CN114569730A

CN114569730A - Felodipine transdermal drug delivery agent combination, felodipine transdermal drug delivery preparation and transdermal delivery device

Info

Publication number: CN114569730A
Application number: CN202210087451.8A
Authority: CN
Inventors: 岳洋; 徐壁雄; 马丹丹
Original assignee: Xinwen Biomedical Technology Jiashan Co ltd
Current assignee: Xinwen Biomedical Technology Jiashan Co ltd
Priority date: 2022-01-25
Filing date: 2022-01-25
Publication date: 2022-06-03
Anticipated expiration: 2042-01-25
Also published as: CN114569730B

Abstract

The invention discloses a felodipine transdermal drug delivery agent combination, a felodipine transdermal drug delivery preparation and a transdermal delivery device, which at least comprise two or more than two of the following components in parts by weight:

compared with the prior art, the method has the following beneficial effects: the felodipine transdermal enhancer combination can improve the permeation flux by 20-400%. Transdermal drug delivery devices incorporating the transdermal delivery system of the transdermal drug delivery system can significantly improve the transdermal flux of felodipine over 24 hours and longer. The transdermal drug delivery device can increase the cumulative skin permeation flux for 24h to 50 mu g/cm²Or more.

Description

Felodipine transdermal drug delivery agent combination, felodipine transdermal drug delivery preparation and transdermal delivery device

Technical Field

The invention relates to the technical field of medicaments, in particular to a felodipine transdermal enhancer combination and a transdermal delivery device. The felodipine transdermal enhancer combination can obviously improve the skin administration of felodipine and enhance the skin permeation flux.

Background

Hypertension is a serious health risk. Prolonged elevation of blood pressure can damage the heart, resulting in changes in the structure and function of the heart. For patients with hypertension, the antihypertensive product which is safe, effective and convenient to use for a long time is very important for maintaining the stability of blood pressure and the health of the cardiovascular system for a long time.

Felodipine is chemically named as (+/-) -2, 6-dimethyl-4- (2, 3-dichlorophenyl) -1, 4-dihydro-3, 5-pyridinedicarboxylic acid methyl ester ethyl ester, is a vascular selective calcium channel blocker, has high selectivity on arterial smooth muscle, has an expansion effect on coronary artery, cerebral vessels and peripheral vessels, can inhibit the electricity and contractile activity of the vascular smooth muscle, and inhibits calmodulin from interfering with the utilization of intracellular Ca2+, thereby achieving the effect of reducing blood pressure.

Available oral hypotensive drugs provide hypotensive effects for a prolonged period of time, which requires administering the drug to a patient several times a day, and are disadvantageous to hypertensive patients because of fluctuations in drug concentration in the body, the concentration in the trough is less than 1/3 in the trough concentration, and the concentration in the trough is highly influenced by food, and hepatic metabolic enzymes are affected by age, etc. to cause blood pressure fluctuations due to the extreme fluctuations in drug concentration in blood. For example, an oral immediate release preparation of the product has an onset time of 1 hour, a maximum effect time of 2-4 hours, an effect lasting 6-9 hours, and a multi-administration effect lasting 12-14 hours. The oral sustained-release preparation has the onset time of 2-5 hours, and the multiple administration effect lasts 24 hours. Meanwhile, patients with long-term hypertension are elderly patients, and even elderly patients suffering from other senile diseases (such as Alzheimer's disease) have difficulty in swallowing oral medicines. For felodipine which is used for a long time or even for life, one more convenient, safe and effective dosage form can greatly improve the compliance of medication, and has great clinical value.

During the administration of felodipine for lowering blood pressure, the drug needs to be continuously administered into the human body. Oral administration is commonly used because of its simplicity. However, oral administration often involves gastrointestinal irritation, and the drug effect is unstable due to drug metabolism in the liver and food influence.

Administration via the human skin (i.e., transdermal drug administration) is an alternative route and may offer advantages over oral administration including avoidance of primary metabolism, controlled delivery, simple dosing regimens, and improved patient compliance, most importantly long term stability of drug efficacy. Transdermal delivery systems are patches containing an active ingredient that are attached to the skin to deliver the active agent by transdermal absorption. After application of a transdermal patch to the skin, the active agent contained in the patch passes or permeates through the skin and can reach its site of action by systemic blood flow. Alternatively, a transdermal patch may be placed at the desired treatment site, such that the drug contained in the patch is delivered locally.

In view of the above, there is a need for a safe and effective administration method that is easy to operate and stable for a long time for patients with hypertension; furthermore, how to significantly improve the drug permeation flux is also an urgent problem to be solved

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the felodipine transdermal drug delivery agent combination, the felodipine transdermal drug delivery preparation and the transdermal delivery device are developed and developed, and the felodipine transdermal drug delivery agent combination can improve the permeation flux by 20-400%.

