A libuticaine composition, libuticaine aerosol and preparation method thereof

Abstract

The present invention relates to the field of pharmaceutical preparations, and in particular to a lidocaine composition, a lidocaine aerosol and a preparation method thereof. The lidocaine composition comprises lidocaine, tetracaine and a pharmaceutically acceptable excipient, wherein the weight ratio of the lidocaine to the tetracaine is 1:5 to 5:1, and the pharmaceutically acceptable excipient is a propellant. The composition enables the lidocaine aerosol to significantly prolong the effective time through the interaction of drugs, and the preparation process is also relatively simple.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a libuticaine composition, a libuticaine aerosol and a preparation method thereof. Background Art

[0002] Premature ejaculation (PE) is a common male sexual dysfunction that seriously affects the physical and mental health and quality of life of patients and their partners.

[0003] At present, the drugs for treating PE in China are divided into four categories: ① Selective serotonin reuptake inhibitors (SSRIs). Common SSRIs include seven types: dapoxetine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram. They are required to be taken 1-3 hours in advance and have side effects such as dizziness and nausea; ② PDE5Is: Common drugs include sildenafil, tadalafil and vardenafil. This product is indicated for impotence. Currently, there are few studies on its use in the treatment of premature ejaculation, so there is insufficient evidence that PDE5Is are effective for premature ejaculation; ③ Central analgesics: tramadol. Tramadol is not effective in the treatment of premature ejaculation. It has a significant dose-related efficacy and side effect ratio in the treatment of PE compared to placebo. Although the dose used for PE treatment (62 mg and 89 mg) is much smaller than the dose used for analgesia (up to 400 mg per day), in May 2009, the US FDA issued a warning letter about the possible addiction and dyspnea caused by tramadol; ④ Local anesthetics: This type of drug is lidocaine and / or prilocaine cream, gel or spray, which is an external preparation. The use of local anesthetics to delay ejaculation is one of the drug treatments for PE that is clearly recommended by international societies, and this product has the advantages of immediate effectiveness and few side effects.

[0004] At present, only lidocaine spray is available in China, and the treatment of PE is off-label. Most of the products for the treatment of premature ejaculation that have been marketed abroad are lidocaine or prilocaine single spray or aerosol, such as KYDuration TM , Endurance TM Spray, etc., all use a variety of excipients to assist in producing penetration-enhancing effects, such as Spray uses diethylene glycol monoethyl ether and isopropyl myristate as penetration enhancers to enhance efficacy. Endurance TM Delay For Men uses isopropyl myristate and peppermint oil as penetration enhancers to enhance efficacy. The addition of penetration enhancers will increase adverse reactions while enhancing efficacy, such as genital numbness (4.5%) and erectile dysfunction (4.4%) in male patients, vulvar burning sensation (3.9%) and genital numbness (1.0%) in female patients, etc.

[0005] Therefore, there is an urgent need for a topical preparation specifically for the treatment of PE that is effective immediately upon use and has high safety. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a libuticaine composition, a libuticaine aerosol and a preparation method thereof, so that the libuticaine aerosol can significantly prolong the effective time through the interaction of drugs, and does not need to add other excipients and the preparation process is simple.

[0007] The above object of the present invention is achieved through the following technical solutions:

[0008] In one aspect, the present invention provides a lidocaine composition, comprising lidocaine, tetracaine and a pharmaceutically acceptable excipient, wherein the weight ratio of lidocaine to tetracaine is 1:5 to 5:1, and the pharmaceutically acceptable excipient is a propellant.

[0009] The weight ratio of lidocaine to tetracaine is 1:5 to 5:1, for example, 1:5, 2:3, 3:4, 4:5 or 5:1, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0010] In some embodiments, the propellant includes one or more of tetrafluoroethane, butane, isobutane, and propane; preferably, the propellant is tetrafluoroethane.

[0011] In some embodiments, the libuticaine composition contains no other excipients besides the propellant.

[0012] It can be understood that the reduction of auxiliary materials added can reduce the difficulty of the process, reduce the irritation to the skin after the addition of other auxiliary materials, and at the same time accelerate the onset time and duration of effect.

[0013] In some embodiments, the weight ratio of lidocaine to tetracaine is 1:1.

[0014] In some embodiments, the weight portion of the propellant is 96-98 parts.

[0015] In some embodiments, the composition comprises the following components by weight:

[0016] Lidocaine 1-5 parts

[0017] Tetracaine 1-5 parts

[0018] Propellant 96-98 parts.

[0019] The weight portion of lidocaine is 1-5 parts, for example, it can be 1 part, 2 parts, 3 parts, 4 parts or 5 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0020] The weight portion of tetracaine is 1-5 parts, for example, it can be 1 part, 2 parts, 3 parts, 4 parts or 5 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0021] The weight portion of the propellant is 96-98 parts, for example, it can be 96 parts, 97 parts or 98 parts, as well as specific points between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0022] On the other hand, the present invention provides a method for preparing a lidocaine composition, comprising melting and mixing lidocaine and tetracaine under heating conditions, and then adding a propellant.

[0023] In some embodiments, the temperature of the heating condition is 45±5°C.

