TW397688B - Compositions effective in enhancing the qualities of skin and comprising macrocyclic ester, diester, ketone or lactone as an active ingredient - Google Patents

Abstract

A composition which is effective in enhancing the qualities of skin and which comprises: (A) a skin-treating compound; (B) a compound having the structure: wherein X and Y are oxygen, A is a group having the structure wherein X and Y are as defined above, m and n are integers having a value 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and R is hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched, with the proviso that when r, p, q and r are 0 and Y is oxygen, m+n is at least 11; (C) a carrier; and optionally (D) a cosmetic additive.

Description

V. Description of the invention (:) Application number: A7 B7 printed by Kangrui Pharmaceutical Co., Ltd., a consumer cooperative of employees of the Central Standards Bureau of the Ministry of Economic Affairs. Example • Example yyy. And zzz Water QS QS Dichloroamine phenylacetic acid LOO% w / w 2,5¾ (diclofenac) glycerol 10.00 10.00 pentadecanolactone 8.00 10.00 Carbonter 1.00 1.00 triethanolamine 1.00 1.00 phenyl alcohol 1.00 1.00 dichloroamine phenylacetic acid (can be in the free acid form or equivalently ester-soluble Dichloramine phenylacetic acid sodium salt) can be incorporated in a suitable vehicle with glycerol (0 to 60%), propylene glycol (0 to 60¾), and pentalactone (0.1 to 30¾) in an amount of 0.1 to 5¾. When applied topically, this product is an effective non-steroidal anti-inflammatory drug (NSAID), which has anti-inflammatory, analgesic, and antipyretic activities, and is suitable for topical treatment. When applied topically, its toxicity is substantially reduced and the treatment is localized. Two preferred practical examples (including preferred concentrations) are exemplified in Examples yyy and zzz (as described above). Paper size applies Chinese National Standard (CNS) A_4 specification (21 × 297 mm) (Please read the notes on the back before filling out this page)

B7 V. Description of Invention (Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. This part of the serial application is one of the serial applications in US No. 713,423 filed on July 5, 1994 (now abandoned). The serial application was filed on December 8, i989b. U.S. Case No. Q7 / 449,]] 7-Succession Case (now U.S. Patent No. 5,023,252), which is one of the U.S. Case No. 138,830 filed on December 28, 1987 Serial Case (now abandoned), part of US Serial No. 899,049 filed on August 21, 1986 (now abandoned), filed on December 4, 1985 Part of the continuous US case No. 8 04,6 61 (now abandoned). FIELD OF THE INVENTION AND PUBLICATIONS PROVIDED This invention relates to physiologically active agents (such as drugs to humans and animals) ) Percutaneous and perineal rotation. It is particularly relevant for the delivery of drugs through the skin and various body cavity membranes (eg, ocular, Nasal, oral, buccal, anal, rectal, vaginal, and blood-brain barriers and other membranes) and can provide a system that promotes speed through skin or membranes. The present invention also relates to a system that can effectively improve the body Composition of physiological conditions. Naturally, various body membranes act as protective barriers against foreign substances and infections. However, the use of transdermal or transmembrane delivery systems to administer drugs can provide improved therapeutic benefits as well as patient benefits. Better compliance. Such systems are known and documented in patent and scientific literature. Examples of such systems are disclosed in the following US patents: 3,921,636; 3,964,482; 3,989,816; 3,996,934; No. 4,201,211; No. 4,291,01 No. 4; No. 4,291,01 No. 5; No. 4,292,203; No. 4,336,243 This paper size applies to China National Standards (CNS) A4 specifications (210x 297 public directors) * · 5 * · 5 Printed by A7 ________, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, V. Invention Description (λ); No. 4,346,709; No. 4,379,454; No. 409,206; No. 460,372 No. 4,486,193 and No. 4,490,322. The use of transdermal and transdermal drug delivery systems for administration has some advantages over traditional oral and systemic administration methods. These advantages include (1) by allowing dose A significant reduction while minimizing drug exposure; (2) providing long-term efficacy in a single dose thereby increasing patient compliance; (3) avoiding the dangers of intravenous or intramuscular treatment and Inconvenience; (4) making drugs with a short biological half-life available; (5) allowing the immediate importation of the drug by simply removing the drug-containing substance; and (6) preventing a drug from passing through the liver for the first time after oral administration The possibility of failure. Examples of drugs that have been used for transdermal administration include scopolamine, nitroglycerin, clonine, estradiol, antibiotics (such as erythromycin, lincomycin, and others), antifungals, and sunscreens. Many of these drugs (e.g., lincomycin, butanamide, and nitroglycerin) have a chemical structure that can penetrate the skin or other body membranes to provide a sufficiently high therapeutic dose for most purposes. However, when a higher therapeutic level is needed, or when the drug substance itself (for example, estradiol-acetate) cannot or cannot pass through the skin sufficiently to provide the required level of drug concentration, then There is a need to use adjuvants that promote the rate of drug penetration. Adjuvants are usually required for the transdermal formulation of most drugs. The transmembrane wheel of medicines Except for the skin, mucous membranes covering the surface areas of various body cavities such as nose, mouth, buccal, anal, rectum and vagina, it protects the body from foreign substances. These films can be used as an alternative medicine. 5 This paper size is applicable to Chinese national standards (cGs> 210x297 mm) ': ~ --- ΓΙΜ ^ 装 βι. ~. 丨 Order ^ Thread (please read the back first For the matters needing attention, fill in this I) V. Description of the invention (3) Approaches, especially for peptides and proteins or other macromolecules (generally, the molecular weight manufactured by genetic engineering or biotechnology is greater than 1000) Daltons). .Hirai, Yashiki and! Vlima on 丨 nternational

Published in Journal of Pharmaceutics, Vol. 9, pp. 165-172, 1981 and International Journal of Pharmaceutics, Vol. 9, pp. 173- 1 84, 1 981. In rats, insulin is promoted by surfactants ( Example of nasal delivery with a molecular weight of 6500 channels). Moses,

Gordon, Carey and Flier in Diabetes Vo 32, pp. 1040-1047, 1983 report further studies in human subjects (using insulin-bile salt sprays). Intranasal spray of insulin may eliminate the need for subcutaneous injection of insulin in diarrhea patients, and may result in higher patient coordination. The use of proteins, peptides, enzymes, nucleic acids, lipids and their complexes as therapeutic agents has been documented in the literature. . Oral administration is not suitable in most cases' because fluoride can be destroyed in the digestive tract. Subcutaneous injections and implants have their inherent disadvantages, such as discomfort in administration, the need to be administered by trained personnel, and patient compliance issues. Percutaneous administration has technical difficulties, printed by Dean Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

Hsieh commented on this in the Transdermal Delivery of Drugs—Chapter 1 Devices for Macro-molecules Volume 1 PP_ 171-193 edited by Agis F_ Kydonieus and Bret Berner and issued by crc Press. Therefore, transmembrane delivery of these macromolecules with an appropriate penetration enhancer is another alternative route of administration. Drug rotation over the blood-brain barrier The brain is surrounded by an endothelial capillary wall commonly called the blood-brain barrier. This barrier protects the brain from potentially harmful chemicals, but it will depend on the family ’s standard 6 paper sizes (CNS) A4 specification (2 丨 0X297 male f) ": '--A7 B7 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 5. Description of the Invention (Capture) When infected, suffering from tumors, or dysfunction, making it difficult for potentially beneficial drugs to reach the damaged brain, Bodor and Farag publish a chemical redox drug delivery system To transport Qin Wu through the blood-brain barrier. (See Bodor, H. ^ Farag, Η.H., " Improved Delivery through Biological Membranes XIV: Brain-specific, Sustained Dekivery of Testosterone Using a Redox Chemical Delivery System ^, in the Journal of Pharmaceutical Science, Vol. 73 ( 3), pp. 385-388, 1984). The drug is bound to a quaternary salt, which can be chemically reduced to a lipid dihydrogen sigma bite carrier. Once administered 'the compound can be spread throughout the body. The lipid-water partition ratio of the carrier allows it to deliver the drug to the brain. The compound is oxidized in the living body and returns to its original form. Except that the blood-brain barrier, which acts in two ways, prevents ionic hydrophilic salts from being eliminated from the brain, the ionic hydrophilic salts can be quickly eliminated from the body. The enzyme removes the drug from the vehicle to provide a sustained drug release to the brain. No penetration enhancer was used in the BoDor study. Compounds that have been used as adjuvants include dimethylsulfinium and its analogs, '1-alkyl-azacycloheptan-2-one (azone), NN dimethylmethylamine, long-chain aliphatic Alkane, alcohols, carboxylic acids and carboxylic acid esters, and other mixed derivatives (such as nansu), cyclohexanol, benzyl alcohol, oxan oxide, and amine or urea derivatives Mixture, C3.4 diols and ethers and "_Cl4 diol mixture with interfacial cleansing agent, eucalyptus brain, urea, ° ratio slightly mixed with: methylmethanamine, 1,3 -Dimethyl imidazoline hexyl f-based amine oxide, hexafluoride and ethylene glycol mono-phenyl hydrazine 2--2-methyl ------ ^ ---,-1 clothing-Φ-. ( Please read the notes on the back before filling out this page) -Order --- Wei 丨 «丨 ---

V. Description of the invention (s) 'Mixed by base, ricinol and —C612 saturated fatty acid by ethoxylated part of glycerol, N-substituted-diisopropylamine' and has the following chemical formula Compound: R10CH2-CH-CH2〇2cI., OP.2

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where R and R2 are hydrogen, 〇) _25 alkynyl, C.2_25 alkynyl, Cim alkynyl, or C2-24 alkenylcarbonyl. All of the above All agents can promote the percutaneous absorption of drugs, but they have certain disadvantages. Some are considered to be toxic (for example, dimethylimine). '(丨 丨) Some may improperly stimulate the skin (for example,' surfactants' ); (丨 丨 丨) some have a thinning effect on the skin when used for a long time (such as oleic acid); and (丨 V) some will change the integrity of the skin structure, thus leading to the looseness of the drug Change (for example, azone). U.S. Patent Nos. 3,921,636; 3,964,482 and 3,996,934 mention that cyclic ketones containing 4 to 10 carbon atoms can be used for transdermal absorption of drugs, but there is no special description of such promoting effects, as evidenced here The result of any transdermal absorption in the presence of a ketone. Furthermore, my research has confirmed that the use of cyclic ketones with 9 to 20 carbon atoms has little or no promotion. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a method for promoting the passage rate of drugs through the skin, various body cavity membranes, blood-brain barriers and the like. Expand or promote

(Please read the notes on the back before filling in this I ·) • Installation.

1T line 5. Description of the invention (A7 Η 7 Another object of the present invention is to provide a drug-containing composition with an increased passing rate through the skin, various body cavity membranes, blood-brain barriers and similar membranes. Another object of the present invention is to provide an adjuvant or penetration enhancer which, when added to a pharmaceutical composition, can 'promote the drugs therein through the skin, various body cavity membranes, blood barriers, and brain barriers and the like. Rate. Another object of the present invention is to provide an adjuvant or penetration enhancer, which is non-toxic and does not cause the drug to pass through the skin, various body cavity mucous membranes, blood-brain barriers and the like. Any physiological effect. Another object of the present invention is to provide an adjuvant or penetration enhancer, which has a small influence on the structure of skin, various body cavity mi barriers and similar membranes. Another object of the present invention is Provide an adjuvant or penetration enhancer that is compatible with disc drugs, pharmaceutical carriers, and polymers. 概要 Summary of the invention According to the present invention, it was found to contain an effective amount- Adding a compound with the following structure can promote the passage rate: The drug passes through the body membrane (read the precautions on the back before filling out this page) • Packing '0 Order YI printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs !

• R (A) r general formula (丨) Φ ms · shape degree Lai Jin _. Jia Zhuan (printed by A7 Consumer Goods Cooperative, Central Standards Bureau, Ministry of Economic Affairs, B7-V. Description of Invention (7), where X and Y are Oxygen, sulfur, or an imine group having a structure of = nr, but it is specified that when y is the imine group, X is a monoimide group, and when y is a sulfur group, X is a fluorene or a monoimide group; A is Has a structure of-Ι_χ, where X and y are as defined above, 'm and η are integers having a value between 1 and 20, and yang + n is not more than 25', and ρ is an integer having a value of 0 or 1 , Q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and R is hydrogen or-is a linear or branched alkyl group having from 1 to 6 carbon atoms, but provides When the values of p, ^, and 1 " are Ό and Y is oxygen, 'm + n is at least 11. The compounds described hereinafter are referred to as accelerators.-When R is an alkyl group.' It may be Methyl, ethyl, propyl, iso.propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and others. Brief description of the drawings. Figures 1 and 2 and 4 to 4 Figure 6, Figures 9 and 10 'and Figures 12 to 19 are for The penetrating patterns of the composition within the scope of the present invention and the control and comparison compositions will be explained. Figures 3 (a) and 3 (b) are photos of body parts, which are used to illustrate the composition within the scope of the present invention. The effect produced. Figures 8, 8 and 11 are diagrams showing the effects of using the composition within the scope of the present invention. Detailed description of the present invention The promoter is dissolved, dispersed, suspended or dissolved in a suitable In solvents, such as alcohols, oils, glycerol, ethylene glycol, propylene glycol, hexane, acetone, freon, water, other polar or non-polar solvents or mixtures thereof, and then it is added to include An effective amount of 10 paper standards applies to Chinese national standards (CNS—) Α4ί ^ (210χ; 7 male thin) " — " " ----- (Please read the precautions on the back before filling this page) C0-order * line ~~ V. Description of the invention (A7 B7 The staff of the Central Standards Bureau of the Ministry of Economic Affairs is consuming together, so in the printed drug composition, the composition is first blended with a quantitative pharmaceutical carrier , So that in containing the drug, pharmaceutical carrier and promotion The concentration of the accelerator in the composition of the accelerator solution is from about 0 wt% to about 50 wt%. Preferably, the concentration of the accelerator is from about 0.01 wt% to about 30 wt%. In some cases In the case, when the accelerator is liquid, the "pure" solution of the accelerator can be directly incorporated into drugs, pharmaceutical carriers and accelerator mixtures, where the roll range of the accelerator ranges from Qiwt% to About 30% by weight. Pharmaceutical carriers include suitable non-toxic carriers and adjuvants in which the drug can be dissolved, dispersed, impregnated, or suspended in solvents such as solvents, amidines, cellulose, and Derivatives, egg proteins and their derivatives collagen, gelatin, polymers, adhesives, sponges, fabrics, and mota analogues, and the addition of adjuvants can provide the drug with a better dissolution in a carrier Such compounds may contain non-toxic surfactants, solubilizers, emulsifiers, chelating agents, binding substances, bone agents, softeners, and the like. Preferably, the compounds of the present invention are cyclic Lactones (where X and Y are both oxygen, q is 1 and " 0), a cyclic diester (where X and Y are both oxygen and q and r are 1), and a cyclic ketone (where 9 and "both are 0 and Y is oxygen in the cyclic diester) , Preferably m + n is at least 3. In this cyclic ketone, m + n is preferably from 11 to 15 and 卩 is preferably 0. The clothing may be a local, intranasal, buccal, ear, rectal, ocular, pharmaceutical, vaginal, or pharmaceutical composition administered via an umbilical administration. It may be in the form of a solution, cream, or spray ' Lotion, aerosol, suppository, or jelly (read the precautions on the back before filling this page)

W 11 Private paper silver scale is applicable to homework standards (CNS) ....... II-1 Hi Λ7 B7 V. Description of the invention Π) 'type, or incorporated into a patch, medicinal film, tape or bandage . The invention will be made clearer by the following examples and the drawings described. These examples and drawings are merely illustrative preferred embodiments of the present invention and are not intended to be limiting. The evaluation of the composition of the present invention on the rate of promotion and drug penetration is carried out on various parts of the body. These areas include the skin, mucous membranes of various body cavities, and blood-brain barriers. The composition of the present invention is evaluated in vitro for promoting the rate of drug penetration through the skin, and its use is performed in vitro according to the preparation procedure described in Chow, Kaka & Pharmaceut. Sci_ 73 (12) 1794-1799 (1984) The obtained pure line Hl7H hairless mice (HRS / J) skin preparations were subjected to penetration studies and data analysis. Animals 2 to 4 months old were selected. In all selected animals, their skin was completely normal and No bite marks, scratches, or assaults. The mice were killed by inhaling CO2 and their skins were removed. Penetration studies were performed using full-thickness skin. Consumption by employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed skin preparations are placed between the supply of a Franz diffusion chamber and a receiving tank. In the receiving tank, the stratum corneum (sc) is exposed to ambient conditions and the dermal side is turned to A phosphate buffer solution of pH 7 · 4, which simulates the physiological pH of the dermal side of pH 7.3-7.4. Before the test sample is applied, the solution of the receiving tank passes through the circulation—a sleeve surrounding the tank and The temperature is 32. (: of the water, while being flat For example, the selection of the temperature reflects the temperature of the sc. In the receiving tank, the mixing of the solution is achieved by magnetic stirring. · 12 private paper scales are applicable to the t_home skirt standard (CNS) M specifications⑺Qx297U · A7 B7 printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (I.) '' A known radioisotope-labeled drug is diluted with a non-radioactive (cold) drug and diluted in It is applied with or without adjuvant to disperse through the 30 surface of the fixed skin. Aliquots of phosphate-buffered saline containing any radioisotope-labeled drug that has been penetrated through the skin into the receptacle As such, it was removed from the side arm of the receiving tank, and a volume of fresh phosphate buffer equal to the volume taken out was added to the receiving tank. Every thirty minutes during the first 2 hours and thereafter Take out aliquots every hour for a period of 10 hours. The total duration of the study lasted to 12 hours. The amount of drug passing through the skin was determined by the liquid flickering in the hydrosol-2 (Αςυ33〇2) of the removed aliquot meter The figure shows the penetration pattern of the drug. These figures are constructed by plotting the amount of drug that has penetrated the skin versus time. For comparison purposes, a control sample (without adjuvant added) and The graphics of the test sample (containing the adjuvant) are drawn in the same diagram. The permeability parameters that are not shown in the table are calculated according to the method described in Ch0w, et al., Page 1795. Example + 1 2% W / V adjuvant was added to a propylene glycol solution containing 4.74 X 10-2 mg / m of gas-labeled acetone elixir compound. The adjuvant tested They are 3-fluorenylcyclopentadecane (丨), cyclopentadecanone (丨 丨), cycloundecanone (⑴ 丨), and dodecane (IV). Each of these cyclic ketones is commercially available. The preparation is tested according to the method described above, and the penetrating pattern of the pyrene and acetone-reduced inflammation pine compounds can be enhanced by each of these adjuvants. This is shown in Figure i. The representative represents each type of __ 13 $ Zhang Zhang Shicai ^ County (CNS) A4 specifications (2iQx297 public director) ~ -------- I -------- I--install. (Please (Read the notes on the back before filling out this page)

1. Line 1T. A7. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (the number of agents is the average of W positions. 瞀) The data shown in Figure 1 is from the linear part of the curve. The total amount and permeation rate (permeability) of the pyrene-labeled acetone-redoxone compounds calculated and obtained are shown in Table 1. Table '1. n3 MAi over-dosage * control group) L ~ g' ^ ° ^ rn! ZilC dpm (xlO ^) Seven%

II III IV 0.70 1.07 0.25 1025 100 437 669 156 156 3.5 4.8 1.5 1 100 350 480 150 170 * The total amount of acetone punctured inflammation pine compounds penetrated at the end of 10 hours Example 2 Insulin absorbed by dogs in the nose The purpose of the study was to confirm the addition of skin enhancers such as cyclopentadenolactone, therapeutic proteins, peptides, sugars, nucleic acids, lipoproteins, mucins, lipoproteins, and other and other macromolecules to live animals And humans can achieve intranasal absorption. Beagles weighing 10 to 12 Kg were used in this study. The formula of the intranasal spray is composed of freon, insulin and cyclopentadeclactone and is packaged in a commercially available metered intranasal spray device. Before administering intranasal spray to the dog, the dog was anesthetized with pentobarbital (Nembutal or pentabarbitol) at a dose of 40-50 mg / kg. Blood samples were taken fifteen minutes before administration. The intranasal spray of insulin is then administered with the aid of an applicator. Blood samples were taken again at 0, 10, 20, 30, 45, 50, 90, 120, and 180 minutes. Measured blood with Y S 丨 glucose analyzer 14 This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0 X 297 mm)

V. Description of the invention (A A7 B7 The employees of the Central Bureau of Standards of the Ministry of Economic Affairs consume the printed glucose of the cooperative and the serum level determined by the radioimmunoassay method. Both methods are commonly used in laboratories. Table 2 Shows blood glucose and insulin blue levels in dogs receiving an intranasal spray containing cyclopentadecanolactone. Obviously, when given in the dog's nasal cavity (spray)-has In the intranasal spray of acid vinegar, the 'serum level' increased sharply to 712uu / m within 10 minutes | and maintained at that level for about 30 minutes, then gradually decreased and reached the level within 3 hours On the other hand, the blood glucose level decreased from .6 m_ at 0 minutes to 51.5 m_ at 30 minutes, while the serum aleurone level went from 2.7 uU / m at 0 minutes. It increased to 671 at 30 minutes. Then, the blood glucose level was maintained at a near-fixed value of about Dazaki clock. Finally, when insulin was consumed at the howling clock, it was 7.9 mg / minute at 180 minutes. _, Blood glucose level will rise from 45.8 mg / dl to 72.7 in the same time mg / dl. Figure 2 shows the time-dependent changes in the sugar and serum levels in dogs before or after receiving an intranasal insulin spray containing cyclopentadecanate. These conditions Shen and similar. Subcutaneous injection of Tengdaosu Table 2 Intranasal absorption time of dogs with insulin pentadecanoic acid vinegar Gold liquid glucose Serum insulin Please read λ, read the precautions of back © and write this page t Thread ( Minutes) -15 0 10 20 (mg / dh 81.0 ± 3 · 2 83 · 6 ± 1.6 80.7 ± 2.7 68.4 ± 9.1 1_7 ± 0.6 2 · 7 ± 1.3 71 · 2 ± 28.3 7δ · 6 ± 6.6 15 This paper is applicable to the standard China National Standard () Specifications (210X297 mm A7 B7 30 45 60 90 120 180 51 · 5 ± 9.5 35.2 ± 6.6 40.1 ± 5_3 38.7 ± 0.4 45 · 8 ± 3.0 72 · 7 ± 8.3 67.1 ± 23.9 53.3 ± 13.6 40.7 soil 1〇_9 14.2 ± 3.9 10.8 ± 2.7 7.9 ± 2.8 Central standard of the Ministry of Economic Affairs, printed by the Consumer Bureau of the Quasi-Bureau 1. Three dogs were used in this study 2. Data are expressed as mean SEM 3. The dose of insulin used in each dog is 1.00 body weight 4. The concentration of cyclopentadenolactone in the fluridin solution A 1% control tank experiment consists of the following groups: (1) a placebo without insulin but containing a skin enhancer, (2) a dish acid buffer solution, and (3) insulin itself. When these control formulations were sprayed on dogs In the nasal cavity, there were no changes in both blood glucose level and serum insulin. Example 2 illustrates the use of macrocyclic molecules in a cavity spray insulin formulation for the treatment of diabetes. The invention is implemented in a spray mode and is not limited to insulin, but is applicable to many therapeutic proteins and peptides. To name a few, there are: interferons for colds, cancers and viral infections, lymphocytes for cancers and immune diseases, growth hormones for dwarfism, and luteinizing hormone-releasing hormone (LHRH) for biologic control. EnkaphaNne for pain relief and more. Example 3 Intranasal Insulin Spray for the Treatment of Diabetes The purpose of this study is to evaluate a compound containing macrocyclic compounds as a penetrating agent. Nasal is only for use (please read the precautions on the back before filling this page) Order- Line: 1 «This paper's standard is applicable to China National Standards (CNS) A4 (210X297mm). The consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs prints A7 ___________._ B7, _ V. Description of invention (咚) Insulin intranasal spray is used for the treatment of diabetes. The methodology used in this study followed the methodology published by two different groups of scientists. One is Insulin Administered Intranasally as an Insulin-Bile Salt Aerosol, published by Alan C. Moses, Gi 丨 Gordon, Martin C. Carey and Jeffrey S. Flier in Diabetes Vol. 32, pp. 104CM047, 1983. The other is by Antonio E. Pontiroli,

Miriam Alberetto, Antonio Secci, Giorgio Dossi, Isabella

Bosi and Guido Pozza in British Medical Journal Vol. 284, p. 303-306, 1982 | nsunn given | nt 「ariasany | nduced

Hypoglycemia in Normal and diabetic Subjects. '' The booster used in this study was 1% cyclopentadecanolactone and the insulin used was U-200 porcine insulin. Subjects received 4 sprays of the booster solution (two sprays per nostril ), Then receive 2 sprays of u_2〇 (one spray per nostril) or the equivalent of 40 U per 60 kg. In the misty night, the individual is fasted for two hours. When intranasal insulin is administered, the individual is required to take a deep breath. A blood sample was taken at Aunt Island for 20 minutes. After spraying, blood samples are taken every 30 minutes. Radioimmunoassay was used to determine blood glucose levels. Four individuals with a history of hyperglycemia were selected to receive insulin intranasal spray. Two individuals receiving only accelerators or insulin were used as a control group. The results obtained from four patients with type 2 diabetes are shown in Table 3. It clearly shows that blood glucose levels can be lowered by receiving an intranasal spray of insulin. In other words, when cyclopentadecanolactone is added to the formula, 17-~~ ——-- (read the notes on the back before filling in this page). -Packing: Order A7 ~~ --- ---—_____ B7-V. Description of the invention (π) Tengdaosu can be absorbed through the nasal membrane. This can be further confirmed by the insulin level obtained from the same gold sample. For those who only received the accelerator spray. Mist ° The blood glucose level did not decrease. It was not reduced for those who received only insulin solutions without promoters. Time between minutes 2030 6090 120 3 Calculation of blood glucose of diabetic patients receiving intranasal insulin spray Individual 1 ^ 00 mg / dl 399 388 342 339 Individual 2 Individual 3 Individual 4 276 mg / dl 384 mg / dl 308 mg / dl 246 334 277 209 325 274-266-279 244 (Please read the notes on the back before filling out this page.) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 趿 马 京 浴液 is U-200 猪Of insulin. 2. The penetration enhancer used is 1% cyclopentadecanolactone in Freon. 3. The four bodies are all patients with type 1 diabetes. 4 _ "-20 points" refers to blood samples collected 20 minutes before intranasal spray. Example 4 Vaginal sponges used to synchronize puberty in Jin Yang The purpose of this study was to prove that by adding The penetration enhancer of cyclopentadecyl lactone, the vaginal absorption of the therapeutic agent reaches the desired therapeutic level. The polymer sponge made of polyurethane or its analogue is 80% 9α_11 Rhenium, 17α-dihydroxy-4-pregnene-3,20-dione (nuororgestorone) and 20% cyclopentadecanolactone were impregnated. The sponge was inserted into the vagina of a female sheep Ling Dazheng 2. Blood samples were collected and measured by radioimmunoassay method 9a ,. 17 α-dihydroxypregnene-18 sheet paper size applicable to Chinese National Standard (CMS) A4iW§- (210X297 ^) 4 order. I ^ — u In Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (p) '3,20-two level. Table 4 shows 9 in females during the processing time. The blood level of 11 Zhao, I7α_dihydroxy_4_pregnene_3,20-di_. The post-treatment period is the decision to synchronize the spring period of female sheep. Refers to 枳. Its fruit clearly indicates that in the later stages of the treatment (ie, 6, 9, and 12 ^; in the female sheep who received sponges with a 'penetration enhancer such as cyclopentadenolactone') The blood level is higher than those without penetration enhancers. Table 4 9 α -11, 7 ^ -dihydroxy winter pregnant cicada _3,20_II, blood 1T treatment days in female sheep— 0 3 6 9 0.20 0.19 0.09 0.16 0.03 -ve control group 1 2 3 X SED 3.61 6.82 0.69 3.70 1.77 0.19 0.48 0.36 0.34 0.08 ng / ml 0.47 0.39 0.36 0.41 0.03 0.22, 0.25 0.07 0.16 0.05 sponge 1 4 0.56 2.61 1.42 2.05 1 11 (None D 5 3.15 3.23 2.26 1.49 1.56 6 5.51 3.26 3.61 2.53 2.41 7 0.80 2.06 1.39 2.05 1.47 X 2.51 2.79 2.17 2.03 1.64 •-_ SED 1.16 0.28 0.52 0.21 0.28 sponge " 8 2.62 2.12 2.06 3.61 2.61 (Yes Promote D 9 0.87 4.27 2.53 2.31 2.13 10 0.82 3.33 2.18 2.39 2.04 11 1.06 2.02 2.22 2.81 2.24 X 1.34 2.94 2.56 2.78 2.23 SED 0.43 0.54 0.10 0.30 Ω 1 Π Blood-brain barrier and central nervous system 0.39 0.19 0.43 0.22 0.31 0.06 ΌΤ " 0.41 0.59 0.63 0 .49 0.07 Blood-brain barrier (BBS) is composed of brain microvascular endothelial cells, which is characterized by tight cell connections, minimal drinking cell activity, and no openings 19 (210X297 mm) This paper is used on a paper scale Chinese National Standard (CNS) M Regulation · B7 V. Invention Description () ~~~~ r '—— Save. These characteristics give microvascular endothelial cells an ability to limit the distribution of small polar molecules (such as the neurotransmitter catechins, peptides, and macromolecules such as proteins) in the blood. Circulate through to the brain. On the other hand, among the cerebral blood vessels, the blood-brain barrier is a dynamic and regular interface, which causes serious obstacles to the delivery of pharmacological drugs to the central nervous system. Example 5. The purpose of printing this research Jiu Jiu by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics is to verify that a cyclopentadenolactone is added to the injection solution and a penetrating agent that can penetrate the central nervous system (such as the brain) The blue dye is used as a marker. First, one gram of cyclopentadecanoic acid vinegar was dissolved in an absolute alcoholic solution of 0.05%. Then, the solution was mixed with 10 ml of a physiological water-staining agent solution. Then, the mixture was filtered through a freshly purged pan to remove excess cyclopentadecanolactone, and made into a solution for infusion and cyclopentadenolactone. 3 m of the above solution was infused into the carotid artery of anesthetized rats weighing about 250 grams. Carefully proceed by clamping other veins and arteries with surgical forceps to ensure that the infusion solution enters one side of the brain. The other side of the brain is used for comparison. Figure 3 shows that the brain and eyes tested in this rat are dark blue & this is due to the promotion of the penetration of the blue stain by the use of cyclopentadecanolactone; The other side remains the normal color. Figure 3 (b) shows the left side or one side of the test. The cross section of the brain appears dark blue. The right side or the opposite side appears normal. S1 to S4 are four different sections of the brain. The results shown in Figures 3 (a) and 3 (b) show that the addition of cyclopentadecanolactone to the infusion solution can affect the chemical substances in rats through the blood-brain barrier. Standard (CNsT ^ 4 specifications (210X297 mm) ----- A7 --------------- 87 V. Description of the invention (, s) — ~~ ^ ~~ '-Wall of Penetrating effect. Studies on the types of macrocyclic compounds as penetration enhancers Xiao Xiushi: The macrocyclic coppers containing more than one carbon are unquestionable, which is purely of a lower quality. What Lai does not have; (2) other macrocyclic rings, such as muskone with an alkyl group in the ring of the macrocyclic ring, have similar promotion properties; (3) other macrocyclic compounds, such as those in the macrocyclic ring The cyclopentadecanolactone with another oxygen in the ring also has promoting properties; (4) Another macrocyclic compound, such as citronone having an unsaturated bond in the ring of the macrocyclic ring, also has promoting properties; (5) Other macrocyclic compounds, such as Acetyl Brazil esters, which are composed of long-chain difluorene and ethylene glycol, have promotion properties. Example 6 Different ring pairs Comparison of transdermal absorption of drugs into the skin of hairless mice. Printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs. In this study, six different rings were used. A comparative study of percutaneous absorption through hairless and stingy skin. These cyclic ketones include cyclononanone (C9), cyclodecanone (C10), cyclodecanone (C11), and cyclododecanone ( C12), cyclotridecanone (C13) and cyclopentadecane = (C1 5). The preparation, penetration studies and experimental data analysis were performed according to the method of Example 1. Each compound was used Five skin samples for transdermal absorption studies. The wave length of the promoter used in the supply room was 2%. When drug penetration has been achieved-stable-at least a few hours'-Perform a 10-hour experiment Figure 4 shows the penetration of hydrocorticosterone through the skin through the hairless mice through the promotion of different cyclic ketones. 21 ^ ^ · The standard is applicable _) A4 size (21 ^ 97 mm) Economy Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Justice of the People's Republic of China A7 ------B7 V. Description of Invention (η) .The order of the effectiveness of different cyclic ir-types to promote absorption properties: cyclopentadecanone > Ring Thirteen Hospital Networks > J Lai Yi Yi Yuan Ketone > cyclononane > ring ten-㈣ > cyclodecane _ (— Decreasing order: calculate the slope of the penetration pattern used to represent the drug's permeability rate and show it in Table ^. Take the control group as 100 as a benchmark to calculate the promotion of different cyclic ketones. Factors. When cyclodecanone and cyclodecanone are used as skin enhancers, the penetration rate of hydrocorticosterone through the skin of hairless mice is slightly reduced. In other words, cyclodecanone and cyclodecanone All of them slightly inhibited the percutaneous absorption of corticosterone through the skin of hairless mice. #When using cyclononane, there is a slight effect on the percutaneous absorption of hydrocorticosterone through the skin of hairless mice. And in the study, when ring dodeca was used, the cortical steel passed through hairless mouse skin? There was a 230% increase in transdermal absorption rate. However, when cyclamidine and cyclamidine were used as skin enhancers, respectively, there was a 524% and 59% increase in the percutaneous absorption of chlorocorticosterone through the skin of hairless mice. In addition, g-cyclopentadecanate, a macrocyclic compound with a single oxygen atom in the ring of the macrocyclic ring, was used in the same study for comparison. There is an oral increase in the rate of percutaneous absorption of hydrocorticosterone through the skin of hairless mice. From this research, it has been clearly proved that (1) Rings that contain more than 碳 carbon atoms have unpredictable desirable characteristics, which are properties that they do not have lower resembling line types. The higher the carbon number in the ring of the giant ring, the higher the penetration rate of corticosterone through the skin of hairless mice. Table 5 Comparison of the penetration rate of different cyclic ketone hydrogen cortices through the skin of hairless mice 22 'The paper size is applicable to the Chinese national standard (CNS> M specification (21〇X 297 mm. Loading W (Please read first Note on the back, please fill in this page) I. I order m9 — ^ ϋ fm _ line

Consumption cooperation by employees of the China Standards Bureau of the Ministry of Economic Affairs. Du V. Invention description (M) Chemical substance penetration rate (ug / cm * cm / hr) Promotion factor (%) None or control group 5.25xT〇 ^ ~~ Burn 11¾ 5.95 × 10'5 113 Cyclodecanone 3.79 × 10 ～ 5 72 Cyclopentamidine—Baking Ketone 3.91 × 10′5 74 Cyclodecyl Ammonium: Ketone 1.21 × 1〇 · 4 230 Cyclodecadione 2.75 × 10 · 4 524 Ring Pentaerythrone 3.10χ10_4 590 cyclopentadecanolactone 8.94χ10.4 · 1 1703 1. The concentration of the chemical substance used in the supply room was 2/0. 2. Calculate the penetration rate from the slope of the penetration pattern. 3. Calculate the promotion factor based on the control group (without chemical greed) as 1,000. Example 7 The method of Example i was repeated except that the adjuvant tested was cyclopentadecanone at a concentration of 0-5, 1, 2, 3, 5 and 10% w / v. Methanol from 0.2 to 0.9 was added to the 2.7 m solution 'to help the ketones dissolve in propylene glycol at a high concentration. As shown by the graphs obtained from a control sample containing methanol, the presence of methanol did not alter the penetration of the skin to an appreciable extent. The penetration pattern is shown in Figure 5, and it can be easily seen that the minimum effective concentration of the adjuvant is 2%. Based on the data presented in Figure 5, the series of transmittances calculated from the linear portion of the graph are shown in Table 6. ---- Γ--: ---------- " Loading €) 丨 (Please read the notes on the back before filling this page) -Order, ---. Line

23 Paper AZ (CNS) V. Description of the invention (A7 B7 3 2 1 0.5 〇 (control group) oxacyclohexan-2-one or cyclopentadecanoic acid within 3.7 X 103 3.7 X 103 〇31χ 1 〇3 〇31χ 1〇3 〇16χ 1〇3 Ester research 3 1 1 ο ο ο 332000 2 2 2 11 ο ο Implementation Example 8 Printing and use by employees of the Central Standards Bureau of the Ministry of Solution Economy The same private sequence as in Example 1 was used to carry out the sample preparation, research, and data analysis. The used core plate rabbits were fine, and the fungus was acetone. And the concentration of cyclopentadecanolactone is 2%. Figure 6 shows that the meridian with the cyclic pentadecanoic acid motif has a propagating effect to reduce inflammation and penetrate without the addition of cyclopentadenoic acid. § Intention, no penetrating drug can be detected in the receiving room. However, when cyclopentadecanate is used at the 2% level, the drug, namely acetone shrinks inflammation pine, can penetrate through without Hairy mouse skin. Self-penetration pattern, analyzes four kinds of penetration parameters, that is, lag time, membrane penetration coefficient (κρ), diffusion constant in the membrane, and partition coefficient between the membrane and the vehicle Km) and listed in Table 7. Table 7 Penetration Parameters Lac Kp D Time (hr) (cm / hr) (c.xx) \ 2l \ vc) Km ^-__ __ cyclopentadecanoic acid 6.03 3 88 4 42 x Ί〇_7 3.51 x 104 lactone (2%) Example. 9 Cream '24 This paper size applies to China National Standard (CNS) A4 Specification (210X297 mm) 1-^ --- (Please read the precautions on the back before filling this page) -Order-

«MB KltA Printed by the Consumers’ Cooperative of the China National Standards Bureau of the Ministry of Economic Affairs —— V. Description of the Invention (Recognition) ~ 'In a different set of experiments, the Xi Hai formula was configured as a gift Film! Tween 20 aqueous solution of cyclic pentadecanoic acid lactone in saline or buffer. In the -boot water bath / ultrasonic vibration, the desired amount of cyclopentadenolactone is combined with Tween 20¾.α and saline, and emulsified by ultrasonic vibration. In this set of experiments, the promotion rate of corticosterone penetration through the skin of hairless mice and human corpses was tested. The concentration of cyclopentadecanic acid in vinegar ranges from 0.001 to 10%. Yi Chujin: Detecting A, __ A very pre-promoting accelerator is combined with a cortisol that is radiolabeled in a concentration of 0.05 mM in saline.

Tween 20 (1 or 0.1 0 / 〇) was placed in the supply chamber to emulsify the accelerator. Fill the receiving room with saline. Figures 7 and 8 depict the effect of cyclopentadenolactone on corticosterone penetration as a function of accelerator concentration. A study on hairless mouse skin showed that in FIG. 7 ', the concentration of cyclopentadecyl lactone was from 0.001% to 100/0. The promotion effect of corticosterone rotation was measured even at as low as 0.001%, but the difference in penetration with the control group was not significant at the 90% confidence level. At 1% cyclopentadecanolactone, the promotion ratio is the largest. Figure 8 contains a similar concentration-dependent study performed on human cadaver skin. A significant (90% confidence level) promotion can be measured at 0.003% cyclopentadenolactone, with the largest promotion occurring at 0.32% and 3.2% of cyclopentadenolactone. For both hairless mouse and human cadaver skin, the scale of the promotion effect is in the range of about 2 to 10; further, it shows that the two skin types are equally sensitive to the cyclopentadenolactone effect. The previous explanation of the spray in Example 2 can be interpreted in the nose of insulin. 25 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 × 297 mm). (Read the precautions on the back before filling this page. ) Line, 0 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention), ~~ '^ — The use of cyclopentadecanolactone in mouth mist can reduce blood glucose in dogs. Similarly, Example 3 illustrates that cyclopentadecanate can be used in an intranasal spray formulation ' for use in the treatment of type 1 diabetes in humans. Example 10 See J. Yeast}, 9-Hydroxytetra-1-one * Follow the procedures described in Example 1 for sample preparation, penetration studies, and data analysis. The accelerator used in this study was 2% citronone in the solution in the supply chamber of a diffusion chamber. Figure 9 shows the penetrating pattern of tritium-labeled acetone shampoo through the skin of hairless mice with or without citronone. The steady-rate penetration rate calculated from the slope of the penetrating pattern is 8.36 x 10_3ug / cm * cm / hr for ketones containing fragrant ketones, and only 1 for those without citronone. OX 10-3tig / cm * cm / hr. When 2% -level citronellone was used as an accelerator, the transdermal penetration rate of acetone-reduced flavonol increased by 76%. Example 11 ^ Hou brazil_acetate or ethylene decadecane dicarboxylate (dica "b〇sv 丨 ate") except that the drug that was thrown off was naproxen HC 丨 and the penetration enhancer used was 10 In addition to the ethylene concentration of ethylene brasinate, the sample preparation, permeability study and data analysis were performed according to the method described in Example 1. The gas-labeled naphthalene anhydrochloride passed through 10% The penetration rate of ethylene brasinate through the skin of hairless mice was 15.8 ug / cm * cm / hr '. Without the accelerator, the fluorene-labeled naproxen HCI passed through the skin of hairless mice. The penetration rate is 5.05 ug / cm * cm / hr. When added. ≫ 26 (Please read the precautions on the back before filling this page).

• 1T. Line 1 1 I I. The scale of private paper waves is applicable to Chinese national standard (€?) 8 4 specifications (2 丨 〇 \ 297 public splash;) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 ______ B7. 5 2. Description of the invention (β) When ethylene vinylidene ester is introduced, the penetration rate in the steady state is increased by three times. Simultaneously, 5% of cyclopentadenolactone was used as a positive control group. The steady state penetration rate is 24.8 ug / cm * cm / hr, a five-fold increase. Figure 10 shows the permeation pattern of the fluorene-labeled naproxen HCI promoted by ethylene vinyl acetate and cyclopentadec acid lactone, respectively. Table 8 lists the penetration parameters obtained from the analysis of the penetration patterns shown in Figure 10, that is, the lag time, the partition coefficient of the carrier to the membrane, the diffusion coefficient, and the permeability coefficient in the membrane. -------- ^ --- " Installation «— (Please read the precautions on the back before filling this page) Table 8 Naxinan's penetration_parameter T hr Kp cm / hr D cm * cm / hr Km S Photo group 2.06E + 00 1.17E-02 1.29E-06 3.63E01 10% ν / ν Ethylene Brazil ester 1.8E + 00 3.68E-02 1.48E-06 9.95E01 5% w / v Cyclopentadecanolactone accelerator 7.2E-01 5.75E-02 3.70E-06 6.21 E + 01 • Example 12 In a different study, a cortisol-labeled hydrocorticone and ethyl acetate were used. A cream formula of brasilin. The contents of the formula were the same as in Example 9 except that the accelerator was replaced. Fig. 11 shows that the promotion ratio of 3-fluorenylcyclopentadecanone and ethylhexyl Brazilian ester to argicorticosterone is a function of skin type. It shows that the transdermal absorption of hydrocorticosterone can be increased by 5.5-fold and 2.5-fold by 10% of 3-fluorenylpentadecanone and 10% of ethylene Brazilian ester. The results obtained from Examples 6 to 12 clearly show that the macrocyclic compound 'includes macrocyclic ketone, macrolide with or without alkyl groups, and 27 paper paper scales applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ) 'A7 V. Description of the invention (αί Poly sl composed of Otome and dicarboxylic acid, has the property of promoting the passage rate of snails through the skin, nasal mucosa and other biological membranes. Type of therapeutic drugs C Examples 13 to 20 illustrate the use of macrocyclic compounds as penetration enhancers for different types of I therapeutic agents. These agents include antihypertensive drugs such as Nexazone and Nexinan, such as benzodiazepine The rate of armor Ϊ steroid hormones such as carbodiol, anti-inflammatory drugs such as corticoids, chlorocorticosteroids, anti-inflammatory drugs such as indomethacin, anti-inflammatory fungus, such as Fu'jin mt 琯 such as the month Anti-scabies drugs, Maian's calcium barriers, anti-diabetic animals such as octavalerone and micromarine, spring-time synchronization drugs such as the corpus luteum, contraceptives such as estradiol, etc. Others through Drugs whose rate can be increased include, but are not limited to, biotin antifungal agents, CNS inhibitors, and sunscreen agents. Example 13 C. Percutaneous absorption of triamcinolone except for the use of 3-methyl grave-ring fifteen In order to promote the addition of 0.3 ml of ethanol to the solution to completely dissolve the adjuvant, repeat the procedure 4 in Example 1 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The graph of the control group showed that the amount of ethanol did not perceptually change the penetration of the skin. The penetration is shown in Figure 12 and it can be easily seen that the minimum effective concentration of the adjuvant is 2% ^ According to the data presented in Figure 12, the transmissivity calculated from the linear part of the curve is listed in Table 9. Table 9 '28 This paper is still applicable_ 家 榡 准 （ .CNs) A4 specifications (21QX297 mm) 5. Description of the invention (a) A7 B7 concentration% penetration rate (dpm / cm2 / hr) ratio (%) 10 0_3x103 3000 5 0.3x103 3000 3 0.22X103 2200 .2 0.15X103 1500 1 0.10X103 1000 0.5 0.013x103 130 0% (with ethanol) 0.025x10s 250 0% (without ethanol) 0.010 × 103 100 Printed in Example 14 by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Percutaneous absorption of psoralens. Except for the drug used, 8-methoxy-psoralen (MOP) with a concentration of 46 mg / ml. ) (Using h3_m〇P dissolved in propylene glycol), and the adjuvant tested in this test is 3-methylcyclopentadecanone ⑴ · 4% w / v) and cycloundecone (melon) (2% w / v), the procedure in Example 1 is repeated. This penetration pattern is shown in Fig. 13. Based on the data presented in Figure 13, the penetration rates calculated from the linear part of the curve are shown in Table 10. Table 10 Penetration rate (dpm / cm2 / hr) 1.88 X 103 8.13 X 103 3.63 X 103 Example 15 Transdermal absorption of clonine except for the use of clonine labeled 1000 times diluted with cold clonine 'Repeat example; method in! _. This test consists of a control group containing 37 4 _ adjuvant 0.4% | 2% 111 ratio (%) 100 432 193 --------- [ref — {Please read the notes on the back before filling Woben ear),-° _ 29 A7 B7. V. Description of the invention (4) Deduction of clonine and 2% (w / v) of propylene glycol in cyclopentadione. The penetration pattern is shown in Figure 14 According to the figure, the penetration rate of the formulation containing the adjuvant is ⑴mg / cm2 / hr. 'Or equal to 1.83 X 106 dPm / cm2 / hr of the respective radioisotope-like drug. Example 16 Benzodiazepine The percutaneous absorption of 萆 was repeated with the procedure in Example 15 except that the benzodiazepine was diluted 1000 times with cold stupid methyldiazine leather. This test consisted of a solution containing [91 mg / ml of Benzodiazepine and 2% can) cycladecanone in propylene glycol solution. The penetration pattern is shown in FIG. 15. Example 17 Percutaneous absorption of benzodiazepine ^ The procedure in Example 1 was repeated except that 14C benzodiazepine 2 diluted 1000 times with cold benzodiazepine was used. The propylene glycol solution is printed by the Consumer Standards Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs. : mg / ml of Benzodiazepine and 2% (w / v) Cyclopentadiene propylene glycol. This penetration pattern is shown in FIG. Example 18 Transdermal absorption of estradiol The procedure in Example 15 was repeated except that 14C estradiol was diluted 1000 times with cold estradiol. The test was carried out with a propylene glycol solution containing estradiol made by tweeting and 2%)) cyclopentafluorene. i ----30 papers ^ 30 V. Description of the invention (a) The penetration pattern is shown in Figure 17. A7 B7 Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs. Duplicate Example 19 Percutaneous absorption of naproxen. Repeat the procedure in Example 15 with the exception of gexinan, which is marked with cold naphthol and dioxin. This test was carried out with a naphthylamidine solution containing 97 x 10-3 mg / m | and a 2% (w /) 3 solution of propylene butadiene. The penetration pattern is shown in FIG. 18. Example 20 Transdermal absorption of valeriangan. The procedure in Example 15 was repeated, except that the valerianan labeled with gas diluted 1,000 times with cold valeriangan was used. This test was carried out with a propylene glycol solution containing valmean of 54 x 10-2 mg / m and 2% (w / v) cyclopentadecanone. The penetration pattern is shown in FIG. 19. Examples 21 and 22 relate to the use of a promoter in a pharmaceutical composition which is administered using a transdermal patch or similar delivery system. In particular, the compatibility of this accelerator with the polymers used in these patches was studied. 'The polymers such as * Dow coring Corporat, Midland, Michigan, or pressure sensitive silicone elastomers Adhesive. The method of evaluation is described as follows: A. Preparation of adhesive solution: A suitable amount of adhesive solution is weighed and added to a known weight of cyclopentadecanone to dry the adhesive after coating (100% Solid state) to get ring fifteen, 0, 1, 5 '20, or 30 wi% (W / W), ----- hI-d, (Please read the precautions on the back before filling this page) Thread 31 k Paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) * -I-..... II 1 I * Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ---_______ B7 V. Description of the invention (Μ) ~~: ^ ~ -— Yuan Gang (penetration enhancer). B • Machine ^ Coating and Lamination: Customized fiberized Meyer rods (40 lines / 忖 'deep. 嶋 ") set the adhesive on the motor scale to 5.5 at a speed of -165 pairs / minute The solution was coated on a Scotchpak 1022 anti-adhesive layer (manufactured by Company, St. Pau), and the anti-adhesive liner (2 mM,) was allowed to air dry for a few minutes. After applying the adhesive solution, the base was cleaned with Frefl PAC. The Tory's adhesive was dried at room temperature and allowed to evaporate. Then, an IPA_extruder was used, followed by a 4.5 lb rubber roller to transfer the film to coat a polyester sheet. These are available in 1 and 2 mil thick 355 BIO-PSA (R) medical grade adhesives and X-7-2920 BIO-PSA (R) anti-amine medical grade adhesives, respectively. c. Test of vertical layer: test the laminate's applicability at the beginning (after a minimum of 24 hours after preparation) or after aging at room temperature (20 to 25 ° C) for two weeks. D. Measurement of patch properties: D_ 1. Surface tack measurement: Pressure-sensitive adhesives have the ability to form a bond with another surface during a brief contact under low dust. This general phenomenon is called stickiness or fast sticking. The strength of this bond will vary depending on the applied pressure, the pause time and the rate of withdrawal. Quantitative adhesion measurement is performed through a Polyken (Tm) trademark probe adhesion tester (prObe Tack Teste ") (Testing Machines, lnc. Amityville, NY). Brief summary, adhesive measurement, 0.5cm / sec performance, 100g / cm2 contact pressure and 0.5cm / sec contact time. This method is based on ASTM D-2979. The adhesive stack is cut to 2_.5 cm X 2.S cm 32-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page} •-I-.-ir--1-! ,, Order-

-Line J B7 V. Description of the invention. . ) ^ The test sample is placed on the top and has a shape of 〃. After every five-piece sequence, the probe was wiped with a lint-free material. Allow the probe to stand for at least 2 seconds after swabbing for average and standard error. , J dries the similarity of the reading D.2. Peeling and releasing the adhesion (peeling force): The resistance of an adhesive benzhan cloth to a peeling force is called peeling or releasing. The peel value is recorded from a method used by the class to test for impurities:. Prepare an adhesive laminate and cut it into a one-inch wide and long anti-adhesive liner (Sc〇 丁 cHPAK (r) attached to a tensile tester at a speed of 40 inches / minute at a rate of 8 The angle of 0 degrees is peeled off. The average value of the entire shape is recorded. The data represents the Satoshi (R) 'adhesive and Machida's compilation film as the average SD (n = 3). When the anti-adhesion layer is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs D.3. Adhesion: Determine the adhesion to a stainless steel test plate. Quantitative adhesion measurement records were obtained by using a one-inch-wide mylar (r) polyacetate patch coated with a layer of adhesive. The patch was glued to a stainless steel plate with a 4 5 | b roller and peeled off and attached to a force tester. The result is expressed in grams per centimeter. Between each test, the test panels were cleaned with acrylic and tri-gas ethylene and allowed to air dry. Unless otherwise indicated, data are expressed as mean + / _ S.D. (N = 3). D.4. Explanation of the patch property test: an arbitrary minimum value of adhesive (> 50 g / cm2) and adhesion (> 200 g / cm2), and the highest value of peeling (< 5) g / cm) is used as a sticker to determine the test samples for the transdermal drug delivery system. 33 This paper size applies to the Chinese National Standard (CNS) M specification (210X297 mm).

A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (citation), 'The benchmark for the appropriateness of the nature of the cloth. Example 21 The purpose of this study was to determine cyclopentafluoropyrene (0, 1, 5, and 10 wt%), a skin penetration enhancer "against 355 BIO-PSA (R) and x7-2920 antiamines. The compatibility of BIO-PSA (R) medical-grade lithone pressure-sensitive adhesives with patch properties (that is, peeling, adhering, and sticking) is compared with the following other accelerators: Azone (R), Acetase, isopropyl myristate, isopropyl palmitate, and eucalyptus brain, and the effects of these promoters on the properties of the patch were initially evaluated under different aging conditions. After the situation, these were evaluated on the properties of the patch. Efficacy of accelerators: 355 8 丨 〇- 卩 38 (only) has been used, and 乂 7-2920 antiamine has been 丨 〇_ PSA (R) has been developed for use in transdermal drug delivery systems And recorded in Testing Adhesive and Liner for Transdermal Drug Delivery I 1 · Published by Huie, Schmidt and Warren in June 1985

AdhesiveAge and Krug and Marecki's Porous and Other

MedicalPressure Sensitive Adhesives, Adhesives Age, November 1983, pages 19-23. Tables 11 to 13 illustrate the effect of the use of promoters and their loading on the properties of initial patches in transdermal drug systems. Cyclopentadecane is soluble in this adhesive before administration. The stack containing 100 wt% cyclopentadecane is transparent. A small amount of obvious crystallization was observed in the stack containing 20 and 30 wt% cyclopentadecanone, which indicates that the amount of resolution of the cyclopentadecane steel at 355 adhesive solids is between 10-20 wt%. 34 This paper size is applicable to China; ^ 隼 (CNS) M specification (ηοχϋή j 一 '· ---, 丨 丨 (Please read the precautions on the back before filling this page), π line A7 B7 Central Ministry of Economic Affairs Printed by Standards Bureau's Consumer Cooperative

V. Description of the invention (A 10 wt% ring fifteen fire-retardant stacks have similar adhesive and patch properties to those of ',', 1 layer. 0,], 5 and 10 wt% of ring fifteen Compatibility effects of alkanones on the initial patch properties of DC force-sensitive adhesives (pSA), and / or other accelerators are shown in Table 11. Comparisons of up to 10 wt% of each accelerator All laminates have very low initial peel forces (M 0 g / cm) and are acceptable for transdermal drug delivery systems. The cyclopentadecanone was found to reduce the adhesion and reduce adhesion in proportion to its loading in Dc 355 and X7-2920 pressure-sensitive adhesion d. The loading level of 10 wt% ring fifteen burners is considered compatible with both KDC 355 (Table 彳 1) and BIO-PSA (R) (Table 12 &amp; 13). Ethanol at a level of 10% by weight has no adverse effect on the properties of both Dc 355 (Table BIO PSA (R) (Tables 12 &13); however, lower alcohols from the time of preparation of the patch to the test It is very likely to have evaporated. The concentration of ethanol in the tested patch can be ignored. Zone (R) isopropyl palmitate and isopropyl myristate are shown to be soluble in two kinds at the amount of wt% in pSA; however, they plasticized the adhesive and caused the adhesive to fail (that is, the adhesive was transferred to the release liner, which remained after peeling, remained on the adhesion test board, and acted as a solvent for the adhesive) The biggest difference between these accelerators and those of 355 and X7-2920 B0-PSA (R) _il is isopropyl pickled vinegar (彳 wt%), isopropyl myristate (5 wt%) ), Azone (R) (1-2 wt%), Eucalyptus Brain (&lt; 5 wt%). In short, cyclopentadecane hydrazone can be incorporated into silicone pressure sensitive higher amounts than other penetration enhancers. In the adhesive, it does not harm the nature of the patch, so it can be used in 35 paper sizes (CNS) A4 size (210X297 mm). <Please read the precautions on the back before filling this page.)

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (θ) 'It is considered to be used in the main body of drug / silicone adhesive or laminated transdermal drug delivery system. Example 22 An aging study was performed on a laminate with DC 355 BLOPSA (R) with each accelerator. 1 wt% loading of cyclopentadecanone, Azone (R), ethanol, isopropyl myristate, isopropyl palmitate, and eucalyptol. Initial applicator properties of a 0.00355 machine-coated laminate. The effects are shown in Table 彳 4. The effects of these accelerators on the patch properties of Dc 355 after two weeks of aging are shown in Table 15. In the control group, the adhesion, peeling, and adhesion values of the DC 355 stack were reduced by 71, 509, and 5%, respectively, from the initial values (Table 14 vs. Table 15). Note that after two weeks of aging 'only cyclopentadecanone increases its adhesion; others decrease its adhesion (Table 15). Examples 21 and 22 illustrate the patch properties obtained from the results of a study on the compatibility of the ring fifteen-burner and the pressure sensitive adhesive of Shi Xiyongj. Hundreds and Fifth Entertainment: Plutonium was found to increase peeling force and reduce adhesion in proportion to its loading in DC 355 and X7-2920 pressure-sensitive adhesives. A maximum of 10 Wt% of cyclopentadecanone in the charge is considered to be compatible with both DC 355 and X7-2920 BIO'PSA (R). Data from a compatibility study show that the maximum phase capacity of other penetration enhancers with DC 355 and X7-2920 BIO-PSA (R) is isopropyl palmitate (1 wt%), eucalyptus contact ( &lt; 5wt%) e In short, pentadecane can be incorporated into silicone pressure sensitive adhesives in higher amounts than other penetration enhancers, and thus can be considered for use in drug / silicone adhesive matrix or transdermal Drug rotation system. 36 This paper size is applicable to tS countries) 8 secrets (210X297 public holiday) ^: ----------- ^^ 丨 (Please read the precautions on the back before filling out this page) m ·, words A7 __________B7 V. Description of the invention (outside) Table 11 Effects of skin penetration enhancers on the properties of the 355 pressure-sensitive adhesive patch properties Printed on the skin by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. cm2) Initial patch properties a Peeling (g / cm) Surveying (g / cm) Control group 0 92.0 1 +/- 0.2 &quot; --- 290.0 CIB-01 1 358.0 1.8 342.0 (ring 15 624.0 7.3 256.3 Alkanone) 10 780.7 9.1 193.7 Ethanol b 1 119.7 1.1 269.3 5 239.0 1.4 263.0 10 314.3 1.1 305.5 Isopropyl 1 407.3 3.5 506.6 Palmitate 5 864.0 9.1 172.6 * 10 284.0 3.9 58.7 ** Azone (R) 1 357.6 1.4 290.4 5 212.7 2.5 322.7 ** 10 113.3 2.5 389.9 ** a The sample was coated on the hand with a No. 8 coated rod. Severe damage of the adhesive tape properties η ′ Adhesion failed (**). 37 This paper size is applicable to China National Standard (CNS) A4 (7ϊ ^ &lt; 2 magic mm) ----------,-1 ^ — — — (Please read the note on the back first Please fill in this page for further details.) Bookmark. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention Measured, Table 12 Skin penetration promotion _X7_292Q Impact of impact-sensitive intestinal impurities Impurity of initial patch properties a Skin filling ~ _ ------ Accelerator wt% Adhesive (g / cm2)- Exfoliation (g / cm) Adhesion (g / cm) Control group 0 612.7 11.8 1170.0 CIB-01 1 573.3 8.4 831.0 (ring fifteen 5 598.0 11.6 2124.0 alkanone) 10 915.3 15.5 2137.0 ethanol b 1 246.3 3.5 sip · 5 297.0 4.2 967.6 10 288.3 5.6 960.1 Isopropyl 1 385.3 6.3 204.5 Palmitate 5 712.0 10.9 204.5 10 524.7 14.1 290.7 ** Azone (R) 1 312.0 1.8 1509.0 5 703.0 16.9 1238.0 ** .10 714.3 22.9 1424.0 ** 38 paper The wave scale applies the Chinese National Standard (CNS) A4 specification (210X29 * 7mm) A7 B7 V. Description of the invention (# The sample was coated with a No. 8 coated rod to the bad, and the adhesion failed (**). / Biomass severe ethanol is quite volatile and evaporates during the borrowing period. Keep in the patch The final ethanol concentration cannot be measured. Table 13 Printed skin penetration enhancer bexham cloth of χ7 · 2920 anti-amine pressure-sensitive adhesive by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. % Initial patch properties a Adhesive (g / .cm2) Peel (g / cm) Adhesive (g / cm) Control group 0 115.0 0.7 +/- 0.9 720 +/- 38 CIB-01 1 105.0 0.2 +/- 0.2 681 +/- 16 (ring fifteen 5 403.0 7.0 +/- 0.2 623 +/- 29 alkanone) 10 857.0 0.7 +/- 1.4 698 +/- 12 ethanol b 1 84.0 1.0 +/- 0.4 697 +/- 10 5 72.0 1.4 +/- 0.7 736 +/- 31 10 60.0 18.9 +/- 1.1 477 +/- 50 isopropyl 1 171.0 1.8 +/- 0.4 639 +/- 38 palmitate 5 845.0 18.6+ /-1.4 400 +/- 71 10 758.0 17.2 +/- 2.8 445 +/- 91 ** Azone (R) 1 758.0 1.4 +/- 0.4 71 6 +/- 46 39 This paper size applies to China National Winter Standard ( CMS> Α4 specifications (210 X 297 male thin) 5. Description of the invention (矸 A7 157 5 10 535. 0 706.0 7-〇 +/- 1.4 723 +/- 57 22.9 +/- 4.2 320 +/- 424 ** --------3 Machine coated samples. The quality of adhesive tape b „叩 叩 扪 severely damaged 'adhesion failure Γ *). Zhizhi is quite volatile and washed away in the preparation of politicians, ^ Dianhu. The ethanol concentration remaining on the patch and the surface cannot be measured Table 14 Compatibility of skin penetration enhancers 〇W CORNING (R) 355 medical $ -grade pressure-sensitive Shixi implant compatibility (please read the precautions on the back before filling in the garden ^. Packing. Set the central standard of the Ministry of Economic Affairs Bureau ’s consumer cooperatives printed the initial patch properties of the skin A, average + Z-SD loading accelerator wt% adhesive% _ (g / cm2) _a peeling% _a (g / cm) adhesion% _a (g / cm ) Control group ^ 0 187.0… 1.4 +/- 0.0 — 466.1 +/- 17.9-CIB-〇1b 1 339.0 +18 2.8 +/- 0.0 +100 458.1 +/- 17.9-2 Azone (R) 1 114.7-38 2.8 +/- 0.4 + 100 502.4 +/- 66.1 +8 Ethanol 1 134.3-28 1.4 +/- 1.0+ 0 554.0 +/- 23.6 + 18 Isopropyl myristate 1 295.3 + 58 7.4 +/- 0.7 + 21 486.2 +/- 27.8 + 4 Isopropyl palmitate vinegar., 1 229.3 + 22 6.3 +/- 0-7 + 350 536.8 +/- 32.0 +15 40- This paper size applies to China National Standard (CNS> Ad specifications (2ί〇χ29? 公 哲) line A7 ___ B7 '______ 5. Description of the invention (Hu ) Eucalyptol 1 158.7-15 1.4 +/- 1.1 + 0 465.4 +/- 23.6-2 a The percentage change in the control value of a machine-coated thin layer (1 mi 丨 thickness). B CIB-01 is cyclopentadecanone Table 15 Compatibility of skin penetrating agent with DOWCORNING (R) 355 medical-grade pressure-sensitive Shi Xi _ occupant! Please read the precautions before filling, and fill in the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Initial patch property A two weeks after printing, average +/- SD skin enhancer. Filled with wt% adhesive (g / cm2) _a peeling% _ (g / cm) _a adhesion% _! (G / cm) Control group 0 53.0-71 0.7 +/- 0.0 -50 444.0 +/- 4.9 -5 CIB-01b 1 103.0-70 1.4 +/- 0.3 +50 515.7 +/- 32.6 +13 Azone (R) 1 90.0- 22 1.8 +/- 0.4 + 36 483.0 +/- 19.3-4 Ethanol 1 48.7 * -63 2.1 +/- 0.4 +50 525.6 +/- 3.2-5 Isopropyl myristate 1 185.7-37 3.9 +/- 0.7 -47 428.5 +/- 78.4 -12 isopropyl palmitate 1 167.3-27 8.1 + /-+30 414.1 +/- 60.8 + 23 eucalyptol 1 41.0 * -74 0.4 +/- 0.7-71 416.6 + / -95.S-10 Ordering line φ This paper · size applies Chinese National Standard (CNS) Λ4 size (210X29 * 7cm) Central of Ministry of Economy Standard Bureau employee consumer cooperatives' printing 5. Description of invention (a _ _ Percentage of change in the nature of the thick machine coated thin layer of the patch from the initial. The nature of the tape is severely broken% (*). C1B-01 is the ring fifteen roasted beer |. The following examples illustrate that other types are also suitable compositions. In these examples, the amount is expressed as a percentage by weight. Example 23 The following emulsion formulation can be prepared to contain from about 0.001% to 1% of estradiol: estradiol cetyl alcohol propylene glycol lauryl sodium pentaerythrone water qs 0.001-1151015 2 100 Examples (24 and 25) illustrate a composition comprising an antifungal agent, namely chlorotribenzimidazole. Evaluations have shown that the presence of an accelerator in the antifungal tincture composition can improve the local rotation of the antifungal agent to the epidermis and real skin. Clotrimazole is a broad-spectrum antifungal agent that is used for the treatment of skin infections by various pathogenic benign ringworms, yeast rash anti-rash bacterium (Ma) assez′a furfui). The main role of clotrimazole is to fight against splitting and growing organisms. It is used to treat surface dermatophyte infections, athlete's feet (tinea pedis), jock itch (femoral habit), and ringworm (made from red hair) Bacteria 42- The size of this paper is applicable to China National Standard (CNS) A4 (21〇X〗 97 cm) (谙 Please read the precautions on the back before filling this page}

W 5. Invention Description u. ) Rubrum, t ulcer, \, 1 He chooses rabbit Trichophyton mentagrophytei,% Epidermal fungus M Ep "_dennopIiyton noccosmn owes' 1, germ running bacteria ^ / ^ 7 / as; 7〇 / ^ / 77 (^ /? Ringworm caused by the public). It is also used to treat recurrent vaginal yeast (Candida) infections caused by Candida albicans 2/6 / c ^ 7S) and local candidiasis caused by Candida albicans and by Bacillus pupae Tinea versicolor. 'Example 24 The following cream formulation containing chloro.triphenylphosphonium sativa, an antifungal agent can be prepared. Mineral oils printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs31 Cyclopentadecanone 1 Chlotribenzimidazole 1 Lubricant 10 Glycerol Stearate 10 Paraffin 8 Water The antifungal composition of Example 25 described below In the form of a gel Example 25 Gas tribenzimidazole 1.0% w / w Cycopentadecanoic acid 4.0 Ethanol 30.0 ----.__: _Δ2_ This paper applies the Chinese National Standard (CNS) Λ4 (210 × 297) A description of the invention (called A7 B7 Glycerin (Glycerol) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 15.0 Propylene glycol 30.0 Carbomer 940 1.5 Trirolamine 1.0! '_ OS Total 100.0% w / w The following suppositories containing a preservative of ethoxylated ammonium chloride can be prepared. Example 26 Benzyl chloride ethoxylate 2 Ring fifteen roasted 1 2 Cocoa butter 80 Tween 61 * 16 * polyethylene-4-sorbitan Films containing procaine hydrochloride below monostearic acid can be injured. Example 27 Procaine hydrochloride 0.562 cyclopentadecanone 2 polyvinyl alcohol 30 polyethylene 0tb acetone 30 ^^ one one • Alcohol QS 100, 44 Medium® Home Standard (CNS) A4 Find grid ί 210χ707Λ &gt; φ) (Please read the precautions on the back before filling in the page} Assembling and ordering B7 B7 Five Invention Instructions (ρ Follow the above method, but the x in the compound used is sulfur or has Structures = imines, and γ is oxygen, sulfur, or structures having a structure = album imines, similar knots n can be obtained to promote the penetration of drugs through body membranes. These cyclic = 'rings, rings Dioxamine and cyclic ceramide can be used as effective promoters. From the embodiments of the present invention, a composition can effectively enhance the skin quality, and it contains: ㈧ a skin-treatment compound; (B)- To promote 'a compound of one of the above formula I; (c) _ a carrier; and: (D)-a cosmetic additive.', Skin-treatment compounds &quot; think of the term-the kind is enhancing one or more Skin is an effective substance in nature, which is statistically significant between the untreated skin and the skin treated with the substance. It can be used at the 95% level, using the Department of Economics familiar with this artist The Central Standards Bureau's Consumer Cooperative Prints $ husband's &amp; quasi-assessment law Examples of skin properties or properties that can be improved by -skin_treatment compounds include: ㈧ smoothing of the skin: thickness of the epidermal layer of the skin; (c) increasing the cell density of the skin; ⑼ lowering the moon = muscle ice ; The elasticity of the skin; and the texture of the skin. The above 31 = skin quality assessment method is familiar to those skilled in the art. &quot; 3 For example, the use of clinical evaluation, photo evaluation, Shi Xi rubber casting ^ skin evaluation, histological examination 'biopsy and patch stripping. The classes of substances used as skin-treatment compounds in the practice of the present invention include, for example, nutrients, repair agents, rejuvenants, hormones, regulators, immunomodulators, humectants, and irritants. Examples of the skin-treatment product f used to implement the present invention include nutrients-vitamins, amino acids, and I — ------- 45 paper-like thorns. Preparation A7 ________ 1Ϊ7 V. Description of the invention (43) 'Cools'; modifiers-melanin and antioxidants; rejuvenants-growth factors and human growth hormones; hormones-estrogen, progesterone and other steroids, and growth hormones; regulation A peptide, protein, and antisense (Chuhua body, immunomodulator / 3 1,3-glucan and acacia alcohol; wetting agent-vegetable oil, beeswax and other waxes, lanolin, fatty acid esters , Mineral oil, and other hydrophobic substances; and stimulants-tocopheryl nicotinic acid 'resins and alpha-acid acids. Several skin-treating compounds can be used in the composition. Improvements by skin-treating compounds provided to the skin and their composition—a statistically significant difference at the lowest percentage improvement, as described above, will vary depending on the nature of the skin being evaluated and the size and distribution of the sample. For example, in assessing the thickness of the epidermis, a 10% or greater improvement is considered by the artist to be a statistically significant difference. On the other hand, in assessing the elasticity of the skin, at least about 30% of the improvement can be regarded as a statistically significant difference by those skilled in the art. The skin-treatment compound is used in combination with the above-mentioned promoter in the range of Chemical Formula I. Several accelerators can be used. Additional improvements in skin texture can be achieved through the use of an angegenic agent in combination with skin-treating compounds. Such improvements can be identified and evaluated by using the same type of methods for skin-treatment compounds mentioned above. Preferred accelerators for practicing the present invention include the macrocyclic ketones and lactones of formula I described above. -A particularly preferred booster is cyclopentadecanolactone β. Skin-treated compounds or mixtures of skin-treated compounds can be used in an amount effective to improve skin quality. To achieve the minimum amount required for improvement will depend on the particular skin-treatment compound or skin_treatment compound used ---_ 46 'Recording Standards (CNS) Λ4 Specification (210 × 297 Public Welfare) ~ — (Please (Read the notes on the back first, then fill out this page)

A 7 H7, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of invention (materials) For most applications, it is believed that the skin-treated compound will account for at least about 0.1 wt% of the composition. Typically, the skin treatment compound will comprise from about 0.1 to about 10 wt% of the composition. Preferably, the skin-treatment compound will comprise from about 0.5 to about 3 wt% of the composition. The booster or a mixture of boosters can be used at least in an amount effective to provide additional skin improvement, i.e., 'in excess of the improvement provided by the skin-treating compound, ie, for most applications, according to It is believed that the accelerator will account for about 0.1 to about 30 wt% of the composition, a preferred range of the accelerator is about 0.5 to about 10 wt%, and a particularly preferred range includes about 2 of the composition To about 5 wt%. The skin-improving composition of the present invention will generally also include a carrier, wherein the other ingredients constituting the composition are dissolved or dispersed in the form of solid particles or droplets. Any suitable substance may be used as a carrier. Agents, such as those suitable for use in pharmaceutical or cosmetic compositions. Examples of carriers include water, alcohol, glycerol, sorbitol, propylene glycol, vegetable or animal-derived oils, waxes, acids, alcohols, esters, ethers, ammonium, ethoxylates, and chemicals. Propionic acid, ethyl and propylene glycol g, mineral oils and soils, sedones, oils and oils, and surfactants. The carrier may include one or more compounds. Generally, the carrier will comprise from about 10 to about 95 wt% of the composition. It is optional, but typically the composition will also include one or more compounds that provide other desirable properties of the composition. Such compounds will typically be included in cosmetic compositions as types of substances that can be used as additives. Examples of such substances are perfumes, colorants containing pigments or dyes, preservatives, thickeners, pH control agents, Stabilizers, surfactants and emulsifiers _ .__ 47 This paper size applies the Chinese national standard Yc? Is_); ----(Please read the precautions on the back before filling in the knowledge page) Order_ 丨 A7 A7 Central Standard of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Bureau of the People's Republic of China. 5. Description of the Invention (40-agent. The composition can be in the form of liquid, semi-solid or solid. The composition can be formulated so that it can be dispensed in a self-spray container. For convenience And easy to apply, the use of the composition in the form of a cream or lotion can be recommended. The skin improving composition can be applied to the skin as often as necessary to achieve the desired improvement. The frequency of application depends on the characteristics of the composition And the skin conditions involved. "Usually, using the composition twice a day (for example, morning and evening) will be appropriate for many conditions and will continue to achieve the desired result. For example, weeks or months or irregularly. In some cases, 'the composition can be applied every two or three days. In treating the skin of the hand, it must be considered to apply the composition after each hand wash. Compositions for treating hair are also within the scope of the present invention. Such compositions may include hair-treating compounds, for example, as a substance for hair conditioning function b and compounds that improve the ease of handling the hair. Such compositions may Contains a hair-treating compound and the above-mentioned promoter of Chemical Formula I, and other ingredients in amounts as described above for the skin-improving composition. The promoter of the present invention can be advantageously used in any type of skin-enhancing composition. In particular, the skin-enhancing composition contains one or more skin-treating compounds that cannot quickly or easily penetrate the epidermal disorders of the skin. Such compositions are known to those skilled in the art. One typical type of such composition Is an anti-oxidant composition. Such a composition typically contains a variety of natural nutrients' including, for example, vitamins, and its function is to restore skin , To delay the traces of the skin and maintain the vitality of the skin deer. In a type that involves ________ 48 t scales, the Chinese National Standards (CNs) Λ4 gauge (2-10X297 Gong) ~ '-(Please read the back Note #Fill in this page)

'1T --- Γ ^ -----: ---] .Μ .Μ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ------------ --- 5. Description of the invention (4ς) 1- Γ Within the scope of the present invention-an antioxidant and a document that has documented the appropriateness of the use of all-retin vitamin A (Retin Α) with anti-biotin h-biomass The performance of the composition of the invention is equivalent to the effect of all-anti-vitamin A in increasing the thickness of the epidermis, but without the side effects of using all-anti-vitamin A in the past. The following examples (Examples 28 to 30) are explanations of antioxidant compositions that promote natural repair processes and delay skin aging by providing natural nutrients that are also beneficial to skin cells. The accelerator used in this composition is cyclopentalactone. It is believed that this promoter is effective in helping to deliver nutrients to the skin cells as its nutrients. This results in rejuvenation of the skin, providing a pre-painted and youthful appearance. The main changes between these compositions are related to differences in viscosity and component concentration. This difference means that the composition can be customized for simple or effective application-for example, repeated use during the day-especially each time the body or body part such as the hand is washed or otherwise cleaned After, or at night before bedtime. (Please read the notes on the back before filling this page)

Example 28—Hand and Body Lotion Vitamin A Palmitate 0.38% w / w Ascorbyl Magnesium Filler 0.75 Vitamin E Acetic Acid S 0.38 α-Pisabolol 0.38 Hydroxypantothenic Acid (Panthenyl Alcohol) 0.25 Ethenic Acid Di Sodium 0.10 Sodium citrate 0.60 49 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 public waste) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _ V. Description of the invention (4T) &quot; Triethanolamine 1.70 Ethanolamine Methoxy Cinnamate (DEA) Oxycin Cinnamate 2.00 Aloe Vera Concentrate 1.00 Beeswax, White 0.50 Mineral Oil, Light 4.00 'Cetyl Palmitate 1.00 Soy Sterol 1.00 Cetyl Alcohol 2.00 Stearate 3.00

Carbomer 934 0.10 Poly (vinyl σ-pyrrolidone) / 1-eicosene copolymer 1.00 methyl paraben 0.20 propyl paraben 0.10 selenium urea (imine urea) 0.30 butyl Hydroxytoluene (ΒΗΤ) 0.20 Cyclopentadecanolactone 4.00

Spice QS

I 0S Total 100.00% w / w Example 29—Hand and Body Cream Vitamin A Palmitate 0.5 0% w / w Ascorbyl Magnesium Phosphate 0.75 50 This paper size is applicable to Chinese National Standard (CNS) A4 specification (2 丨 0X297 (Public Note) (Please read the precautions on the back before filling out this page) —Booking Line-0- · V. Description of Invention (发明) A7 B7 Vitamin E Acetate 1.50 α-Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs Pizzaopol. 1.00 'Via pantothenic acid (panthenyl alcohol) 1.00 Disodium edetate 0.10 Sodium citrate 0.60 Triethanolamine 0.50 Diethanolamine methoxycinnamate (DEA oxycinnamate) 2.00 reed · gel concentrate 1.00 Low pour point high-grade lubricating oil 3.00 Lusteryl ester 2.00 Stearyl alcohol 4.00 PEG-40 stearic acid. Ester 4.00 Glyceryl monostearate 3.00 Ethyl p-hydroxybenzoate 0.20 Propyl p-paraben 0.10 Imidazolidine Base urea (imine urea) 0.30 Butylated hydroxybenzene (ΒΗΤ) 0.20 Silicone oil 5.50 Cycpentadecanoic acid 4.00 Fragrance QS OS Total 100.00% w / w Example 30 ~~ Night cream (please read the back first) Note for filling in.

-° Line 51 This paper size applies Chinese National Standards (CNS) Λ4 specifications (210X297gt) Exhaust --- 1 A7 B7 Printed invention description printed by the Industrial and Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (4)-Vitamin A Palmitate 0.375% w / w Ascorbyl Magnesium Phosphate 3.000 Vitamin E Acetate 1.500 α-Pisabolol 1.000 Via Pantothenic Acid (Panthenyl alcohol) 1.000 Disodium edetate 0.100 Sodium citrate 0.600 Triethanolamine 0.500 Diethanolamine methoxycinnamate (DEA) Oxycin Cinnamate 2.000 Aloe Vera Concentrate 1.000 Low Freezing Point Advanced Lubricating Oil 3.000 Rare Earth S 2.000 Mineral Oil, Light 4.000 Stearyl Alcohol 4.000 PEG-40 Stearate 2.500 Glyceryl Monostearate 4.500 methyl paraben 0.200 propyl paraben 0.100 imidazolidinyl urea (imine urea) 0.300 butylated hydroxybenzene (BQT) 0.200 silicone oil 5.000 cyclopentadenolactone 4.000 perfume QS 52 ( (Please read the notes on the back before filling out this page)

i!, 1T ·, 0ΊΨ .. This paper size applies to Chinese National Standards (CNS) Λ4 specifications (210X 297 漦) Λ7 H7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (cut) Total 100.00% w / w 'The ingredients of the compositions of Examples 28 to 30 are formulated into a substantially homogeneous composition, such as at 40-90 with a standard mixing, stirring or shearing device. (: Forms a cream-like emulsion or emulsion with a smooth feel. The resulting composition can be suitably packaged in a plastic tube, glass jar or bottle. The composition is true even in extreme environments, such as at 60χ There are 3 months of stability. Evaluate the effectiveness of the hand and body cream of Example 29 in human (15 Caucasians, 50 or more years) test. Subjects of this test are blind • The composition of Example 29 or a soothing cream was used 2 months before the coding, and then all subjects used the composition of Example 29. The test composition was taken every night before the test subject went to bed Rub it on your hand. The following techniques are used to evaluate the effectiveness of the composition on the back of your hand ... (A) Photograph; (B) Silicone rubber casting CC) Ultrasound B-type scan; (D) Biology of histological examination Specimen; and ii) ballistometry. The overall effect observed in the evaluation of the composition of the examples is summarized below. Based on the photo evaluation (A) described above, the comparison of the subjects showed that the results of using the composition of Example 29 showed a gradual improvement in the appearance of the back surface of the hand. Photographic studies have shown a reduction in the number of lines, a decrease in the depth of the interosseous muscle, and a general improvement in the smoothness of the skin. The use of the composition of Example 29 shows that it improves the properties of the epidermal stratum corneum and the reduction of the water and the depth of the epidermis and the dermis. The improvement in the depth of the interosseous muscle is obvious, indicating the improvement of the dermis. The above ⑻ 之 石 夕 rubber casting was evaluated by two independent scorers and 53 by m-I--i. -------1 ^ 1 --HI I ^ r-nj € t (Read the notes on the back and fill in this page)

-IT --- S-line Comparison of this paper's standard for financial and financial standards (2! QX 297: ^ y Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 V. Invention Description UI). Changes in the topography of the skin are evaluated according to the following criteria: positive reactions; no reactions or changes; and negative reactions or deterioration. These results are then averaged. At 30 days, there was no significant difference in the condition of the skin. At 90 days, 'the silicone rubber casting showed that 60% of the subjects showed a positive response on the skin's shape' and at 180 days, 73% of the subjects had a positive response. Based on the ultrasonic evaluation of (c) above, the overall effect produced by using the composition of Example 29 can be synthesized into three observations: (1) The epidermis of most subjects becomes thicker and Water and sex are better; (2) the degree of bifurcation of the papillary dermis increases; and (3) the density of the reticular dermis increases. The time course of the event showed a gradual increase in thickness and density of up to three or four months. After this period, the increase reaches a steady state or decreases slightly. These findings suggest that the product had an initial hyperplastic effect on the epidermis, followed by reorganization of the dermis. In the examination of the tissues of (D) above, the stained sections were examined and evaluated with the following indicators: (1) thickness of the epidermis; (2) size of the granular layer; (appearance of the stratum corneum of the epidermis; and appearance of the epidermis. The thickness increased by 19% during the course of this study. In some subjects, there was an increase in the thickness of the epidermis. The granular layer increased at least twice the thickness in all subjects. This increase was caused by the number of granular cells It is estimated that the appearance of the cuticle cuticle is significantly different among the reexaminers of the knife. From-dense initial appearance, ^ cuticle angle, layer presentation-a reticular wave pattern associated with younger surfaces. Evaluation of the skin It is difficult to evaluate without the use of special stains. Overall, most of the subjects will show an increase in the cellular composition of the dermis. This ---__ (Please read the precautions on the back before filling this page) Order --- -"-Line-φ --- A'7 B7 Member of the Central Standards Bureau of the Ministry of Economic Affairs X Consumer Cooperatives Co., Ltd. 5. Description of the invention () found to be consistent with the reorganization process of the dermis. The above-mentioned (E) ballistic gauge was evaluated as Benchmark, ten The subjects had a positive response and no significant change in the four subjects.-One subject had a negative response. This test estimates changes in the dermis (non-epidermal changes) and implies that some dermal reorganization has occurred. Based on the data obtained in evaluating the use of the composition of Example 29, the following conclusions can be made for the use of the composition of Example 29 only. (U The product is effective in increasing the thickness of the epidermis; the product is effective Produces a smooth, well-structured cuticle of the epidermis; ⑶ The product increases the proliferation of the epidermis; ⑷ The product increases the elasticity of the skin; ⑽ The product helps restore the structure of the dermis; 'and (6) The product effectively restores aging hands to a lower level Youthful appearance. The following two examples illustrate the use of the promoters of the present invention in sunscreen compositions. Such compositions typically contain several sunscreen agents which absorb various potentially harmful UV rays. A compound that protects the skin. Sunscreen compounds have a combination of properties such as: (A) basic ability to absorb related radiation; (B) continuous absorption of radiation for prolonged periods The ability to resist time and time; and (C) the ability to resist exfoliation due to exposure to moisture and / or sweat. Various sunscreens are known to penetrate the skin fairly quickly, then lose in the lower skin layer (dermis) and finally Enter the system cycle. In the development of the present invention, it has been seen that the sunscreen agent contained in the composition of the present invention can retain a higher concentration in the epidermis for a longer time. I believe that the concentrated anti-exposure agent in the epidermis helps Provides natural resistance to shedding caused by exposure to physical contact and exposure to water (including sewage). This, and to the extent that it retains its effectiveness, may confer specific mothproofing agents and carriers and accelerators used It depends on the density. In practice ___ 55 This paper size applies the Chinese National Standard (CNS) specifications (~ 2 丨 0297297 p A7 117 Member of the Central Standards Bureau of the Ministry of Economic Affairs JC. Consumer Cooperatives India and Li V. Description of the Invention) Example 31 The promoter used in each of the compositions and 32 is cyclopentadecanolactone. Example 31-Sunscreen lotion dibenzone-3 (oxybenzophenone) 3.0% w / w monoethanolamine methoxycinnamate (DEA 曱 oxycinnamate) '3.0 cyclopentadenolactone 4.0 silicone oil 5.0 Glyceryl monostearate 5.0 PEG-40 stearate 1.0 sodium lauryl sulfate 0.5 stearyl alcohol 7.1 cetyl ester 5.0 propyl p-hydroxybenzoate 0.2 butylated hydroxytoluene (BHT) 0.2 two Ethylene glycol monomethyl ether 30.0 OS 100.0% w / w in total Example 3 ?,-sunscreen lotion benzophenone_3 (oxybenzophenone) 3.0% w / w diethanolamine oxy cinnamate (DEA methoxyl) Cinnamate) 3.00 56 This paper size is applicable to China Standard (CNS) Λ4 size (210X 297 cm) (Please read the precautions on the back before filling, this page);

Line 1T—φ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ 7 Β7 II__ 5. Description of the Invention (Wen) Cyclopentanolactone 4.00 Silicone Oil 1.00 Glycerin (Glycerol) 5.00 Propylene Glycol 5.00

Carbomer 941 0.25 Low freezing point premium lubricant 3.00 Stearate 1.50 Cetyl ester 0.50 Cetyl alcohol 0.50 Glyceryl monostearate 3.00 PEG-40 stearate 1:50 Triethanolamine 0.50 Paraben Ester 0.20 propyl paraben 0.10 imidazolidinyl urea (imine urea) 0.30

Spice QS

The total QS of water is 100.00% w / w. It is clear that the present invention provides a tool for effectively improving various types of substances having beneficial effects on the body. 57 This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 cm) (#Read the precautions on the back before filling this page)

V. Description of the invention (:) Application number: A7 B7 printed by Kangrui Pharmaceutical Co., Ltd., a consumer cooperative of employees of the Central Standards Bureau of the Ministry of Economic Affairs. Example • Example yyy. And zzz Water QS QS Dichloroamine phenylacetic acid LOO% w / w 2,5¾ (diclofenac) glycerol 10.00 10.00 pentadecanolactone 8.00 10.00 Carbonter 1.00 1.00 triethanolamine 1.00 1.00 phenyl alcohol 1.00 1.00 dichloroamine phenylacetic acid (can be in the free acid form or equivalently ester-soluble Dichloramine phenylacetic acid sodium salt) can be incorporated in a suitable vehicle with glycerol (0 to 60%), propylene glycol (0 to 60¾), and pentalactone (0.1 to 30¾) in an amount of 0.1 to 5¾. When applied topically, this product is an effective non-steroidal anti-inflammatory drug (NSAID), which has anti-inflammatory, analgesic, and antipyretic activities, and is suitable for topical treatment. When applied topically, its toxicity is substantially reduced and the treatment is localized. Two preferred practical examples (including preferred concentrations) are exemplified in Examples yyy and zzz (as described above). Paper size applies Chinese National Standard (CNS) A_4 specification (21 × 297 mm) (Please read the notes on the back before filling out this page)

Α7 Β7 V. Description of the invention () Example n n η gg_iiL SfiSha Minox 彳 Η solution Long pressure set 2.0 ¾ w / v ethanol. 60.0 ¾ v / v Fifteen hospital esters 4.0% w / v

Propylene glycol QS long-pressing can be incorporated in quantities of 0.1 to 10¾ with ethanol (30 to 90¾), pentalactone (0.1 to 30¾) and proptol (QS). If necessary, water (0 to 30¾) can be included to change the dissolution properties. The solution thus functions as a hair growth stimulus. A preferred embodiment (including the preferred concentration) is exemplified in Example n n η. (As described above).丨 L- 丨 N——Install! (Please read the precautions on the back before filling in this page.) Order Φ 印 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper is again applicable to the Chinese National Standard (CNS) Α4 size (210x297 mm)

Claims (1)

Announcement Form A8 B8 C8 D8 6. Scope of Patent Application It: No. 84108678 Patent Application Amendment to Patent Scope Amendment Date: April 1987 1. A composition that can effectively improve the quality of skin, which contains: (A) a skin treatment compound; (B) a Compounds of structural formula; II V: II 1.11 -_ | _.R Na 2 know General formula (I) where X and γ are oxygen, and A is a group having the following structure, printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Y II -CX where the definitions of ¥ and i are the same as above, m and n Is an integer having a value from 1 to 20, and its total m + n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1., r Is an integer having a value of 0 or 1 and R is hydrogen or an alkyl group having 1 to 6 carbon atoms and which may be straight or branched, but when p, q and r are 0 and γ is oxygen M + n is at least 11; (C) a carrier; and optionally (D) a cosmetic additive. 2. For example, if the composition of the jade item of the patent scope is claimed, it includes the skin treatment compound and the compound ⑺). 3. If the composition of the scope of patent application No. 2 contains 0.5 to 3 wt% ΜΛ Zhang scale applicable to Chinese National Standard (CNS) A4 specification (2ι0χ297 mm) Announcement Form A8 B8 C8 D8 6. Scope of Patent Application It: No. 84108678 Patent Application Amendment to Patent Scope Amendment Date: April 1987 1. A composition that can effectively improve the quality of skin, which contains: (A) a skin treatment compound; (B) a Compounds of structural formula; II V: II 1.11 -_ | _.R Na 2 know General formula (I) where X and γ are oxygen, and A is a group having the following structure, printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Y II -CX where the definitions of ¥ and i are the same as above, m and n Is an integer having a value from 1 to 20, and its total m + n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1., r Is an integer having a value of 0 or 1 and R is hydrogen or an alkyl group having 1 to 6 carbon atoms and which may be straight or branched, but when p, q and r are 0 and γ is oxygen M + n is at least 11; (C) a carrier; and optionally (D) a cosmetic additive. 2. For example, if the composition of the jade item of the patent scope is claimed, it includes the skin treatment compound and the compound ⑺). 3. If the composition of the scope of patent application No. 2 contains 0.5 to 3 wt% ΜΛ Zhang scale applicable to Chinese National Standard (CNS) A4 specification (2ι0χ297 mm) Cyclic pentadecanolactone such as β-cyclic pentadecanolactone in item 2 of the patent application. Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α8 Β8 C8 D8 VI. The skin treatment compound in the scope of patent application and 0.5 to 10 wt% of the compound (B). 4. The composition of item 3 of the Shenyan Patent Fanyuan, which contains 2 to 5 wt% of the compound. 5. 'Item 2 of the scope of patent application ^^^^ \ It is an antioxidant composition', and the skin compound contains an antioxidant substance. 6 · If the application for the scope of the fifth item of the patent ^ where the compound (B) contains, where the compound (B) contains (please read the precautions on the back before filling in this page)