CN110305030B - Amino acid ester hydrochloride and preparation method and application thereof - Google Patents
Amino acid ester hydrochloride and preparation method and application thereof Download PDFInfo
- Publication number
- CN110305030B CN110305030B CN201910584126.0A CN201910584126A CN110305030B CN 110305030 B CN110305030 B CN 110305030B CN 201910584126 A CN201910584126 A CN 201910584126A CN 110305030 B CN110305030 B CN 110305030B
- Authority
- CN
- China
- Prior art keywords
- amino acid
- acid ester
- ester hydrochloride
- transdermal
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses amino acid ester hydrochloride and a preparation method and application thereof, which are characterized in that amino acid, alcohol and p-toluenesulfonic acid are added into toluene, reflux reaction is carried out for 4 hours at 130-140 ℃, reaction liquid is extracted for 3 times by NaOH solution with the mass percentage concentration of 5%, an organic layer is dried overnight by using anhydrous sodium sulfate, a solvent is evaporated, and column chromatography is carried out by using mixed liquid of petroleum ether and isopropanol with the volume ratio of 5-6: 1 as an eluent, so as to obtain colorless liquid amino acid ester; introducing dry hydrogen chloride gas into the amino acid ester for 1-1.5 h to obtain amino acid ester hydrochloride; the amino acid ester hydrochloride has good using effect in a transdermal drug delivery system as a penetration enhancer, promotes transdermal absorption of the drug, enhances the fluidity of keratinocytes and effectively increases the transdermal dose of the drug.
Description
Technical Field
The invention relates to amino acid ester hydrochloride and a preparation method and application thereof, belonging to the technical field of external administration.
Background
The Transdermal Drug Delivery System (Transdermal Drug Delivery System) is a preparation which is absorbed through the skin, enters the systemic blood circulation to achieve effective blood concentration and realize the treatment or prevention of diseases; the preparation can avoid the defects of intravenous injection administration and oral administration, has low toxic and side effects, no liver first-pass effect, no influence of gastric emptying rate and the like, and high bioavailability; convenient use, fixed absorption area and stable blood concentration, and is a new way of non-invasive administration. Transdermal preparations can act not only locally but also systemically, and are one of the hot spots in research on external preparations.
The skin is the largest organ in the human body, which covers the entire body and prevents foreign substances from penetrating into the body from the environment. In transdermal drug delivery systems, the largest obstacle to the absorption of drugs is the outermost layer of the skin (Stratum Corneum, SC). The stratum corneum is the outermost layer of the skin, and due to its special structure, drug molecules are difficult to penetrate the stratum corneum into local or systemic circulation. It is a major obstacle to transdermal drug penetration. Transdermal absorption Enhancers (PE), which are substances that accelerate the Penetration of drugs through the skin without causing severe irritation and damage to the skin, are important components of transdermal drug delivery systems. Conventional penetration enhancers include sulfoxides, azones, fatty acids, fatty alcohols, and the like. In recent years, terpenes, amino acid derivatives, surfactants, menthol ester derivatives, carveol ester derivatives, polypeptides and other compounds are proved to have transdermal penetration enhancing activity in sequence. However, a significant proportion of the compounds have not been clinically used due to irritation and other yet unclarified safety concerns.
Amino acid ester hydrochloride is receiving attention because of its good biodegradability and higher safety. The myristyl unit takes natural Amino Acid [ Amino Acid, AA ] and protonated Amino Acid Ester [ Amino Acid Ester, AAE ] as cations respectively, and forms ionic liquid with various anions (such as halogen, NO3, BF4 and the like) through acidification and salt formation. The compound has good biological regeneration and biodegradability; ② the chiral center of the amino acid can be kept; and thirdly, functional reconstruction can be simply and conveniently carried out by changing the side chain. However, the application of the compound as a penetration enhancer in a transdermal drug delivery system is not reported.
Disclosure of Invention
The structural formula of the amino acid ester hydrochloride is as follows:
wherein R is a variable group of an amino acid, the amino acid being glycine, leucine, proline, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, threonine, aspartic acid, glutamic acid, lysine, arginine, or histidine; except glycine, the compound is in L-type configuration; r' = (CH2)nCH3N =8 to 14 and is an integer.
