CN1067875C - Estradiol weekly-acting percutaneous absorption adhesive plaster - Google Patents

Abstract

A weekly transdermal absorption patch for estradiol, which uses azofenone penetration enhancer or a mixed penetration enhancer containing azone, which has a good penetration-enhancing effect, and each patch (10cm ² ) penetrates into the skin every day The amount of estradiol can reach 30-50 micrograms, and a stable and effective blood concentration of estradiol can be maintained within a week. Administered once a week, it is a safe, effective, long-acting and convenient transdermal absorption preparation.

Description

Estradiol weekly transdermal patch

The estradiol weekly transdermal absorption patch of the invention relates to a medicinal transdermal absorption patch.

Women's climacteric syndrome and osteoporosis are common diseases of women, and its pathogenesis is related to the decline of ovarian function and the decrease of estrogen secretion. The existing conventional estrogen replacement therapy is oral or injection estrogen supplementation. The former has a very low potency due to liver inactivation, and long-term use will affect liver function, causing the concentration of several liver proteins, such as corticosteroids β-globulin (CBG) and thyroxine-binding globulin (TBG), to increase. And cause non-physiological levels of estrone concentration increased. The latter is painful, inconvenient to use, and not suitable for long-term treatment. Since the discovery that skin penetration enhancers such as ethanol can help estrogen to be absorbed through the skin, resulting in a smooth and effective blood level. Countries all over the world have done a lot of research on estrogen transdermal preparations. In 1987, the Swiss Ciba-Gelgy Pharmaceutical Factory successfully developed the film-controlled estradiol patch (Estraderm TTS) for administration twice a week. It uses ethanol as a skin penetration enhancer, see patent US 4379454 (1983), and US Patent 5223261 (1993) also announced a polyacrylate pressure-sensitive adhesive, and isopropyl myristate and glycerin A mixed penetration enhancer composed of lauric acid esters and an estradiol paste composed together, but the maintenance time of the drug effect has not been announced. In the estrogen paste composition, the skin penetration enhancer plays a very important role in improving the skin penetration of estrogen, so it is still an interesting topic to find a new skin penetration enhancer to use it to make a An estrogen transdermal absorption patch with good penetration-promoting effect and long-lasting drug effect.

For this reason, the object of the present invention provides a kind of estradiol weekly transdermal absorption patch, adopts lauroazepine (1-dodecyl azepan-2-one, Azone) to promote penetration in the patch The penetration enhancer or mixed penetration enhancer containing laurocapram has a good penetration enhancer effect, and the drug effect can be maintained stably for a week. The amount of estradiol per patch (10cm ² ) permeating the skin can reach 30-50 micrograms per day about.

The estradiol weekly transdermal absorption patch of the present invention is a sheet-like transdermal absorption preparation composed of a back layer and a viscous polymer laminated together.

The backing layer is required to be flexible, soft and comfortable when attached to the skin, and plays the role of covering and protecting the drug storage. The backing material is an impermeable film, which can be used in high-density polyethylene, low-density polyethylene, polypropylene, polyvinyl chloride, Ethylene-vinyl ester copolymer, polyester, polyvinyl pyrrolidone, polyvinyl alcohol, polyurethane, metal aluminum foil, etc. or a composite film of metal aluminum foil and the aforementioned high polymer, preferably low-density polyethylene Polyethylene-aluminum-polyethylene composite film, low-density polyethylene film or polyurethane film made of metallic aluminum.

The adhesive polymer layer comprises an adhesive polymer, the drug estradiol, and a skin penetration enhancer. It has two functions of drug storage and adhesion. The viscous polymer layer of the present invention uses polymers such as polyacrylate pressure-sensitive adhesives as the controlled-release framework material, and a certain dose of estradiol is dissolved in the lauroazepine penetration enhancer or the mixed penetration enhancer containing lauroazepine Afterwards, the liquid microlibrary was evenly distributed in the framework by solvent evaporation method. The release rate of estradiol from the patch was adjusted by changing the drug content in the polymer, the density of the liquid micro-reservoir, and the ratio of the penetration enhancer. The adhesive polymer layer can be a single-layer or 2-5-layer structure, and the drug concentration and penetration enhancer ratio in each layer can be different, so that the release rate of estradiol can be better adjusted, so that each patch (10cm ³ ) can The penetration into the skin reaches about 30-50 micrograms, and can be maintained stably for a week.

