TW565457B - Transdermal drug delivery system - Google Patents

Abstract

A transdermal drug delivery system is provided comprising a release liner; a dosage unit dispersed throughout the release liner comprising an anti-asthma drug, an adhesive polymer and a penetration enhancer such as fatty alkanolamide; and a backing film placed on the other side of the dosage unit opposit to the release liner, serving as a protective cover for the dosage unit.

Description

565457 Case No. 85108117 A_η is a modified drug transdermal absorption and delivery system V. Description of the invention (1) Title of the invention: 4. Summary of the invention An anti-asthma drug, an adhesive and a penetration enhancer, which can be oxyethylated amine (Fatty alkanolamide), acid) or fatty ester; and a protective film covering the drug unit and separating the upper and lower layers of the release film, the purpose of which is to protect the drug It is a drug transdermal absorption and delivery system, which includes a release film; a drug unit covering the release film, and the drug unit includes the penetration enhancer fatty acid (fa 11 y protective film 'the protection Placed in the pharmacy unit. Description of the invention Patches with a physiologically active agent and a small amount of penetration enhancer. In terms of agents, improving the form of the agent has been the main research target in this field. In many cases, the disease requires and It is more than free from side effects. For example, when taking an oral medicine, it is a medicine that cannot be successfully delivered and the method of delivery, which is convenient. There are many and are already prescriptions of nitroglycerin. These have a sustained release of the drug (such as a transdermal or a drug that is transmitted through the skin is a new drug or an existing drug) and its delivery method. The main research in the future The eye volume often exceeds the actual cause. The main reasons are the digestion of the digestive system or the use of a product that can release continuously and allow the patient to use a more transdermal absorption and transmission system. The special transmission system is obviously the system of the present invention. Enhance the physiological activity. Regardless of the dosage form and the safe dosage of the agent, some oral medicines are taken to the affected area. Therefore, the effect can be achieved. Recently, several commercial medicines have been absorbed through the skin.

Page 5 565457 _m, 85118117__ year 3 a Correction _ one, five, invention, description (2), point 'and avoid the problem of similar oral drugs being absorbed and metabolized by the digestive tract. At the same time, it reduces the patient's drug intake, and achieves the same effect as high-dose oral drugs. Nonetheless, the drug percutaneous absorption and delivery system has so far been limited by a decrease in drug efficacy and a drug's solubility in water after a decrease in the drug amount. These restrictions come from the skin and tissue membranes of animals, which cause insurmountable obstacles' and the bodies and systems that can use this method are quite limited.

A current effort is to extend the method to more agents' and overcome the limitations of the animal's skin surface tissue membrane. Therefore, the focus of research and development is to increase the ability of the animal to spread through the above-mentioned obstacles from the drug transdermal absorption and delivery system. On the other hand, it is committed to improving the permeability of the skin surface layer and the tissue membrane itself. The results of recent efforts have confirmed some effects, but excessive and frequent use of the drug can cause tissue necrosis, irritation at the site where the drug is used, and undesirable side effects. Taking asthma as an example, the number of people suffering from asthma in China has increased 5-6 times in the past two decades. Among them, children and the elderly are the most common. Albuterol (also known as Albuterol) is currently used. The largest anti-asthma drugs, the commonly used dosage forms are oral lozenges and oral inhalants, but because their half-life is very short (< 4 hours), they must be taken ^ 4 times a day. Onset, at this time the drug effect has been reduced + no 'to achieve the purpose of controlling the disease. Therefore, the development of a long-acting asthma drug for transdermal absorption patches, a, M 'can provide sufficient doses in the most serious conditions to timely and check the production-to receive the treatment effect and reduce the overdose ( 〇verd 〇se) side effects. ~ ^ it ® τ τ percutaneous absorption patch with sabutan, the product specifications must be full only conditions: (1) the dosage can be 1-3 mg per day, the patch is large