The invention also provides a preparation method of the amino acid ester hydrochloride, which comprises the following specific steps:
(1) esterification reaction: adding amino acid, alcohol and p-toluenesulfonic acid into toluene, carrying out reflux reaction at 130-140 ℃ for 4h, extracting the reaction solution for 3 times by using a NaOH solution with the mass percentage concentration of 5%, drying an organic layer overnight by using anhydrous sodium sulfate, evaporating the solvent, and carrying out column chromatography by using a mixed solution of petroleum ether and isopropanol in a volume ratio of 5-6: 1 as an eluent to obtain colorless liquid amino acid ester;
(2) and (3) acidification reaction: and (2) introducing dry hydrogen chloride gas into the amino acid ester in the step (1) for 1-1.5 h, wherein the molar ratio of the hydrogen chloride gas to the amino acid is 1.05-1.15: 1, and thus obtaining the amino acid ester hydrochloride.
The amino acid in the step (1) is glycine, leucine, proline, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, threonine, aspartic acid, glutamic acid, lysine, arginine or histidine.
The alcohol in the step (1) is n-octanol or dodecanol.
The molar ratio of the amino acid to the alcohol to the p-toluenesulfonic acid in the step (1) is (0.8-1.8) - (0.8) for the amino acid to the alcohol to the p-toluenesulfonic acid = 1.
The adding amount of the toluene in the step (1) is 30-50 times of the amount of the amino acid substances.
The reaction equation of the preparation method of the invention is as follows:
wherein R is a variable group of an amino acid, the amino acid being glycine, leucine, proline, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, threonine, aspartic acid, glutamic acid, lysine, arginine, or histidine; r' = (CH2)nCH3N =8-14 and is an integer.
The invention also provides the application of the amino acid ester hydrochloride as a penetration enhancer in a transdermal drug delivery system, the effect of the amino acid ester hydrochloride as the penetration enhancer for transdermal drug delivery is verified by adopting a Franz diffusion cell method, experimental results show that the ER value of the amino acid ester hydrochloride is about 4 times of that of a control group, hydrophilic drugs 5-FU and lipophilic drugs hydrocortisone are respectively selected as the drugs, and the amino acid ester hydrochloride as the penetration enhancer has the promotion effect on transdermal drug delivery of lipophilic and hydrophilic drugs.
The mass concentration of the amino acid ester hydrochloride serving as a penetration enhancer is 0.1-10%, and different concentrations in the range have penetration enhancing effects on the medicine.
The lipophilic medicament hydrocortisone related in the invention is a glucocorticoid, has the functions of immunosuppression, antitoxic and antishock, is mainly used for the substitution treatment of adrenocortical insufficiency and the treatment of congenital adrenocortical hyperplasia, can also be used for rheumatoid arthritis, rheumatic fever, gout, bronchial asthma and allergic diseases, and can be used for the treatment of severe infection and antishock and the like. The hydrophilic drug 5-FU is thymidylate synthase inhibitor, is a derivative of uracil with fluorine substituted hydrogen at 5-position, and 5-FU is not only the earliest anticancer drug but also the most widely applied anti-pyrimidine drug at present, has good curative effect on digestive tract cancer and other solid tumors, and plays an important role in the medical treatment of tumors.
Compared with the prior art, the invention has the advantages that: (1) the amino acid ester hydrochloride has the advantages of no toxicity, easy obtaining, small irritation and strong solubility. (2) The synthetic method has the advantages of high yield, less time consumption and simple purification. (3) The amino acid ester hydrochloride is used as a penetration enhancer to promote the transdermal absorption of the medicament, enhance the fluidity of the keratinocytes and effectively increase the transdermal amount of the medicament. The transdermal penetration enhancer can effectively improve the solubility of the medicine, improve the absorption rate of the medicine, improve the treatment effect and have wide application prospect.