The adhesive polymer layer contains:

A, drug estradiol is 17-beta estradiol or its derivative ethinyl estradiol, its content accounts for 0.2-10% (W/W) of the total weight of the viscous polymer layer, and the optimum content is 1-6 %;

B. Viscous polymers are required to be chemically inert to estradiol. Polyacrylate pressure-sensitive adhesives, polyisoprene, polyisobutylene or silicone copolymers can be used. Most preferred are polyacrylate pressure sensitive adhesives or polyisobutylene. Its content accounts for 20-80% (W/W) of the total weight of the sticky polymer layer, and the optimum content is 40-60%;

C, skin penetration enhancer, its effect is to improve the skin permeability of estradiol. What the present invention adopts is lauroazepine penetration enhancer or mixed penetration enhancer containing lauroazepine. The laurocaprine penetration enhancer may comprise 3-15% (W/W) of the total weight of the adhesive polymer layer. The mixed penetration enhancer is composed of (1) azazone, (2) saturated or unsaturated fatty acids and their esters (such as capric acid, myristic acid, oleic acid, lauric acid, stearyl sarcosine, diethyl Glycol Distearate, Diethylene Glycol Dilaurate, Diethylene Glycol Monocinnamate, Diethylene Glycol Monolaurate, Diethylene Glycol Monostearate, Triglycerol Monostearate ester, hexaglyceryl monostearate, decaglyceryl octaoleate, decaglyceryl decaoleate, isopropyl myristate, isopropyl palmitate, ethyl oleate, ethyl lactate, etc. and (3) Alcohols (such as ethanol, propylene glycol, oleyl alcohol, lauryl alcohol, cetyl alcohol, polyethylene glycol, terpineol, etc.); silicones (such as simethicone); sulfoxides (such as dimethyl sulfone, lauryl methyl sulfoxide, etc.); terpenes (such as eucalyptol, menthol, etc.); amides (such as N,N-dimethylformamide, N,N-dimethylacetamide, etc. ); Lactams (such as dodecyl azazone, farnesyl azazone, etc.); phenols (such as rysyrol, etc.); Such as Tween 80, caprylic monoglyceride, etc.). The best skin penetration enhancer is a mixed penetration enhancer composed of laurocapram, lauric acid and propylene glycol. The contents of the above three components account for the viscous polymer layer in turn. The total weight is 0.5-10%, 1-15%, 10-70% (W/W), and the optimal content is 2-6%, 6-12%, 20-50%.

Sometimes in order to increase the adhesion of the patch or adjust the penetration rate of the drug, an adhesive layer can be added on the surface of the adhesive polymer layer. Polyacrylate pressure sensitive adhesives, polyisobutylene or silicone copolymers can be used as materials.

The production method of the estradiol week-effect transdermal absorption patch of the present invention can be carried out by the conventional method of generally making a medicinal patch, and the viscous polymer, the drug estradiol, the lauroazepine penetration enhancer or the lauryl nitrogen-containing The mixed penetration enhancer of ketone and the solvent are evenly mixed, and then coated on the polyester release layer treated with silicone oil, then dried, cooled, and covered with a backing layer. Each square centimeter of patch contains Estradiol 0.02-0.4 mg.

