JPH03501386A - Permeation enhancers including ethanol and glycerol monooleate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Permeation enhancers including ethanol and glycerol monooleate Field of the invention The present invention relates to transdermal administration of drugs and other biologically active agents. In particular, the present invention is a novel method for promoting transdermal absorption of drugs when incorporated into transdermal drug delivery systems. METHODS AND COMPOSITIONS.

Furthermore, more particularly, and without limitation thereto, the present invention relates to glycerol monooleate ( G? 'IO) and ethanol for transdermal administration of the drug.

Background of the invention The transdermal route of parenteral administration of drugs offers many advantages over other routes of administration. However, systems for the administration of various drugs or other effective agents are described, for example, in U.S. Pat. No. 598.122; No. 3.598.123; No. 4,379,454; No. 4. No. 286.592; as described in No. 4,314,557 and No. 4,568,343. Referenced: All of these patents are incorporated herein by reference. . In many instances, drugs that appear to be ideal candidates for transdermal administration are With such low permeability as I know I can't give it to you.

pretreating the skin with various chemical agents in an effort to increase skin permeability; It has been proposed to administer the drugs simultaneously, or in the presence of permeation enhancers. this For this purpose, U.S. Pat. No. 3.896,238, No. 3,903,256, No. 3.952.099, No. No. 4,046,886, No. 4.130.643, No. 4.130,667, No. No. 4,299,826, No. 4,335.115, No. 4,343,798, No. No. 4,379,454, No. 4,405,616, and No. 4,746,515 (all of which are incorporated herein by reference) British Patent No. 1 , 001, No. 949 and Idson's "Vercutinious Absorber" Percutancous Absorption Pharm/Sci (J, Pharm/Sci, ) Volume 64, No. b6, June 1975 May, pp. 901-924 (preferably pp. 919-921). , various substances have been suggested.

To be considered useful, a permeation enhancer must have at least one and a preferred In particular, it must have the ability to increase skin permeability to a significant number of drugs. stomach. More importantly, the permeation enhancer is suitable for use in reasonably sized systems (preferably 5-50 increase skin permeability so that the rate of drug administration from the cell is at therapeutic levels. must be able to Furthermore, the accelerator, when applied to the skin surface, Must be non-toxic and non-irritating on long-term exposure and under occlusion, and should be non-irritating for repeated exposure. It must be non-sensitizing. The accelerator is preferably odorless and has no burning or burning sensation. It must be possible to administer drugs that do not cause stinging.

The present invention greatly increases drug permeability through the skin, and also improves drug application to the skin. Reduce the time lag between achieving the desired therapeutic effect.

Although combinations of permeation enhancers are known in the art, the present invention using novel combinations of GMOs and GMOs; the effects of those combinations are A significant and surprising improvement over the use of either O or ethanol alone It is.

Summary of the invention Drugs, ethanol and G? Simultaneous use of IO on the body surface of animals and humans It is an object of the present invention to increase the permeability of, in particular the permeability of the skin.

Drawing brief description FIG. 1 is a cross-sectional view of one of the transdermal drug delivery systems according to the present invention; Use membrane.

FIG. 2 is a cross-sectional view of another embodiment of the transdermal drug delivery system of the present invention.

FIG. 3 is a cross-sectional view of yet another embodiment of a transdermal drug delivery system according to the present invention; Use a temperature control membrane.

FIG. 4 is a cross-sectional view of another embodiment of the transdermal drug delivery system of the present invention; and FIG. 5 is a cross-sectional view of another embodiment of a transdermal drug delivery system according to the present invention, with adhesive - use barley.

Figure 6 is a bar chart showing transdermal flow through cadaver skin at 35 #C; Rocortidine versus the permeation enhancer used; Figure 7 is a three-component phase diagram, ethanol/glyc Cerol monooleate/water mixture, room temperature (22#C) and 35#C! Here, showing the range of solubility and insolubility of; and FIGS. 8 and 9 are plots showing increased skin permeability resulting from embodiments of the present invention. It is a cut.

