A safe and efficient non-pronil general-purpose external anthelmintic for dogs and cats and its preparation method

Abstract

The present invention relates to the field of external veterinary drugs, and in particular to a safe and efficient non-pronil general external anthelmintic for dogs and cats and a preparation method thereof. The anthelmintic, measured by mass percentage, comprises at least: 5-12% non-pronil, 4-15% adjuvant, 1-15% auxiliary agent, and the remainder is supplemented by solvent. The external anthelmintic provided by the present invention is safe and efficient and is universal for cats and dogs. It has no adverse reactions when used by cats and dogs. It can avoid the first-pass effect of the liver and the influence of the gastrointestinal tract on the drug. On the other hand, the anthelmintic provided by the present application can not only effectively kill adult worms, but also further inhibit the development of worm eggs, thereby playing a long-term inhibitory and anthelmintic effect.

Description

Technical Field

[0001] The invention relates to the field of external veterinary drugs, in particular to a safe and efficient non-pronil general-purpose external anthelmintic for dogs and cats and a preparation method thereof. Background Art

[0002] As pets become more and more family members, people pay more attention to the health and care of pets. For dogs and cats, external and internal parasitic diseases have always been of particular concern to pet lovers. Parasites not only harm the health of pets, but also indirectly affect the quality of life of pet owners. According to existing statistics, about one-third of the pet medicines consumed worldwide each year are external anthelmintics, and the amount of external anthelmintics used far exceeds everyone's general perception.

[0003] Fipronil is a new type of phenylpyrazole insecticide that binds to the r-aminobutyric acid (GABA) receptors on the membrane of insect central nervous cells, closes the chloride ion channels of nerve cells, and thus interferes with the normal function of the central nervous system and causes the death of insects. It mainly works through stomach poison and contact killing, and is a highly targeted, safe and effective surface anthelmintic. The amount used in the prevention and treatment of external parasites of pets is also increasing. However, at the same time, the use of a single Fipronil can only be used to kill adult insects, such as fleas, ticks, etc., and has no effect on insect eggs, and cannot have a long-term insecticidal and anthelmintic effect. The existing Chinese invention patent application (CN201810698108.0) provides a compound preparation of fepronil and an insect growth regulator, which blocks the chloride ion regulation channel of the insect central nervous system through the compounding effect of fepronil and the growth regulator, interferes with the insect central system, and thus achieves dual killing of adults and larvae. However, in the actual preparation, it does not take into account the physical properties of the preparation itself. The compounding of the two or more agents cannot be stably and evenly present for a long time, and the technical problems that may be caused by the instability of fepronil itself are not considered.

[0004] Therefore, in order to solve the above problems, the present invention provides a general-purpose external anthelmintic for dogs and cats that can achieve excellent insecticide and egg-killing effects and has long-term continuous anthelmintic performance. Summary of the invention

[0005] In order to solve the above problems, the first aspect of the present invention provides a safe and efficient non-pronil universal external anthelmintic for dogs and cats. The raw materials include at least 5-12% non-pronil, 4-15% adjuvant, 1-15% auxiliary agent, and the solvent supplements the balance.

[0006] As a preferred embodiment, the adjuvant is at least one of methoprene, thiophanate-methyl, thiourea, chlorfenapyr, buprofezin, cypermethrin, chlorfenapyr, chlorfenapyr, chlorfenapyr, chlorfenapyr, fenthiocarb, pyriproxyfen, and pyriproxyfen.

[0007] As a preferred solution, the adjuvant is methoprene.

[0008] As a preferred solution, the mass ratio of the fepronil to the auxiliary drug is 8-10:6-12.

[0009] As a preferred solution, the mass ratio of the fipronil to the adjuvant is 9:8.

[0010] As a preferred solution, the auxiliary agent is at least two of a flavoring agent, an inhibitor, a cosolvent, a transdermal agent, an emollient, an antioxidant, an antibacterial agent, a dispersant, an antifreeze agent, and a thickening and film-forming agent.

[0011] As a preferred solution, the auxiliary agent includes an inhibitor, and the inhibitor is a crystallization inhibitor polyvinyl pyrrolidone; the mass ratio of polyvinyl pyrrolidone to fepronil and the auxiliary drug is 3-6:8-10:6-12.

[0012] As a preferred solution, the mass ratio of polyvinyl pyrrolidone to fepronil and the auxiliary drug is 5:9:8.

[0013] As a preferred solution, the K value of the polyvinyl pyrrolidone is 10-30.

[0014] As a preferred solution, the K value of the polyvinyl pyrrolidone is 17.

[0015] As a preferred solution, the auxiliary agent includes a co-solvent, and the co-solvent is at least one of ethanol, Tween-80, and propylene carbonate.

[0016] As a preferred solution, the co-solvent is ethanol.

[0017] In the present application, by selecting polyvinyl pyrrolidone with a specific K value as a crystallization inhibitor of the preparation, it can synergize with the main auxiliary drug and the solvent cosolvent, greatly improve the use effect of the preparation, and improve the stability of the preparation of the present application. The applicant believes that when a polyvinyl pyrrolidone with a K value of 17 is used, and the mass ratio of polyvinyl pyrrolidone to fepronil and the auxiliary drug is 5:9:8, at this time, fepronil and methoprene can form a droplet system wrapped by multiple layers in the liquid system under the synergistic effect of process stirring and auxiliary agents, and the drug is wrapped by the oil phase of the nanoemulsion as the droplet core in the system, which can effectively avoid the demulsification caused by direct external contact of fepronil, reduce its own instability risk, and thus improve the storage stability of the overall preparation under various conditions.

[0018] As a preferred solution, the auxiliary agent includes an antioxidant, and the antioxidant is at least one of an organic phenol and an organic ether.

[0019] As a preferred solution, the antioxidant is at least one of 2,6-di-tert-butyl-p-methylphenol, tert-butyl-4-hydroxyanisole, tocopherol, and butylated hydroxyanisole.

[0020] As a preferred solution, the antioxidant is any two of 2,6-di-tert-butyl-p-methylphenol, tert-butyl-4-hydroxyanisole, and butylated hydroxyanisole.

[0021] As a preferred solution, the antioxidant is 2,6-di-tert-butyl-p-methylphenol and tert-butyl-4-hydroxyanisole, and the mass ratio of the two is 1-5:1-5.

[0022] As a preferred solution, the mass ratio of the 2,6-di-tert-butyl-p-methylphenol to tert-butyl-4-hydroxyanisole is 1-2:2-3.

[0023] As a preferred solution, the auxiliary agent includes a transdermal agent, and the transdermal agent is at least one of azone, propylene glycol, laurocaprylic acid and capric triglyceride.

[0024] As a preferred embodiment, the transdermal agent is azone.

[0025] As a preferred solution, the solvent is any one of diethylene glycol monoethyl ether, deionized water, benzyl alcohol, N-methylpyrrolidone, methanol, and acetone.

[0026] As a preferred solution, the solvent is diethylene glycol monoethyl ether.

[0027] As a preferred solution, the safe and highly effective non-pronil general-purpose external anthelmintic for dogs and cats is in the form of drops or pour-ons; preferably drops.

[0028] The second aspect of the present invention provides a method for preparing the above-mentioned safe and efficient non-prednisolone universal external anthelmintic for dogs and cats, comprising the following steps: (1) adding 90% of the formula amount of solvent and all the co-solvents, mixing and stirring; (2) adding 50-80% of the formula amount of crystallization inhibitor, emulsifying and mixing, and then adding non-prednisolone and auxiliary drugs to dissolve; (3) adding other auxiliary agents, mixing evenly, adding the remaining crystallization inhibitor again, and continuing to mix and emulsify until all are dissolved; (4) adding the remaining solvent to make up to volume, stirring and emulsifying for 20-60 minutes to obtain the product.

[0029] Beneficial effects:

[0030] 1. The non-pronil topical anthelmintic provided in the present application is safe, efficient and universal for cats and dogs. It has no adverse reactions when used by cats and dogs. It can avoid the first-pass effect of the liver and the influence of the gastrointestinal tract on the drug. On the other hand, the anthelmintic provided in the present application can not only effectively kill adult worms, but also further inhibit the development of worm eggs, thereby playing a long-term inhibitory anthelmintic effect, and the anthelmintic itself has excellent stability as an external drop, which greatly improves the storage stability of the product.

[0031] 2. The present application provides a non-pronil topical anthelmintic, which can synergize with the main and auxiliary drugs and the solvent cosolvent by selecting polyvinyl pyrrolidone with a specific K value as the crystallization inhibitor of the preparation, greatly improving the use effect of the preparation while improving the stability of the preparation of the present application, forming a droplet system wrapped by multiple layers in the liquid system, and wrapping the drug in the system as the droplet core by the oil phase of the nanoemulsion, which can effectively avoid the demulsification caused by direct external contact of non-pronil and reduce its own instability risk. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The invention discloses a product preparation process of the nonpronil external insect repellent provided by the invention. DETAILED DESCRIPTION

[0033] Example 1

[0034] Example 1 The first aspect provides a safe and efficient non-pronil general-purpose external anthelmintic for dogs and cats. The raw materials include at least 9% non-pronil, 8% adjuvant, 13.5% auxiliary agent (5% crystallization inhibitor, 6% cosolvent, 2% transdermal agent, 0.5% antioxidant), and the solvent supplements the balance.

[0035] Among them, the excipient is methoprene; the crystallization inhibitor is polyvinyl pyrrolidone; the K value of polyvinyl pyrrolidone is 17, and the polyvinyl pyrrolidone K17 product is purchased from Jinan Rongzheng Chemical Co., Ltd.; the cosolvent is ethanol; the transdermal agent is azone; the antioxidants are 2,6-di-tert-butyl-p-methylphenol and tert-butyl-4-hydroxyanisole, and the mass ratio of the two is 1:2.

[0036] The anthelmintic comes in the form of drops.

[0037] The second aspect of the present embodiment provides a method for preparing the above-mentioned safe and efficient non-prednisolone universal external anthelmintic for dogs and cats, comprising the following steps: (1) adding 90% of the formula amount of solvent and all the co-solvents, mixing and stirring; (2) adding 60% of the formula amount of crystallization inhibitor, emulsifying and mixing, and then adding non-prednisolone and auxiliary drugs to dissolve; (3) adding other auxiliary agents, mixing evenly, adding the remaining crystallization inhibitor again, and continuing to mix and emulsify until all are dissolved; (4) adding the remaining solvent to make up to volume, stirring and emulsifying for 30 minutes to obtain the product.

[0038] Example 2

[0039] The specific implementation of this embodiment is the same as that of embodiment 1, except that: the formula contains 10% of fepronil, 6% of auxiliary drugs, and 3% of crystallization inhibitor.

[0040] Comparative Example 1

[0041] The specific implementation of this comparative example is the same as that of Example 1, except that: the formula contains 8% of fepronil, 8% of auxiliary drugs, and 1% of crystallization inhibitor.

[0042] Comparative Example 2

[0043] The specific implementation of this comparative example is the same as that of Example 1, except that the K value of the crystallization inhibitor polyvinyl pyrrolidone is 30.

[0044] Comparative Example 3

[0045] The specific implementation of this comparative example is the same as that of Example 1, except that the K value of the crystallization inhibitor polyvinyl pyrrolidone is 17.

[0046] Performance Evaluation

[0047] Stability test: Stirring test, the samples of the embodiment and comparative example were placed in a 100 mL measuring cylinder, 20 mL of pure water was added, and the mixture was vibrated evenly for 100 times. The foam volume was read after 1 minute. The smaller the volume, the better the stability performance of the drop.

[0048] Storage test: The samples prepared in the examples and comparative examples were stored in a 50° C. constant temperature box, and the time for the precipitation of the heterogeneous phase was counted during the storage process.

[0049] Table 1

[0050]

[0051]

[0052] Through the examples, comparative examples and Table 1, it can be seen that the non-pronil topical insect repellent provided by the present invention has excellent stability, can diffuse on the surface of pet skin through oil, and has excellent dispersion and efficacy. Among them, Example 1 obtains the best performance index under factors such as the best raw material ratio and preparation process.

Claims

1. A safe and highly effective non-pronil general-purpose external anthelmintic for dogs and cats, characterized in that: In terms of percentage by mass, the raw materials include: 9% of fepronil, 8% of auxiliary drugs, 5% of crystallization inhibitors, 6% of cosolvents, 2% of transdermal agents, 0.5% of antioxidants, and the balance of solvent supplements; Among them, the adjuvant is methoprene; the crystallization inhibitor is polyvinyl pyrrolidone; the K value of polyvinyl pyrrolidone is 17; the cosolvent is ethanol; the transdermal agent is azone; the antioxidant is 2,6-di-tert-butyl-p-methylphenol and tert-butyl-4-hydroxyanisole, the mass ratio of the two is 1:2; the solvent is diethylene glycol monoethyl ether; The anthelmintic comes in the form of drops; The preparation method of the safe and efficient non-prednisolone general-purpose external anthelmintic for dogs and cats comprises the following steps: (1) adding 90% of the formula amount of solvent and all the co-solvents, mixing and stirring; (2) adding 60% of the formula amount of crystallization inhibitor, emulsifying and mixing, and then adding non-prednisolone and auxiliary drugs to dissolve; (3) adding other auxiliary agents, mixing evenly, adding the remaining crystallization inhibitor again, and continuing to mix and emulsify until all are dissolved; (4) adding the remaining solvent to make up to volume, stirring and emulsifying for 30 minutes to obtain the product.

Images