The patch of the present invention is subjected to human skin penetration test results in vitro, showing that its estradiol penetration rate is the same as that of Ciba Pharmaceuticals' Estraderm TTS, that is, about 30-50 micrograms/10cm ² /day. The clinical verification results show that the patch of the present invention has a significant curative effect on five main clinical manifestations such as hot flashes, sweating, insomnia, mood swings, dizziness, and vaginal dryness caused by low ovarian function, and the total effective rates are 98.9%, 92.0, 91.4%, 90.5%, 78.0%. After the patch (10cm ² ) of the present invention is applied to the skin of the lower abdomen of menopausal women, the blood drug concentration is measured by radioimmunoassay, and the results show that a stable and effective blood drug concentration can be maintained in seven days, which is higher than the baseline level before medication. Elevate more than 30Pg/ml, there is no shedding phenomenon in seven days, also no stimulation, allergy phenomenon occurs. Paste estradiol patch ^20cm of the present invention (equivalent to 330 times of clinical dosage) on white guinea pig intact skin and damaged skin in addition and do acute toxicology test, test result animal does not all appear poisoning symptom, none dies, It shows that the patch of the present invention has no toxicity to guinea pigs. Therefore, the patch of the invention is a safe, effective, long-acting and convenient transdermal absorption preparation, which can be used for the prevention and treatment of climacteric syndrome and osteoporosis in women.

The estradiol weekly transdermal absorption patch of the present invention has the advantages of adopting a laurocapram penetration enhancer or a mixed penetration enhancer of laurozone, which is cheap and easy to obtain, and has a good penetration promoting effect. The patch of the invention can simulate physiological secretion to make the estradiol enter the body continuously through the skin at a low speed, and maintain a stable and effective plasma concentration of the estradiol within a week. Therefore, it is convenient for patients to administer medicine only once a week.

The present invention is further illustrated by the following examples, but the scope of the present invention is not limited.

Example 1

Polyacrylate pressure-sensitive adhesive (PSA, solid matter accounts for 40%) 135g, 17-beta estradiol (E ₂ ) 1.5g, azone (AZ) 3g, lauric acid (LA) 16.5g, propylene glycol ( PG) 75g, solvent ethyl acetate 100g, put into a wide-mouth bottle together, the bottle mouth is sealed, shake about 15 hours on the shaker, stand until the bubble disappears. It was then coated on a 0.1 mm thick polyester release layer treated with silicone oil at a thickness of 0.46 mm, followed by drying at 40°C for 4 minutes, 60°C for 2 minutes, and 90°C for 2 minutes. The dried viscous polymer layer contains PSA36%, _E21 %, AZ2%, LA11%, PG50%. After the viscous polymer layer is cooled, it is covered with a 0.06 mm thick polyethylene-aluminum-polyethylene composite film backing layer , cut into 5 or 10cm ² size patch, using Valia-chien double-chamber permeation cell device to measure its permeability to human skin in vitro, the receiving liquid is 40% polyethylene glycol (PEG) saline solution, the penetration rate It was 0.16 μg/cm ² /h.

Example 2

PSA liquid 225g, E2 _9g , AZ14.4g, LA5.4g, PG61.2g, ethyl acetate 125g, operate as in Example 1, apply with a thickness of 0.49mm, dry at 40°C for 4 minutes, 60°C for 2 minutes, 90°C °C for 2 minutes. The dry viscous polymer thin layer contains PSA50%, _E25 %, AZ8%, LA3%, PG34%. After the thin layer is slightly cooled, it is covered with a 0.03 mm thick low-density polyethylene film backing layer, and cut into 5 or 10 cm ² patches. The measured permeation rate was 0.22 μg/cm ² /h.

Example 3

300g of PSA solution, 16g of ethinyl estradiol, 10g of AZ, 14g of LA, 40g of PG, 134g of ethyl acetate, operate as in Example 1, apply with a thickness of 0.51 mm, dry at 40°C for 4 minutes, 60°C for 3 minutes, and 90°C for 2 minutes. The thin viscous polymer layer after drying contains 60% of PSA, 8% of ethinyl estradiol, 5% of AZ, 7% of LA and 20% of PG. Cover the thin layer with a 0.03 mm thick polyurethane film backing layer and cut into 5 or 10 cm ² size patches. The measured permeation rate was 0.30 μg/cm ² /h.