Description of the invention The present invention co-administers GMOs and ethanol to aid in transdermal drug administration. G Both MO and ethanol are known permeation enhancers, but the combination of both according to the present invention The effect of ethanol on drug permeability when comparing the use of either ethanol or GMO alone It has been shown to dramatically increase (on the order of 10-20 times or more) the The improved permeation increase according to the present invention can be achieved over a relatively wide range of ethanol/GMOs. can be obtained over a range of weight ratios. In the present invention, the ethanol/G150 weight ratio is In the range of about 5795 to 97/3, and preferably from 80/20 to 40/60 Think within the range of.

The present invention finds particular utility in increasing permeability through the skin. deer However, the present invention is also useful in increasing flow through mucous membranes. Furthermore , the present invention is useful in the administration of active drugs both systemically and locally. we According to the invention of Related drugs, ethanol and GMOs, preferably pharmaceutically acceptable placed in a carrier and maintained there for the desired amount of time. drugs, Tanol and G? IO can be used, for example, in ointments, gels, etc., as described more fully below. It can be applied directly to the body as a tablet, cream, suppository or sublingual or buccal tablet. obtained, typically dispersed within a physiologically compatible matrix or carrier. When dispersing ethanol and GMOs in a liquid vehicle for topical application to the skin , ethanol, GMO and vehicle concentrations for these components, a single liquid phase When selected to be present, a greater increase in drug flux is observed. Skin used in the form of liquids, ointments, lotions, creams or gels applied directly to When dosing, close the side of the dosing to prevent evaporation of other volatile components such as ethanol and water. It is preferable to close it. Such compositions include sucrose monococoate suc rose monococoate, stabilizers like salicylic acid, dyes/diluents agents, pigments, stabilizers, vehicles, inert sources, gelling agents, and topical agents known in the art. Other components of the composition include other permeation enhancers.

In other embodiments, the drug and permeation enhancer are administered orally, as described more fully below. Administered through a skin administration device.

In one embodiment, at least one of the devices includes a device for administering excess drug to the skin; two ethanols or GMOs simultaneously at a controlled, preferably fairly constant rate. administered. The rate of drug administration is a facilitator whose rate is intentionally controlled. determined by the rate of administration.

In this embodiment, the dosage form comprises a body: (a) having a basic surface; (i) time for an area at least equal to the area of the skin to be treated (ii); (iii) whereby the drug and accelerator is present in the skin area for absorption (b) be associated with the underlying surface to provide drug to the underlying surface over that period of time; (C) providing the promoter at the basal surface for said period of time; including a supply of GMO and ethanol in communication with the base surface to supply; and ( b) Optionally the base surface is provided with at least one of GMO or ethanol. including means for maintaining such speed.

In one embodiment, for a substantial portion of the period, the underlying surface is provided with The amount of drug applied is in excess of the amount that can be absorbed by the treated skin surface. and the rate at which one of the GMOs or ethanol is provided is substantially The drug is delivered so as to be substantially constant over the entire area. Its speed is (i) the surface of the skin is below the maximum rate of absorption; and (ii) the drug is Commonly used with other permeation enhancers to substantially increase the permeability of that skin surface to be minute.

The method of the invention is (a) applying the drug to the skin surface for a period of time; and b) Includes common use of GMOs and ethanol on its skin surface.

As used herein, a "substantial portion of a period of time is defined as at least about 60% of a period of time, preferably at least about 60% of a period of time" means approximately 90% of the period. “Substantially constant” in terms of correlation means that It means a change within ±20%, preferably within ±10%.

The present invention relates to the broad concept of drugs commonly administered through human body surfaces and membranes, including the skin. It is believed to have uses related to the administration of substances.

