Construction and application of amino-acid ester biodegradable penetration enhancer system

Abstract

The invention discloses a construction method and application of an amino-acid ester biodegradable penetration enhancer system. The amino-acid ester biodegradable penetration enhancer system comprises the following raw materials in percentage by weight of solid content of a preparation matrix: 0.1-20% of an amino-acid ester biodegradable penetration enhancer and 0.5-20% of a substance for adjusting the release speed of a medicine or the amino-acid ester penetration enhancer from the matrix; and 0.5-20% of a substance for adjusting the distribution speed of the drug and the amino-acid ester penetration enhancer to the cuticle. According to the biodegradable penetration enhancer system disclosed by the invention, an efficient percutaneous penetration enhancing effect can be realized aiming at medicines with different physicochemical properties in a percutaneous administration preparation, a skin local external preparation and a functional skin care product; meanwhile, the amino-acid ester penetration enhancer in the system can be degraded into non-toxic and harmless substances in the skin, so that the safety of the skin is guaranteed. The invention provides a new strategy for developing a simple, efficient and safe skin administration method.

Description

Technical Field

[0001] The present invention relates to a penetration-enhancing technology for transdermal preparations, and more specifically, to the composition of an amino acid ester biodegradable penetration-enhancing agent system, and its application in transdermal preparations, external skin preparations and functional skin care products. Background Art

[0002] The transdermal drug delivery system is the third largest drug delivery system after oral administration and injection. It has a wide demand in multiple therapeutic areas due to its characteristics such as no obvious first-pass liver effect, fewer adverse gastrointestinal reactions, constant blood drug concentration, and excellent patient compliance. Since the skin is a barrier that is difficult to penetrate for most drugs, the amount of penetration of many drugs after transdermal administration does not meet the treatment requirements, so it is necessary to use appropriate penetration-enhancing methods to increase the transdermal absorption of drugs. Among the many penetration-enhancing methods, transdermal penetration enhancers have the advantages of simple use, strong prescription compatibility, and relatively low cost, and have greater commercialization potential.

[0003] However, in the use of transdermal penetration enhancers, there may be the following two problems:

[0004] First, there may be skin safety issues. For most current penetration enhancers, there is a certain contradiction between their penetration effect and skin safety. That is, in order to achieve the ideal penetration effect, the transdermal penetration enhancers such as laurocapram that can strongly weaken the stratum corneum barrier will inevitably penetrate further into the deep active tissues of the skin after playing a penetration-enhancing role in the stratum corneum, and may mediate the production of inflammatory factors in the active epidermis and dermis, causing skin safety issues.

[0005] Second, the penetration effect is often poor. The main mechanism of action of percutaneous penetration enhancers is to weaken the stratum corneum barrier. The traditional view is that as long as the penetration enhancer can weaken the stratum corneum barrier, it can reduce the difficulty of drugs passing through the stratum corneum, thereby achieving the effect of promoting drug percutaneous penetration. However, in recent years, a large number of studies have shown that the permeation enhancer is selective in the percutaneous permeation effect of drugs, that is, a permeation enhancer can only produce a permeation effect on a few specific drugs, but not on other drugs. In response to the above problems, although several research teams have used the oil-water partition coefficient logP of drugs and permeation enhancers as characteristic indicators to explore the matching rules between the two, the research results are not ideal, and the law of the effect of permeation enhancers on drugs in the complex relationship between preparations and skin and other factors cannot be explained. At present, in order to increase the percutaneous permeation of a certain drug, it can only be blindly selected from more than a hundred permeation enhancers or screened one by one. It is not only time-consuming and laborious, but often fails to obtain a better permeation effect in the end. Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to provide an amino acid ester biodegradable penetration enhancer system. Adding the penetration enhancer system to a transdermal drug delivery preparation can enable the target drug to achieve a higher transdermal permeation amount. At the same time, the amino acid ester penetration enhancer in the penetration enhancer system can be degraded into non-toxic and harmless substances in the skin, thereby ensuring the safety of the skin. The penetration enhancer system can be used in transdermal drug delivery preparations, topical skin preparations, and functional skin care products.

[0007] Technical solution: The biodegradable penetration enhancer system for transdermal drug delivery preparations, topical skin preparations or functional skin care products described in the present invention is composed of three types of substances: A, B and C. In terms of percentage by weight, the A type substances are 0.1% to 20%, the B type substances are 0.5% to 20%, and the C type substances are 0.5% to 20%. Among them, the A type substances are fatty alcohol amino acid ester biodegradable penetration enhancers, the B type substances are substances that can adjust the release speed of drugs or A type substances from the preparation matrix, and the C type substances are substances that can adjust the distribution speed of drugs or A type substances to the stratum corneum.

[0008] The biodegradable penetration enhancer system, the Class A substance fatty alcohol amino acid ester penetration enhancer, has a fatty alcohol as one of its raw materials with a carbon chain length of 8 to 14 and a double bond number of 0 to 2; the amino acid as the second raw material is a protein amino acid or a non-protein amino acid existing in human skin and in the body; the ester formed by the two raw materials has a mechanism of disrupting the orderly arrangement of lipids between stratum corneum cells, and can be biodegraded by skin esterase below the stratum corneum into amino acids and fatty alcohols without obvious cytotoxicity.

[0009] The biodegradable penetration enhancer system, wherein the Class B substance can adjust the release rate of the drug or Class A substance from the matrix, comprises one or more of surfactants, polyols, fatty acids and their esters.

[0010] The biodegradable penetration enhancer system, wherein the C-type substance can adjust the distribution rate of the drug or penetration enhancer to the stratum corneum, includes one or more of pyrrolidine, ether, terpene, fatty acid and its ester, surfactant, and polyol.