Example 4

An estradiol patch with a three-layer adhesive polymer layer structure was fabricated with the following ingredients:

(I) 3.6g of 17-βestradiol (E ₂ ), 45g of polyacrylate pressure-sensitive adhesive (PSA, accounting for 40% solid matter), 1.2g of lauroazepam (AZ), 2.4g of lauric acid (LA) g, 16 g of propylene glycol (PG), and 31 g of ethyl acetate (EtAc), put them together in a wide-mouth bottle, seal the bottle mouth, vibrate on a shaker for about 15 hours, and place until the bubbles disappear. Then coated on a 0.06 mm thick polyethylene-aluminum-polyethylene composite film backing with a thickness of 0.45 mm, followed by drying at 40°C for 4 minutes, 60°C for 2 minutes, and 90°C for 2 minutes;

(II) _E2 2.4g, PSA (solid matter accounts for 40%) 45g, AZ1.2g, LA2.4g, PG16g, EtAc31g, operate as above, apply the thickness of 0.45 mm on the surface of 0.1 mm thick and treat with silicone oil On the polyester anti-adhesive layer, then dry, 40 ° C for 4 minutes, 60 ° C for 2 minutes, 90 ° C for 1 minute;

(Ⅲ) _E2 1.2g, PSA (40% of solid matter) 45g, AZ1.2g, LA2.4g, PG16g, EtAc31g, operate as above, with a thickness of 0.45 mm, coated on the surface of 0.1 mm thick and treated with silicone oil on the polyester release layer, followed by drying at 40°C for 4 minutes, 60°C for 2 minutes, and 90°C for 1 minute.

Laminate (II) on (I), peel off the anti-adhesive layer, and then laminate (III) on it to form a patch product with a three-layer adhesive polymer layer structure, which is punched into 5 or 10cm ² size patches. The patch contains 6% E ₂ (I:II:III=3:2:1), AZ3%, LA6%, PG40%, PSA45%. Using the apparatus of Example 1, the permeation rate was measured to be 0.19 μg/cm ² /h.

Example 5

E ₂ 3.6g, AZ7.2g, LA15.6g, PG14.4g, polyisobutylene polymer 79.2g, solvent system (cyclohexane/hexane/heptane 1:1:1 mixture) 316.8g put together in a In a wide-mouth bottle, seal the mouth of the bottle, shake it on a shaker for about 22 hours to dissolve completely, and place it until the bubbles dissipate. It is then coated on a 0.1 mm thick polyester release layer treated with silicone oil at a thickness of 0.55 mm, followed by drying at 40° C. for 4 minutes, 60° C. for 2 minutes, and 90° C. for 2 minutes. The dry viscous polymer thin layer contains polyisobutylene polymer 66%, _E2 3%, AZ6%, LA13%, PG12%, after the thin layer is slightly cooled, it is covered with polyethylene-aluminum-polyethylene composite film backing layer , cut into patches with a size of 5 or 10 cm ² , using the device in Example 1, the measured permeation rate was 0.15 μg/cm ² /h.

Example 6

E ₂ 2.4g, AZ8.4g, PSA123.09g (solid matter accounts for 40%), EtAC91g, put together into a wide-mouth bottle, seal the bottle mouth, vibrate on the oscillator for about 15 hours, and place until the bubbles dissipate. Then it is coated with a thickness of 0.55 mm on a 0.1 mm thick polyester release layer treated with silicone oil, followed by drying at 40°C for 4 minutes, 60°C for 2 minutes, and 80°C for 2 minutes. The dried viscous polymer is thin The layer contains ₄ % E2, AZ14%, and PSA82%. After the thin layer is slightly cooled, it is covered with a 0.06mm thick polyethylene-aluminum-polyethylene composite film backing layer, cut into 5 or 10m ² patches, and the same The measured permeation rate of the device in Example 1 was 0.17 μg/cm ² /h.

Example 7

E ₂ 2.8g, AZ3.5g, PSA159.25g (40% solid matter), EtAC120g, put together into a wide-mouth bottle, seal the mouth of the bottle, vibrate on the shaker for about 20 hours, and place until the bubbles dissipate. It was then coated on a 0.1 mm thick polyester release layer treated with silicone oil at a thickness of 0.53 mm, followed by drying at 40°C for 4 minutes, 60°C for 2 minutes, and 90°C for 2 minutes. The thin viscous polymer layer after drying contains 4% E ₂ , 5% AZ, and 91% PSA. After the thin layer is slightly cooled, cover the polyethylene-aluminum-polyethylene composite film backing layer with a thickness of 0.06 mm, cut into 5 or ¹⁰ cm patches, and the penetration rate measured by the device in Example 1 is 0.14 μg/cm ² /h.