As used herein, the expressions "drug" and "drug" are used interchangeably. as a therapeutically active substance that produces normal, effective, and desirable effects when administered to living organisms. intended to be interpreted very broadly. Generally, this expression includes antibiotics and Anti-infective drugs such as anti-viral drugs, analgesics and combination analgesics, appetite suppressants, anti-arthritic drugs. medicines, anti-asthma drugs, analgesics, anti-depressants, anti-diabetic drugs, anti-diarrheal drugs, anti-histamine drugs, Inflammatory drugs, anti-migraine drugs, motion sickness drugs, antiemetics, anti-tumor drugs, anti-Parkinson's drugs, Anti-itch drugs, antipsychotics, antipyretics, analgesics including gastrointestinal and urinary tract, anticholinergic Contains sex drugs, sympathomimetics, xanthine derivatives, and calcium channel blockers. cardiovascular preparations, beta-blockers, antiarrhythmics, antihypertensives, diuretics, systemic vascular, coronary Vasodilators including blood vessels, peripheral blood vessels and cerebral blood vessels, medial nervous system stimulants, antitussives and cold medicines, decongestants, diagnostic drugs, hormones, sleeping pills, immunosuppressants, muscle relaxants, Parasympathomimetic agents, parasympathomimetics, neurostimulants, sedatives, and tranquilla in all major therapeutic areas including (but not limited to) Contains therapeutic agents.

The present inventors are responsible for the use of hydrocortisone, tetracaine, lidocaine, and PIROXICAN. , indomethacin, nisoldipine, nifedipine, nicradibine and nitre Ethanol and as permeation enhancers for several dissimilar drugs such as ndipine. The usefulness of the mixture with Koo 0 was demonstrated. The inventor also found that it is applicable to more drugs. I believe in combinations. Representative non-limiting drugs include, for example, scopolamine, Rubido, nitroglycerin, estradiol, clonidine, cortisone, theo Filine, phenylephrine, terbutaline, ephedrine, narcotine, quini gin, estradiol diacetate, progesterone, pirocarbin, furosemide, Tetracycline, insulin, chlorpheniramine, sulfathiazide, Lopranolol, Testosterone, Norgestrel, Lidocaine, Morphinone , morphine, dihydrocodine, dihydromorphine, oxycodone, hydrocodone Codine, Norcodine, Hydromorphine, Normorphine, Norlevorfa Nor, dihydrocodine, ouabain, bromocriptine, haloperidol, Guanabenz, salbutamol, oxybrenolol, dibucaine, arteno- Pindolol, Verapamil, Prazosin, Doxazosin, Diltiazem, Its role as a permeation enhancer for certain drugs is rutenol, and timolol. The effect of a mixture of 0 and ethanol on cadaver skin or other membranes is In vitro permeation measurements performed with diffusion cell tests as well as e.g. blood concentrations or This will be readily assessed by those skilled in the art by in vivo measurements of urinary concentrations.

One aspect of the invention is shown in FIG. 1, which shows a transdermal drug delivery device 10. be better understood. The device 10 is a multilayer laminate consisting of five layers: The overback layer includes a permeation enhancer reservoir 14, a permeation rate control membrane 16, a drug reservoir 18, Adhesive 120 and peelable release liner 22, the reservoir 14 of which extends throughout A gel or polymer matrix with a permeation enhancer or drug dispersed in it. The device 10 may be comprised of a therapeutically acceptable contact adhesive 20 or other carrier. held in place by means. Additional drugs, G? 'IO and/or ethanol can be contained in the adhesive layer 20. The composition and thickness of the adhesive layer preferably ,G? Selected not to constitute a significant barrier to IO or ethanol can. During manufacture and use of system 10, adhesive layer 20 along with other layers is in equilibrium. and the amount of GMO, elastomer, depending on the composition and thickness of layer 20 and the length of its period. It will contain tanol and drugs. Contact adhesive set suitable for use as layer 20 The compositions are disclosed in U.S. Patents 3,797,494 and 4,031,894. . A peelable release liner 22, suitable for removal prior to application, is typically included in the package. will be included in the product.

Layer 14 is a continuous GMO/ECO material that also includes one or more co-vehicles such as water. It may contain a tanol phase. Preferably, the continuous phase contains 5 to 75% water by weight. It is in the form of a gel that can contain. Carboxypolymethylene, ethylene anhydride Leic acid, hydroxyethyl cellulose, polyacrylamide, ethyl hydroxide ethyl cellulose, hydroxypropyl cellulose, and poly(methyl vinyl) Known gelling agents such as maleic anhydride) are included in the continuous phase. The layer 14, which can turn the continuous phase into a gel, contains a diluent, a stabilizer, a vehicle, and a gel. It may also contain a curing agent or the like.

