzed degradation of ivermectin. Table 14 also shows that the formulation, MS H, does not contain benzyl benzoate₂B₁a and H₂B₁The peak area ratio (%) of a is 2 to 3 times that of the preparation containing benzyl benzoate. Therefore, the benzyl benzoate and the HEL-40 are combined for use, and the catalytic hydrolysis of the ivermectin by the acid can be more effectively inhibited. The inhibition of the acid-catalyzed degradation of ivermectin by benzyl benzoate was further verified by the acid-catalyzed degradation test (control-2 and control-3 in table 14) in which benzyl benzoate was added to the imported product (control-1).

Several representative preparations in Table 14 were used as test samples, and they were further tested for H in 0.1M hydrochloric acid solution according to the dissolution rate determination method described in the pharmacopoeia₂B₁Dissolution of a and acid catalyzed degradation. The results are shown in Table 15.

TABLE 15 dissolution and hydrolysis of ivermectin in 0.1M hydrochloric acid

3. Base-catalyzed degradation test: taking 1.00 g of sample, adding 18 ml of water into a 25 ml test tube with a plug, oscillating for 5 minutes, then adding 2 ml of 1M sodium hydroxide solution, mixing uniformly, reacting for 2 hours at 20-23 ℃, immediately sucking 4 ml of reaction liquid, adding about 0.4 ml of 1M hydrochloric acid solution, mixing uniformly, adding 4 ml of methanol, mixing uniformly, filtering by using a 0.45um membrane, detecting the filtrate by HPLC, recording the peak area, calculating 2-epimer H₂B₁area of a peak is H₂B₁a percent peak area (%), see table 16.

TABLE 16 base catalyzed degradation test

Comparing table 16 with table 3 of paragraph [ 0037 ], it is evident that HEL-40 also has significant inhibitory effect on the base-catalyzed degradation of ivermectin. The data presented in Table 16 also show that the formulation without benzyl benzoate, 2-epimer H₂B₁a occupies H₂B₁The peak area percentage (%) of a is 3-4 times that of the formulation containing benzyl benzoate. Therefore, the benzyl benzoate and the HEL-40 are combined for use, so that the catalytic degradation of ivermectin by alkali can be more effectively inhibited. The repression of benzyl benzoate during the base-catalyzed degradation of ivermectin was further confirmed by the base-catalyzed degradation test (control-2 and control-3 in Table 16) with benzyl benzoate added to control-1 (the imported product).

In order to eliminate test errors, M102, M103, M104, M105, M106, N0.12-2 and N0.13-1 are further selected from the formula as test samples, and repeated tests of base catalytic degradation are carried out, wherein the test method comprises the following steps: adding the sample into 0.1M NaOH solutionReacting at 20-22 deg.C for 2 hr and 20 hr, and detecting H in the reaction solution by HPLC₂B₁a and 2-epimer H₂B₁a, recording chromatogram and calculating 2-epimer H₂B₁area of a peak is H₂B₁a percentage (%) of peak area. The test results are shown in Table 17. [0097]TABLE 17 results of repeated experiments with base-catalyzed degradation

In Table 17, M103-1 is a sample containing no benzyl benzoate and prepared according to the formulation of the published patent application, and controls-5 and-6 are samples containing benzyl benzoate as a control (imported product), and M102, M103, M104, M105, N0.12-2, and N0.13-1 are samples containing benzyl benzoate. As is evident from the numbers in the table, the 2-epimer H of the test sample containing benzyl benzoate reacted for 2 hours₂B₁The production of a is much lower than the test article without benzyl benzoate, by a factor of 3-8. Reaction for 20 hours, 2-epimer H from M105₂B₁a and H₂B₁The peak area ratio of a is only 42 percent of that of the imported product. Alkali degradation test carried out by using ivermectin crystal shows that 2-epimer H in reaction liquid reacts for 28-33 minutes₂B₁a and H₂B₁a peak area ratio of 44.60%, based on the initial amount of reaction, of H₂B₁a calculation of the 2-epimer H₂B₁a and H₂B₁a peak area ratio of 18 to 25%, and, H₂B₁a has degraded by about 50% (see table 3 in paragraph [ 0037 ]).