Drawings
FIG. 1 is a nuclear magnetic spectrum hydrogen spectrum of octyl glycinate hydrochloride salt of example 1;
FIG. 2 is a nuclear magnetic spectrum carbon spectrum of octyl glycinate hydrochloride salt of example 1;
FIG. 3 is a nuclear magnetic spectrum hydrogen spectrum of octyl leucine hydrochloride of example 2;
FIG. 4 is a carbon spectrum of a nuclear magnetic spectrum of octyl leucine hydrochloride of example 2;
FIG. 5 is a NMR spectrum of dodecyl leucine ester hydrochloride of example 3;
FIG. 6 is a carbon spectrum of a nuclear magnetic spectrum of the hydrochloride salt of lauryl leucine ester of example 3;
FIG. 7 is a NMR spectrum of octyl prolinate hydrochloride of example 4;
FIG. 8 is a carbon spectrum of a nuclear magnetic spectrum of octyl prolinate hydrochloride of example 4;
FIG. 9 is a graph of the cumulative transdermal absorption of hydrocortisone for examples 1-4;
FIG. 10 is a graph of the cumulative permeation through transdermal absorption of example 1-45-FU.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
The preparation method of glycine octyl ester hydrochloride comprises the following specific steps:
(1) esterification reaction: dissolving 26.6nmol of glycine, 21.3nmol of n-octanol and 21.3mmol of p-toluenesulfonic acid in 800mmol of toluene, refluxing and reacting at 130 ℃ for 12 hours, extracting the reaction solution for 3 times by using 200mL of NaOH solution with the mass percent concentration of 5%, drying an organic layer overnight by using anhydrous sodium sulfate, evaporating the solvent, and performing column chromatography by using mixed liquid of petroleum ether and isopropanol in a volume ratio of 5:1 as an eluent to obtain colorless liquid of octyl glycinate;
(2) and (3) acidifying, namely introducing hydrogen chloride gas into the octyl glycinate obtained in the step (1) for 1h, wherein the molar ratio of the introduced hydrogen chloride gas to the amino acid is 1.05:1, so as to obtain octyl glycinate hydrochloride ([ L-GlyC8] Cl) as white powder with the yield of 80%.
The synthesis method equation is as follows:
the nuclear magnetic resonance detection of the product obtained in this example is performed, and the obtained hydrogen spectrum and carbon spectrum data are shown in fig. 1 and fig. 2, and the data are as follows:
hydrogen spectrum data: 1H NMR (600 MHz, Chloroform-d) δ 8.34 (s, 2H), 4.04 (t, J = 8.1 Hz, 1H), 3.90 (s, 1H), 1.94-1.44 (m, 1H), 1.44-0.83 (m, 13H), 0.76 (q, J = 11.0, 9.5 Hz, 3H).
Carbon spectrum data: 13C NMR (151 MHz, Chloroform-d) delta 167.61, 66.05, 40.32, 31.41, 28.88, 28.81, 27.98, 25.41, 22.24, 22.22, 13.66.
From the hydrogen spectrum and the carbon spectrum, the chemical formula of the product obtained in the example is consistent with the result of the equation.
Example 2
The preparation method of the leucine octyl ester hydrochloride comprises the following specific steps:
(1) esterification reaction: dissolving 15.186nmol of leucine, 16.705nmol of n-octanol and 16.705mmol of p-toluenesulfonic acid in 600mmol of toluene, carrying out reflux reaction at 140 ℃ for 4h, extracting the reaction solution for 3 times by using 200mL of NaOH solution with the mass percent concentration of 5%, drying an organic layer overnight by using anhydrous sodium sulfate, evaporating the solvent, and carrying out column chromatography by using a mixed solution of petroleum ether and isopropanol in a volume ratio of 5.5:1 as an eluent to obtain colorless liquid which is octyl leucine;
(2) and (3) acidification reaction: and (2) introducing hydrogen chloride gas into the octyl leucine ester in the step (1) for 1h, wherein the molar ratio of the introduced hydrogen chloride gas to the amino acid is 1.05:1, so that the octyl leucine ester hydrochloride ([ L-LeuC8] Cl) is obtained as white powder with the yield of 82%.
The synthesis method equation is as follows:
the nuclear magnetic resonance detection of the product obtained in this example is performed, and the obtained hydrogen spectrum and carbon spectrum data are shown in fig. 3 and 4, and the data are as follows:
hydrogen spectrum data: 1H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 3H), 4.21 (dt, J = 10.5, 6.9 Hz, 1H), 4.15 (dt, J = 10.6, 6.7 Hz, 1H), 4.07 (t, J = 6.9 Hz, 1H), 2.04-1.91 (m, 2H), 1.85 (td, J = 10.2, 5.1 Hz, 1H), 1.66 (p, J = 7.0 Hz, 2H), 1.38-1.18 (m, 10H), 0.99 (dd, J = 6.2, 2.8 Hz, 6H), 0.88 (t, J = 7.0 Hz, 3H).