The rate control membrane 16 controls the rate of drug inside and outside the delivery device. It can be constructed from any permeable, semi-permeable or porous material known in the art. Appropriate The materials include polyvinyl acetate and ethylene vinyl acetate polymers.

The size of the device of this invention can vary from 1 to 220 d. However, typical The device will have a size in the range of 5-50 cd of drug.

Various materials suitable for the construction of various layers are disclosed in the aforementioned patents. drug storage The matrix of 18 is an aqueous gel or an anhydrous matrix. non-limiting anhydrous Examples of matrices are natural and synthetic rubber or other polymeric materials, concentrated minerals, Contains petroleum oil or petroleum jelly. A preferred embodiment according to the present invention is disclosed in U.S. Pat. Ethylene/vinyl acetate (EVA) copolymers (preferably Preferably, the drug is composed of 28 to 60% by weight of vinyl acetate content. Especially good Good results were obtained using a copolymer with a vinyl acetate content of 40% by weight (EνA40). Obtained using.

Drug reservoir 18 contains drugs with equilibrium concentrations of GMOs and ethanol. storage The amount of drug in the system depends on the rate and expected absorption of the drug from the system by the skin. will depend on the duration of treatment.

The reservoir 18 contains dyes, diluents, pigments, stabilizers, vehicles, inert fillers, excipients, etc. including excipients, gelling agents and conventional components of conventional therapeutic products or transdermal therapeutic systems. be able to.

The following classes of drugs are highly soluble in permeation enhancers. In these cases, transparent The superenhancer reservoir layer 14 is a permeation enhancer reservoir for the drug contained within the matrix 18. first saturated with drug to ensure diffusion towards the skin rather than into the It's probably there. The drug ultimately administered is usually in excess of the saturation drug reservoir 18. will be included within.

Embodiments such as device lO where the drug and permeation enhancer supplies are separate drugs and permeation enhancers are impractical or undesirable, or Is separation of drug and permeation enhancer advantageous if it facilitates the selection of rate-controlling membranes? or necessary.

The initial amounts of ethanol and GMO in device 10 are determined to provide the desired drug over the treatment period. The rate at which the permeation enhancer is delivered from the system to the skin depends on the rate at which the permeation enhancer is delivered from the system to the skin. Ru.

The back member 12 promotes permeation of the drug through the surface of the gel layer away from the skin. Its role is to prevent the passage of agents and provide support for the system if necessary. The back member may be flexible or non-flexible. Non-limiting of that back member Specific examples are cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymer, polyethylene terephthalate, Nylon, high and low density polyethylene, polypropylene, metallized polyester film Coated flexible fibrous backings such as films, polyvinylidene chloride, paper and cloth Such backing materials, including rings and aluminum foils, are free from heat, contact agents or other in the form of a precast film or cloth foil that is bonded to the reservoir by means; Alternatively, the back member can be coated onto the reservoir itself. In a preferred embodiment, the diversion Heat so that the chair is sealed around the perimeter to prevent evaporation of the ethanol. It is to utilize a sealable back member. The heat seal is shown in Figure 124. It is indicated by.

In operation, the skin is virtually free of wrinkles, folds or creases, and the area of the skin is Applicable. Various locations on the torso, such as the flank or shoulder, offer suitable sites for transdermal applications. provide When the device is placed on the skin, it is used to protect the user from drugs, ethanol and Co-administration of glycerol monooleate and glycerol monooleate will be initiated.

A second aspect of the invention is illustrated in FIG. The transdermal drug delivery device 2 6 is a permeation enhancer reservoir 28, a back member 30, a drug reservoir 32, an adhesive layer 34 and and a peelable release liner 36.

No rate controlling membrane is used in this embodiment of the invention.