According to the analysis of the test results, the HEL-40 in the preparation has obvious inhibition effect on the catalytic degradation of alkali; (2) the combined application of HEL-40 and benzyl benzoate can make the suppression effect stronger.

EXAMPLE 4 formulation of Ivermectin with acacia and dissolution and acid catalyzed hydrolysis tests thereof

1. Preparation of the preparation: mixing 0.66 g of ivermectin, 6 g of HEL-40, 2 g of benzyl benzoate and 2.1 g of 1, 2-propylene glycol, stirring and dissolving at 60-65 ℃, cooling to about 40 ℃, adding 30 ml of aqueous solution containing 20% of Arabic gum, fully mixing, adding 83 g of corncob powder, stirring, mixing uniformly and drying to obtain the preparation (the preparation number is M-113). The comparative formulation (M-113-1) did not contain benzyl benzoate, and was otherwise identical to M-113.

2. Test methods for acid-catalyzed degradation: adding 800 ml of 0.1M hydrochloric acid solution into a dissolution cup, controlling the stirring speed to be 49-51 r/min, stirring and heating until the temperature of a dissolution medium is stabilized at 36-37 ℃ and the pH value is 0.85-0.87, adding 40.00 g of a sample into the dissolution medium, and reacting for 3 hours under the conditions that the temperature is controlled at 36-37 ℃, the stirring speed is 49-51 r/min and the pH value is 0.85-0.87. Sampling 4 ml at 1 hr, 2 hr and 3 hr, adjusting pH with 10% sodium hydroxide solution about 0.2 ml, adding 4 ml methanol, mixing, filtering with 0.45 μm, collecting filtrate 20 μ l, detecting by HPLC, recording chromatogram, and calculating MS H₂B₁area of a peak and dissolved H₂B₁a ratio (%) of peak area, calculating H₂B₁Dissolution (%) of a. The test results are shown in Table 18.

TABLE 18 results of acid catalyzed degradation tests of M-113 and M-113-1 formulations

As can be seen from Table 18, the formulations prepared with acacia, benzyl benzoate and HEL-40 showed high dissolution and strong inhibition of acid-catalyzed degradation of ivermectin. We believe that the formulation containing gum arabic deserves further systematic studies (including clinical efficacy and pharmacokinetic trials) and has the potential to be the most elegant of the same class of drugs.

Example 5 stability of representative formulations

(1) High-temperature test: standing the sample at 60 deg.C for 14 days, collecting sample 1 g, extracting with 20 ml methanol under shaking for 10 min, filtering with 0.22 μm membrane, collecting filtrate, and detecting MS with HLPCH₂B₁a、2-epimer H₂B₁a (abbreviated to 2-epimer in Table 19) and H₂B₁a, recording peak area, calculating MS H₂B₁a peak area and H₂B₁a peak area ratio (%), 2-epimer peak area and H₂B₁a peak area ratio (%) and H at 14 days₂B₁area of a peak and H at day 0₂B₁a ratio (%) of peak areas. The results are shown in Table 19.

As can be seen from Table 19, the samples were incubated at 60 ℃ for 14 days, preferably with benzyl benzoate-containing formulation 2-epimerH₂B₁a is produced in significantly lower amounts than in the formulation without benzyl benzoate. And preparations (NO.12-2 and NO.13-1) containing benzyl benzoate but not containing a solid dispersion medium (glyceryl monostearate or PEG-6000, etc.), 2-epimer H₂B₁a is produced in a small amount.

TABLE 19 high temperature test results

(2) Accelerated stability test at constant temperature of 40 ℃ for 3 months

It is generally accepted that the degradation rate of a drug after being left at 40 ℃ for 3 months is equivalent to the degradation rate after being left at room temperature for 1 to 2.5 years. Therefore, we examined that a representative preparation was left at a constant temperature of 40 ℃ for 2-3 months and MS H in the test sample₂B1a、2-epimeH₂B₁a and H₂B₁The content of a varies. The test results are shown in tables 20-1 to 20-3.