565457 Λ_η said that the correction gas, Zhenming 1 arm 5 (3) agent compatible 0 " t (square 3 cm or less; (2) 'Human skin can be attached to the &)' for long-term use can be stored in the room At least two years at low temperature (less than 30 degrees Celsius), the cost is low, and it is easy to obtain; and (5) non-toxic, no use on the human body < worry. The existing transdermal absorption patches can only meet the 4-knife item mentioned above, but they cannot satisfy all the conditions at the same time. Therefore, one of the main objectives of the present invention is to provide a drug transdermal absorption and delivery system, including: a · —release 貘; b · —a medicament unit covering the release film, and the medicament The unit includes an anti-asthmatic drug, an adhesive, and a penetration enhancer. The penetration enhancer may be a oxyamidine; and

c. A protective film covering the drug unit and being separated from the release film on the upper and lower layers of the drug unit to protect the drug unit. 0 Another main purpose of the present invention is to provide a Drug transdermal absorption and delivery system. The penetration enhancer includes about 50% of 1 aur ic acid, as well as myristic acid, palmitic acid, and myristic acid. . The second purpose of the present invention is to provide a drug for transdermal absorption and delivery system. The permeation enhancer includes about 50% of lauric acid, and myristic onion and standard acid. The fourth main object of the present invention is to provide a drug transdermal absorption and delivery system. The penetration enhancer includes about 70% oleic acid (〇1 eic acid), and 1 inoleic acid, palmitic acid and Stearic acid. The fifth object of the present invention is to provide a drug for percutaneous absorption and transmission.

565457 Case No. 85108117 Λ_η Revision V. Description of the Invention (4) System, the penetration enhancer is man n id e monoo1 eate. The present invention provides a drug transdermal absorption and delivery system that combines anti-asthmatic drugs with The penetration enhancer is mixed to form a new formula, and the pressure-sensitive adhesive made of the acrylic glue solution is used to form a pharmaceutical unit, which is placed on a release film and covered with a protective film to form a long-lasting animal. Dermal absorption patch. In order to make the above and other objects, features, and advantages of the present invention more comprehensible, a preferred embodiment is given below in conjunction with the accompanying drawings for detailed description as follows: Brief description of the drawings: FIG. 1 It is a schematic cross-sectional view of a drug transdermal absorption and delivery system according to a preferred embodiment of the present invention. Example Please refer to FIG. 1. The most specific representation of the present invention is a patch that exists in a single-layer transdermal formulation, including a release film 1 of a fixed thickness; a 1 buter ο 1), penetration enhancer 3 and adhesive 4, for example, acrylic pressure-sensitive adhesive, anti-asthmatic medicine 2, penetration enhancer 3 and adhesive 4 are mixed to form a medicament unit 6, and evenly spread on A mold film 1; and a protective film 5 on the other side of the release film 1 next to the drug unit 6. The medicine unit 6 is a combination of an anti-asthma medicine 2, a penetration enhancer 3, and an adhesive agent 4. The protective film 5 functions as a protective cover for the medicine unit 6 and provides support. The protective film 5 needs to be able to cover the medicine unit 6, so it can be as large as or slightly larger than the medicine unit 6 in size, so as to achieve the purpose of tighter bonding with the skin.