Example 8

(I) _E2 6.3g, AZ7.2g, LA2.7g, PG28.8g, polyisobutylene 45g, solvent system (cyclohexane/hexane/heptane 1:1:1 mixture) 180g put together In the mouth bottle, the mouth of the bottle is sealed, shake on the shaker for about 22 hours to completely dissolve, and place until the bubbles escape. It was then coated at a thickness of 0.55 mm on a 0.06 mm thick polyethylene-aluminum-polyethylene composite film backing, followed by drying at 40°C for 5 minutes, 60°C for 3 minutes, and 90°C for 2 minutes. This is the adhesive polymer layer.

(II) Polyisobutylene 8.2g, solvent system (cyclohexane/hexane/heptane 1:1:1 mixture) 90.2g, with the thickness of 0.30 millimeters, be coated on the polyisobutylene that the surface of 0.1 millimeters is thick with silicone oil On the ester release layer, followed by drying at 40°C for 5 minutes, 60°C for 3 minutes, and 90°C for 2 minutes. This is the adhesive layer.

Composite (I) and (II), die-cut into 5 or 10cm ² patches. The patch adhesive polymer layer contains E ₂ 7%, AZ8%, LA3%, PG32%, polyisobutylene 50%. The permeation rate measured by the device of Example 1 was 0.18 μg/cm ² /h.

Claims (8)

1. An estradiol weekly transdermal absorption patch, which comprises a backing layer and a viscous polymer layer containing drug estradiol, a viscous polymer and a skin penetration enhancer, characterized in that the viscous polymer layer Include: A, drug estradiol, it accounts for 0.2-10% in the total weight of adhesive polymer layer; B, adhesive polymer can adopt polyacrylate pressure-sensitive adhesive, polyisobutylene, polyisoprene or silicone copolymer, and it accounts for 20-80% in the total weight of adhesive polymer layer; C. The skin penetration enhancer is composed of (1) laurocaprazine, (2) saturated or unsaturated fatty acids and their esters, (3) alcohols, silicones, sulfoxides, terpenes, amides, lactams, phenols, The mixed penetration enhancer composed of pyrrolidone or surfactant, the three components in the mixed penetration enhancer account for 0.5-10%, 1-15%, and 10-70% respectively in the total weight of the viscous polymer layer. 2. The patch as claimed in claim 1, characterized in that on the sticky polymer layer of the patch, an additional layer can be added using polyacrylate pressure-sensitive adhesive, polyisobutylene or silicone copolymer as material for bonding. agent layer. 3. The patch according to claim 1, characterized in that the drug estradiol contained in the adhesive polymer layer is 17-beta estradiol or its derivative ethinyl estradiol. 4. The patch according to claim 1 or 2, characterized in that the adhesive polymer layer of the patch can be a single layer or a 2-5 multilayer structure, and the drug concentration and penetration enhancer ratio in each layer can be different . 5. The patch as claimed in claim 1 or 2, characterized in that the drug estradiol represents 1-6% of the total weight of the adhesive polymer layer. 6. The patch as claimed in claim 1 or 2, characterized in that the adhesive polymer is polyacrylate pressure sensitive adhesive or polyisobutylene, which accounts for 40-60% of the total weight of the adhesive polymer layer. 7. The patch according to claim 1 or 2, characterized in that the skin penetration enhancer is a mixed penetration enhancer composed of laurocapram, lauric acid and propylene glycol, and the three are respectively in the total weight of the adhesive polymer layer. Accounting for 2-6%, 6-12%, 20-50%. 8. The patch according to claim 1 or 2, characterized in that the patch contains 0.02-0.4 mg of estradiol per square centimeter.