TABLE 20-1.40 deg.C for 1 month

TABLE 20-2.40 deg.C for 2 months

TABLE 20-3.40 deg.C for 3 months

As can be seen from Table 20, the samples were kept at a constant temperature of 40 ℃ for 90 days, preferably 2-epimerH, a benzyl benzoate-containing formulation₂B₁a is produced in significantly lower amounts than in the formulation without benzyl benzoate. And preparations (NO.12-2 and NO.13-1) containing benzyl benzoate but not containing a solid dispersion medium (glyceryl monostearate or PEG-6000, etc.), 2-epimer H₂B₁a is produced in a smaller amount. The preparation other than NO.35-1 is left at constant temperature of 40 deg.C for 90 days, and its H content is₂B₁The degradation rate of a is less than 3 percent. This indicates that the preferred formulations have good stability. From the viewpoint of stability methods, they all meet the quality requirements for becoming commercial products. If there are general considerations (including dissolution problems, degradation problems in acidic gastric juices, stability problems), they can differ greatly from one another in terms of quality as a commercial product.

EXAMPLE 6 differences in stability of formulations containing Carrier materials at different pH values

The commercial pest control product is prepared by using corncob powder as a carrier material, and through detection, the particle size of the product is regular, the uniformity of active components is good, the dissolution rate is high, and the product has the performance of resisting acid/alkali catalytic degradation. According to the description of the relevant patent, the main auxiliary components of the preparation are water-soluble nonionic surfactant and water-insoluble nonionic surfactant, and also contain antioxidant and auxiliary emulsifier, and a small amount of organic acid (such as citric acid) is added into the premix to inhibit 2-epimer H₂B₁a is produced in order to extend the shelf life of the formulation. Taking 4 g of imported product, soaking the imported product in 20 ml of water, and detecting and displaying: the pH value is 4.47-4.53. According to investigation and detection of corncob meal sold in domestic markets, the results show that the corncob meal produced by different manufacturers has larger pH difference. Therefore, to investigate the relationship between the pH of the carrier material and the degradation of ivermectin, two commercially available materials were used in this studyCorncob powder with different pH values is used as a carrier material, the benzylze-35 is used as a solubilizer, and acid/alkali regulators such as citric acid and the like are not added into the preparation, and substances such as benzyl benzoate and the like which have strong inhibition on the catalytic degradation of acid/alkali are not added. The specific test process is as follows:

1. preparation of test samples M-79 and M-80

(1) Preparation of sample M-79: melting 1.5 g of beneze-35, 0.13 g of monoglyceride and 0.16 g of PEG-6000 at 80 ℃, adding 0.3 ml of ethyl acetate solution containing 0.061 g of ivermectin, uniformly mixing, adding 3 ml of water, uniformly stirring, adding 8.2 g of corn cob powder with the pH value of 6.2-6.4 (the particle size is between 30-80 meshes), fully mixing, and drying at room temperature to obtain 10.39 g of a sample (M-79). (2) Preparation of sample M-80: melting 1.5 g of beneze-35, 0.13 g of monoglyceride and 0.16 g of PEG-6000 at 80 ℃, adding 0.3 ml of ethyl acetate solution containing 0.061 g of ivermectin, uniformly mixing, adding 3 ml of water, uniformly stirring, adding 8.2 g of corn cob powder with the pH value of 4.9-5.1 (the particle size is between 30-80 meshes), fully mixing, and drying at room temperature to obtain 10.32 g of a sample (M-80).

2. High temperature test

Accurately weighing 3 parts of each of samples M-79 and M-80, wherein the weighing amount is 1.0000 g/part, placing the samples in a 25 ml test tube, sealing the test tube, placing the test tube in a 59-61 ℃ test box, standing the test tube at a constant temperature for 15 days, then shaking and extracting the test tube by using 20 ml of methanol for 10 minutes, filtering the test tube by using a 0.22 mu M membrane, taking filtrate, and detecting MS H by using HLPC (high-Density polyethylene carbonate)₂B₁a、2-epimer H₂B₁a and H₂B₁a, recording peak area value, and calculating MS H₂B₁a peak area value and H₂B₁a ratio (%) of peak area value, 2-epimer peak area value and H₂B₁a ratio of peak area values (%) to 15 days H₂B₁a peak area value and H at 0 day₂B₁a ratio (%) of peak area values. The results are shown in Table 21.