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Fifth, the invention said ¥ (5+) ------- The material used in the shroud film 5 must be able to prevent the penetration of sand cloth soil and medicine. Polyethylene suitable for the protective film 5 or low-density or low-density polyethylene, the material of the heart f 5 can be local secret purpose, poly S purpose, all of the $ 1 permanent propylene, & lice vinyl, Polyurethane + S: metal poise or attached to the appropriate polymer film 5 can be made of any thickness, metal on the mouth, since. Paul I. Only the cans R and D, the functions of holding bk, keeping away, and supporting are 5 ,, π ^^, and 1 to 200. The more suitable thickness is from 5 case number 8510S11 to 50%. / Taken is about 0 to 100 microns. The content of asthma 2 is not fixed, as long as the anti-asthma drug 2 can provide the therapeutically effective content of the percutaneous absorption wheel system of the animal. Usually, the stomach contains about 8% (w / w) of sabutan in the pharmaceutical unit 6, which provides a sufficient amount for transdermal absorption. The content of sabutam also varies depending on the required skin penetration rate and the adhesive 4 in the medicament unit 6. Generally speaking, the most effective and most suitable content is about 0.5% to 20% (w / w) of the pharmaceutical unit 6. Among the components of the pharmaceutical unit 6, the adhesive 4 used must be acceptable to the organism and compatible with other components. Specific adhesives (the composition of which is alkylester, amide, fatty acid, polyaminoacrylate, or the like) can meet the above conditions and are better used today By. The pressure-sensitive adhesive, which causes only slight allergies, accounts for about 50% to 96% (w / w) of the pharmaceutical unit 6. Another component of the medicament unit 6 is a penetration enhancer 3, whose composition may be an alkoxyamidate, a fatty acid or a fatty ester, and the chemical formula of the alkoxyamidate is represented by the following general formula:

Page 9 565457 No. 85108117 said Amendment R2 V. Description of the invention (6) 0

Rl-C \ R3 According to a preferred embodiment of the present invention, R1 can be CH3 (CH2) nCH2-'η The value ranges from 6 to 16, and R2 is preferably hydroxy, methoxy ( methoxy), ethoxy or isopropoxy; and R3 is preferably hydroxyl, methoxy, ethoxy or isopropoxy; more suitably the penetration enhancer 3 may be lauryl di Laurie acid diethanolamide (LAD), or diethoxybenzidine glutamate, wherein the molecular formula of lauryl diethanolamide is C12H25CON (OC2H5) 2. The fatty acid used as the penetration enhancer 3 may be a saturated fatty acid or a non-fatty acid, and its chemical formula is represented by the following, CnH2n + lcO2H, or kH2, n_3CO2H, and the value of η ranges from 10 to 17. More suitable penetration enhancers can be lauric acid, myristic acid, stearic acid, palmitic acid, linoleic acid or 3

acid. For example, Tween 20, which includes about 50% of lauric acid, and myristic acid, palmitic acid, and stearin. T, Shiyi-9, Tween 21, which includes about 50% of lauric acid, and meat ugly acid He Zi Fu Kui, as well as linoleic acid and uric acid; Tween 80 which includes about 70% oleic acid, M flu π π ^ and stearic acid. In addition, as the penetration enhancer 3: is oleic acid manna, such as ARLACELe agent 3 system. A drug transdermal absorption transmission system prepared by the Ming Dynasty ~~-> 1 ^ 2, a mixture of permeation enhancer 3 and adhesive 4 565457 ___Case No. 85108117_year Dan-Japanese amendment ____ V. Description of the invention (7) Stir to form a homogeneous solution. The mixture was then allowed to stand for several hours to remove the air remaining therein. Then, the undulating compound is applied to a suitable material, such as the protective film 5, using a coating knife. The thickness of the application is between about 1000 and 600 microns, and preferably between about 150 and 450 microns. Then, the solvent is evaporated at a high temperature (50 to 80 ° C), dried to be cured, and then cooled, and finally, the protective film 5 is covered thereon. After being adhered, the film is cut into pieces. And the following method is used to evaluate a drug percutaneous absorption and delivery system according to a preferred embodiment of the present invention. (1) In vitro skin penetration study This experiment was performed using frozen human cadaver skin. By the thermal separation method proposed by Kigma and Christophers, the skin of the corpse was exposed to heat at 60 ° C for one minute 'to separate the epidermis from the dermis. Then gently peel the epidermis from the skin. The epidermis is placed between two hemispherical containers each having a cross-section of 64 square centimeters, and the side of the epidermis covered with stratum corneum is facing the above-mentioned container containing a drug percutaneous absorption and delivery system according to a preferred embodiment of the present invention. Descent. The side of the epidermis that was originally connected to the dermal layer was in contact with a buffer solution containing an acid value of 7.4. The buffer solution must be maintained at 3 2 ° C for 24 hours. Sabutan permeates through the stratum corneum layer through the drug transdermal absorption and delivery system. The friendly epidermis layer enters the buffer solution. After a certain time interval, the buffer solution containing the butatan is removed and immediately replaced with a new buffer solution. Use a high-efficiency liquid chromatography to determine the content of sabutan in the buffer solution. Add the content of sabutan in all buffer solutions to get the total accumulation of sabutan through the skin. The amount of time, as a function of the cumulative amount of sabotan permeation, charted to determine the transdermal rate of sabutan per square centimeter per hour