[0024] In a third aspect, the present invention provides a libuticaine aerosol, wherein the aerosol comprises the libuticaine composition.

[0025] In a fourth aspect, the present invention provides a method for preparing a lidocaine aerosol, the method comprising: melting and mixing lidocaine and tetracaine under heating conditions to obtain a molten mixture, then filling the molten mixture, and then filling the propellant.

[0026] In some embodiments, the temperature of the heating condition is 45±5°C.

[0027] The libuticaine aerosol provided by the present invention has the following advantages:

[0028] 1. The preparation of the present invention can significantly increase and prolong the effective time of the drug through the interaction of drugs;

[0029] 2. The preparation of the present invention does not need to add other auxiliary materials except the propellant, thus avoiding irritation to the skin caused by other auxiliary materials;

[0030] 3. The preparation process of the preparation of the present invention is relatively simple and more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a graph showing the delivery uniformity of the libuticaine aerosol prepared in Prescriptions 1-5 in Example 1;

[0032] Figure 2 This is a melting state diagram of the libuticaine aerosol prepared by Prescription 1 and Prescription 6-8 in Example 2;

[0033] Figure 3 This is a comparison diagram of the melting state of libuticaine in prescription 9 in Example 2 after filling (left) and the melting state after shaking (right);

[0034] Figure 4 This is a graph showing the uniformity of the delivery of the libuticaine aerosol prepared in Prescription 1 and Prescriptions 6-8 in Example 2;

[0035] Figure 5 This is the particle size distribution diagram of the libuticaine aerosol prepared by prescription 1 in Example 1. DETAILED DESCRIPTION

[0036] Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar modifications without violating the connotation of the present invention, so the present invention is not limited to the specific implementation disclosed below.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0038] The weight of each component mentioned in the description of the embodiments of the present invention can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of each component of the gel patch preparation is proportionally enlarged or reduced according to the description of the embodiments of the present invention, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the weight parts mentioned in the description of the embodiments of the present invention can be μg, mg, g, kg and other weight units known in the medical field, and of course can also be regarded as weight percentages.

[0039] Example 1 Investigation of the types of libuticaine aerosol propellants

[0040] Table 1 Prescription 1-Prescription 5 Prescription table

[0041]

[0042] Preparation process:

[0043] Melt and mix the prescribed amount of lidocaine and tetracaine at 45±5°C, then heat-preserve and quantitatively fill 5 mL into a 17 mL aluminum aerosol can or vial (for observing the melting state), and then fill in the prescribed amount of propellant.

[0044] Each press of the aluminum aerosol can provides 50 μL of product. The planned spray frequency is 50 presses. The delivery uniformity of libuticaine aerosols with different propellant types was observed. The delivery uniformity results of prescriptions 1-5 are as follows: Figure 1 shown.

[0045] according to Figure 1 The results show that the delivery uniformity of different types of propellants meets the requirements. Considering that tetrafluoroethane has been registered and publicized in CDE and is easy to purchase, tetrafluoroethane is preferred as the propellant.

[0046] Example 2 Investigation of the Proportion of Libucaine Aerosol Propellant

[0047] Table 2 Prescription table for prescription 6-prescription 9

[0048]

[0049] Preparation process:

[0050] Melt and mix the prescribed amount of lidocaine and tetracaine at 45±5°C, then heat-preserve and quantitatively fill 5 mL into a 17 mL aluminum aerosol can or vial (for observing the melting state), and then fill in the prescribed amount of propellant.

[0051] According to the melting state of the vial after filling, it was found that Prescription 1 and Prescriptions 6-8 were all clear solutions, while Prescription 9 was slightly turbid and became a clear solution after shaking.

[0052] Each press of the aluminum aerosol can can provide 50 μL of product. The planned spraying frequency is 50 presses. The delivery uniformity of libuticaine aerosol with different propellant ratios was observed. The delivery uniformity results of prescription 1 and prescriptions 6-8 are as follows: Figure 4 As shown (considering the risk of uneven mixing of prescription 9, the delivery uniformity at this ratio is not considered).

[0053] according to Figure 4 It can be seen that prescription 6 exceeds the upper and lower limits, and its delivery uniformity does not meet the requirements, while the other prescriptions meet the requirements. The spray state will be further investigated based on the results of the active ingredient ratio investigation.

[0054] Example 3 Investigation of the ratio of active ingredients in libuticaine aerosol

[0055] Table 3 Prescription 10-Prescription 13 Prescription table

[0056]

[0057] Preparation process:

[0058] Melt and mix the prescribed amount of lidocaine and tetracaine at 45±5°C, then heat-preserve and quantitatively fill 5 mL into a 17 mL aluminum aerosol can or vial (for observing the melting state), and then pour in the prescribed amount of tetrafluoroethane.

[0059] The efficacy test of the libuticaine aerosol prepared by prescription 1 and prescription 10-13 for the treatment of male premature ejaculation was conducted to examine the efficacy and duration. The examination method and results are as follows:

[0060] Twenty male rabbits were taken and the libuticaine aerosol prepared by prescription 1 and prescriptions 10-13 was sprayed on their genitals twice, once every 12 hours. The final test results are shown in Table 4 below.

[0061] Table 4 Results of the efficacy test on the treatment of male premature ejaculation

[0062]

[0063] According to the efficacy results, the efficacy of the libuticaine aerosol prepared according to prescription 1 was the best, so the three samples prepared according to prescription 1 were used to investigate the spray state. The Malvern SPRAYTEC equipment was used for the investigation, and the results are shown in Figure 5.

[0064] Table 5 Spray state investigation test results

[0065]

[0066] According to the experimental results, the SD values ​​of D10, D50 and D90 measured for the three samples were all less than 5, proving that the spray state of the samples prepared according to prescription 1 had good reproducibility.

[0067] Example 4 Skin irritation test

[0068] A skin irritation test was conducted on the libuticaine aerosol prepared by Prescription 1, Prescription 7, Prescription 8, Prescription 10, Prescription 11, Prescription 12, and Prescription 13: 42 rabbits weighing 3-3.5 kg (half male and half female) were divided into 7 groups and skin irritation tests were conducted separately.

[0069] 24 hours before administration, the hair on both sides of the rabbit's spine was removed, and the hair removal area on each side was 15 cm 2 24 hours after depilation, check the depilated skin condition and select rabbits with intact skin for the experiment; use the tip of a sterilized needle to scratch the depilated and sterilized rabbit skin into a cross shape, with the wound size not exceeding 10 mm. 2, pay attention to avoid bleeding. Each group has three male rabbits and three female rabbits; the left and right sides of the same body are compared, the left hair removal area is pressed once, the quantitative valve is 50μ / press, and the right hair removal area is coated with matrix as a control, fixed with gauze and adhesive tape, and the residual test substance is removed with warm water after 24 hours of application, and the test substance is removed for 1h, 24h, and 48h after the test substance is removed. Record whether there is erythema and edema at the application site, and the results are shown in Table 6 below.

[0070] Table 6 Skin irritation test results

[0071]

[0072]

[0073] This shows that aerosol spray is less irritating to the skin and wounds.

[0074] Example 5 Skin allergy test

[0075] According to the Technical Guidelines for the Study of Irritancy, Allergy and Hemolysis of Chemical Drugs, the skin allergy test was conducted on the libuticaine aerosols prepared from Prescription 1, Prescription 7, Prescription 8, Prescription 10, Prescription 11, Prescription 12 and Prescription 13:

[0076] 90 SPF guinea pigs (half male and half female) were selected, and the hair on both sides of the back spine was trimmed 24 hours before the experiment. 70 of them were used for the experimental group, and 10 were used for the blank control group and the positive control group (positive allergen: 2,4-dinitrochlorobenzene). On the 1st, 8th and 15th days of the experiment, the right hair-removed area was locally sensitized; on the 29th day of the experiment, the left hair-removed area was stimulated with drug administration, and the skin allergic reaction was observed 6h, 24h and 48h after stimulation. The results are shown in Table 7 below.

[0077] Table 7 Skin allergy test results

[0078]

[0079]

[0080] The results showed that the allergy test scores of the libuticaine aerosol prepared by prescription 1, prescription 7, prescription 8, prescription 10, prescription 11, prescription 12, and prescription 13 were all in the range of 0-0.49, which can be evaluated as non-irritating; while the average value of the stimulation reaction of the positive control group was 5.05, which was moderately irritating. This shows that the libuticaine aerosol prepared by prescription 1, prescription 7, prescription 8, prescription 10, prescription 11, prescription 12, and prescription 13 has no allergic effect on the skin.

Claims

1. A libuticaine composition, characterized in that: The invention comprises lidocaine, tetracaine and pharmaceutically acceptable excipients, wherein the weight ratio of lidocaine to tetracaine is 1:5 to 5:1, and the pharmaceutically acceptable excipient is a propellant.

2. The composition according to claim 1, characterized in that The propellant includes one or more of tetrafluoroethane, butane, isobutane and propane.

3. The composition according to claim 1, characterized in that The propellant is tetrafluoroethane.

4. The composition according to claim 1-3, characterized in that The weight ratio of lidocaine to tetracaine is 1:

1.

5. The composition according to claim 1-4, characterized in that The weight portion of the propellant is 96-98 parts.

6. The composition according to claim 1-5, characterized in that The composition comprises the following components by weight: 1-5 parts of lidocaine, 1-5 parts of tetracaine, and 96-98 parts of propellant.

7. A method for preparing the libuticaine composition according to any one of claims 1 to 6, characterized in that: Under heating conditions, lidocaine and tetracaine are melted and mixed, and then the propellant is added.

8. The preparation method according to claim 7, wherein the temperature of the heating condition is 45±5°C.

9. A libuticaine aerosol, characterized in that: The aerosol comprises the libuticaine composition according to any one of claims 1 to 6.

10. A method for preparing the libuticaine aerosol according to claim 9, characterized in that: The preparation method comprises the following steps: melting and mixing lidocaine and tetracaine under heating conditions to obtain a molten mixture, then filling the molten mixture, and then filling the propellant.

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