Carbon spectrum data:13C NMR (151 MHz, Chloroform-d) δ 169.99, 77.40, 77.19, 76.98, 66.52, 66.49, 51.79, 39.59, 39.56, 31.81, 31.79, 29.21, 29.20, 29.18, 29.16, 28.37, 28.36, 25.82, 24.54, 22.66, 22.32, 22.29, 22.28, 22.18, 14.12。
from the hydrogen spectrum and the carbon spectrum, the chemical formula of the product obtained in the example is consistent with the result of the equation.
Example 3
The preparation method of the leucine dodecyl ester hydrochloride comprises the following specific steps:
(1) esterification reaction: dissolving 15.186nmol of leucine, 22.779nmol of dodecanol and 27.3348mmol of p-toluenesulfonic acid in 610mmol of toluene, refluxing and reacting at 135 ℃ for 8 hours, extracting the reaction solution for 3 times by using 200mL of NaOH solution with the mass percent concentration of 5%, drying an organic layer overnight by using anhydrous sodium sulfate, evaporating the solvent, and performing column chromatography by using mixed solution of petroleum ether and isopropanol in a volume ratio of 6:1 as an eluent to obtain colorless liquid which is leucine dodecyl ester;
(2) and (3) acidification reaction: and (2) introducing hydrogen chloride gas into the lauryl leucine ester in the step (1) for 1.5h, wherein the molar ratio of the introduced hydrogen chloride gas to the amino acid is 1.15:1, so that the lauryl leucine ester hydrochloride ([ L-LeuC12] Cl) is obtained as white powder with the yield of 82%.
The synthesis method equation is as follows:
the nuclear magnetic resonance detection of the product obtained in this example is performed, and the obtained hydrogen spectrum and carbon spectrum data are shown in fig. 5 and 6, and the data are as follows:
hydrogen spectrum data:1H NMR (600 MHz, Chloroform-d) δ 8.76 (s, 3H), 4.37 – 3.92 (m, 3H), 2.01 (td, J = 13.0, 7.0 Hz, 2H), 1.93 – 1.80 (m, 1H), 1.66 (q, J = 7.5 Hz, 2H), 1.54 – 1.09 (m, 18H), 1.07 – 0.92 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H)。
carbon spectrum data:13C NMR (151 MHz, Chloroform-d) δ 65.96, 39.10, 31.58, 29.32, 29.30, 29.24, 29.19, 29.02, 28.86, 28.00, 25.47, 24.18, 22.33, 21.92, 21.84, 13.75。
from the hydrogen spectrum and the carbon spectrum, the chemical formula of the product obtained in the example is consistent with the result of the equation.
Example 4
The preparation method of proline octyl ester hydrochloride comprises the following specific steps:
(1) esterification reaction: dissolving 17.372nmol of proline, 31.2696nmol of n-octanol and 27.7952mmol of p-toluenesulfonic acid in 868mmol of toluene, refluxing and reacting at 130 ℃ for 8 hours, extracting the reaction solution for 3 times by using 200mL of NaOH solution with the mass percent concentration of 5%, drying an organic layer overnight by using anhydrous sodium sulfate, evaporating the solvent, and performing column chromatography by using a mixed solution of petroleum ether and isopropanol at the volume ratio of 6:1 as an eluent to obtain colorless liquid of octyl proline;
(2) and (3) acidification reaction: and (2) introducing dry hydrogen chloride gas into the proline octyl ester in the step (1) for 1.2h, wherein the molar ratio of the introduced hydrogen chloride gas to the amino acid is 1.1:1, and the proline octyl ester hydrochloride ([ L-ProC8] Cl) is white powder with the yield of 82%.