Page 11 565457 Case No. 85108117 Amendment V. Description of the invention (8) Skin absorption. (2) Evaluation method of skin irritation The test of the degree of skin irritation by the drug transdermal absorption and delivery system is the method of D r a i z e. This method routinely uses rabbits as the object of experiments, so rabbits are also selected for experiments here. Five kilograms of mature white New Zealand rabbits were selected as research objects. It will take about four hours before the test to cut off the rabbit's hair. For each rabbit tested, three sites were selected for testing. These sites should not have wounds to prevent the test results from being affected. In each test, three different patches were used for each rabbit. One was a transdermal drug delivery system according to a preferred embodiment of the present invention, one was a non-medicated patch, and the other was used. A known Transderm S c p patch (as a control group). Each patch is fixed with a tape that does not irritate the skin. After 24 hours, remove the adhesive tape and patch. The degree of erythema and edema at the test site was examined on each rabbit according to Table 1. Add the scores of erythema and edema at each site and add the total score divided by 18 to calculate the main stimulus index (P I I). Based on past experience, when the main stimulus index is 5 or more, the effect of the patch on the skin must be carefully considered (see Table 2). Table 1: Index of skin irritation to animals Index 0 1 Erythema and bedsore formation No erythema ......... Very slight erythema

Page 12 565457 _Case No. 85108117_ Year Month Revision_ V. Description of the invention (9) General erythema ... ..2 Moderate to severe erythema .............. ......... 3 Severe erythema with slight bedsores ... 4 Puffiness formation without edema ... ............... 0 Very slight puffiness ... .................. 1 General swelling (slightly raised around) ... ............. 2 Moderate puffiness (protrusions about 1 mm) .............. 3 Severe edema (protrusions more than 1 mm) ........ 4 Table 2: Evaluation of the main stimulus index (PII) PI I 0. 00 0.04-0. 99 1.00- 1. 99 2.00- 2.99 3.00- 5.99 6.00- 8.00 Evaluate no stimulus hardly produce a little irritation Slight irritation Moderate irritation Severe irritation Use the following example to further show When lauryl diethanolamine is added in the present invention, not only the sabutan can be absorbed through the skin more easily, but it also can hardly cause thorns on rabbit skin. Excited. Table 3 lists the results of the first group of experiments No. 1 to No. 4, which consist of

Page 13 565457 Case No. 85108117 Amended on May 5, V. The description of the invention (10) includes about 4% sabutan, about 8 1-9% 6% acrylic pressure sensitive adhesive (Duro Taka2070) and about 0.1 ~ 15% lauryl diethanolamine. Table 3 Effect of lauryl diethanolamine (LAD) on the penetration rate of sabutan through human cadaver skin 'Q24 § mg / cm2 Ingredient (W / F / o) Number of times Jss § § mg / an2 / m Sabutan Adhesive I * LAD Enhancement Index 1 4 4 0. 64 ± 0. 29 1 96 0 12. 64 ± 5. 56 91 2 4 4 2. 41 Soil 0 · 3 8 3. 5 46. 6 3 ± 6. 88 3 4 4 3 · 3 2 Soil 0 · 8 5 5 · 86 1 5 64. 5 2 ± 15. 60 81 4 4 4 6 · 69 ± 1. 37 12. 5 2 0 1 57 · 41 ± 42 · 11 Then Agent I *: acrylic pressure sensitive adhesive (Duro Taka 2 0 7 0)

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IS Page 14 565457 Case No. 85108Π7 Revised W ". 誃 来 ···, 1st, 5. Description of the invention (11) Q24 § ·· The cumulative amount of sabutan absorbed through the skin within 24 hours J ss § §: Stable permeation flow rate through the skin Table 4 lists the experimental results of the second group No. 5 to No. 8. Its composition includes about 10% sabutan, about 60 ~ 90% pressure-sensitive adhesive ( Dur ur Taka 2154) and about 0.1 to 30% of lauryl \ diethanolamine. Table 4 Effect of lauryl diethanolamine (LAD) on the penetration rate of sabutan through human cadaver skin Q24 § mg / cm2 Composition (W / W%) Number of times J ss § mg / an2 / m Agent Π * LAD enhancement index 5 4 10 2. 75 ± 1. 20 1. 90 6 0. 77 ± 25. 49 6 4 10 8.41 ± 2. 03 3 80 10 1 82. 84 ± 56. 46 7 4 10 17 90 ± 2. 70 6 70 20 376.51 ± 62.42

565457 Case No. 85108117 Amendment _ Xia_ V. Description of the invention (12) 8 4 10 23.11 ± 2. 31 8 60 30 52 2.78 ± 56.77 Adhesive Π *: Pressure-sensitive adhesive (D ur ο T aka 2 1 5 4) Q 2 4 §: 2 Cumulative amount of sabutan absorbed through the skin in 4 hours

JSS § §: Transdermal Penetration Stable Flow Rate N Tested for the major irritation indices of Experiment Nos. 4, 7, 8 and Trans d e m S c o p a patch, and the results are listed in Table 5. Table 5 The main irritation index of sabotan patch absorbed through the skin Number of experiments Number of main stimuli 4 6 0. 9 7 6 1. 6 8 6 4. 1 Transdem Scopa 12 1,5 Known from the preferred embodiment, the application The drug transdermal absorption and delivery system of the preferred embodiment of the present invention has the following advantages: 1. It has little irritation to the skin. 2. The cumulative amount of sabotan penetrated through the skin within 24 hours reached the desired target. 3. The drug percutaneous absorption and delivery system can make the skin penetration drug dose up to

ml p. 16 Μ 565457-. ', <,...: r: 1 · \-/,-',-_ Case No. 85108117_ Year, month, and month Amendment _5. Description of the invention (13) To stabilize the flow rate. Although the present invention has been disclosed as above with a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can make some modifications and retouching without departing from the spirit and scope of the present invention. The scope of protection of the invention shall be determined by the scope of the attached patent application.

565457 Case No. 85108117 Λ ___ 1 Amendment

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Claims (1)

565457 Case No. 85108117 fe%, VI. Patent application scope 1. A drug is transdermal a. — Release film; b. — Medicament unit This medicament unit includes 0.1 drug; an acrylic pressure of 50% to 9 Between 6%; including oxodonyl ester, in which the alkoxy R1 group is CH3 (CH2) nCH milk group, ethoxy group and propylethoxy group and propoxy group c. A protective film The release film is placed on the drug element. 2. If applying for a patent, the alkoxyamidamine 3. If applying for a patent, the protective film thickness receiving and transmitting system includes:, the pharmaceutical unit is covered on the release film, and 5% to 20% of the sand Butan is used as an anti-asthmatic adhesive, the content of which is between the total weight of the pharmaceutical unit and a penetration enhancer, the penetration enhancer contains at least 1% to 30% of the total weight of the pharmaceutical unit The molecular formula of the ester is R1CONR2R3, and 2-, η is between 6 and 16; R 2 is one of a hydroxyl group and a methoxy group, and R 3 is one of a hydroxyl group, a methoxy group, and one of the groups; and The protective film covers the drug unit and two layers above and below the drug unit to protect the drug transdermal delivery system described in item 1 of the drug list, and the ester is lauryl diethanolamine. The transdermal drug delivery system described in item 1 ranges between 10 and 100 microns. Page 19