TABLE 21 high temperature test results

As can be seen from the data in Table 21, the samples were treated at 60 ℃ for 15 days, and the 2-epimer H of the sample (M-80) prepared from corncob meal having a pH of 4.9 to 5.1₂B₁Production of a, MS H₂B₁a production amount and H₂B₁The degradation amount of a is obviously lower than that of a sample (M-79) prepared by using corncob meal with the pH value of 6.2-6.4. The test results show that the pH of the carrier material has a significant effect on the stability of the formulation. Accordingly, we further analyzed the commonly used pharmaceutical additives, and the results showed that both gypsum powder and starch are suitable carrier materials for preparing the preparation of the present invention, while the commonly used additives such as glucose, calcium carbonate, etc. are not suitable for preparing the preparation of the present invention.

Example 7 preparation of a 0.6% Ivermectin solid formulation

Taking 0.66 g of ivermectin with the purity of 90%, 0.75 g of benzyl benzoate, 3 g of HEL-35 and 0.6 g of 1, 2-propylene glycol, putting the ivermectin, the benzyl benzoate, the HEL-35 and the 1, 2-propylene glycol into a 500 ml beaker, stirring and dissolving in a water bath at the temperature of 80-85 ℃, cooling to about 40 ℃, adding 20 ml of water, fully stirring and uniformly mixing, then adding 30 g of corn cob powder (the particle size is between 40-100 meshes), fully stirring and uniformly mixing, and drying to obtain medicine-carrying particles; melting 5 g of glyceryl monostearate at 80-85 ℃, adding the drug-loaded particles, fully and uniformly mixing, then adding the corncob powder to 100 g, and uniformly stirring to obtain the 0.6% ivermectin solid preparation.

Example 8 preparation of 0.1% selamectin powder

Taking 0.11 g of 90% selamectin, 0.8 g of caprylic/capric triglyceride, 1.1 g of HEL-60, 0.4 g of PEG-6000 and 0.6 g of glycerin monostearate, putting the mixture into a 200 ml beaker, stirring and dissolving the mixture in water bath at the temperature of 80-85 ℃, adding 88 g of fried fish meal (the particle size is between 24-60 meshes), fully and uniformly mixing, cooling to room temperature, and sieving by a 18-mesh sieve to obtain 0.1% selamectin powder. The product is used for preventing and treating the parasitic diseases of dogs and cats, and is taken at one time, wherein 0.2 g of the product is taken per kilogram of body weight once a month.

Example 9 preparation of 0.1% Ivermectin granules

Taking 0.11 g of ivermectin with the purity of 90%, 0.2 g of azone, 0.6 g of HEL-40 and 0.1 g of 1, 2-propylene glycol, putting the components into a 100 ml beaker, stirring and dissolving in a water bath at the temperature of 80-85 ℃, adding 4-5 ml of water when the temperature is reduced to 35-40 ℃, fully stirring to form emulsion, adding 8 g of corn cob powder (the particle size is between 100 and 200 meshes), fully mixing uniformly, and drying at the temperature of 25-35 ℃ to obtain the ivermectin/corn cob powder drug-loaded particles. Mixing 30 g of fried beef powder, 40 g of starch and 10 g of polyvinylpyrrolidone with the drug-loaded particles, adding absolute ethyl alcohol, granulating, sieving with a 12-mesh sieve, grading, and drying to obtain 0.1% ivermectin granules. The preparation is used for preventing and treating parasitic diseases of dogs and cats, and is administered once a month, and 0.2 g of the preparation is administered per kilogram of body weight.

Example 10 preparation of a 0.6% Ivermectin solid formulation

0.66 g of ivermectin with the purity of 90 percent, 2.5 g of benzyl benzoate, 8 g of HEL-60, 3 g of PEG-6000 and 8 g of monoglyceride are taken to be dissolved in a 500 ml beaker at the temperature of 80-85 ℃, 40-100 meshes of corncob powder 77.8 g is added, the mixture is fully stirred, cooled to the room temperature after being mixed uniformly, and sieved by a 30-mesh sieve, thus obtaining the 0.6 percent ivermectin solid preparation. The agent is used for preventing and treating pig parasitosis, and 1 kg of the agent is added into each ton of feed for continuous feeding for 7-10 days.

Example 11 preparation of a 0.3% doramectin solid formulation

Dissolving 0.33 g of doramectin with the purity of 90%, 2 g of benzyl benzoate, 2.4 g of HEL-60, 1.2 g of PEG and 1.2 g of glyceryl monostearate at the temperature of 80-85 ℃ in a 500 ml beaker, adding 92.8 g of 40-100 mesh corn cob powder, fully stirring, uniformly mixing, cooling to room temperature, and sieving with a 30-mesh sieve to obtain the 0.3% doramectin solid preparation.

Example 12 preparation of a 0.3% Ivermectin solid formulation

Taking 0.33 g of 90% ivermectin, 0.75 g of benzyl benzoate, 2.1 g of HEL-60 and 0.3 g of 1, 2-propylene glycol, putting the mixture into a 200 ml beaker, stirring and dissolving the mixture in water bath at 80-85 ℃, adding 20 ml of water when the temperature is reduced to 35-40 ℃, fully stirring the mixture to form emulsion, adding 50 g of corncob powder (the particle size is between 40 and 100 meshes of sieve pores) into the emulsion, uniformly stirring the mixture, naturally drying the mixture, removing water, adding the corncob powder to the total weight of 100 g, and uniformly mixing the mixture to obtain the 0.3% ivermectin solid preparation.

Example 13 preparation of a 0.6% Ivermectin solid formulation

Taking 0.66 g of ivermectin with the purity of 90%, 0.75 g of benzyl benzoate, 3 g of HEL-40 and 0.6 g of 1, 2-propylene glycol, putting the mixture into a 500 ml beaker, stirring and dissolving the mixture in water bath at the temperature of 80-85 ℃, adding 30 g of corncob powder (the particle size is between 40-100 meshes of sieve pores), fully stirring and uniformly mixing the mixture, cooling the mixture to room temperature, adding the corncob powder to 100 g, stirring and uniformly mixing the mixture, and obtaining the 0.6% ivermectin solid preparation.

Example 14 preparation of a solid formulation of 0.25% ivermectin, 6% albendazole

Taking 0.27 g of ivermectin with the purity of 90%, 0.15 g of benzyl benzoate, 3.25 g of HEL-40, 3.25 g of glyceryl monostearate and 0.2 g of 1, 2-propylene glycol, stirring and dissolving in a water bath at the temperature of 80-85 ℃ in a 100 ml beaker, adding 20 g of corn cob powder (the particle size is between 100 plus 200 mesh openings), fully stirring and uniformly mixing, and cooling to room temperature to obtain ivermectin/corn cob powder drug-loaded particles; and adding 20 ml of water into 6 g of albendazole and 0.5 g of polyvinylpyrrolidone, fully stirring, adding 60 g of corncob powder in portions, mixing uniformly, drying, and mixing uniformly with the ivermectin/corncob powder drug-loaded particles and 6 g of iron oxide black micro powder to obtain a solid preparation of 0.25% of ivermectin and 6% of albendazole.

Example 15 preparation of a solid formulation of 0.2% ivermectin, 5% oxybenzidazole

Taking 0.22 g of ivermectin with the purity of 90%, 0.15 g of benzyl benzoate, 3.25 g of HEL-40, 3.25 g of glyceryl monostearate and 0.2 g of 1, 2-propylene glycol, stirring and dissolving in a water bath at the temperature of 80-85 ℃ in a 100 ml beaker, adding 20 g of corncob powder (the particle size is between 100 plus 200 mesh openings), fully stirring and uniformly mixing, and cooling to room temperature to obtain ivermectin/corncob powder drug-loaded particles; adding 20 ml of water into 5 g of oxybenzone and 0.5 g of polyvinylpyrrolidone, stirring fully, adding 61 g of corn cob powder in portions, mixing fully, drying, and mixing uniformly with the ivermectin/corn cob powder drug-loaded particles and 5 g of iron oxide black micro powder to obtain a solid preparation of 0.2% of ivermectin and 5% of oxybenzone.

Example 16 preparation of a 0.2% Abamectin solid formulation

0.22 g of abamectin with the purity of 90 percent, 0.9 g of benzyl benzoate, 2.86 g of HEL-40 and 6.6 g of glyceryl monostearate are taken and stirred and dissolved in a 200 ml beaker in water bath at the temperature of 80-85 ℃, 50 g of corncob powder (the particle size is between 40-100 meshes of sieve pores) is added, the mixture is fully stirred and uniformly mixed, the temperature is reduced to the room temperature, and the corncob powder is supplemented until the final weight is 100 g, so that the 0.2 percent abamectin solid preparation is obtained.

Example 17 preparation of a 0.3% Doradine solid formulation

Mixing 0.33 g of delamectin, 10 g of HEL-35, 1 ml of 1, 2-propylene glycol and 9 g of caprylic/capric triglyceride, stirring at 75-85 ℃ to completely dissolve the medicine, then adding the corncob powder to 100 g of the liquid, fully stirring and uniformly mixing, and then cooling the material to room temperature to obtain the 0.3% delamectin solid preparation.

Example 18 preparation of a 1% Moxidecin solid formulation

Mixing 1 g of moxidectin, 10 g of HEL-35, 1 ml of 1, 2-propylene glycol and 5 g of caprylic/capric triglyceride, stirring at 75-85 ℃ to completely dissolve the medicine, adding 8 g of glyceryl monostearate, continuously stirring to melt and uniformly mix the materials, adding the corncob powder to 100 g at 75-85 ℃, fully stirring, uniformly mixing, and then cooling the materials to room temperature to completely solidify the materials, thus obtaining the 1% moxidectin solid preparation.

Example 19 preparation of 0.1% selamectin powder

Stirring 0.11 g of selamectin, 0.3 g of HEL-40, 0.5 ml of 1, 2-propylene glycol and 0.2 g of caprylic/capric triglyceride at 75-85 ℃ to completely dissolve the medicaments, cooling to about 40 ℃, and adding 7 ml of water under the stirring condition to prepare emulsion; then mixing the emulsion and 14 g of corncob meal uniformly to enable the emulsion to permeate or partially permeate into pores of the corncob meal, then drying, mixing the dried mixture and melted 2 g of glycerin monostearate uniformly, cooling to room temperature, and adding the beef powder to 100 g to obtain the agent. The agent is suitable for preventing and treating parasitic diseases of dogs and cats.

Example 20 preparation of a 0.3% Ivermectin solid formulation

Mixing 0.3 g of ivermectin, 3 g of HEL-40, 0.5 ml of 1, 2-propylene glycol, 1 g of benzyl benzoate and 20 ml of ethanol solution containing 1.5 g of polyvinylpyrrolidone, stirring at the temperature of 60-70 ℃ to completely dissolve the medicines, adding the corn cob powder between 40-80 meshes, fully stirring, uniformly mixing and drying to obtain the medicine-carrying particles. Melting glyceryl monostearate at 80-85 deg.C, adding the obtained drug-loaded particles at the temperature, stirring, cooling to room temperature, and solidifying to obtain 0.3% ivermectin solid preparation.

Claims (6)

1. An oral solid preparation containing an antiparasitic drug, which is characterized by comprising the following components:

a. each 1 kilogram of the solid preparation contains 0.1-20 grams of active ingredients, wherein the active ingredients comprise one of abamectin, ivermectin, doramectin, moxidectin, acetamido abamectin and selamectin;

b. polyoxyethylene (40) hydrogenated castor oil, in a formulation in an amount of from 3 to 20 times the amount of said active ingredient, at most added in an amount not exceeding 20% by weight of the formulation;

c. carrier material, added up to 1 kg; the carrier material comprises one or more of corncob powder, zeolite powder, stone powder, diatomite, gypsum powder, starch, fish meal, beef powder, chicken powder, pork liver powder and chicken liver powder;

d. 1-10 g of 1, 2-propylene glycol is contained in each 1 kg of the oral solid preparation;

e. the oral solid preparation comprises 16.7-110 wt% of hydrophobic medium corresponding to the weight of the polyoxyethylene (40) hydrogenated castor oil in each 1 kg of oral solid preparation; the hydrophobic medium is benzyl benzoate;

each 1 kilogram of the oral solid preparation also comprises 10-220 grams of solid dispersion, and the solid dispersion comprises one or more than one composition of glyceryl monostearate or solid-state polyethylene glycol.

2. The solid preparation according to claim 1, wherein said 1 kg oral solid preparation contains 10-100 g of other antiparasitic drug selected from albendazole, albendazole oxide, fenbendazole, oxfendazole and insect growth regulator.

3. Solid preparation according to claim 1, characterized in that 10 to 150 g of gum arabic or polyvinylpyrrolidone are present per kg of preparation.

4. The solid preparation according to claim 1, wherein the corncob meal has a pH of 4.4 to 5.7.

5. The solid preparation according to claim 1, wherein said solid preparation is prepared by one of the following methods:

mixing an ivermectin drug or a solution containing the ivermectin drug dissolved by a solvent with the polyoxyethylene (40) hydrogenated castor oil, adding 1, 2-propylene glycol, adding the hydrophobic medium benzyl benzoate, stirring at 70-85 ℃ to completely dissolve the drug, adding the solid dispersion, continuously stirring to melt and uniformly mix the solid dispersion, adding the carrier material at 70-85 ℃, fully stirring, uniformly mixing, cooling the material to room temperature, removing the solvent after the material is completely solidified or dried, and sieving by a 24-mesh sieve to obtain a sieved product, namely the solid preparation; the solvent is ethanol or ethyl acetate or the combination of the ethanol and the ethyl acetate;

mixing the ivermectin drug, the polyoxyethylene (40) hydrogenated castor oil and the 1, 2-propylene glycol, adding the hydrophobic medium benzyl benzoate, stirring at 70-85 ℃ to completely dissolve the drug, cooling to 30-45 ℃, adding water with the weight 5-70 times that of the ivermectin drug under the stirring condition, and preparing into emulsion; then mixing the carrier material with 5 times of the emulsion in an amount equal to the weight of the emulsion with the emulsion, fully stirring, uniformly mixing, and drying to obtain medicine-carrying particles; melting the solid dispersion at 70-95 ℃, adding the prepared drug-loaded particles under the temperature condition, fully stirring, uniformly mixing, cooling to room temperature, solidifying, and sieving with a 24-mesh sieve to obtain the solid preparation.

6. The solid preparation according to claim 3, wherein the solid preparation is prepared by a method selected from the group consisting of:

mixing ivermectin medicines, polyoxyethylene (40) hydrogenated castor oil and 1, 2-propylene glycol, adding the hydrophobic medium benzyl benzoate, stirring at 70-85 ℃ to completely dissolve the medicines, cooling to 30-45 ℃, adding an aqueous solution or an ethanol solution containing polyvinylpyrrolidone or an aqueous solution containing Arabic gum under stirring, and fully and uniformly mixing to prepare a slightly viscous emulsion or solution; then mixing the carrier material with the emulsion or the solution, stirring and mixing evenly, and drying to obtain medicine-carrying particles, wherein the carrier material is equal to or 5 times the weight of the emulsion or the solution; and melting the solid dispersion at 70-95 ℃, adding the prepared drug-loaded particles at the temperature, fully stirring and uniformly mixing, cooling to room temperature, solidifying, and sieving to obtain the solid preparation.