The synthesis method equation is as follows:
the nuclear magnetic resonance detection of the product obtained in this example is performed, and the obtained hydrogen spectrum and carbon spectrum data are shown in fig. 7 and 8, and the data are as follows:
hydrogen spectrum data:1H NMR (600 MHz, Chloroform-d) δ 10.43 (s, 1H), 8.98 (s, 1H), 4.53 (s, 1H), 4.41 – 3.98 (m, 2H), 3.72 – 3.47 (m, 2H), 2.31 – 1.92 (m, 4H), 1.86 – 1.49 (m, 2H), 1.31 (ddt, J = 29.2, 14.9, 8.0 Hz, 10H), 0.89 (q, J= 6.3 Hz, 3H)。
carbon spectrum data:13C NMR (151 MHz, Chloroform-d) δ 168.96, 66.94, 59.26, 46.08, 31.67, 29.06, 28.85, 28.28, 25.67, 23.60, 22.54, 14.01。
in vitro transdermal assay of hydrocortisone with amino acid ester hydrochloride prepared in examples 1-4:
(1) taking male Kunming mouse (weight 20 + -2 g), killing after neck is cut off, peeling off abdominal skin, shearing off mouse hair with electric shaver, removing subcutaneous fat and connective tissue, washing with normal saline repeatedly, and storing in refrigerator at-20 deg.C;
(2) loading rat skin on a Franz diffusion cell, wherein the stratum corneum layer of the rat skin faces to a supply cell, the supply cell in an experimental group is a methanol-water (methanol: water volume ratio 1: 9) solution with the mass percent concentration of 5% of amino acid ester hydrochloride and the concentration of hydrocortisone drug being 1mg/mL, a receiving cell is filled with 0.01mol/L PBS buffer solution (pH = 7.4) receiving liquid, the supply cell in a blank group is a methanol-water (methanol: water volume ratio 1: 9) solution with the concentration of hydrocortisone drug being 1mg/mL, the receiving cell is filled with 0.01mol/L PBS buffer solution (pH = 7.4) receiving liquid, the stratum corneum of the rat skin faces upwards, the subcutaneous fat part is fully contacted with the receiving liquid in the receiving cell, the water temperature in the cell is 37 ℃, carrying out constant temperature magnetic stirring, the timing is started after the sample is added and balanced for 1h, 2h and 4h respectively, 1mL of receiving solution is taken out from the sample receiving pool at 6h, 8h, 10h, 12h and 24h, meanwhile, the same amount of receiving solution with the same temperature is added into the receiving pool, the taken receiving solution sample is filtered by a 0.45 mu m microporous membrane, the release amount of each group of medicaments is measured by an HPLC method, and the cumulative permeation amount per unit area Q (mu g/mL) is calculated, and the result is shown in figure 9.
From the results in FIG. 9, it can be seen that the cumulative permeation amount and transdermal rate of hydrocortisone containing the amino acid ester hydrochloride of examples 1-4 are greater than those of the blank group without the addition of the amino acid ester hydrochloride within 24 hours for the ester soluble drug hydrocortisone with the same drug amount, wherein the most effective permeation is proline ester hydrochloride; the cumulative permeation at 24 hours was about 6 times that of the blank, followed by leucine dodecyl ester hydrochloride.
Examples 1-4 in vitro transdermal evaluation of amino acid ester hydrochloride on 5-FU:
(1) taking male Kunming mouse (weight 20 + -2 g), killing after neck is cut off, peeling off abdominal skin, shearing off mouse hair with electric shaver, removing subcutaneous fat and connective tissue, washing with normal saline repeatedly, and storing in refrigerator at-20 deg.C;
(2) loading rat skin on a Franz diffusion cell, wherein the stratum corneum layer of the rat skin faces to a supply cell, the supply cell in an experimental group is a methanol-water (methanol: water volume ratio of 1: 9) solution with the mass percent concentration of 2mL amino acid ester hydrochloride of 5% and the concentration of 5-FU drug of 1mg/mL, a receiving cell is filled with 0.01mol/L PBS buffer solution (pH = 7.4) receiving solution, the supply cell in a blank group is an aqueous solution with the concentration of 5-FU drug of 5mg/mL, the receiving cell is filled with 0.01mol/L PBS buffer solution (pH = 7.4) receiving solution, the stratum corneum of the rat skin faces upwards, the subcutaneous fat part is fully contacted with the receiving solution in the receiving cell, the water temperature in the cell is 37 ℃, carrying out constant temperature magnetic stirring, and starting timing after balancing for 1h after loading, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h respectively, and taking out 1mL receiving solution from a sample receiving cell, simultaneously, the same amount of the same temperature of the receiving solution was added to the receiving cell, and the sample of the receiving solution taken out was filtered through a 0.45 μm microporous membrane, the amount of each group of drugs released was measured by HPLC, and the cumulative permeation amount per unit area Q (μ g/mL) was calculated, and the results are shown in FIG. 10.
From the results in FIG. 10, it can be seen that the cumulative permeation rate and transdermal rate of 5-FU in examples 1-4 are much greater than those of the blank group without the penetration enhancer in 24 hours for the water-soluble drug 5-FU under the condition of keeping the same drug amount, wherein the leucine dodecaester hydrochloride is the best permeation effect; the cumulative permeation at 24 hours was about 5 times that of the blank, followed by leucine octyl ester hydrochloride.
The results show that the amino acid ester hydrochloride has permeation promoting effect on lipophilic drug hydrocortisone and hydrophilic drug 5-FU, the cumulative permeation amount in 24 hours is far greater than that of the blank group, and the permeation promoting efficiency is obvious.
Claims (2)
1. The application of the amino acid ester hydrochloride in preparing a penetration enhancer of a transdermal drug delivery system is that the amino acid ester hydrochloride is proline octyl ester hydrochloride, and the drug is hydrocortisone.
2. The application of amino acid ester hydrochloride in preparing a penetration enhancer of a transdermal drug delivery system is disclosed, wherein the amino acid ester hydrochloride is leucine dodecaester hydrochloride, and the drug is 5-fluorouracil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910584126.0A CN110305030B (en) | 2019-07-01 | 2019-07-01 | Amino acid ester hydrochloride and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910584126.0A CN110305030B (en) | 2019-07-01 | 2019-07-01 | Amino acid ester hydrochloride and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110305030A CN110305030A (en) | 2019-10-08 |
| CN110305030B true CN110305030B (en) | 2021-10-15 |
Family
ID=68078271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910584126.0A Active CN110305030B (en) | 2019-07-01 | 2019-07-01 | Amino acid ester hydrochloride and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110305030B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322548A (en) * | 1980-02-13 | 1982-03-30 | Kay Fries, Inc. | Resolution of racemic mandelic acid |
| JPH04275234A (en) * | 1991-03-01 | 1992-09-30 | Lintec Corp | Percutaneous absorption-promoting agent |
| EP0552405A1 (en) * | 1992-01-24 | 1993-07-28 | LINTEC Corporation | A percutaneous absorption promoter, a tape plaster and a method of promoting percutaneous absorption |
| WO2004074235A1 (en) * | 2003-02-24 | 2004-09-02 | UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové | Transdermal penetration enhancers |
| CN101899085A (en) * | 2009-05-26 | 2010-12-01 | 首都医科大学 | Saturated fatty chain alcohol Glu-Asp-Gly tripeptide ester, synthetic method and application thereof |
| WO2014138708A1 (en) * | 2013-03-08 | 2014-09-12 | Yu Benjamin M | Methods and compositions for transdermal delivery of caffeine in the forms of solution or suspension |
| WO2015000076A1 (en) * | 2013-07-02 | 2015-01-08 | Alectos Therapeutics Inc. | Photochemical process for the fluortnation of an organic compound having an unactivated sp3 c-h bond |
| CN105669497B (en) * | 2014-11-18 | 2017-04-26 | 中国科学院兰州化学物理研究所 | Amino-acid derivative organic micromolecular gelator, preparation method therefor and application of amino-acid derivative organic micromolecular gelator |
| CN106674063A (en) * | 2016-12-21 | 2017-05-17 | 中国科学院兰州化学物理研究所 | Amphiphilic small organic molecule gelator, and preparation method and application thereof |
-
2019
- 2019-07-01 CN CN201910584126.0A patent/CN110305030B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322548A (en) * | 1980-02-13 | 1982-03-30 | Kay Fries, Inc. | Resolution of racemic mandelic acid |
| JPH04275234A (en) * | 1991-03-01 | 1992-09-30 | Lintec Corp | Percutaneous absorption-promoting agent |
| EP0552405A1 (en) * | 1992-01-24 | 1993-07-28 | LINTEC Corporation | A percutaneous absorption promoter, a tape plaster and a method of promoting percutaneous absorption |
| WO2004074235A1 (en) * | 2003-02-24 | 2004-09-02 | UNIVERZITA KARLOVA V PRAZE Farmaceuticka Fakulta V Hradci Kralové | Transdermal penetration enhancers |
| CN101899085A (en) * | 2009-05-26 | 2010-12-01 | 首都医科大学 | Saturated fatty chain alcohol Glu-Asp-Gly tripeptide ester, synthetic method and application thereof |
| WO2014138708A1 (en) * | 2013-03-08 | 2014-09-12 | Yu Benjamin M | Methods and compositions for transdermal delivery of caffeine in the forms of solution or suspension |