[0011] The biodegradable penetration enhancer system, wherein the Class A substance is selected from n-decyl tryptophan ester, n-octanol tyrosine ester, n-octanol glycine ester, n-decyl serine ester, lauryl lysine ester, lauryl methionine ester, n-octanol valine ester, lauryl glutamine ester, lauryl leucine ester, and n-decyl histidine ester.

[0012] In the biodegradable penetration enhancer system, the type B substance is selected from polyethylene glycol 400, isopropyl myristate, and 1,3-propylene glycol.

[0013] In the biodegradable penetration enhancer system, the C-type substance is selected from diethylene glycol ethyl ether, limonene, dodecyl glucoside, and N-methylpyrrolidone.

[0014] The method for preparing the Class A substance in the biodegradable penetration enhancer system comprises the following steps:

[0015] Amino acid and p-toluenesulfonic acid are added, and fatty alcohol is added after mixing. The temperature is raised to 100-150° C., and the water is refluxed to separate. When no water is separated and the reaction is stopped after TLC detection is qualified; the reaction solution is adjusted to pH 9-11 with sodium hydroxide solution, extracted with ethyl acetate 2-5 times, the organic layers are combined, washed with saturated sodium chloride solution, dried and evaporated to remove the solvent; column chromatography is performed on a silica gel column, and a mixed solution of petroleum ether and ethyl acetate is used as an eluent, and the eluent is evaporated to obtain a colorless liquid.

[0016] In the preparation method, the molar ratio of the added amounts of amino acid and p-toluenesulfonic acid is 1:1 to 1:3.

[0017] The amino acid ester biodegradable penetration enhancer system is used in transdermal drug delivery preparations, local skin preparations, and functional skin care products.

[0018] According to one aspect of the present invention, there is provided a composition of a biodegradable penetration enhancer system, which is composed of three types of substances: A, B, and C. Wherein the A-type substance is a fatty alcohol amino acid ester biodegradable penetration enhancer, the B-type substance is a substance in the system that adjusts the release rate of the drug or the A-type substance from the preparation matrix, and the C-type substance is a substance in the system that adjusts the distribution rate of the drug or the A-type substance to the stratum corneum. On the one hand, the two types of substances B and C jointly regulate the total rate at which the drug and the A-type substance are released from the preparation matrix and distributed into the stratum corneum, that is, the rate at which the drug and the A-type substance reach the stratum corneum is equivalent. On the other hand, the A-type substance includes biodegradable fatty alcohol amino acid esters formed by different fatty alcohols and different amino acids, which have different diffusion rates in the stratum corneum and are rich and varied, thereby ensuring that drugs with different stratum corneum diffusion rates can all be matched to the A-type substance with a stratum corneum diffusion rate equivalent thereto. By simultaneously satisfying the above two conditions, the efficient improvement of the transdermal penetration of different drugs is finally achieved.

[0019] Preferably, the amino acid ester biodegradable penetration enhancer A is characterized by: 1) the carbon chain length of the fatty alcohol of one of its raw materials is 8 to 14, and the number of double bonds is 0 to 2; 2) the amino acids of the second raw material include protein amino acids and non-protein amino acids existing in human skin and body; 3) the ester formed by the two raw materials has a mechanism of disrupting the orderly arrangement of lipids between stratum corneum cells, and can be biodegraded by skin esterases under the stratum corneum into amino acids and fatty alcohols without obvious cytotoxicity. The Class B substance that can adjust the release rate of the drug from the preparation matrix is ​​preferably one or more of surfactants, polyols, fatty acids and their esters. The Class C substance that can adjust the distribution rate of the drug to the stratum corneum is preferably one or more of terpenes, fatty acids and their esters, pyrrolidines, surfactants, and polyols.

[0020] Preferably, the addition ratio of each component in the penetration enhancer system (calculated as a percentage of the weight of the solid content of the preparation matrix) is 0.1% to 20% for Class A substances; 0.5% to 20% for Class B substances; and 0.5% to 20% for Class C substances.

[0021] According to another aspect of the present invention, a preparation is provided, which comprises the penetration enhancer system of the present invention.

[0022] The preparations include, but are not limited to, patches, poultices, ointments, creams, gels, solutions, suspensions, emulsions, pastes, films, lotions and other transdermal preparations, topical preparations for skin application or dosage forms of functional skin care products.

[0023] The applicant of the present invention has long been committed to the study of the molecular mechanism of action of transdermal penetration enhancers, and has previously discovered the important research value of the transdermal dynamic behavior of drugs and transdermal penetration enhancers. Figure 1 As shown, the inventors divide the transdermal dynamic behaviors of drugs and permeation enhancers into release behavior in the preparation matrix, distribution behavior to the stratum corneum, and diffusion behavior in the stratum corneum. "Release behavior" refers to the process in which a drug or permeation enhancer moves from the preparation matrix to the skin surface in a skin administration preparation; "distribution behavior" refers to the process in which a drug or permeation enhancer enters the stratum corneum from the skin surface; "diffusion behavior" refers to the process in which a drug or permeation enhancer diffuses from the shallow part of the stratum corneum to the deep part. The inventors found that the transdermal dynamic behaviors of drugs and permeation enhancers interact with each other and jointly affect the transdermal permeation enhancement effect. More importantly, the inventors found that when the following two characteristics of transdermal dynamic behaviors are met at the same time, the perdermal permeation enhancer can produce a better permeation enhancement effect on a certain drug: 1. The perdermal permeation enhancer and the drug in the preparation reach the stratum corneum at the same time, that is, the total rates of the two in the "release behavior" and "distribution behavior" are roughly equivalent; 2. The diffusion rate of the perdermal permeation enhancer and the drug in the stratum corneum is roughly equivalent.

[0024] The inventors have taken into account both the penetration enhancing effect and skin safety of the transdermal penetration enhancer and constructed an amino acid ester biodegradable penetration enhancer system. The penetration enhancer system has two characteristics: on the one hand, the amino acid ester penetration enhancer in the penetration enhancer system enters the active epidermis and dermis after acting on the stratum corneum, and can be biodegraded by the esterase therein into amino acids and fatty alcohols and other substances without obvious cytotoxicity, thereby ensuring skin safety; on the other hand, the penetration enhancer system can achieve a good transdermal penetration enhancing effect on drugs with different physical and chemical properties.

[0025] Beneficial effects: Compared with the prior art, the present invention has the following outstanding features: (1) The raw materials of the amino acid ester biodegradable penetration enhancer described in this scheme are easily available, and the synthesis method is simple. The synthesized amino acid ester penetration enhancer is combined with specific substances to form an amino acid ester biodegradable penetration enhancer system, which can achieve efficient percutaneous penetration enhancement effect for drugs with different physical and chemical properties such as logP, molecular weight, acidity and alkalinity. (2) The amino acid ester biodegradable penetration enhancer in the amino acid ester penetration enhancer system can be biodegraded by skin esterase below the stratum corneum of the skin into amino acids and fatty alcohols without obvious cytotoxicity, thereby ensuring the safety of the skin. At the same time, the penetration enhancer system can be applied to various dosage forms such as percutaneous drug delivery preparations, local skin external preparations and functional skin care products, and has a wide range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Schematic diagram of the transdermal dynamic behavior of drugs and transdermal penetration enhancers (including release behavior, distribution behavior, and diffusion behavior). DETAILED DESCRIPTION

[0027] The specific implementation modes of the present invention are described in detail below in conjunction with the table, but it should be understood that the protection scope of the present invention is not limited by the specific implementation modes. Among them, the abbreviation of n-decyl tryptophan ester is Dec-Trp, the abbreviation of n-octanol tyrosine ester is Oct-Tyr, the abbreviation of n-octanol glycine ester is Oct-Gly, the abbreviation of n-decyl serine ester is Dec-Ser, the abbreviation of lauryl lysine ester is Dod-Lys, the abbreviation of lauryl methionine ester is Dod-Met, the abbreviation of n-octanol valine ester is Oct-Val, the abbreviation of lauryl glutamine ester is Dod-Gln, the abbreviation of lauryl leucine ester is Dod-Leu, the abbreviation of n-decyl histidine ester is Dec-His, the abbreviation of polyethylene glycol 400 is PEG 400, the abbreviation of isopropyl myristate is IPM, the abbreviation of 1,3-propylene glycol is 1,3-PG, the abbreviation of diethylene glycol ethyl ether is TP, the abbreviation of limonene is Limon, the abbreviation of N-methylpyrrolidone is NMP, and the abbreviation of dodecyl glucoside is LG.

[0028] Example 1

[0029] This embodiment provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% of n-decyl tryptophan ester of class A substance, 5% of polyethylene glycol 400 of class B substance, and 2% of diethylene glycol ethyl ether of class C substance.

[0030] The general synthesis method of the amino acid ester biodegradable penetration enhancer is as follows: add 1 mol (1 eq) of amino acid and 2 mol (2 eq) of p-toluenesulfonic acid to a 50 mL round-bottom flask, mix well, add excess fatty alcohol, heat to 125°C, reflux and separate water, and stop the reaction after no water is separated and TLC test is qualified. The reaction solution is adjusted to pH 9-11 with sodium hydroxide solution, extracted three times with ethyl acetate, the organic layers are combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate for a period of time, and the solvent is evaporated. Column chromatography (silica gel is 200-300 mesh), petroleum ether and ethyl acetate (volume ratio 15:1-3:1) are eluents, and the eluent is evaporated to obtain a colorless liquid, which is Class A substance. Mix Class A, B, and C substances.

[0031] In this embodiment, the amino acid is tryptophan and the fatty alcohol is n-decanol.

[0032] Example 2

[0033] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 15% n-octanol tyrosine ester of Class A substance, 3% isopropyl myristate of Class B substance, and 1% limonene of Class C substance.

[0034] Example 3

[0035] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% n-octanol glycine ester of Class A substance, 3% 1,3-propylene glycol of Class B substance, and 2.5% limonene of Class C substance.

[0036] Example 4

[0037] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% of n-decyl serine ester of Class A substance, 2% of polyethylene glycol 400 of Class B substance, and 5% of dodecyl glucoside of Class C substance.

[0038] Example 5

[0039] Referring to the preparation method of Example 1, this embodiment provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 2.5% lauryl lysine ester of Class A substance, 5% 1,3-propylene glycol of Class B substance, and 7% diethylene glycol ethyl ether of Class C substance.

[0040] Example 6

[0041] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8.5% lauryl methionine ester of Class A substance, 6% polyethylene glycol 400 of Class B substance, and 1% N-methylpyrrolidone of Class C substance.

[0042] Example 7

[0043] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 10% lauryl methionine ester of Class A substance, 4.5% polyethylene glycol 400 of Class B substance, and 5% N-methylpyrrolidone of Class C substance.

[0044] Example 8

[0045] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 6% n-octanol valine ester of Class A substance, 4% 1,3-propylene glycol of Class B substance, and 6% dodecyl glucoside of Class C substance.

[0046] Example 9

[0047] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 2% lauryl glutamine ester of Class A substance, 11% polyethylene glycol 400 of Class B substance, and 1.5% limonene of Class C substance.

[0048] Example 10

[0049] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 12% lauryl leucine ester of Class A substance, 1.5% isopropyl myristate of Class B substance, and 2% diethylene glycol ethyl ether of Class C substance.

[0050] Comparative Example 1

[0051] Referring to the preparation method of Example 1, only 7% of Class A substance, n-decyl tryptophan ester, is contained, in terms of percentage by weight.

[0052] Comparative Example 2

[0053] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 6% of n-decyl tryptophan ester of Class A substance, 2% of isopropyl myristate of Class B substance, and 8% of diethylene glycol ethyl ether of Class C substance.

[0054] Comparative Example 3

[0055] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% of n-octanol tyrosine ester of Class A substance, 3% of isopropyl myristate of Class B substance, and 2% of limonene of Class C substance.

[0056] Comparative Example 4

[0057] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% n-octanol glycine ester of Class A substance, 1% 1,3-propylene glycol of Class B substance, and 3% limonene of Class C substance.

[0058] Comparative Example 5

[0059] Referring to the preparation method of Example 1, only 15% of Class A substance, n-octanol tyrosine ester, is contained, in terms of percentage by weight.

[0060] Comparative Example 6

[0061] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 15% n-octanol tyrosine ester of Class A substance, 1% 1,3-propylene glycol of Class B substance, and 3% dodecyl glucoside of Class C substance.

[0062] Comparative Example 7

[0063] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 15% of n-decyl serine ester of Class A substance, 3% of polyethylene glycol 400 of Class B substance, and 2% of dodecyl glucoside of Class C substance.

[0064] Comparative Example 8

[0065] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 14% lauryl lysine ester of Class A substance, 2.5% 1,3-propylene glycol of Class B substance, and 1.5% diethylene glycol ethyl ether of Class C substance.

[0066] Comparative Example 9

[0067] Referring to the preparation method of Example 1, only 8% of Class A substance, n-octanol glycine ester, is contained, in terms of percentage by weight.

[0068] Comparative Example 10

[0069] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% n-octanol glycine ester of Class A substance, 1% isopropyl myristate of Class B substance, and 4% N-methylpyrrolidone of Class C substance.

[0070] Comparative Example 11

[0071] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 6% lauryl methionine ester of Class A substance, 4% polyethylene glycol 400 of Class B substance, and 1% N-methylpyrrolidone of Class C substance.

[0072] Comparative Example 12

[0073] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% lauryl methionine ester of Class A substance, 1.5% 1,3-propylene glycol of Class B substance, and 3% dodecyl glucoside of Class C substance.

[0074] Comparative Example 13

[0075] Referring to the preparation method of Example 1, only 10% of Class A substance, n-decyl alcohol serine ester, is contained, calculated as a percentage by weight.

[0076] Comparative Example 14

[0077] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% of n-decyl serine ester of Class A substance, 1% of isopropyl myristate of Class B substance, and 2% of N-methylpyrrolidone of Class C substance.

[0078] Comparative Example 15

[0079] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% of n-octanol valine ester of Class A substance, 1% of 1,3-propylene glycol of Class B substance, and 3% of dodecyl glucoside of Class C substance.

[0080] Comparative Example 16

[0081] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% lauryl glutamine ester of Class A substance, 3% polyethylene glycol 400 of Class B substance, and 1.5% limonene of Class C substance.

[0082] Comparative Example 17

[0083] Referring to the preparation method of Example 1, only 5% of lauryl lysine ester of Class A substance is contained, calculated as a percentage by weight.

[0084] Comparative Example 18

[0085] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 2.5% lauryl lysine ester of Class A substance, 1% isopropyl myristate of Class B substance, and 10% N-methylpyrrolidone of Class C substance.

[0086] Comparative Example 19

[0087] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 3% lauryl leucine ester of Class A substance, 2% isopropyl myristate of Class B substance, and 12% diethylene glycol ethyl ether of Class C substance.

[0088] Comparative Example 20

[0089] Referring to the preparation method of Example 1, this example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 3% of n-decyl histidine ester of Class A substance, 10% of polyethylene glycol 400 of Class B substance, and 1% of limonene of Class C substance.

[0090] Comparative Example 21

[0091] Referring to the preparation method of Example 1, only 11% of Class A substance, lauryl methionine ester, is contained, in terms of percentage by weight.

[0092] Comparative Example 22

[0093] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 10% lauryl methionine of Class A substance, 2% 1,3-propylene glycol of Class B substance, and 2% dodecyl glucoside of Class C substance.

[0094] Comparative Example 23

[0095] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8.5% of n-decyl tryptophan ester of Class A substance, 1% of isopropyl myristate of Class B substance, and 4% of diethylene glycol ethyl ether of Class C substance.

[0096] Comparative Example 24

[0097] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8.5% of n-octanol tyrosine ester of Class A substance, 1.5% of isopropyl myristate of Class B substance, and 3% of limonene of Class C substance.

[0098] Comparative Example 25

[0099] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 11% n-octanol glycine ester of Class A substance, 1.5% 1,3-propylene glycol of Class B substance, and 1% limonene of Class C substance.

[0100] Comparative Example 26

[0101] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 10% n-octanol tyrosine ester of Class A substance, 2% 1,3-propylene glycol of Class B substance, and 5% dodecyl glucoside of Class C substance.

[0102] Comparative Example 27

[0103] Referring to the preparation method of Example 1, only 9% of Class A substance, n-octanol valine ester, is contained, in terms of percentage by weight.

[0104] Comparative Example 28

[0105] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 7% n-octanol valine ester of Class A substance, 2.5% isopropyl myristate of Class B substance, and 2.5% limonene of Class C substance.

[0106] Comparative Example 29

[0107] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 8% of n-decyl serine ester of Class A substance, 7% of polyethylene glycol 400 of Class B substance, and 1% of dodecyl glucoside of Class C substance.

[0108] Comparative Example 30

[0109] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 6% lauryl lysine ester of Class A substance, 1.5% 1,3-propylene glycol of Class B substance, and 6% diethylene glycol ethyl ether of Class C substance.

[0110] Comparative Example 31

[0111] Referring to the preparation method of Example 1, only 4% of lauryl glutamine ester of Class A substance is contained, calculated as a percentage by weight.

[0112] Comparative Example 32

[0113] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 3% lauryl glutamine ester of Class A substance, 8% 1,3-propylene glycol of Class B substance, and 1% diethylene glycol ethyl ether of Class C substance.

[0114] Comparative Example 33

[0115] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 5% n-octanol glycine ester of Class A substance, 1% isopropyl myristate of Class B substance, and 4% N-methylpyrrolidone of Class C substance.

[0116] Comparative Example 34

[0117] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 3% lauryl methionine ester of Class A substance, 5% polyethylene glycol 400 of Class B substance, and 3% N-methylpyrrolidone of Class C substance.

[0118] Comparative Example 35

[0119] Referring to the preparation method of Example 1, only 14% of lauryl leucine ester of Class A substance is contained, calculated as a percentage by weight.

[0120] Comparative Example 36

[0121] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 13% lauryl leucine ester of Class A substance, 2% 1,3-propylene glycol of Class B substance, and 2% N-methylpyrrolidone of Class C substance.

[0122] Comparative Example 37

[0123] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 12.5% ​​of n-octanol valine ester of Class A substance, 1% of 1,3-propylene glycol of Class B substance, and 1.5% of dodecyl glucoside of Class C substance.

[0124] Comparative Example 38

[0125] Referring to the preparation method of Example 1, this comparative example provides an amino acid ester biodegradable penetration enhancer system, which comprises, by weight percentage: 12% lauryl glutamine ester of Class A substance, 1.5% polyethylene glycol 400 of Class B substance, and 2.5% limonene of Class C substance.

[0126] Experiment 1: Experiment on the total rate of release and allocation

[0127] A total of 55 mg of 5% of the drug, 0.1% to 20% of the amino acid ester biodegradable penetration enhancer A (1.1 mg to 220 mg); 0.5% to 20% of the substance B (5.5 mg to 220 mg) for adjusting the release of the drug or penetration enhancer from the matrix; 0.5% to 20% of the substance C (5.5 mg to 220 mg) for adjusting the distribution of the drug and penetration enhancer to the stratum corneum, and 0.8 g of ethanol are added to a small beaker, and the mixture is shaken to dissolve. Subsequently, 2.5 g of pressure-sensitive adhesive 4098 is added, the mixture is sealed, and magnetic stirring is performed for 1.5 hours to mix the mixture evenly. Thereafter, the mixture of the drug-penetration enhancer system-pressure-sensitive adhesive is evenly spread on the anti-adhesive layer using a 400 μμm thick applicator, and the mixture is placed at room temperature for 20 minutes, dried in an oven at 40°C for 15 minutes, and taken out after the solvent is evaporated. The surface of the pressure-sensitive adhesive layer is covered with a backing layer to obtain a drug-containing patch with the penetration enhancer system added. A Franz diffusion cell (V = 6.5 mL, S = 2.54 cm 2 ), add a small rotor to the receiving pool, and place the patch with the anti-adhesive layer removed close to the pig skin, with the dermis of the pig skin facing the receiving liquid, and place it in a diffusion device. Add the receiving liquid to the receiving pool, and no bubbles should be left between the receiving liquid and the skin. Place it in a transdermal diffusion instrument at 32°C and 400rpm for continuous stirring. The transdermal experiment was completed at 4h, 8h, and 12h, and 2mL of samples were taken from the receiving pool. The content of the drug and the amino acid ester penetration enhancer in the receiving liquid was detected by liquid chromatography or gas chromatography-mass spectrometry to obtain the amount Q in the receiving liquid. 收 . After the transdermal application is completed, the patch on the pig skin is gently removed. The pig skin with the patch removed is washed three times in clean water, and the surface moisture is absorbed with filter paper, and the pig skin is cut into pieces with scissors. 3 mL of ethyl acetate or methanol is added thereto, and the sample is homogenized at a speed of 15,000 rpm using a handheld high-speed homogenizer. After 2 minutes, the sample is ultrasonicated at a frequency of 100 Hz for 30 minutes at room temperature, and centrifuged at 8,000 rpm for 10 minutes. 1 mL of the supernatant is taken and preserved. The content of the drug and the amino acid ester penetration enhancer in the sample is analyzed by liquid chromatography and triple quadrupole gas chromatography-mass spectrometry to obtain the amount Q of the drug and the amino acid ester penetration enhancer in the skin. 皮 The total amount released and distributed is the amount in the skin Q 皮 The amount Q in the receiving liquid 收 Calculate the Q of 4h, 8h, and 12h respectively 皮 +Q 收The slope of the curve is the total rate of release and uptake Vμg / cm 2 / h, the results are shown in Tables 1 to 10.

[0128] Experiment 2: Experiment on the diffusion rate of the stratum corneum

[0129] Rinse the pig skin with saline, place the active epidermis side of the excised pig skin downward on a filter paper soaked in trypsin solution in a glass dish, digest it in a 28°C water bath for 12 hours, and then use tweezers to peel off and remove other tissues attached to the stratum corneum. Wash the separated stratum corneum with distilled water for many times, spread the clean stratum corneum slices on a cellophane membrane, and place them in a dryer to dry to constant weight at constant temperature and humidity (temperature: 25°C ± 2°C, humidity 20% ± 5%). The supply liquid is a mixed solution of octylphenol polyoxyethylene ether 10 (OP-10) and caprylic decanoic acid glyceride (ODO) in a ratio of 6:4 as the solvent, and add the amino acid ester biodegradable penetration enhancer of type A, type B substance, and type C substance according to the proportion in the example, and then ultrasonically dissolve. The receiving liquid is a 20% 2-hydroxypropyl-β-cyclodextrin aqueous solution. Franz diffusion cell (V = 6.5mL, S = 2.54cm 2 ), add a small rotor to the receiving pool, and place the dried ex vivo stratum corneum in the diffusion device. Add receiving liquid to the receiving pool. No bubbles should be left between the receiving liquid and the skin. Add 400μL of supply liquid to the supply pool. Place in a transdermal diffuser at 32°C and stir continuously at 400rpm. Take 2mL of sample from the receiving pool after 4h, 8h, and 12h, and add an equal amount of fresh receiving liquid. The sample is quantitatively detected by liquid chromatography or gas chromatography-mass spectrometry to obtain the amount of drug or amino acid ester penetration enhancer in the stratum corneum. Draw a curve with time as the horizontal axis and stratum corneum penetration as the vertical axis. The slope of the curve is the stratum corneum diffusion rate Kμg / cm 2 / h, the results are shown in Tables 1 to 10.

[0130] Tables 1 to 10 show the total release and uptake rates and diffusion rates in the stratum corneum of 10 model drugs and different amino acid ester penetration enhancers. Drug is the total rate of release and uptake of the model drug, V A is the total rate of release and uptake of the amino acid ester penetration enhancer; K Drug is the diffusion rate of the model drug in the stratum corneum, K Ais the diffusion rate of the amino acid ester penetration enhancer in the stratum corneum. The bold data in the table are the penetration enhancer systems with the closest total release and uptake rates of the drug and the amino acid ester penetration enhancer, and the stratum corneum diffusion rate. Correspondingly, the penetration enhancer system has the best penetration-enhancing effect on the drug in Tables 11 to 20. For example, the amino acid ester penetration enhancer n-decyl tryptophan ester (Dec-Trp) in Example 1 has the closest diffusion rate to progesterone in the stratum corneum, and the closest total release and uptake rate, so the penetration enhancer system represented by Example 1 has the best penetration-enhancing effect on progesterone. Similarly, the penetration enhancer system that is closest to the total rate of release and uptake of cetirizine and the stratum corneum diffusion rate is Example 2; the penetration enhancer system that is closest to the total rate of release and uptake of diphenhydramine hydrochloride and the stratum corneum diffusion rate is Example 3; the penetration enhancer system that is closest to the total rate of release and uptake of blonanserin and the stratum corneum diffusion rate is Example 4; the penetration enhancer system that is closest to the total rate of release and uptake of ondansetron and the stratum corneum diffusion rate is Example 5; the penetration enhancer system that is closest to the total rate of release and uptake of finasteride and the stratum corneum diffusion rate is Example 6. The penetration enhancer system with the closest stratum corneum diffusion rate is Example 6; the penetration enhancer system with the closest total rate of release and uptake of linagliptin and stratum corneum diffusion rate is Example 7; the penetration enhancer system with the closest total rate of release and uptake of zolmitriptan and stratum corneum diffusion rate is Example 8; the penetration enhancer system with the closest total rate of release and uptake of rotundine and stratum corneum diffusion rate is Example 9; the penetration enhancer system with the closest total rate of release and uptake of ferulic acid and stratum corneum diffusion rate is Example 10.

[0131] Table 1 Total release and uptake rate and stratum corneum diffusion rate of progesterone and amino acid ester penetration enhancers

[0132]

[0133] Table 2 Total release and uptake rate and stratum corneum diffusion rate of cetirizine and amino acid ester penetration enhancers

[0134]

[0135]

[0136] Table 3 Total release and uptake rate of diphenhydramine hydrochloride and amino acid ester penetration enhancers, stratum corneum diffusion rate

[0137]

[0138] Table 4 Total release and uptake rate and stratum corneum diffusion rate of blonanserin and amino acid ester penetration enhancers

[0139]

[0140]

[0141] Table 5 Total release and uptake rate of ondansetron and amino acid ester penetration enhancers, stratum corneum diffusion rate

[0142]

[0143] Table 6 Total release and uptake rate and stratum corneum diffusion rate of finasteride and amino acid ester penetration enhancer

[0144]

[0145]

[0146] Table 7 Total release and uptake rate and stratum corneum diffusion rate of linagliptin and amino acid ester penetration enhancers

[0147]

[0148] Table 8 Total release and uptake rate and stratum corneum diffusion rate of zolmitriptan and amino acid ester penetration enhancers

[0149]

[0150]

[0151] Table 9 Total release and uptake rate of Rotundine and amino acid ester penetration enhancers, stratum corneum diffusion rate

[0152]

[0153]

[0154] Experiment 3: Investigating the transdermal effect of drug-containing patches with added penetration enhancer system

[0155] A total of 55 mg of 5% of the drug, 0.1% to 20% of the amino acid ester biodegradable penetration enhancer A (1.1 mg to 220 mg); 0.5% to 20% of the substance B (5.5 mg to 220 mg) for adjusting the release of the drug or penetration enhancer from the matrix; 0.5% to 20% of the substance C (5.5 mg to 220 mg) for adjusting the distribution of the drug and penetration enhancer to the stratum corneum, and 0.8 g of ethanol are added to a small beaker, and the mixture is shaken to dissolve. Subsequently, 2.5 g of pressure-sensitive adhesive 4098 is added, the mixture is sealed, and magnetic stirring is performed for 1.5 hours to mix the mixture evenly. Thereafter, the mixture of the drug-penetration enhancer system-pressure-sensitive adhesive is evenly spread on the anti-adhesive layer using a 400 μm thick applicator, and the mixture is placed at room temperature for 20 minutes, dried in an oven at 40° C. for 15 minutes, and taken out after the solvent is evaporated. The surface of the pressure-sensitive adhesive layer is covered with a backing layer to obtain a drug-containing patch with the penetration enhancer system added. A Franz diffusion cell (V = 6.5 mL, S = 2.54 cm 2), add a small rotor to the receiving pool. Place the patch with the anti-adhesive layer removed close to the pig skin, with the dermis of the pig skin facing the receiving liquid, and place it in a diffusion device. Add 6.5mL of receiving liquid to the receiving pool. No bubbles should be left between the receiving liquid and the skin. Place it in a transdermal diffusion instrument at 32°C and 400rpm for continuous stirring. Take 2mL of samples from the receiving pool after 4h, 12h, and 24h, and add an equal amount of fresh receiving liquid. The sample is quantitatively detected by liquid chromatograph to obtain the transdermal permeation of the drug. Calculate the permeation enhancement ratio ER, ER = 24h cumulative permeation of the drug after adding the permeation enhancer system / no permeation enhancer system added.

[0156] Tables 11 to 20 respectively list the permeation enhancement ratios ER values ​​of 10 model drugs after the addition of permeation enhancer systems, wherein the bold parts are the permeation enhancer systems with the best permeation enhancement effect on the drug. Among them, the permeation enhancer system with the best permeation enhancement effect on progesterone is Example 1, and correspondingly, the permeation enhancer system with the closest total rate of progesterone release and uptake and stratum corneum diffusion rate is also Example 1, which is consistent with the law discovered by the inventor. Similarly, the penetration enhancer system with the best penetration enhancing effect on cetirizine is Example 2; the penetration enhancer system with the best penetration enhancing effect on diphenhydramine hydrochloride is Example 3; the penetration enhancer system with the best penetration enhancing effect on blonanserin is Example 4; the penetration enhancer system with the best penetration enhancing effect on ondansetron is Example 5; the penetration enhancer system with the best penetration enhancing effect on finasteride is Example 6; the penetration enhancer system with the best penetration enhancing effect on linagliptin is Example 7; the penetration enhancer system with the best penetration enhancing effect on zolmitriptan is Example 8; the penetration enhancer system with the best penetration enhancing effect on rotundine is Example 9; and the penetration enhancer system with the best penetration enhancing effect on ferulic acid is Example 10.

[0157] Table 11 Progesterone penetration enhancement ratio after adding different penetration enhancer systems

[0158]

[0159] Table 12 Penetration enhancement ratio of cetirizine after adding different penetration enhancer systems

[0160]

[0161] Table 13 Penetration enhancement ratio of diphenhydramine hydrochloride after adding different penetration enhancer systems

[0162]

[0163] Table 14 Penetration enhancement ratio of blonanserin after adding different penetration enhancer systems

[0164]

[0165] Table 15 Penetration enhancement ratio of ondansetron after adding different penetration enhancer systems

[0166]

[0167] Table 16 Penetration enhancement ratio of finasteride after adding different penetration enhancer systems

[0168]

[0169] Table 17 Penetration enhancement ratio of linagliptin after adding different penetration enhancer systems

[0170]

[0171] Table 18 Penetration enhancement ratio of zolmitriptan after adding different penetration enhancer systems

[0172]

[0173] Table 19 The penetration enhancement ratio of rotundine after adding different penetration enhancer systems

[0174]

[0175] Table 20 Ferulic acid penetration enhancement ratio after adding different penetration enhancer systems

[0176]

[0177] Experiment 4: Degradability of amino acid ester penetration enhancer

[0178] The rats were shaved 12 h before the experiment and anesthetized with urethane (6 mL / kg, 20% w / v, intraperitoneal injection). The abdomen was fixed upward, and the hair in the abdominal area was trimmed and shaved without damaging the skin. The rats were fasted. The abdominal skin was divided into four 3.14 cm 2The skin treated with ODO without penetration enhancer was used as a blank control, and the other skin parts were treated with 0.5% concentration of amino acid ester penetration enhancer (ODO dissolved). The skin treatment method is: take 200μL of the corresponding treatment solution and evenly apply it on the marked shaved area, so that it is placed at 22±2℃ and 50±5% relative humidity for 1h, and then use cotton balls to remove the residual amino acid ester penetration enhancer on the skin surface to complete the skin treatment. Fix the pretreated skin on the filter paper and flush the stratum corneum. Stick the tape evenly on the skin, remove the tape after applying a certain force, and repeat the above action 20 times to separate the stratum corneum of the skin. Collect the remaining active epidermis and dermis after peeling in a test tube to obtain a sample. 1.5 mL of ethyl acetate was added to the active epidermis and dermis samples, and homogenized with a handheld high-speed homogenizer at a speed of 15,000 rpm. After 2 min, the above samples were ultrasonicated at a frequency of 100 Hz at room temperature for 30 min. After centrifugation at 8,000 rpm for 10 min, 1 mL of the supernatant was taken and preserved, and the content of fatty alcohol in the samples was analyzed by triple quadrupole gas chromatography-mass spectrometry.

[0179] Table 21 shows the biodegradation percentage of various amino acid ester biodegradable penetration enhancers in the skin. The hydrolysis percentage of various amino acid ester penetration enhancers within 1 hour is between 30% and 40%. It can be inferred that most amino acid ester penetration enhancers can be rapidly degraded in the skin to ensure skin safety.

[0180] Table 21 Biodegradation percentage of amino acid ester penetration enhancer

[0181]

[0182] Experiment 5: Skin irritation test of amino acid ester biodegradable penetration enhancer

[0183] 24h before the test, the back of the rabbit was depilated, and the shaved skin of the rabbit back was restored for one day. The back skin of each rabbit was divided into multiple 1.4*1.4cm square parts, labeled. The transdermal patches containing the amino acid ester penetration enhancer system were prepared according to the proportions of each substance in Examples 1 to 10, and the patch preparation method was the same as the preparation method in "Experiment 3: Investigating the transdermal effect of the drug-containing patch with the penetration enhancer system added". In addition, a 5% SDS aqueous solution was prepared as a positive control, and a blank patch without any penetration enhancer was prepared as a negative control. The prepared patch was cut into small squares of 1.4*1.4cm, the anti-adhesive layer was torn off and attached to the marked shaved area, and then fixed with two layers of gauze, non-irritating adhesive tape and bandage, and the patch was gently removed after waiting for 1h, and the skin reaction was observed under natural light or full-spectrum light. Skin erythema and edema were scored according to the scoring criteria. 1h, 4h, and 8h after the patch is removed, observe with the naked eye and record whether there is erythema and edema at the application site. At the same time on the second day, observe with the naked eye and record the score. Apply the patch to the marked shaved area for the second time, wait for 1h, then gently remove the patch and observe and record the score; observe and record the score 6h after the patch is removed. The same operation is performed on the third day. The experiment is terminated after one observation at the same time on the fourth day. The scoring standard for skin irritation reaction is shown in Appendix 1, Skin irritation intensity evaluation standard

[12] See Appendix 2.

[0184] Table 22 shows the skin irritation scores of the synthetic amino acid ester biodegradable penetration enhancer system. It can be seen from Table 22 that the three-day average scores of all penetration enhancer systems are between 0 and 0.5 points, and the skin returns to its original state on the third day. According to the scoring criteria, it is non-irritating. Therefore, the penetration enhancer system of this patent has a higher skin safety.

[0185] Table 22 Irritation of amino acid ester biodegradable penetration enhancer system to skin

[0186]

[0187]

[0188] Appendix 1 Skin irritation reaction scoring standard

[0189]

[0190] Appendix 2 Skin irritation intensity evaluation standard

[0191]

Claims

1. A biodegradable penetration enhancer system for transdermal drug delivery preparations, topical skin preparations or functional skin care products, characterized in that: The biodegradable penetration enhancer system is composed of three types of substances: A, B, and C. In terms of percentage by weight, the A type substances are 0.1% to 20%, the B type substances are 0.5% to 20%, and the C type substances are 0.5% to 20%. Among them, the A type substances are fatty alcohol amino acid ester biodegradable penetration enhancers, the B type substances are substances that can adjust the release speed of drugs or A type substances from the preparation matrix, and the C type substances are substances that can adjust the distribution speed of drugs or A type substances to the stratum corneum.

2. The biodegradable penetration enhancer system according to claim 1, characterized in that: The Class A substance fatty alcohol amino acid ester penetration enhancer, one of the raw materials of which is a fatty alcohol with a carbon chain length of 8 to 14 and a double bond number of 0 to 2; the amino acid of the second raw material is a protein amino acid or a non-protein amino acid existing in human skin and body; the ester formed by the two raw materials has a mechanism of disrupting the orderly arrangement of lipids between stratum corneum cells, and can be biodegraded by skin esterase below the stratum corneum into amino acids and fatty alcohols without obvious cytotoxicity.

3. The biodegradable penetration enhancer system according to claim 1, characterized in that: The B-type substance can adjust the release rate of the drug or the A-type substance from the matrix, and includes one or more of surfactants, polyols, fatty acids and esters thereof.

4. The biodegradable penetration enhancer system according to claim 1, characterized in that: The C-type substance can adjust the distribution rate of the drug or penetration enhancer to the stratum corneum, and includes one or more of pyrrolidine, ether, terpene, fatty acid and its ester, surfactant, and polyol.

5. The biodegradable penetration enhancer system according to claim 1, characterized in that: The Class A substance is selected from n-decyl tryptophan ester, n-octanol tyrosine ester, n-octanol glycine ester, n-decyl serine ester, lauryl lysine ester, lauryl methionine ester, n-octanol valine ester, lauryl glutamine ester, lauryl leucine ester, and n-decyl histidine ester.

6. The biodegradable penetration enhancer system according to claim 1, characterized in that: The B-type substance is selected from polyethylene glycol 400, isopropyl myristate, and 1,3-propylene glycol.

7. The biodegradable penetration enhancer system according to claim 1, characterized in that: The C-type substance is selected from diethylene glycol ethyl ether, limonene, dodecyl glucoside, and N-methylpyrrolidone.

8. A method for preparing the Class A substance in the biodegradable penetration enhancer system according to claim 1, characterized in that: The following steps are involved: Amino acid and p-toluenesulfonic acid are added, and fatty alcohol is added after mixing. The temperature is raised to 100-150° C., and the water is refluxed to separate. When no water is separated and the reaction is stopped after TLC detection is qualified; the reaction solution is adjusted to pH 9-11 with sodium hydroxide solution, extracted with ethyl acetate 2-5 times, the organic layers are combined, washed with saturated sodium chloride solution, dried and evaporated to remove the solvent; column chromatography is performed on a silica gel column, and a mixed solution of petroleum ether and ethyl acetate is used as an eluent, and the eluent is evaporated to obtain a colorless liquid.

9. The preparation method according to claim 8, characterized in that: The molar ratio of the amino acid and p-toluenesulfonic acid added is 1:1 to 1:

3.

10. Use of the amino acid ester biodegradable penetration enhancer system according to any one of claims 1 to 7 in transdermal drug delivery preparations, topical skin preparations, and functional skin care products.

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