Like device 10, device 26 preferably has a heat sealed around the periphery.

Another embodiment of the invention is shown in FIG. Devices 40 are common rather than separate repositories The drug and permeation enhancer are contained in a reservoir 42 of the drug. The device 40 is non-transparent a specific amount of drug and/or permeation enhancer as the sexual backing 44 and the primary application agent. A device 40 having a therapeutically acceptable contact adhesive 40 that may include a therapeutically acceptable contact adhesive 40. It also has a peelable release device liner 48. Device 40 is even faster. It has a temperature adjustment membrane 50. The entire device is connected to its surroundings as shown by line 52. is heat sealed.

The drug may be in completely solution form or in dissolved or undissolved form uniformly dispersed in a reservoir. The initial amount of drug in the 0 layer 42 present in the reservoir 42 at is equal to that in the continuous phase. It will depend on the solubility and intended lifetime of system 40. Layer 42 is drug and permeable. In addition to the promoter, a diluent, stabilizer, vehicle, gelling agent, etc. may be included.

This layer contains one or more liquids, such as water, to alter the solubility of the drug in said phase. Similarly, the amount of permeation enhancer in the reservoir, which may include a co-vehicle, The enhancer is used in the system to achieve the desired degree of drug permeation enhancement over the treatment period. depends on the rate at which it is administered to the skin.

The rate control member 50 contains a dense or is made from a porous polymeric film. This membrane contains a small amount of permeation enhancer or drug. Drug and permeation through the layer 50 to control the rate at which the drug is delivered to the skin. The specific flux of the enhancer depends on the layer thickness and the drug and permeation enhancement through that layer. Depends on the permeability of the agent. Preferably, the rate control member 50 is connected to other components of layer 42. Examples of polymeric films that can be used to create layer 50 that is substantially impermeable to is described in U.S. Patents 3,797,494 and 4.031.894 (incorporated herein). It is listed.

FIG. 4 shows yet another embodiment of the invention, in which system 54 the drug, GMO and and ethanol are contained in a common reservoir 56.

Like system 40, system 54 includes an impermeable backing 58, a contact adhesive 60 and a peelable The release liner 62 consists of a flexible release liner 62. The system 54 has its surroundings as shown by the line 64. Instead, it is preferably heat sealed. In this embodiment a rate control agent is used. Not yet.

FIG. 5 shows a system having an adhesive overlay 68 to hold the system 66 on the skin 70. 66 is shown. Means 68 for adhering the system to the skin are also included together with the remaining elements. can be configured separately. Multilayer laminate 66 includes GMO/ethanol gel layer 72, speed control It consists of a membrane 74 and a drug reservoir 76.

In some cases, the adhesive overlay is a system that adversely affects the adhesion of the in-line adhesive. For this reason, it is preferred over in-line contact adhesives when components of Preferably, impermeable backing layer 78 is slightly thicker than ethanol reservoir 72. (Seeping from the reservoir 720 base and acting adversely on the adhesive in the overlay 68) Reservoir 72 does not contain any substances that cause it. The system 66 also includes a peelable release liner. , which is removed before use.

Real-JLJL-=1 Several test samples contained donor vehicles containing excess hydrocortisone above saturation. To measure hydrocortisone flux (42 g/cJ-hr) from Made. The donors are water alone, ethanol alone, G110 alone, and ethanol. It is a mixture of GMO, GMO, and water, and its role is shown below.

-TχHOGMOETOR Transdermal flux was obtained using human integument at 35°C in a standard diffusion cell. Ta. Samples using cadaver skin, all using separate water, ethanol and GMO - exhibits an in vitro drug flux of less than 51 g/c1il-hr throughout The sample using the inventive GMO and ethanol mixture was 304! g A hydrocortisone flux of greater than /cill-hr was achieved. The data is This is shown graphically in FIG.

As is clear from the above, the GMO/ethanol permeation enhancer according to the present invention contains GMO It exhibits substantially greater flux than when using ethanol alone and ethanol alone.