| WO2015000076A1 (en) * | 2013-07-02 | 2015-01-08 | Alectos Therapeutics Inc. | Photochemical process for the fluortnation of an organic compound having an unactivated sp3 c-h bond |
| CN105669497B (en) * | 2014-11-18 | 2017-04-26 | 中国科学院兰州化学物理研究所 | Amino-acid derivative organic micromolecular gelator, preparation method therefor and application of amino-acid derivative organic micromolecular gelator |
| CN106674063A (en) * | 2016-12-21 | 2017-05-17 | 中国科学院兰州化学物理研究所 | Amphiphilic small organic molecule gelator, and preparation method and application thereof |
Non-Patent Citations (8)
| Title |
|---|
| A type II aqueous cholesteric lyomesophase;MAHMUT ACIMIS AND LEONARD W. REEVES;《CAN. J. CHEM.》;19801231;第58卷;第1533-1541页 * |
| Amino acid derivatives as transdermal permeation enhancers;Barbora Janusova等;《Journal of Controlled Release》;20121112;第165卷;第91-100页 * |
| Investigation of the physicochemical and biological properties of proline-based surfactants in single and mixed surfactant systems;Nausheen Joondan等;《J Surfact Deterg》;20161107;第20卷;第103-115页 * |
| RN: 168144-85-2等;Chemical Abstract Service;《CA网络版STN Registry数据库》;19950928 * |
| Synthetic Ceramide Analogues as Skin Permeation Enhancers: Structure–Activity Relationships;Katerina Vavrova等;《Bioorganic & Medicinal Chemistry》;20031231;第11卷;第5381-5390页 * |
| 含氨基酸分子膜的合成、相转移作用及与生物脂协同组织形态的研究;江纪修;《中山大学学报(自然科学版)》;19930131;第32卷(第1期);第46-52页 * |
| 张兴盈等.氨基酸酯类离子液体的经皮促渗活性考察.《中国医药工业杂志》.2017,第48卷(第4期),第536-542页. * |
| 氨基酸酯类离子液体的经皮促渗活性考察;张兴盈等;《中国医药工业杂志》;20171231;第48卷(第4期);第536-542页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110305030A (en) | 2019-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2777549T3 (en) | Body sculpting | |
| JP5466006B2 (en) | Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate | |
| JP6693999B2 (en) | Transdermal absorption enhancer and transdermal absorption enhancer | |
| CN107303263B (en) | Tripterygium glycosides nanoemulsion gel and preparation method thereof | |
| CN116120402B (en) | Cyclic peptide, and composition and application thereof | |
| Yuan et al. | Solubility and permeation enhancement of poor soluble drug by cholinium-amino acid based ionic liquids | |
| CN104474551A (en) | Melatonin phospholipid complex, melatonintransdermal drug deliverypreparation and preparation method of melatonin phospholipid complex | |
| CN101357126A (en) | Stable taxone albumin lipid drug-loading system and preparation method thereof | |
| Zhu et al. | Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy | |
| JP4897970B2 (en) | Tripeptide complex which is an agonist of MSH | |
| CN108164512B (en) | Maleimide prodrug with biological adhesion function and application thereof in oral drug delivery | |
| CN110305030B (en) | Amino acid ester hydrochloride and preparation method and application thereof | |
| Jin et al. | Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice | |
| CN101361746A (en) | Stable adriablastina albumin lipid drug-loading system and preparation method thereof | |
| Bergonzi et al. | Evaluation of skin permeability of sesquiterpenes of an innovative supercritical carbon dioxide Arnica extract by HPLC/DAD/MS | |
| CN103880754A (en) | Alkaline amino acid ester salt of propofol | |
| CN1813678A (en) | Hepatitis B vaccine liposome and its trans dermal drug delivery system | |
| CN111793030A (en) | Absorption enhancer and preparation method and application thereof | |
| CN101597276B (en) | Propylidene derivative of N-(Alpha, Beta-dimercapto-Beta-carboxyl propionyl)-amino acid and synthetic method and application thereof | |
| JP5855599B2 (en) | Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate | |
| CN113041361B (en) | Diagnosis and treatment integrated material responding to HDAC and CTSL and preparation method and application thereof | |
| WO2016121753A1 (en) | Method for controlling skin penetration | |
| JP7279461B2 (en) | skin penetration enhancer | |
| CN115845077A (en) | Polyethylene glycol supported abiraterone prodrug and preparation method thereof | |
| JP6165816B2 (en) | Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |