A rapid delivery melatonin transdermal delivery system

Abstract

The application discloses a quick and efficient melatonin transdermal delivery system, which is characterized by comprising the following structures arranged from top to bottom: at least one protective layer; at least one polymer base layer; and a multilayer structure of an anti-adhesion layer; wherein the polymer base layer comprises the following components by weight: compared with the prior art, the system has the following beneficial effects: compared with oral use of melatonin, the melatonin efficient delivery system reduces the dosage of melatonin by 50% to 400% and reduces side effects, and can improve the transdermal penetration rate of melatonin within the first two hours.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicaments, in particular to a rapid and efficient transdermal delivery system of melatonin. BACKGROUND

[0002] Melatonin is a natural neurohormone produced by the human body, mainly secreted by the pineal gland in the brain. The pineal gland is a small endocrine gland located in the brain, located in the upper hypothalamus. The pineal gland in the human brain is very small, with a mass of only 100-150 milligrams, and it is responsible for the production of melatonin and the regulation of wake-sleep patterns and circadian rhythm functions. Melatonin is only produced at night. Under normal biological clock conditions, it usually starts to be produced around 8 pm, and reaches a peak concentration in the blood between 2-4 am, which is 5-10 times higher than during the day. Around 5 am, the secretion of melatonin begins to decrease, and by around 9 am, the concentration of melatonin in the blood has decreased to a low level during the day.

[0003] Pharmacokinetic studies have shown that endogenous melatonin is rapidly metabolized in the human body as a two-phase first-order reaction, with a half-life of minutes: t1 1 / 2 = 5.6 min ± 0.5, t2 1 / 2 = 43.6 ± 1.5. Therefore, during sleep at night, melatonin is continuously secreted and rapidly metabolized in the human body, maintaining a stable relative concentration and a stable sleep state. The normal daily secretion of melatonin in the human body is only 28.8 μg / day (i.e. 0.0288 mg / day). Pharmacokinetic studies have also shown that the bioavailability of orally administered melatonin in humans is very low.

[0004] In the sleep state, after the age of 35, the glandular function of the human body decreases, and the secretion of melatonin decreases significantly, with an average decrease of 10-15% every 10 years. The decrease in melatonin in elderly patients with sleep disorders is even more pronounced, with a secretion amount of only 1 / 10 of the peak period. Therefore, for most people with physiological insomnia, appropriate external supplementation of melatonin will greatly benefit sleep.

[0005] The current market commonly used melatonin supplementation method is mainly oral, with a dose of 3-12 mg / tablet, which is 100-400 times the natural secretion of 0.03 mg per day in the human body. The bioavailability of orally administered melatonin is very low (<15%), and the half-life (t 1 / 2 ) is very short, rapidly metabolized and excreted, reaching a C max(peak concentration) only 40 minutes, and the concentration in the blood will exceed the normal human night secretion is 100-400 times, forming a strong "dumping effect. Large dose oral through the liver metabolism, causing a great burden on the liver, prone to adverse side effects. Less than 2 hours after oral melatonin and substantially completely metabolized excretion, can not reach the normal human needs of 6-8 hours of sleep time.

[0006] In summary, there is an urgent need for a fast and efficient melatonin transdermal delivery system, which not only compared with oral use of melatonin, the melatonin delivery system reduces the use of melatonin dose 50% ~ 400%, reduces side effects, but also can improve the first two hours of transdermal rate of melatonin. SUMMARY

[0007] The technical problems to be solved by the present application are:

[0008] The present application develops a high-efficiency melatonin transdermal delivery system, which reduces the use of melatonin dose 50% ~ 400% compared with oral use of melatonin, reduces side effects; can improve the first two hours of transdermal rate of melatonin.

[0009] In order to achieve the above purpose, the present application adopts the following technical scheme:

[0010] A fast and efficient melatonin transdermal delivery system, the system comprises the following structure from top to bottom:

[0011] At least one protective layer;

[0012] At least one high polymer substrate layer;

[0013] A multi-layer structure of an anti-adhesion layer;

[0014] Among them,

[0015] The high polymer substrate layer comprises the following components by weight:

[0016]

[0017] As a further improvement of the present application, the protective layer is a polyethylene, polyethylene vinyl acetate, aluminum foil, nylon, medical non-woven fabric of any one or more combinations of laminated film.

[0018] As a further improvement of the present application, the anti-adhesion layer is a polyethylene, polyethylene vinyl acetate of any one or more combinations of laminated film which is siliconized or specially treated on the surface.

[0019] As a further improvement of the present solution, the high polymer pressure sensitive adhesive is any one or more of polyacrylate, polyisobutylene, silicone polymer, natural rubber.

[0020] As a further improvement of the present solution, the alcohol of 8 to 18 carbon atoms is any one or more of sorbitol, oleyl alcohol, myristyl alcohol or lauryl alcohol.

[0021] As a further improvement of the present solution, the saturated and unsaturated fatty acid of 8 to 18 carbon atoms is any one or more of sorbic acid, linolenic acid, stearic acid, linoleic acid, oleic acid, lauric acid, myristic acid and palmitic acid.

[0022] As a further improvement of the present solution, the antioxidant combination is any one or more of vitamin C, vitamin E, sodium metabisulfite, dibutyl hydroxytoluene.

[0023] As a further improvement of the present solution, the transdermal enhancer composition includes any two or more of polyvinylpyrrolidone, tartaric acid, lactic acid, benzyl alcohol, tris(hydroxymethyl)aminomethane, glycerol monooleate, sorbitan monolaurate, myristoyl sarcosine, N-oleoyl sarcosine, N-lauroyl sarcosine, dimethyl sulfoxide, propylene glycol;

[0024] As a further improvement of the present solution, the transdermal enhancer composition includes any one or any combination of 3% to 15% polyvinylpyrrolidone, 3 to 8% N-oleoyl sarcosine, N-lauroyl sarcosine, 3 to 8% dimethyl sulfoxide;

[0025] As a further improvement of the present solution, the system includes the following structures arranged from top to bottom:

[0026] At least one protective layer;

[0027] At least one high polymer base layer;

[0028] A multi-layer structure consisting of at least one release layer;

[0029] The high polymer base layer includes the following components by weight:

[0030] High polymer pressure sensitive adhesive 60 to 95 parts;

[0031] Melatonin 4 to 15 parts;

[0032] Alcohol or fatty acid of 8 to 18 carbon atoms 4 to 15 parts;

[0033] The antioxidant combination includes one or any combination of the following, totaling no more than 5 parts

[0034] (1) Vitamin E

[0035] (2) sodium metabisulfite

[0036] (3) butylated hydroxytoluene

[0037] Other combinations of penetration enhancers include one or more of the following in combination, in a total amount of no more than 20 parts

[0038] (1) 3 to 15 parts of polyvinylpyrrolidone;

[0039] (2) 3 to 8 parts of dimethylsulfoxide;

[0040] (3) 3 to 8 parts of N-oleoyl sarcosine or N-lauroyl sarcosine.

[0041] Compared with the prior art, the present application has the following beneficial effects:

[0042] The present application provides a transdermal delivery system capable of significantly improving the transdermal delivery efficiency of melatonin. Through the transdermal delivery of melatonin by the transdermal device, the side effects of melatonin use can be effectively reduced compared with oral use of melatonin, the dosage of melatonin use is reduced by 50% to 400%, and the stable rate of melatonin delivery is maintained for 12 hours.

[0043] In the present application, the cumulative flux of transdermal penetration of melatonin is confirmed by in vitro penetration test, which refers to a Franz diffusion cell model penetration test using pig skin with epidermis (stratum corneum and epidermis) as a penetration membrane. In the in vitro penetration test, the high-efficiency delivery system of the present application can increase the cumulative penetration flux to 200 μg / cm 2 or more in 12 hours or more.

[0044] In the present application, the in vitro penetration test refers to a Franz diffusion cell model using pig skin with epidermis (stratum corneum and epidermis) as a penetration membrane. In some embodiments, the transdermal delivery device can provide a transdermal penetration flux of 10 μg / cm 2 / h or more.

[0045] In the present application, a high-efficiency delivery system comprising a melatonin transdermal delivery device is provided, which can significantly improve the skin penetration flux in 12 hours. For example, the transdermal delivery device can increase the cumulative skin penetration flux in 12 hours to 200 μg / cm 2 or more.

[0046] In the present application, a high-efficiency delivery system comprising a melatonin transdermal delivery device is provided, and the transdermal delivery device using the high-efficiency delivery system can rapidly deliver melatonin in 2 hours, and the cumulative skin penetration flux in 2 hours is increased to 30 μg / cm 2 or more. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 Graphical representation of the permeation test results in Example 1;

[0048] Figure 2 Graphical representation of the permeation test results in Example 2;

[0049] Figure 3 Graphical representation of the permeation test results in Example 3;

[0050] Figure 4 Graphical representation of the permeation test results in Example 4;

[0051] Figure 5 Graphical representation of the permeation test results in Example 5;

[0052] Figure 6 Graphical representation of the permeation test results in Example 6;

[0053] Figure 7 Graphical representation of the permeation test results in Example 7. DETAILED DESCRIPTION

[0054] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described below in combination with embodiments:

[0055] Example 1

[0056] Polymer base component of Example 1

[0057]

[0058] The preparation process of Example 1 is as follows:

[0059] The corresponding melatonin, antioxidant, penetration enhancer and pressure-sensitive adhesive are weighed into a container in order and solvent is added. A rotating and shaking stirring method is used to stir for more than 4 h until complete dissolution. A coating doctor blade is used for coating and drying.

[0060] The Franz diffusion cell is used for transdermal diffusion, the diffusion conditions are temperature 32℃, the receiving liquid is a buffer solution added with pH 7.2 phosphate buffer, and the sample is detected by HPLC method.

[0061] Example 2

[0062] Polymer base component of Example 2

[0063]

[0064] The preparation process of Example 2 is as follows:

[0065] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for 4 hours or more using a rotating stirrer until completely dissolved. The mixture was coated using a doctor blade and dried.

[0066] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C and a receiving solution of pH 7.2 phosphate buffer. The sample was detected using HPLC.

[0067] Example 3

[0068] Polymer base component of Example 3

[0069]

[0070] The preparation process of Example 3 is as follows:

[0071] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for 4 hours or more using a rotating stirrer until completely dissolved. The mixture was coated using a doctor blade and dried.

[0072] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C and a receiving solution of pH 7.2 phosphate buffer. The sample was detected using HPLC.

[0073] Example 4

[0074] Polymer base component of Example 4

[0075]

[0076] The preparation process of Example 4 is as follows:

[0077] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for 4 hours or more using a rotating stirrer until completely dissolved. The mixture was coated using a doctor blade and dried.

[0078] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C and a receiving solution of pH 7.2 phosphate buffer. The sample was detected using HPLC.

[0079] Example 5

[0080] Polymer base component of Example 5

[0081]

[0082] The preparation process of Example 5 is as follows:

[0083] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for more than 4 hours using a rotating stirring method until completely dissolved. The mixture was coated using a coating blade and dried.

[0084] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C, a receiving liquid of a buffer solution added with pH 7.2 phosphate buffer salt, and a sample detection using an HPLC method.

[0085] Example 6

[0086] The sample of Example 6 was prepared according to the following formulation

[0087]

[0088] The preparation process of Example 6 was as follows

[0089] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for more than 4 hours using a rotating stirring method until completely dissolved. The mixture was coated using a coating blade and dried.

[0090] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C, a receiving liquid of a buffer solution added with pH 7.2 phosphate buffer salt, and a sample detection using an HPLC method.

[0091] Example 7

[0092] The sample of Example 7 was prepared according to the following formulation

[0093]

[0094] The preparation process of Example 7 was as follows

[0095] The corresponding melatonin, antioxidant, penetration enhancer, pressure sensitive adhesive were weighed into a container in order and solvent was added. The mixture was stirred for more than 4 hours using a rotating stirring method until completely dissolved. The mixture was coated using a coating blade and dried.

[0096] The transdermal diffusion was performed using a Franz diffusion cell with a temperature of 32°C, a receiving liquid of a buffer solution added with pH 7.2 phosphate buffer salt, and a sample detection using an HPLC method.

[0097] From the comparison of Examples 1-8, it can be seen that the transdermal delivery system of the present application for melatonin uses a combination of various components, such as polyvinylpyrrolidone, lauric acid, lauryl alcohol, N-oleoyl sarcosine, N-lauryl sarcosine, dimethyl sulfoxide, and the effect of enhancing penetration is very obvious. The skin penetration flux of melatonin can be significantly improved within 12 h, and the delivery rate remains substantially constant, which helps the sustained and stable effect of melatonin. The transdermal delivery device can increase the cumulative skin penetration flux of 12 h to 200 μg / cm 2 or more. From the comparison of Example 7, it can be seen that the transdermal delivery system of the present application can obviously and quickly deliver melatonin within 2 h, and the cumulative penetration flux is quickly up to 30 μg / cm 2 or more.

[0098] The above only describes the preferred embodiments of the present application, and does not limit the patent scope of the present application, and any equivalent transformation made by using the present application is within the patent protection scope of the present application.

Claims

1. A fast delivery melatonin transdermal delivery system, characterized in that, The system comprises the following multi-layer structure arranged from top to bottom: at least one protective layer; at least one polymer base layer; one anti-sticking layer; wherein, the polymer base layer is composed of the following components by weight: melatonin 0.5 parts, polyvinylpyrrolidone 0.5 parts, N-lauroyl amino acid 0.2 parts, sorbitol 0.4 parts, antioxidant vitamin E 0.025 parts, pressure sensitive adhesive Durotak 2287 5.47 parts; or, melatonin 0.25 parts, polyvinylpyrrolidone 0.5 parts, lauric acid 0.4 parts, lauryl alcohol 0.4 parts, antioxidant vitamin E 0.015 parts, antioxidant BHT 0.015 parts, pressure sensitive adhesive BASF B12 2.43 parts, pressure sensitive adhesive BASF N100 0.98 parts; or, melatonin 0.25 parts, polyvinylpyrrolidone 0.5 parts, N-lauroyl amino acid 0.2 parts, lauric acid 0.2 parts, antioxidant vitamin E 0.01 parts, antioxidant BHT 0.01 parts, pressure sensitive adhesive BASF B12 2.83 parts, pressure sensitive adhesive BASF N1001 part.

2. The fast delivery melatonin transdermal delivery system according to claim 1, wherein, The protective layer is a laminated film of any one or more layers of polyethylene, polyethylene vinyl acetate, aluminum foil, nylon, and medical non-woven fabric.

3. The fast-onset melatonin transdermal delivery system according to claim 1, wherein, The anti-sticking layer is a laminated film of any one or more layers of polyethylene and polyethylene vinyl acetate with siliconized surface treatment.

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