A suitable composition for hydrocortisone distribution is one in which excess hydrocortisone is dispersed therein. Approximately 42-76-t% GMO and 17-38-t% ethanol in water containing Such a composition consisting of 5 to 331 g/all- Hydrocortisone furasox can be provided within hr.

Figure 7 shows the composition, E, F and G plotted at room temperature (22°C) and at 35°C. Water/G at °C? 1 is a phase diagram of lO/ethanol.

As is clear from the above, compositions E and F all have compositions that are single-phase solutions. and they all have a two-phase composition. gives a higher flux than composition G present as . In the present invention, further To obtain maximum flux, its composition is such that it exists as a single phase. Select it to be in the gram section.

Implementation - one dish, one dish ■ A transdermal device constructed as shown in Figure 1 for the distribution of hydrocortisone is It will have the following composition: MEDPAR backing layer 12, 95% ethanol From 98wt% ethanol gel and 2i% hydroxypropyl cellulose Permeation enhancer reservoir 14; EVA 9%-VA copolymer rate modifier component 16 ; Hydrocortisone 30wt%, glycerol monooleate 30ilt% and and EVA 40%-VA copolymer 40-t% Polymer drug depot 1 8 and a peelable release liner 22° During storage, all components are in equilibrium; There is therefore an equilibrium concentration of ethanol in the drug reservoir 18 and a permeation enhancer reservoir. There will be an equilibrium concentration of GMOs in the stockpile.

Jitsuji”L”L-1 and Various ethanol/glycerol monooleate donor compositions are available in aqueous sinks (s The effect on drug flux across human epidermis at 35 °C during It was measured. The test data has 2.5d of donor solution and 21m of receptor solution. It was obtained using a 2.2 d horizontal flux cell.

Solution composition (呵χ) Average drug flux The flux is also 20/80.40 /60 and 60/40 ethanol/GMO ratios. The amount of ethanol As increasing hydrocortisone flux from ethanol/GMO compositions was found to increase. In addition, the effect of water inclusion in the donor composition has also been investigated. It was done. Lower hydrocortisone flux occurs when the donor composition is separated into two phases. I got the cous. - The inclusion of water has an effect on drug flux from the phase-phase donor composition. It did not affect the degree of righteousness.

Real-TV Various ethanol/glycerol monooleate donor compositions are compatible with tetracaine. tested together and that for drug flux across human epidermis at 35°C. We measured the influence of Is the test data 2.5% of donors? liquid and 10 mρ Sebtar? 1,13c with solution (acetate buffer, pH 4,5, 0.05M) Obtained using a +II wet-wet horizontal flux cell.

The use of the ethanol/GMO permeation enhancer composition of the present invention is as follows.

Provides rapid therapeutic effect. Anesthetics may be painful, such as injections, vein punctures, or minor surgeries. This is very beneficial when administered transdermally prior to a surgical procedure. for such purposes A topical anesthetic that can be used for is tetracaine, and the application of tetracaine is At least 1 hour was required to achieve sufficient anesthesia. However, tetra G of the invention to Kainkel? Contamination with IO/ethanol permeation enhancers dramatically affects the skin After installation the anesthesia onset time was reduced to approximately 30 minutes.

A double blind test was conducted on 10 subjects. The active gel composition contains 10 It was placed on the human subject's clothed miso, and the placebo was placed on the left at the same time. So gel (0,65m) is 5dPVC covered with two polyester cloth discs It was placed in a cup and had the following composition:

Symptom: Double Meng Li Puj Gojinjihong Tetracaine 20% 0% Glycerol monooleate 21.90% 27.90% ethanol (95χ) 32.85% 41.85% Pure water 18.25% 23.25% Phenethyl alcohol 7% 7% The gel was left in place for 30 minutes. Anesthesia is performed after removal of the composition and blood is removed at each site. Assessed by standard venous puncture using a 22-gauge needle without draining fluid. Ta. The subject then states that they feel no pain, but only a slight pain (chiku). They were asked which pain they thought was confusing: a stinging pain) or a normal pain (venous puncture). . On the active side, 5 subjects felt no pain and 3 subjects perceived slight pain. The remaining two felt normal pain.