The present invention is directed to solving the above-mentioned problems of the prior art, and provides a felodipine transdermal enhancer composition, a felodipine transdermal preparation, and a felodipine transdermal delivery device.

In order to achieve the purpose, the invention adopts the following technical scheme:

a transdermal delivery system of felodipine is composed of at least two or more of the following components in parts by weight:

as a further improvement of the present solution,

the alcohol is any one or more of oleyl alcohol or lauryl alcohol;

the fatty acid is any one or more of linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid and palmitic acid;

the fatty acid ester is one or more of isopropyl myristate, diisopropyl adipate and isopropyl palmitate;

the fatty acid glyceride is fatty acid glyceride with 8-22 carbon atoms, and the fatty acid glyceride is any one or more of monoglyceride, diglyceride and triglyceride; wherein the fatty acid component forming the fatty glyceride comprises any one or more of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and oleic acid;

the acyl amino acid is any one or more of oleoyl sarcosine, myristoyl sarcosine and N-lauroyl sarcosine;

the polyalcohol is one or more of glycerol, ethylene glycol, propylene glycol, 1, 3-butanediol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol and isosorbide;

as a further improvement of this solution, other types of percutaneous absorption enhancers are also included:

including any one or more of lactic acid, tartaric acid, 1,2, 6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), tris (hydroxymethyl) aminomethane, Glycerol Monooleate (GMO), Sorbitan Monolaurate (SML), Sorbitan Monooleate (SMO), laureth-4 (laureth-4) (LTH).

As a further improvement of the present solution,

comprises 3-6% of lauryl alcohol or lauric acid or esters thereof in a drug-containing skeleton layer and 3-6% of N-oleoylsarcosine and N-lauroylsarcosine in the drug-containing skeleton layer.

A felodipine transdermal drug delivery preparation is a skeleton type transdermal drug delivery preparation with a high polymer colloid skeleton, and comprises the following components in parts by weight:

60-95 parts of a high polymer colloid framework;

3-7 parts of felodipine;

the felodipine transdermal enhancer combination comprises

(1) 3-6 parts of lauryl alcohol or lauric acid and esters thereof

(2) 3-6 parts of N-oleoyl sarcosine or N-lauroyl sarcosine.

As a further improvement of the scheme, the high polymer colloid framework is any one or more of silicone pressure-sensitive adhesive, polyacrylate and polyisobutylene.

A percutaneous device comprises

A backing layer;

a drug-containing basal layer;

and (4) a protective layer.

Compared with the prior art, the invention has the following beneficial effects:

the transdermal enhancer composition can obviously improve the drug permeation flux, and can effectively reduce side effects and improve compliance by transdermal administration aiming at the continuous treatment of hypertension through a transdermal device.

In the present invention, the cumulative flux of transdermal permeation of felodipine was confirmed using an in vitro permeation test, which refers to a Franz cell model permeation test using piglet skin having epidermal layers (horny layer and epidermis) as a permeation membrane. In an in vitro permeation test, the permeation enhancer composition can improve the permeation flux by 20 to 400 percent within 24 hours and above.

In the present invention, the in vitro permeation test refers to a Franz cell model using piglet skin having epidermal layers (horny layer and epidermis) as a permeation membrane. In some embodiments, the transdermal delivery device can provide a transdermal permeation flux of 2.5 μ g/cm2/hr or greater.

In the invention, a transdermal delivery device containing the transdermal delivery device of the felodipine is provided, and the transdermal delivery device using the transdermal delivery device can obviously improve the skin permeation flux of the felodipine in 24 hours and longer time.

In the present invention, transdermal delivery devices having an amount of felodipine, fatty acids and their ester derivatives, acyl acid combinations and pressure sensitive adhesives significantly improve skin permeation flux within 24 hours. For example, a transdermal drug delivery device can increase the cumulative skin permeation flux over 24 hours to 50 μ g/cm²/hr or more.

In the present invention, the selection of different permeation enhancer species in combination contributes to the overall improvement in transmittance. For example, fatty acids may interact with the phospholipid layer and disrupt the lipid layer structure, thereby enhancing penetration enhancement, while acyl acids, such as oleoyl sarcosine, as a surfactant, may disrupt the lipid and protein alignment in the stratum corneum, with a significant synergistic effect when both types of penetration enhancers are used together.

Drawings

FIG. 1 is a schematic diagram showing a curve of the permeation rate of a sample detected by the HPLC method in example 1;

FIG. 2 is a schematic diagram showing the permeation curve of a sample detected by the HPLC method in example 2;

FIG. 3 is a schematic diagram showing the permeation curve of a sample detected by the HPLC method in example 3;

FIG. 4 is a schematic diagram showing the permeation curve of a sample detected by the HPLC method in example 4;

FIG. 5 is a schematic diagram showing the permeation curve of a sample detected by the HPLC method in example 5;

FIG. 6 is a graph showing the permeation rate curve of a sample detected by the HPLC method in example 6;

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:

example 1

Sample composition of example 1

The preparation process of example 1 is as follows:

weighing corresponding felodipine, auxiliary materials, a penetration enhancer and a pressure-sensitive adhesive into a container in sequence, stirring for more than 4 hours in a rotary shaking stirring mode, and after completely dissolving, coating and drying by using a coating scraper.

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 1.

Example 2

The samples were prepared according to the following formulation

The preparation process comprises the following steps

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 2.

Example 3

The samples were prepared according to the following formulation

The preparation process of example 3 is as follows:

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 3.

Example 4

The samples were prepared according to the following formulation

The preparation process comprises the following steps

Weighing corresponding felodipine, auxiliary materials, a penetration enhancer and a pressure-sensitive adhesive into a container in sequence, stirring for more than 4 hours in a rotary shaking stirring manner, and coating and drying by using a coating scraper after complete dissolution.

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 4.

Example 5

The samples were prepared according to the following formulation

The preparation process comprises the following steps

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 5.

Example 6

The samples were prepared according to the following formulation

The preparation process comprises the following steps

The transdermal diffusion was performed using a Franz diffusion cell under conditions of 32 ℃ temperature, a receiving solution of a buffer solution to which 40% methanol was added, and the detection sample was detected by the HPLC method, and the permeation amount is shown in fig. 6.

As can be seen from comparison of examples 1-6, the transdermal drug delivery system of felodipine has no obvious effect on the transdermal drug delivery system of felodipine by using the fatty acid alone as the transdermal enhancer, such as lauric acid, using the fatty acid ester alone, such as lactic acid laurate, and using the acyl creatine alone as the transdermal enhancer, such as N-lauroyl sarcosine. The two components are used together, so that the penetration promoting effect can be improved by 600-700%.

The above description is only for the preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention are within the scope of the present invention.

Claims

1. A felodipine transdermal enhancer combination is characterized by at least comprising two or more of the following components in parts by weight:

2. the felodipine transdermal enhancer combination of claim 1, wherein the alcohol is any one or more of oleyl alcohol or lauryl alcohol.

3. The felodipine permeator combination of claim 1, wherein; the fatty acid is any one or more of linoleic acid, oleic acid, linolenic acid, stearic acid, lauric acid, isostearic acid and palmitic acid.

4. The felodipine permeator combination according to claim 1, characterized in that the fatty acid ester is any one or more of isopropyl myristate, diisopropyl adipate, isopropyl palmitate.

5. The felodipine transdermal enhancer combination of claim 1, wherein the fatty acid glycerides are any one or more of monoglycerides, diglycerides, triglycerides; wherein the fatty acid component forming the fatty acid glyceride comprises any one or more of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and oleic acid.

6. The felodipine permeation enhancer combination according to claim 1, wherein the acyl amino acid is any one or more of oleoyl sarcosine, myristoyl sarcosine, N-lauroyl sarcosine.

7. Felodipine permeator combination according to claim 1, characterized in that the polyol is any one or more of glycerol, ethylene glycol, propylene glycol, 1, 3-butylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide.

8. The felodipine transdermal enhancer combination of claim 1, further comprising a transdermal absorption enhancer comprising any one or more of lactic acid, tartaric acid, 1,2, 6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), tris (hydroxymethyl) aminomethane, Glycerol Monooleate (GMO), Sorbitan Monolaurate (SML), Sorbitan Monooleate (SMO), laureth-4 (laureth-4) (LTH).

9. The felodipine transdermal enhancer combination according to claim 1, comprising 3-6% of lauryl alcohol or lauric acid or esters thereof in the drug-containing matrix layer and 3-6% of N-oleoylsarcosine, N-lauroylsarcosine in the drug-containing matrix layer.

10. A felodipine transdermal drug delivery preparation is characterized in that the felodipine transdermal drug delivery preparation is a skeleton type transdermal drug delivery preparation with a high polymer colloid skeleton, and comprises the following components in parts by weight:

60-95 parts of a high polymer colloid framework;

3-7 parts of felodipine;

the felodipine transdermal enhancer combination comprises

(1) 3-6 parts of lauryl alcohol or lauric acid and esters thereof

(2) 3-6 parts of N-oleoyl sarcosine or N-lauroyl sarcosine.

11. The transdermal felodipine delivery formulation of claim 1, wherein the polymeric colloid matrix is any one or more of silicone pressure sensitive adhesive, polyacrylate, and polyisobutylene.

12. A felodipine transdermal delivery device, which is characterized by comprising sequentially arranged felodipine transdermal delivery devices

A backing layer;

a drug-containing basal layer;

and (4) a protective layer.