Terbinafine hydrochloride needleless injection, percutaneous injection for treating superficial fungal infection and administration device thereof

Abstract

The invention discloses a terbinafine hydrochloride needleless injection, a transdermal injection for treating superficial fungal infection and an administration device of the transdermal injection, belongs to the technical field of pharmaceutical preparations, and successfully develops the terbinafine hydrochloride needleless injection which takes benzyl alcohol and ethanol as auxiliary materials, the invention provides a terbinafine hydrochloride needleless injection or an injection administration device thereof, which is used for preparing the terbinafine hydrochloride needleless injection, and proves that a prescription containing low-concentration ethanol can have good safety and excellent infiltration and absorption promoting capability, and the medicine can quickly reach a focus part and has long effective action time. The invention also provides the administration device of the terbinafine hydrochloride needleless injection or the injection thereof. According to the dosing device, the replaceable injection head and the injection assembly are used, cross infection can be reduced, and the purity of liquid medicine is kept.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a needle-free injection of terbinafine hydrochloride, a percutaneous injection for treating superficial fungal infections and a drug delivery device thereof. Background Art

[0002] Onychomycosis is a disease caused by dermatophytes, yeasts and other fungi invading the nail plate and / or nail bed. Fungi have extremely strong vitality and cross-infection characteristics. If drug treatment is not persisted, the fungi are not completely killed and will multiply again in large numbers after a period of time, causing "relapse", so it is stubborn and difficult to treat.

[0003] Currently, the treatment of onychomycosis mainly includes oral medication, topical medication and other auxiliary treatment methods. Oral medications have high antibacterial activity and a broad antibacterial spectrum, but the medication cycle is long and may cause side effects. Patients may not be very accepting of oral medication.

[0004] Topical drugs are mainly concentrated in ointments, liniments, tinctures and patches based on compound Chinese medicine, supplemented by steroid hormones, which directly act on the infected nail and can reduce the side effects of systemic medication. However, due to the limitations of the permeability barrier of the nail plate and the susceptibility to the external environment, the effective ingredients are less attached, resulting in the local drug failing to reach an effective concentration or the effective maintenance time being too short. Limited by the drug's permeability barrier, the cure rate is not high. Therefore, choosing the right drug and an effective way of administration is critical.

[0005] Terbinafine hydrochloride is an active drug for clinical antifungal treatment. Currently, its dosage forms are mostly concentrated in oral preparations and topical preparations. Although there are a variety of terbinafine hydrochloride solutions (for topical use) containing ethanol excipients on the market, their ethanol content is relatively high. However, when the ethanol content exceeds 6.1%, it is no longer suitable for intradermal / subcutaneous injection. In addition, there are the following difficulties in developing its injection form:

[0006] (1) Terbinafine hydrochloride is easily soluble in methanol or ethanol, and its maximum solubility in water is 0.5%. However, during the preparation of a 0.5% terbinafine hydrochloride aqueous solution, it was found that terbinafine hydrochloride was not fully dissolved in water, and some drug particles remained on the wall of the vessel. Furthermore, after needle-free injection, terbinafine hydrochloride in the aqueous solution showed poor absorption, resulting in erythema, edema, and even ulceration at the injection site. Therefore, the solubility problem must be solved first in the development of injections.

[0007] (2) The logP value of terbinafine hydrochloride is 5.68, which shows its strong lipophilic characteristics. It is a strong lipophilic drug and is not easily absorbed. At the same time, terbinafine hydrochloride has the characteristics of low permeability and high retention after percutaneous penetration. Since terbinafine hydrochloride interacts with lipids and keratin in the stratum corneum, terbinafine hydrochloride is easy to diffuse and retain in the stratum corneum, but difficult to diffuse further from the stratum corneum into the epidermis / dermis.

[0008] Therefore, based on the existing methods, how to develop a safer, more effective, and more compliant terbinafine hydrochloride needle-free injection for the treatment of superficial fungal infections and use it correctly is of great value for practical applications. Summary of the invention

[0009] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0010] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0011] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a terbinafine hydrochloride needle-free injection.

[0012] In order to solve the above technical problems, the present invention provides the following technical solutions: comprising:

[0013] a) 0.1-0.5wt% of terbinafine hydrochloride;

[0014] b) 0.1 to 6.1 wt% of ethanol.

[0015] As a preferred embodiment of the terbinafine hydrochloride needle-free injection of the present invention, it further comprises benzyl alcohol and pharmaceutically acceptable water for injection.

[0016] As a preferred embodiment of the terbinafine hydrochloride needle-free injection of the present invention, the content of ethanol in the terbinafine hydrochloride needle-free injection is 0.57-6.1 wt %.

[0017] As a preferred embodiment of the terbinafine hydrochloride needle-free injection of the present invention, the content of benzyl alcohol in the terbinafine hydrochloride needle-free injection is 1-4 wt %.

[0018] As a preferred embodiment of the terbinafine hydrochloride needle-free injection of the present invention, the terbinafine hydrochloride needle-free injection is a colorless clear solution with a pH of 2-4.

[0019] As a preferred embodiment of the terbinafine hydrochloride needle-free injection of the present invention, the osmotic pressure of the terbinafine hydrochloride needle-free injection is 280-320 mmol / L.

[0020] Another object of the present invention is to provide a method for preparing an injection for treating superficial fungal infection using a needle-free injection of terbinafine hydrochloride.

[0021] Another object of the present invention is to provide a percutaneous injection for treating superficial fungal infection, which comprises the terbinafine hydrochloride needle-free injection.

[0022] As a preferred embodiment of the percutaneous injection for treating superficial fungal infection of the present invention, the injection is absorbed through percutaneous injection and has no irritation to the local skin at the injection site.

[0023] Another object of the present invention is to provide a drug delivery device for percutaneous injections.

[0024] In order to solve the above technical problems, the present invention provides the following technical solutions: a connected needle-free syringe, comprising:

[0025] A housing 201, and a handle 202 disposed at the bottom of a side wall of the housing 201;

[0026] The dosage adjustment component 203 is linked with the pneumatic component 204. The extension length of the rotary plug 203a provided at the end of the dosage adjustment component 203 is adjustable, thereby realizing the control of the injection amount of the liquid medicine;

[0027] The pneumatic component 204 cooperates with the dosage adjustment component 203 to complete the injection of the drug solution;

[0028] The end of the housing 201 is detachably mounted with an injection assembly 205, and a striker 204b disposed at the end of the pneumatic assembly 204 penetrates the inner side of the injection assembly 205;

[0029] The handle 202 includes an air cavity 202a, a limiting cavity 202b and a sliding cavity 202c;

[0030] The linkage member 102 passes through the limiting cavity 202b and extends to the outside thereof; the pressing member 103 slides along the inner wall of the sliding cavity 202c.

[0031] Beneficial effects of the present invention:

[0032] The present invention successfully develops a needle-free injection of terbinafine hydrochloride, using benzyl alcohol and ethanol as excipients, and proves that a prescription containing a relatively low concentration of ethanol can have good safety and excellent penetration and absorption promoting abilities, and the drug can quickly reach the lesion site and has a long effective action time. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0034] Figure 1 This is a diagram of the intradermal irritation results of the terbinafine hydrochloride needle-free injection formulations with different penetration enhancers according to Example 1 of the present invention (before dissection).

[0035] Figure 2 This is a diagram showing the intradermal irritation results of the terbinafine hydrochloride needle-free injection formulations with different penetration enhancers according to Example 1 of the present invention (after autopsy).

[0036] Figure 3 Schematic diagram of the method of taking A in the experiment of Example 2 of the present invention.

[0037] Figure 4 This is a graph showing the results of terbinafine hydrochloride content in the nails and nail beds of large-eared rabbits in the experiment of Example 3 of the present invention.

[0038] Figure 5 This is a graph showing the results of a local irritation experiment of Example 3 of the present invention.

[0039] Figure 6 This is a graph showing the results of terbinafine hydrochloride content in the nails and nail beds of large-eared rabbits in the experiment of Example 4 of the present invention.

[0040] Figure 7 This is a graph showing the results of the terbinafine hydrochloride content in serum and nail in the experiment of Example 5 of the present invention.

[0041] Figure 8 This is a schematic diagram of rabbit nail sample collection in the experiment of Example 6 of the present invention.

[0042] Fig. 9 This is a schematic diagram of the terbinafine hydrochloride content in rabbit shells in the experiment of Example 6 of the present invention.

[0043] Fig.10 This is a schematic diagram of the material collection requirements in the experiment of Example 7 of the present invention.

[0044] Fig.11 This is a graph showing the results of detecting the drug content of terbinafine hydrochloride in different skin areas in the experiment of Example 7 of the present invention.

[0045] Fig.12 Result diagram of transdermal permeation curves of different terbinafine hydrochloride drugs in the experiment of Example 8 of the present invention.

[0046] Fig.13 This is a cross-sectional view of the needle-free syringe connection according to Example 9 of the present invention. DETAILED DESCRIPTION

[0047] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0048] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0049] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0050] Unless otherwise specified, the raw materials used in the present invention are all commercially available in the art, as shown in Table 1.

[0051] Table 1

[0052]

[0053]

[0054] The physicochemical properties of the active substance terbinafine hydrochloride used in the present invention are shown in Table 2.

[0055] Table 2

[0056]

[0057] Example 1

[0058] This example is used to explore the intradermal irritation and absorption of terbinafine hydrochloride needle-free injection formulations containing different penetration enhancers. Japanese big-eared rabbits are used as animal models. Terbinafine hydrochloride needle-free injection formulations containing different penetration enhancers are injected into the back skin without a needle to observe the irritation of the drug to the skin under different penetration enhancer formulations. Specifically:

[0059] 1) Preparation of injection drugs (dosage):

[0060] The injection prepared with water was used as the irritation positive group, and the injection with normal saline was used as the irritation negative group. The prescriptions of the needle-free injection containing different penetration enhancers, terbinafine hydrochloride, were as follows:

[0061] ①0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol / water for injection;

[0062] ②0.5% terbinafine hydrochloride / 3.9% Tween 80 / 2% benzyl alcohol / water for injection;

[0063] ③0.5% terbinafine hydrochloride / 3.11% sulfobutyl beta-cyclodextrin sodium / 2% benzyl alcohol / water for injection;

[0064] ④0.5% terbinafine hydrochloride / 3.2% polyethylene glycol 300 / 2% benzyl alcohol / water for injection;

[0065] ⑤0.5% terbinafine hydrochloride / 2% benzyl alcohol / water for injection;

[0066] ⑥0.5% terbinafine hydrochloride / 1.26% poloxamer 188 / 2% benzyl alcohol / water for injection.

[0067] At this time, 0.5% terbinafine hydrochloride was fully dissolved in each group.

[0068] 2) Grouping and methods:

[0069] Three Japanese big-eared rabbits were prepared, and the back skin of the experimental rabbits was divided into sections, and the drugs were administered in the following order from top to bottom: ① 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol / water for injection; ② 0.5% terbinafine hydrochloride / 3.9% Tween 80 / 2% benzyl alcohol / water for injection; ③ 0.5% terbinafine hydrochloride / 3.11% sulfobutyl beta-cyclodextrin sodium / 2% benzyl alcohol / water for injection; ④ 0.5% terbinafine hydrochloride / 3.2% polyethylene glycol 300 / 2% benzyl alcohol / water for injection; ⑤ 0.5% terbinafine hydrochloride / 2% benzyl alcohol / water for injection; ⑥ 0.5% terbinafine hydrochloride / 1.26% poloxamer 188 / 2% benzyl alcohol / water for injection; ⑦ normal saline, and the skin irritation was observed at 0h and 24h after injection. After the observation, the back skin was dissected to observe the drug absorption.

[0070] The results are as follows Figure 1 , Figure 2 As shown, Figure 1 For skin irritation before autopsy, Figure 2 This is the skin irritation after autopsy. It can be seen that 24 hours after injection, the terbinafine aqueous solution in the positive group was the most irritating, causing erythema and edema of the skin tissue, while there was no abnormality in the negative saline group. By touching and observing the injection point, the foreign body sensation of the penetration enhancers ethanol, Tween, and poloxamer was relatively mild, and the drug absorption was good. When the penetration enhancers were ethanol, Tween, and poloxamer, the skin showed relatively mild irritation, so they can be used as alternative penetration enhancers.

[0071] Example 2

[0072] This example further explores the drug absorption of terbinafine hydrochloride needle-free injection prescriptions containing different penetration enhancers through pharmacokinetics. Using Japanese big-eared rabbits as animal models, terbinafine hydrochloride needle-free injections containing different penetration enhancers were injected into both sides of the toes without needles. By detecting the drug content in the experimental rabbit nails, a penetration enhancer screening study for injection prescriptions was carried out. Specifically:

[0073] 1) Grouping

[0074] Divide the Japanese jackrabbit into 4 groups:

[0075] Group A: 4 rabbits, nail samples were collected 4 hours after injection, and 4 drugs were injected, namely 0.5% terbinafine hydrochloride / 2% benzyl alcohol, 0.5% terbinafine hydrochloride / 0.6% ethanol / 2% benzyl alcohol, 0.5% terbinafine hydrochloride / 0.2% Tween 80 / 2% benzyl alcohol and 0.5% terbinafine hydrochloride / 15% poloxamer / 2% benzyl alcohol. The first finger of the forelimb was injected, and the fourth toe of the hindlimb was injected. The four drugs were injected in a counterclockwise direction on one experimental rabbit to reduce the detection effect caused by the difference between the front and back nails;

[0076] Group B: 4 mice, samples were taken 12 hours after injection, and the injection method was the same as that of group A;

[0077] Group C: 4 mice, samples were collected 24 hours after injection, and the injection method was the same as that of group A;

[0078] Group D: 2 mice, blank control group, no drug was injected and only the A samples were collected.

[0079] 2) Methods

[0080] Fourteen Japanese big-eared rabbits were prepared. After anesthesia, the hair on both sides of the toes was removed using an electric shaving shaving machine. Care should be taken not to cause skin damage or redness during shaving. Then, the drugs were injected according to the groups. 0.1 mg (calculated according to the content of terbinafine hydrochloride) was administered to each nail. The model nails were removed using sterile forceps and surgical scissors at 4 h, 12 h, and 24 h after administration. The method of removing the nails was referred to Figure 3 (The left side is the internal nail bed tissue, and the right side is the external nail tissue). The nail shell and nail bed were separated, treated with sterile saline, placed in a centrifuge tube, and stored at -20°C. Finally, HPLC-MS / MS was used to detect the content of terbinafine hydrochloride in the nail. The results are as follows Figure 4 shown.

[0081] Figure 4 (a) is the content of terbinafine hydrochloride in the rabbit beetle, Figure 4 (b) is the content of terbinafine hydrochloride in the nail bed of big-eared rabbits. According to the test results, among the three penetration enhancers studied, ethanol has the highest content of terbinafine hydrochloride in the nail and nail bed.

[0082] Example 3

[0083] This example is used to explore the effect of a diol system composed of different alcohols and ethanol on the prescription performance of terbinafine hydrochloride needle-free injection, specifically:

[0084] ① Prescription selection for ethanol / polyethylene glycol system injection:

[0085] 1%, 2% and 3% polyethylene glycol were added to 0.5% terbinafine hydrochloride / 0.57% ethanol solution respectively. The results showed that there was no significant change in the solution when 1% polyethylene glycol was added; when 2% polyethylene glycol was added, the solution was slightly milky white; and when 3% polyethylene glycol was added, the solution turned white. Based on the above results, the composition of the subsequent experimental prescription was selected as 0.5% terbinafine hydrochloride / 0.57% ethanol / 1% polyethylene glycol;

[0086] ② Selection of ethanol / propylene glycol injection formula: The experiment found that the concentration of propylene glycol had no correlation with the ability to dissolve terbinafine hydrochloride. At the same time, the FDA indicated that the maximum dosage of propylene glycol for subcutaneous injection was 1.4%. The composition of the subsequent experimental formula was 0.5% terbinafine hydrochloride / 0.57% ethanol / 1.4% propylene glycol.

[0087] Local irritation test:

[0088] Using Bama pigs as animal models, needle-free injection was performed on the abdominal skin, with 25 μl of drug administered at a single point. Skin irritation was observed after 48 hours. The injected drugs were as follows from top to bottom:

[0089] 0.5% terbinafine hydrochloride / 0.57% ethanol / 1.4% propylene glycol;

[0090] 0.5% terbinafine hydrochloride / 0.57% ethanol / 1% polyethylene glycol;

[0091] 0.5% terbinafine hydrochloride aqueous solution;

[0092] 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol.

[0093] The results are as follows Figure 5 As shown in the figure, 48 hours after injection, the aqueous solution positive group showed obvious edema and erythema, indicating the presence of skin irritation. It can be clearly seen from the figure that the severity of skin irritation is: ethanol / benzyl alcohol < ethanol / propylene glycol < ethanol / polyethylene glycol. Based on this, subsequent experiments further explored the injection compliance of ethanol / propylene glycol and ethanol / benzyl alcohol systems

[0094] Pain test

[0095] Using SD rats as an animal model, the drug was injected into the rat's paw. The specific operation was a single administration of 10μl, for a total of 3 times, and the compliance of the injection solution was comprehensively evaluated. When SD rats received the injection and felt pain, they usually showed reactions such as arched back behavior, intense screaming, and reduced social behavior.

[0096] The specific operation was as follows: the left hind paw was injected with normal saline without a needle as the control group, and the right hind paw was injected with two diol systems (ethanol / propylene glycol and ethanol / benzyl alcohol system) without a needle, and the reactions of SD rats were recorded. The results are shown in Table 3.

[0097] Table 3

[0098]

[0099] When the control group was injected with saline, the SD rats had no abnormal behavior and almost no reaction; however, when injected with ethanol / propylene glycol, the SD rats made intense calls and arched their backs after administration. After the administration, the SD rats initially took a supine position to avoid secondary pressure on the soles of their feet, and then gradually returned to normal, and began to lick their paws, wash their faces, comb their hair, etc. These observations showed that after the injection of the ethanol / propylene glycol system injection, the SD rats showed obvious pain reactions and poor compliance. Similarly, the SD rats injected with saline on the left hind paw as the control group had no significant abnormal behavior and almost no reaction after administration; while when the ethanol / benzyl alcohol injection was injected on the right hind paw, although there was occasional weak calls, the SD rats did not show other abnormal behaviors as a whole. Therefore, ethanol / benzyl alcohol showed better compliance.

[0100] A comprehensive comparison of three prescription systems, 0.5% terbinafine hydrochloride / 0.57% ethanol / 1.4% propylene glycol, 0.5% terbinafine hydrochloride / 0.57% ethanol / 1% polyethylene glycol, and 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, is shown in Table 4.

[0101] Table 4

[0102]

[0103] The comprehensive evaluation results show that the most feasible excipient composition for terbinafine hydrochloride as injection is ethanol / benzyl alcohol diol system.

[0104] Combined with the analysis of Example 2, ethanol and benzyl alcohol can constitute a diol plastid transdermal drug delivery system, which has the characteristics of stable properties, high bioavailability, and sustained release. The combined use of ethanol and benzyl alcohol in this patent enhances the stability, safety, and penetration and absorption ability of terbinafine hydrochloride needle-free injection, and the effect is more excellent compared with other diol combinations.

[0105] Example 4

[0106] This example is used to explore the hemolysis of terbinafine hydrochloride needle-free injection prescriptions with different ethanol concentrations, specifically:

[0107] 1) Preparation of 2% red blood cell suspension

[0108] Take an appropriate amount of whole blood from a healthy rabbit, stir the blood with a glass rod, remove fibrinogen, and make it defibrillated blood. Add about 10 times the amount of 0.9% sodium chloride solution, shake well, centrifuge at 1500 rpm for 15 minutes, remove the supernatant, and wash the precipitated red blood cells with 0.9% sodium chloride solution at least 3 times according to the above method until the supernatant is no longer red. Prepare the obtained red blood cells into a 2% suspension with 0.9% sodium chloride solution, store at 2-8℃, and use it later.

[0109] 2) Hemolysis and agglutination test

[0110] Take clean colorimetric tubes and number them. Tube 1 is the negative control tube, tube 2 is the positive control tube (complete hemolysis control), and the rest are test sample groups. Add 2% red blood cell suspension, normal saline, purified water, and test sample in sequence as shown in the table below;

[0111] The final concentration of ethanol in the test solution is 2.0%, 4.0%, 6.0%, 8.0%, 10.0%, 12.0%, 15.0%, and 20.0%. See Table 5 below for specific information.

[0112] Table 5

[0113]

[0114] After the sample is mixed, it is immediately placed in a constant temperature incubator at (37±0.5)°C for incubation. It is observed every 15 minutes at first. After 1 hour, it is observed every 1 hour for 3 hours. The results are shown in Table 6 below.

[0115] Table 6

[0116]

[0117]

[0118] From the results in the above table, we can see that ethanol concentration within 10% has little effect on blood cells and no hemolysis occurs. When the ethanol concentration reaches above 12%, the blood gradually changes, the blood color begins to darken and finally the blood clots. Therefore, ethanol concentration within 10% is considered a safe concentration.

[0119] In summary, from Examples 1 to 3, combined with non-clinical safety evaluation and drug absorption tests, in the study of three penetration enhancers, ethanol has no skin irritation, no hemolysis within 10% ethanol content, and exhibits excellent penetration and absorption promoting abilities. Therefore, ethanol is preferably used as one of the excipient components in the prescription of terbinafine hydrochloride needle-free injection.

[0120] Example 5

[0121] This example is used to explore the drug absorption of terbinafine hydrochloride needle-free injection prescriptions containing different ethanol concentrations. Japanese big-eared rabbits are used as animal models. Terbinafine hydrochloride needle-free injections containing different ethanol contents are injected into both sides of the toes without needles. By detecting the drug content in the experimental rabbit nails, the ethanol content screening study of the injection prescription is carried out. Specifically:

[0122] 1) Injection of medication

[0123] Hemolysis experiments show that ethanol is safe within 10%. At the same time, the maximum unit dose of ethanol subcutaneous injection approved by the FDA inactive ingredient database is 6.1% (v / v), so the ethanol content in the prescription of terbinafine hydrochloride needle-free injection should not exceed 6.1%. In addition, it has been found through research that the minimum ethanol content required to completely dissolve terbinafine hydrochloride is 0.57%, so the ethanol content range explored is 0.57-6.1%, and the injection drugs are:

[0124] 0.5% terbinafine hydrochloride / 2% benzyl alcohol;

[0125] 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol;

[0126] 0.5% terbinafine hydrochloride / 3% ethanol / 2% benzyl alcohol;

[0127] 0.5% terbinafine hydrochloride / 6% ethanol / 2% benzyl alcohol.

[0128] 2) Grouping

[0129] Divide the Japanese jackrabbit into 3 groups:

[0130] Group A: 4 rabbits, samples were taken 4 hours after injection, and 4 drugs were injected, namely 0.5% terbinafine hydrochloride / 2% benzyl alcohol, 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, 0.5% terbinafine hydrochloride / 3% ethanol / 2% benzyl alcohol and 0.5% terbinafine hydrochloride / 6% ethanol / 2% benzyl alcohol. The first finger of the forelimb was injected, and the fourth toe of the hindlimb was injected. 0.1 mg was administered to a single nail (calculated according to the content of terbinafine hydrochloride). The four drugs were injected in a counterclockwise direction on one experimental rabbit to reduce the detection effect caused by the difference between the front and back nails.

[0131] Group B: 4 mice, samples were collected 24 hours after injection, the method was the same as that of Group A;

[0132] Group C: 2 mice, blank nails, no drug injection, only nail samples were collected.

[0133] 3) Methods

[0134] Ten Japanese big-eared rabbits were prepared. After anesthesia, the hair on both sides of the toes was removed using an electric shaving shaving machine. Be careful not to cause skin damage or redness when shaving. Then the nails were injected according to the grouping. Sterile forceps and surgical scissors were used to remove the model nails 4h and 24h after administration, and the nail shell and nail bed were separated. After being treated with sterile saline, they were placed in a centrifuge tube and stored at -20℃. Finally, HPLC-MS / MS was used to detect the content of terbinafine hydrochloride in the nails. The results are as follows: Figure 6 shown.

[0135] Figure 6 (a) is the content of terbinafine hydrochloride in the rabbit beetle, Figure 6 (b) is the content of terbinafine hydrochloride in the nail of the big-eared rabbit. According to the test results, when the ethanol concentration is 0.57%, the content of terbinafine hydrochloride in the nail / nail bed is the highest. However, after the t test, it was found that there was no significant difference between the three groups of data, so it is better to choose a small dose of 0.57% ethanol.

[0136] Example 6

[0137] This example is used to explore the drug absorption of terbinafine hydrochloride needle-free injection prescriptions with different terbinafine hydrochloride (API) contents, and to conduct a screening study on the terbinafine hydrochloride content of the needle-free injection prescription by detecting the drug content in the fingernails / toenails and plasma of experimental rabbits.

[0138] 1) Grouping:

[0139] Divide the Japanese jackrabbit into 4 groups:

[0140] Group A: 8 rats, 4 for nail sample collection and 4 for plasma sample collection. The injected drug was 0.1% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, injected into the first nail of the forelimb and the fourth toe of the hindlimb, and 20 μl was administered to each nail.

[0141] Group B: 8 rats, 4 for collecting A samples and 4 for collecting plasma samples. The injection drug was 0.3% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, and the method was the same as that of Group A;

[0142] Group C: 8 rats, 4 for collecting A samples and 4 for collecting plasma samples. The injection drug was 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, and the method was the same as that of Group A;

[0143] Group D: 2 mice, blank nails, no drug injection, only nail samples were collected.

[0144] 2) Methods

[0145] Fourteen Japanese big-eared rabbits were prepared. After anesthesia, the hair on both sides of the toes was removed using an electric shaver. Care should be taken not to damage or redden the skin during shaving. Then, the drug was injected according to the grouping, with 20 μl injected into each finger.

[0146] 3) Collect samples

[0147] Collecting plasma samples

[0148] Four experimental rabbits were selected from group A / B / C. 1 ml of blood was collected from the rabbit ear vein using a blood collection needle and anticoagulant tube before injection, 0.5 h, 1 h, 4 h and 8 h, respectively. The collected plasma samples were centrifuged at 4000 rpm for 15 min, and the supernatant serum was stored at -20°C.

[0149] Collecting nail samples

[0150] For the remaining experimental rabbits in groups A / B / C / D, surgical scissors and sterile tweezers were used to remove the model nails 1 hour after administration, and the nail shell and nail bed were separated. After being treated with sterile saline, they were placed in centrifuge tubes and stored at -20°C.

[0151] 3) Results

[0152] The content of terbinafine hydrochloride in plasma was detected by HPLC-MS / MS. Figure 7 shown.

[0153] Figure 7 (a) The results of testing the content of terbinafine hydrochloride in serum showed that the drug content was almost undetectable in the 0.1% API prescription, while in the 0.5% API prescription, the drug concentration reached a peak of 4.93ng / ml at 0.5h and then began to decrease. Literature data show that after oral administration of 0.25g of terbinafine hydrochloride tablets, the average peak plasma concentration reached 1.3mg / ml after 1.5h, which is about 260,000 times that of local injection. In contrast, the plasma concentration of local injection is significantly lower than that of oral administration.

[0154] Figure 7 (b) The results of drug content in A showed that the terbinafine hydrochloride content in the prescription was positively correlated with the terbinafine hydrochloride content in A. When the terbinafine hydrochloride content in the prescription was 0.5%, the drug content in A was 0.38 μg / ml, indicating that the drug was rapidly distributed to the lesion site (A) 1 hour after local injection.

[0155] The above results demonstrate that local injection can effectively deliver terbinafine hydrochloride to the lesion site while reducing systemic drug exposure, thereby potentially reducing side effects and improving toxicity issues.

[0156] Example 7

[0157] This example is used to explore the periarticular PK of a terbinafine hydrochloride needle-free injection of 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, specifically:

[0158] 1) Grouping

[0159] Japanese jack-eared rabbits were divided into 7 groups;

[0160] Group A: 4 mice, nail samples were collected 1 day after needle-free injection. The injection drug was 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol, the injection site was the first finger of the forelimb, and the fourth toe of the hindlimb, and 0.1 mg was administered per nail (calculated according to the content of terbinafine hydrochloride) to reduce the detection effect caused by the difference between the front and back nails;

[0161] Group B: 4 mice, samples were collected 3 days after injection, and the injection method was the same as that of group A;

[0162] Group C: 4 mice, samples were taken 5 days after injection, and the injection method was the same as that of group A;

[0163] Group D: 4 mice, samples were collected 10 days after injection, and the injection method was the same as that of group A;

[0164] Group E: samples were collected 20 days after injection, and the injection method was the same as that of Group A;

[0165] Group F: samples were collected 30 days after injection, and the injection method was the same as that of Group A;

[0166] Group G: 2 mice, blank control group, no drug injection, only nail samples were collected.

[0167] 2) Methods

[0168] 26 Japanese big-eared rabbits were prepared. After anesthesia, the hair on both sides of the toes was removed using an electric shaver. Be careful not to damage or redden the skin when shaving. Then the rabbits were injected according to the grouping. The rabbits were given the following injections on the 1st, 3rd, 5th, 10th, 20th, and 30th days after administration: Figure 8 As shown in the figure, rabbit nail samples were collected, and the model nail was removed using sterile tweezers and surgical scissors. After being treated with sterile saline, it was placed in a centrifuge tube and stored at -20°C. Finally, HPLC-MS / MS was used to detect the content of terbinafine hydrochloride in the nail. The results are shown in the figure. Fig. 9 shown.

[0169] It can be seen that high concentrations of the drug can be detected on the first day after injection, indicating that the drug diffuses rapidly in the rabbit nail; the content of terbinafine hydrochloride reaches a peak on the 10th day after injection; the drug content is 290 ng / g on the 30th day after injection, which is higher than the MIC90 of dermatophytes (the literature indicates that the MIC90 of dermatophytes = 0.25 μg / ml). The above results indicate that terbinafine hydrochloride can maintain an effective concentration locally in the Japanese big-eared rabbit nail for at least 30 days.

[0170] Example 8

[0171] Considering the physiological and anatomical similarities between Bama pigs and humans, and pig skin has been used as a good transdermal model for the study of key parameters such as drug permeability in the skin, which can more accurately predict the absorption and distribution of drugs in the human body, this example uses Bama pigs as an animal model to further study the local absorption of 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol terbinafine hydrochloride needle-free injection. Specifically:

[0172] Bama pigs were used as animal models. 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol were injected without needles. The distribution range of the drug in the skin tissue at the injection site and the local concentration of the drug were studied 1h, 4h, 8h, and 24h after administration. 0.05mg was administered at a single point. Two parallel samples were set for each concentration at each time point of the experiment.

[0173] After the animals were given the drug, the local skin tissue at the injection site was dissected and sampled to detect the content of terbinafine hydrochloride in the skin. The sample collection requirements are as follows: Fig.10 As shown in the figure, the skin at the injection site was dissected. A circular skin tissue with a diameter of 2 cm was cut with the injection port as the center. Then the skin tissue was divided into Fig.10 The skin samples were cut into ①②③④⑤ areas with the outer edge as the point and the interval of 0.2cm, and then the drug content of terbinafine hydrochloride was tested for these five samples.

[0174] Test results such as Fig.11As shown in the figure, it can be seen that after local injection, the drug can diffuse from the injection point to the surrounding area. A large amount of terbinafine hydrochloride was detected at the 5mm position 1h after injection, with a content of 1762.25ng / g. It may be because the sampling time was too short that only a trace amount of terbinafine hydrochloride was detected at the 25mm position; as time goes by, the drug further diffuses to the surrounding area of ​​the injection point. At 8h after injection, 276.54ng / g of terbinafine hydrochloride was detected at the 25mm position. At 24h after injection, the drug content at the 25mm position increased to 352.53ng / g. The drug content at the 25mm position at 8h and 24h was higher than the MIC90 (0.250μg / ml) of dermatophytes, indicating that terbinafine hydrochloride can exert an antifungal therapeutic effect within 25mm of the injection site; it can also be seen from the figure that the terbinafine hydrochloride content at each distance point 24h after injection is higher than that at 1h after injection, indicating that the drug is still continuing to diffuse to the surrounding area within 24h.

[0175] In summary, the local absorption of terbinafine hydrochloride was evaluated using Bama pigs as an animal model. It was found that terbinafine hydrochloride diffused at least 25 mm around the injection point and could maintain an effective antibacterial concentration (greater than MIC90 of dermatophytes = 0.250 μg / ml) for at least 24 hours.

[0176] Example 9

[0177] This example compares the transdermal absorption capacity of terbinafine hydrochloride cream and injection by in vitro Franz absorption cell method, specifically:

[0178] 1) Methods

[0179] Healthy male mice weighing 200±20g were selected, and the abdominal skin hair was shaved. It was necessary to be careful not to scratch or damage the stratum corneum of the skin. They were divided into a terbinafine hydrochloride cream application group (calculated as 1.83mg according to the terbinafine hydrochloride content) and a needle-free intradermal injection group (calculated as 0.5mg according to the terbinafine hydrochloride content). After administration, they were quickly killed, and a 2.5×2.5cm injection site skin was taken with a scalpel, and the outer surface of the skin was rinsed with normal saline to avoid contamination of the skin with blood. Note that the skin integrity is maintained when taking the skin, that is, the stratum corneum, epidermis and dermis are all completely separated together.

[0180] 2) Transdermal penetration test

[0181] Add receiving solution to the receiving chamber of the Franz diffusion cell, place the treated mouse skin between the receiving chamber and the sample chamber, ensure that the mouse skin is in full contact with the receiving solution without bubbles, add an appropriate amount of PBS to the sample chamber to ensure that the rat skin is moist, stir magnetically at 200 rpm / min, 32°C ± 1°C, sample 2 ml at 2, 4, 6, 18, 24, and 27 hours, and immediately add the corresponding volume of receiving solution after sampling. Use liquid phase to determine the content of terbinafine hydrochloride in the sample.

[0182] 3) Results

[0183] The permeation curve was drawn with cumulative permeability as the ordinate and time as the abscissa. The results are shown in Fig.12 As shown in the chart, the higher the cumulative permeability, the stronger the ability of the drug to penetrate the skin (stratum corneum, epidermis and dermis). It can be seen that the cumulative permeability of the cream application group in 27 hours was 10.21%, while the cumulative permeability of the intradermal injection group was as high as 71.86%, a difference of about 7 times. This result shows that the needle-free injection of terbinafine hydrochloride has a significant advantage in transdermal absorption.

[0184] Based on the above results, the optimal formulation of the terbinafine hydrochloride needle-free injection of the present invention is 0.5% terbinafine hydrochloride / 0.57% ethanol / 2% benzyl alcohol / water for injection. The physicochemical properties of the injections prepared in different batches were measured, and the results are shown in Table 7.

[0185] Table 7

[0186] batch Osmotic pressure (m0sm) pH First batch 313 3.09 Second batch 282 3.04 The third batch 320 3.08

[0187] After testing, all the physical and chemical properties of the prescription of the present invention meet the current drug standards for injection.

[0188] Example 10

[0189] The terbinafine hydrochloride needle-free injection / percutaneous injection in the present invention can be injected through any commercially available needle-free syringe. This embodiment only provides a feasible continuous needle-free syringe, specifically:

[0190] Reference Fig.13 This embodiment provides a continuous needle-free injector for injecting the needle-free injection / percutaneous injection of terbinafine hydrochloride of the present invention.

[0191] In this embodiment, it includes a housing 201, a grip 202, a dose adjustment component 203, a pneumatic component 204 and an injection component 205;

[0192] The housing 201 is a metal plate structure, and the angle between the handle 202 and the housing 201 is greater than ninety degrees; preferably one hundred degrees; the angle is an obtuse angle so that it is easier to operate and hold the device, giving the operator a better experience during the operation.

[0193] The handle 202 includes an air cavity 202a opened therein, and an air pipe is connected to the end of the air cavity 202a; high-pressure gas can enter the air cavity 202a through the air pipe. Furthermore, the outer wall of the handle 202 is provided with a depression.

[0194] The dosage adjustment component 203 includes a rotating plug 203a, a feed screw sleeve 203b, a connecting sleeve 203c and a balancing valve 203d. The rotating plug 203a is arranged in the middle of the feed screw sleeve 203b, the connecting sleeve 203c is arranged on the outer ring of the feed screw sleeve 203b, and the balancing valve 203d is arranged between the pneumatic component 204 and the rotating plug 203a. The connecting sleeve 203c and the balancing valve 203d are coaxially matched.

[0195] It should be noted that a silencer is provided at the end of the rotary plug 203a, and the silencer is provided on the side of the rotary plug 203a. The groove in the middle of the feed screw sleeve 203b is slidably matched with the rotary plug 203a. An adjusting rod is connected to the end of the feed screw sleeve 203b. The adjusting rod passes through the connecting sleeve 203c and the balancing valve 203d and contacts the right end of the pneumatic component 204. A second spring is provided on the outside of the balancing valve 203d, and the second spring is coaxially matched with the balancing valve 203d.

[0196] Furthermore, the pneumatic component 204 includes a piston 204a and a striker rod 204b, the piston 204a is arranged on the side of the striker rod 204b, and the connecting sleeve 203c is arranged on the other side of the striker rod 204b; a spring is arranged at the end of the piston 204a, and the piston 204a slides inside the sleeve arranged inside the shell 201.

[0197] In this embodiment, the connecting sleeve 203c divides the right side and the left side of the outer shell 201 and forms a closed first chamber on the right side. The side wall of the connecting sleeve 203c is provided with an air hole. The connecting sleeve 203c and the balancing valve form a second chamber. The first chamber and the second chamber are connected through the air hole.

[0198] Furthermore, the right end of the balance valve 203d can contact the left end of the piston 204a, and a rubber sealing gasket is provided at the contact position between the two.

[0199] Furthermore, during the spiral feeding process, the left end of the feed screw sleeve 203b contacts the right end of the piston 204a; as the feed screw sleeve 203b extends through the balancing valve 203d, the gap between the piston 204a and the balancing valve 203d becomes larger; at the same time, the right end of the outer sleeve of the pneumatic component 204 contacts the balancing valve 203d; thereby, a fourth chamber can be formed between the piston 204a and the balancing valve 203d.

[0200] Furthermore, the injection assembly 205 includes an injection head 205d, a docking head and a push block in an integrated structure. The docking head is engaged with the top cone. When the top cone is reset, the push block is pulled backward to generate a negative pressure effect in the cavity to be injected, so that the sealing ball compresses the spring that cooperates with it, and the liquid medicine flows out of the bracket to fill the cavity to be injected. At this time, the one-way rubber plug of the injection head 205d is affected by the negative pressure, and the outer wall of the one-way rubber plug is stretched open, and the injection head end forms a seal. Before pushing the injection, the protective cap and the bracket need to be removed from the device, and then the syringe filled with liquid medicine is installed to the position where the bracket is installed, and then the injection is pushed.

[0201] In summary, the present invention successfully developed a needle-free injection of terbinafine hydrochloride, using benzyl alcohol and ethanol as excipients, proving that a prescription containing a lower concentration of ethanol can have good safety and excellent penetration and absorption promoting abilities, and the drug can quickly reach the lesion site and has a long effective action time.

[0202] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A terbinafine hydrochloride needle-free injection, characterized in that: contain: a) 0.1-0.5wt% of terbinafine hydrochloride; b) 0.1 to 6.1 wt% of ethanol.

2. The terbinafine hydrochloride needle-free injection according to claim 1, characterized in that: It also includes benzyl alcohol, and pharmaceutically acceptable water for injection.

3. The terbinafine hydrochloride needle-free injection according to claim 1, characterized in that: The content of ethanol in the terbinafine hydrochloride needle-free injection is 0.57-6.1 wt %.

4. The terbinafine hydrochloride needle-free injection according to claim 1, characterized in that: The content of benzyl alcohol in the terbinafine hydrochloride needle-free injection is 1-4 wt %.

5. The terbinafine hydrochloride needle-free injection according to claim 4, characterized in that: The terbinafine hydrochloride needle-free injection is a colorless clear solution with a pH value of 2-4.

6. The terbinafine hydrochloride needle-free injection according to claim 5, characterized in that: The osmotic pressure of the terbinafine hydrochloride needle-free injection is 280-320 mmol / L.

7. Effect of the terbinafine hydrochloride needle-free injection according to any one of claims 1 to 6 in the preparation of an injection for treating superficial fungal infections.

8. A percutaneous injection for treating superficial fungal infections, characterized in that: A needle-free injection of terbinafine hydrochloride comprising any one of claims 1 to 6.

9. The percutaneous injection for treating superficial fungal infection according to claim 8, characterized in that: The injection is absorbed through skin injection and has no irritation to the local skin at the injection site.

10. A transdermal injection drug delivery device, characterized in that: The drug delivery device is a needle-free syringe, which comprises: A housing (201), and a handle (202) disposed at the bottom of a side wall of the housing (201); A dosage adjustment component (203) is linked to the pneumatic component (204); the extension length of the rotary plug (203a) provided at the end of the dosage adjustment component (203) is adjustable, thereby realizing control of the injection volume of the liquid medicine; The pneumatic component (204) cooperates with the dosage adjustment component (203) to complete the injection of the drug solution; An injection assembly (205) is detachably mounted on the end of the housing (201), and a striker (204b) disposed on the end of the pneumatic assembly (204) penetrates the inner side of the injection assembly (205); The handle (202) comprises an air cavity (202a), a limiting cavity (202b) and a sliding cavity (202c); The linkage member (102) passes through the limiting cavity (202b) and extends to the outside thereof; the pressing member (103) slides along the inner wall of the sliding cavity (202c).

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