On the Blasibo side, 2 people did not feel pain and 3 people felt slight pain and remained. The five people thought it was normal pain. Six hours after removal, eight subjects were on the active side. felt the anesthesia and all felt no anesthesia on the placebo side.

Real-JLJΔ-U A transdermal device configured as shown in Figure 2 for the distribution of tetracaine is shown below. will have a composition of: MEDPAR backing phase 30; primarily 95% ethanol 98 wt% ethanol gel and 2 wt% hydroxypropyl cellulose Permeation enhancer reservoir 28 consisting of 30 wt% tetracaine, 30 wt% GMO and and EVA 40%-VA copolymer 40wt% polymeric drug reservoir 32. Therapeutically acceptable in-line contact adhesive 34 and peelable release During storage in the liner 36° all components reach equilibrium and therefore There is an equilibrium concentration of ethanol and an equilibrium concentration of GMO in the permeation enhancer reservoir 28. There will be degrees.

Suni vn- Lidocaine is a topical anesthetic that can be used in connection with minor surgical operations. Li Topical excipients, including docaine (EMLA), have shown no significant effects when applied to the skin. Ethanol was reported to take approximately 1 hour to achieve local anesthesia. 41.6 wt%, GMO (Myver commercially available from Eastman Kodak) A vehicle composition according to the invention containing 30 wt% of water and 28.4% of water was prepared. and 34 wt% lidocaine base was added thereto. The mixture so formed 0.5 g of the compound was absorbed into a 0.75 inch diameter foam pad and placed on the subject's cheek surface. applied and held for 15 minutes and 30 minutes with a 1.625 inch diameter adhesive overlay. It was. The area was checked for pain by pricking the area with a needle. by needle prick No pain was detected, and the pain was mainly caused by 2IIIB around its common site. I felt it through the stabbing. No difference in the degree of anesthesia was observed between 15 and 30 minutes. won.

Implementation - Implementation 1■-1■ various ethanols according to the invention through the cadaver skin into an aqueous sink at 35°C. Flacks obtained from GMO compositions and other vehicles compared to The results are shown in Figures 8-9. A, B, , C and D The so-called composition has the following composition, with sufficient docaine added and sampled during the experiment: The pull was saturated with lidocaine.

A. 40-Tsu) reulose monococoate (SMC) in ethanol/water B. Ethanol 60-t%, GMO 40wt% B', ethanol 60-1%, My verol 40wt%C, GMo 27.4wt%, ethanol 41.25h t%, water 22.5wt%, phenethyl alcohol 8.75wt% D. Mineral oil E, C5, 4d 10A 2.5m F, 40wt% A + 60wt% B'G, 50wt% A + 50wt% B' H, 60 syt% A + 40 t% B'1, 70 ivt% A + 30 wt% The results of the B′1 set of experiments are the best, as is clear from the 0 drawings shown in High adhesive docaine fluxes are obtained from compositions C and B. A sufficient improvement in transmission is , composition, was also observed in mixtures of B' and ^. A is another known permeation enhancer SMC, which may be combined with other ethanol/GMC permeation enhancers of the present invention. It is indicated that the use of permeation enhancers is also included in the invention.

Emperor - Shi Yi Koichi ■ The transdermal device shown in FIG. 5 for distribution of therapeutic agents includes a MEOP backing layer. 44; 95% ethanol and GMO with excess drug evenly dispersed Permeation enhancer/drug reservoir consisting primarily of a single phase solution 42; EVA 9 speed Control membrane 50: pharmaceutically acceptable in-line contact adhesive 46 and peelable A release liner 48 is included.

The present invention has been described in accordance with the preferred embodiments. It is understood that changes in

The next day of disclosure A mixture of ethanol and glycerol monooleate can be administered through the skin or mucous membranes. Disclosed for promoting drug permeation.

FIG.6 FIG.8 Tokoroma Procedural amendment phantom January 1991? number one

Claims (19)

[Claims] 1. Enhanced permeation of the drug to be administered and a single phase aqueous mixture of GMO and ethanol applied to a surface or membrane of the human body to administer a drug by permeation through the human body containing an amount of composition of matter for 2. further comprising a carrier comprising said single phase aqueous mixture of GMO and ethanol and said drug. The composition of claim 1 comprising: 3. The composition of claim 1, wherein said human body membrane is skin. 4. The drugs include hydrocortisone, tetracaine, lidocaine, piroxicam ( plroxlcam), indomethacin, nisoldipin e), nifedipine, nicardipine pine) and nitrendipine 4. The composition of claim 3 which is selected. 5. selected substances from the group consisting of sucrose monococoate and salicylic acid. The composition of claim 1 further comprising. 6. a) Single phase aqueous mixture of drug and glycerol monooleate with ethanol b) drugs, glycerol monooleate and ethanol; If the substance is applied to the skin during Drugs, glycerol monomers, etc. on the patient's skin, including means of holding metastases against Dosage Forms for Transdermal Administration of Reate and Ethanol. 7. At least one of the drug, ethanol or glycerol monooleate is so that the rate of metastasis to the skin remains substantially constant over a substantial portion of the period. 7. The dosage form of claim 6, further comprising means for: 8. At least one of the ethanol or glycerol monooleate is is metastasized to the skin at a rate below the maximum rate at which the skin can absorb it; and the rate of administration of other ingredients to substantially increase the permeability of the skin surface to the drug. 8. The dosage form of claim 7, wherein said means maintain a velocity such that the combination is sufficient. 9. 9. The dosage form of claim 8, wherein said means maintains the rate at which ethanol is delivered to the skin. . 10. the drug is transferred to the skin at a rate below the maximum rate at which the skin can absorb it; 9. The dosage form of claim 8, wherein said means maintains a speed at which 11. of drugs and single-phase aqueous substances of ethanol and glycerol monooleate 11. The dosage form of claim 6, 7, 8, 9 or 10, wherein the supplies are mixed in a common reservoir. 12. of drugs and single-phase aqueous substances of ethanol and glycerol monooleate 11. The dosage form of claim 6, 7, 8, 9 or 10, wherein the supplies are contained in separate reservoirs. 13. The drugs include hydrocortisone, tetracaine, lidocaine, and piroxicam. (plroxlcam), indomethacin, nisoldipine (nisoldipi) ne), nifedipine, nicardipine ipine) and nitrendipine 11. The dosage form of claim 6, 7, 8, 9 or 10 selected from: 14. Selected substances from the group consisting of sucrose monococoate and salicylic acid 11. The dosage form of claim 6, 7, 8, 9 or 10 further comprising: 15. a) The presence of a drug in the drug that metastasizes in relation to the planned surface of the skin for a scheduled period of time. Place the source; b) Ethanol and glycerol simultaneously transferred in relation to said surface of the skin. Single phase aqueous ethanol and glycerol monooleate in monooleate Place the source of the mixture, and c) a rate that is sufficient to substantially increase the permeability of the surface of the skin to the drug; Administer ethanol and glycerol monooleate from a single-phase aqueous mixture with a method of administering a drug to a predetermined area of a patient's skin at an increased rate for a predetermined period of time, including Law. 16. The drug is free from ethanol and glycerol monooleate on the skin surface. 16. The method of claim 15, wherein the method is administered at a rate in excess of the rate that can be absorbed in the body. 17. At least one of the ethanol and glycerol monooleate permeation enhancers one species is administered at a rate that is substantially constant over a substantial portion of the period, and This rate is below the maximum rate at which the skin can absorb the drug, and the skin 17. The method of claim 15 or 16, wherein the method is sufficient to substantially increase the permeability of the surface. 18. 18. The method of claim 17, wherein ethanol is administered at a substantially constant rate. 19. The drugs include hydrocortisone, tetracaine, lidocaine, and piroxicam. (plroxlcam), indomethacin, nisoldipine (nisoldipi) ne), nifedipine, nicardipine ipine) and nitrendipine 17. The method of claim 15 or 16, selected from: