KR0167583B1 - Compositions and complex for skin permeation - Google Patents

Abstract

Skin penetration promoter compositions have been provided that increase the permeability of the skin to a percutaneously administered pharmaceutical active. These compositions include selected pharmaceutically active agents and sorbitan esters, and may also include C ₁ -C ₄ aliphatic alcohols. Medicine delivery systems and methods are provided that have a stacked matrix or drug reservoir.

In the medicine reservoir type (indicated by 10) of FIG. 1, a backing layer 12, a medicine reservoir 14 and a two-piece peeling liner 16a and 16b were provided. In the stacking type, indicated by 18 in FIG. 2, a backing film 20, a reservoir 22, an annular layer 24 of adhesive, a membrane layer 26 and a sealable inner liner were provided.

Description

[Name of invention]

Compositions and Laminated Composites for Transdermal Dosing

[Brief Description of Drawings]

1 shows a schematic cross-sectional view of a matrix type transdermal system of the laminate of the present invention.

2 shows a percutaneous system of the liquid reservoir type of the stack of the present invention.

Detailed description of the invention

[Technical Field]

The present invention relates to percutaneous administration of a pharmaceutical active.

More specifically, it relates to compositions that promote the permeability of the skin to such active agents.

[Background of invention]

The delivery of medication through the skin offers many advantages. Primarily, such delivery means is the administration of a comfortable, convenient, noninvasive medication. Variations in the rate of absorption and metabolism experienced by oral therapy can be avoided, and other inherent inconveniences (eg, inflammation of the stomach and the like) are also eliminated. Percutaneous medication delivery also enables a high degree of control over blood levels of certain medications.

The skin is structurally complex and a relatively thick membrane. Molecules that move through intact skin from the outer world must first pass through some material on the surface of the epidermal and stratum corneum. The molecules must then pass through the blood stream or lymphatics through the viable epidermis, the papillary dermis, and the capillary walls. To be absorbed in this way, molecules must overcome other resistances to penetration in angular tissue. Delivery through the skin membrane is such a complex phenomenon. However, the main obstacle to the absorption of topical compositions or percutaneous penetration medications is the stratum corneum of the epidermis. The stratum corneum of the epidermis is a thin layer of dense, highly keratinized cells approximately 10-15 μm thick throughout most of the body.

Agents that promote penetration (or penetration enhancers herein) to promote skin permeability and, in particular, to increase the permeability of the stratum corneum of the epidermis (ie to achieve enhanced penetration of the drug to be administered percutaneously). May be pre-processed). In a preferred alternative, the medicament and the penetration enhancer are administered simultaneously.

The present invention relates to a novel composition for promoting penetration of the pharmaceutically active agent through the skin. However, this composition is based on sorbitan esters and will be described below. This composition may or may not contain an aliphatic alcohol as an additional component. The inventors have found that the sorbitan ester composition is particularly effective in enhancing the penetration of pharmaceutical actives through the skin.

Although there are numerous patents and publications relating to the percutaneous administration of medicaments and skin penetration enhancer compositions, the applicants suggest that sorbitan esters are useful as penetration enhancers without additional penetration promoters, or the inventors No technique is known for describing sorbitan ester / aliphatic alcohol composites as claimed.

The systems and methods of the present invention are useful for administering a variety of medications and pharmaceutical classes.

For example, the present invention also focuses on facilitated transdermal administration of steroids.

In another specific example, the system and invention of the present invention relate to the percutaneous administration of nitroglycerin with improved percutaneous fluxes. Nitroglycerin is a medicine that has been administered as a vasodilator that acts quickly in the relief and treatment of angina.

Nitroglycerin has also been used in rather high single doses in the treatment of congestive heart disease. The main pharmacological action of nitroglycerin is in the relaxation of the smooth muscles of blood vessels to produce vasorelaxant effects on peripheral arteries and veins.

Nitroglycerin was originally administered orally and later buccally. More recently, a transdermal system has been developed that has been found to enhance the systemic bioavailability of the systemic system of medicine. Examples of currently available percutaneous nitroglycerin systems are Nitro-Dur Percutaneous Acupuncture Systems manufactured and sold by Key Pharmaceuticals (kenilworth, New Jersey), Nitrodisc, Bolar Pharmaceuticals manufactured by Searle Pharmaceuticals (Chicago, Illinois). Nitroglycerin Percutaneous System of Copiague, New York, Transderm-Nitro supplied by CIBA Pharmaceutical Company (Summit, New Jersey) Systems and Minitran from Riker Pharmaceuticals (St, Paul, Minnesota) Systems.

One of several problems with percutaneous administration of nitroglycerin is tolerance to medication resulting from prolonged administration. More single doses are required for patients receiving long-term nitroglycerin treatment, which requires the use of larger transdermal patches. This is clearly uncomfortable and undesirable. Accordingly, the present invention relates to methods and systems for administering nitroglycerin percutaneously using smaller patches of more convenient size, at relatively high percutaneous flux.

The present invention may be useful for angina and other indications that require high single doses of nitroglycerin (eg, generation of controlled hypotension during congestive heart disease or surgical and surgical periphery). The present invention includes percutaneous administration of nitroglycerin and low irritation skin penetration enhancers, details of which will be described below.

[Explanation of Technology]

The following references relate to one or more aspects of the invention.

Skin penetration enhancers (generally): Various compounds are known in the technical literature that improve skin permeability. U.S. Patents 4,006,218, 3,551,554 and 3,472,931 are dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF), respectively. N, N-dimethylacetamide (DMA) has been shown to be used to enhance the absorption of pharmaceutical actives across the stratum corneum of the epidermis.

Other compounds that have been used to enhance skin penetration include decylmethylsulfoxide (C ₁₀ MSO); diethylene glycol monoethyl ether; Polyethylene glycol monolorate (PEGML; see eg US Pat. No. 4,568,343); Glycerol monolorate (US Pat. No. 4,746,515); Propylene glycol monororate; Ethanol (eg, US Pat. No. 4,379,454); Eucalyptol (US Pat. No. 4,440,777); Lecithin (US Pat. No. 4,783,450), 1-substituted azacyclo heptane-2-one, in particular 1-n-dodecylcycloacycloheptan-2-one (trademark Azone made by Nelson Research Development Co., Irvine, CA) This is on the market. See US Patents 3,989,816, 4,316,893, 4,405,616, 4,557,934; Propylene glycol in combination with fatty acids such as linoleic acid (European Patent Publication 261429); N- (hydroxyethyl) pyrrolidone in combination with extracellular membrane disrupting compounds such as methyl laurate or oleic acid (US Pat. No. 4,537,776); C ₃ -C ₄ diols (US Patent 4,552, 872, European Patent Application Publication 043738); Or two-component systems of oleic acid and oleine (or oleyl alcohol combined with lower alcohols).

Sorbitan analogs (specifically) as penetration enhancers: Ogiso et al. (J. Pharmacobio-Dyn. 9: 517-525 (1986)) published a study on percutaneous absorption in vivo and the penetration of indomethacin in vitro. . Sorbitan 1 oleate was tested as a penetration enhancer in combination with a dimethylsulfoxide (DMSO) gel, which proved to be ineffective.

In 1989, Ogiso et al. (J. Pharm. Sci., 78 (4): 319-323) described the percutaneous absorption of salicylic acid from several nonionic surfactants, such as sorbitan palmitate and sorbitan 3 oleate. Explain the effect.

In the latter two references, sorbitan esters are used in conjunction with DMSO. U. S. Patent No. 4,637, 930 to Konno et al. Percutaneously for the administration of nicardipine hydrochloride containing a mixed liquid consisting of urea and an additional compound, which may be a sorbitan intermediate chain (which may be a 6-12 carbon atom) fatty acid ester). Describe the method.

Percutaneous Administration of Nitroglycerin: U.S. Patent 4,751,087 to Wick describes adhesive tapes based on acylates for delivering nitroglycerin percutaneously.

This system optionally comprises (i) fatty acid esters and (ii) glyceryl 1 laurate as a skin penetration promoting combination. Gale et al. 4,615,699 describe a transdermal delivery system for administering nitroglycerin in combination with ethanol as a skin penetration enhancer.

U.S. Patent 4,764,381 to Bodor et al. Describes nitroglycerin mixtures for transdermal administration, containing oleic acid as penetration enhancer. US Patent 4,559,222 to Enscore describes a matrix mixture for percutaneous medicament administration, which consists of mineral oil, polyisobutylene, and colloidal silicon dioxide. US Pat. No. 4,698,062 to Gale et al. Relates to a percutaneous drug delivery device that affects the pulsatile delivery of nitroglycerin to a patient. U.S. Patent 4,814,168 to Saboltsky et al. Found that a percutaneous drug delivery system is useful for the administration of nitroglycerin, which is a drug storage of vinylacetate, polyethylene, rubber, and multicomponent polymers of tackifying agents. Contains groups.

PCT publication WO83 / 00093 shows a diffusion matrix by polymerization for the percutaneous administration of nitroglycerin, which comprises two polyvinyl alcohol components and glycerol. PCT publication WO86 / 00814 to inventor Sablotsky et al. Shows an adhesive bilayer transdermal delivery system for the administration of nitroglycerin.

[Summary of invention]

Therefore, the main object of the present invention is to provide a method for promoting the rate of passage of the pharmaceutical active through the skin. It is yet another object of the present invention to provide a composition for incorporating a therapeutically effective amount of a selected pharmaceutically active agent into a mixture of penetration enhancers containing sorbitan esters to select areas of the skin.

Another object of the invention is (1) sorbitan esters; Or (2) to provide a process for producing a penetration accelerator in which sorbitan esters in combination with aliphatic alcohols, as described in detail herein, are essential components.

It is a further object of the present invention to provide a penetration promoter mixture consisting essentially of a pharmaceutically active agent and (1) sorbitan esters or (2) sorbitan esters in combination with aliphatic alcohols.

Another object of the present invention is to provide a transdermal system in the form of a layered mixture designed to adhere to the skin. This composition contains a penetration accelerator mixture comprising sorbitan esters and optionally aliphatic alcohols as well as selected pharmaceutical active agents to be administered.

It is still another object of the present invention to provide a method of transdermal administration of nitroglycerin together with a hypoallergenic skin penetration accelerator.

It is another object of the present invention to provide a method of transdermal administration of nitroglycerin with a skin penetration promoter mixture to be defined herein.

Another object of the present invention is to simultaneously administer nitroglycerin and skin penetration accelerator using a layered mixture as a transdermal patch. By the way, this transdermal patch contains a drug and selected penetration promoters in one or more drug storage layers.

Another object of the present invention is to provide a transdermal system for the administration of nitroglycerin, which provides a drug flux at least 50% higher than that obtained in the absence of a skin penetration enhancer.

Another object of the present invention is to provide a method and composition for improved transdermal administration of steroid medications.

Further objects, advantages and novel features of the invention will be addressed in part in the description which follows.

In one aspect, the present invention provides a pre-determination of a penetration accelerator comprising (1) an agonist and (2) a sorbitan ester, or a sorbitan ester comprising a sorbitan ester in combination with a C ₁ -C ₄ aliphatic alcohol. It is a composition for transdermal administration of a pharmaceutically active agent to obtain a relatively high percutaneous flux by administration over time.

In a preferred embodiment, the skin penetration enhancer and the medicament are administered in a single mixture.

Because of the high removal rate of many medications from the body, it is generally desirable to administer them fairly continuously through the time selected for patch application.

In another aspect of the invention, a composition of matter is provided, which is useful for the delivery of a pharmaceutical active through the skin. The composition of this material composition is as follows.

(a) a therapeutically effective amount of a pharmaceutically active agent;

(b) the amount of penetration promoter mixture effective to enhance penetration of the pharmaceutically active agent through the skin. The penetration accelerator here consists essentially of sorbitan esters or sorbitan esters combined with C ₁ -C ₄ aliphatic alcohols.

Another aspect of the present invention is that the therapeutic system is in the form of a skin patch used to administer the drug transdermally at a relatively high flux as mentioned above.

This skin patch is a highly impermeable to the medication, an upper backing layer and at least one drug / promoter reservoir (where one of the drug / promoter reservoirs forms the basal surface of the device and is in use). Preference is given to the form of a matrix-type laminate mixture, which is designed to adhere to the skin. This reservoir is a matrix containing a medicament and a penetration enhancer as described above. Such insect mixtures preferably comprise removable release liners that are thinly coated on the base surface of the drug reservoir.

This release liner is a disposable component designed to protect exposed reservoir surfaces prior to use. Alternatively, a percutaneous treatment system is provided in a liquid storage layered mixture, for example as described in Chang et al. US Pat. No. 4,849,224, the discovery of the complexes described above is embodied in this reference.

In another aspect, the present invention percutaneously administers nitroglycerin by simultaneously administering (1) nitroglycerin (2) penetration accelerator for a predetermined time period through a predetermined skin area to obtain a relatively high percutaneous flux. That's how.

In a preferred specific example, the skin penetration promoting agent and the medicament are administered in a single mixture containing both. Since the rate of removal of nitroglycerin from the body is quite high, it is preferred to continue administration for the time selected for patch use.

The present invention generally relates to the administration of nitroglycerin to people in need of nitroglycerin therapy, and thus relates to various types of indications (e.g., relief and treatment of angina, congestive heart disease, and the like). Includes percutaneous methods and systems designed for.

In another aspect of the invention, the treatment system is provided in the form of a skin patch to administer nitroglycerin percutaneously, at a relatively high flux as mentioned above. The skin patch includes an upper backing layer and at least one medication / promoter reservoir that is highly impermeable to the medication. By the way, either the drug reservoir or the accelerator reservoir forms the basic surface of the device and is adhered to the skin during use. This reservoir includes nitroglycerin and a penetration enhancer as described herein.

Another aspect of the invention is that such laminate composites comprise a removable protective peeling liner, which is thinly coated on the base surface of the drug reservoir.

This release liner is a disposable component designed to protect exposed reservoir surfaces prior to use. This release liner is preferred for its dual structure to facilitate removal.

In this dual structure, the first detachable shroud partially overlaps the second detachable shroud, resulting in a ring strap extending from the base surface of the patch.

Detailed Description of the Invention

Before describing the configuration, system and method of the present invention in detail, it should be understood that the present invention is limited to a specific drug, sorbitan ester, aliphatic alcohol, or the lamination material introduced herein (also other lamination materials). It is not limited. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

It should be noted that the terminology used in the specification and the appended claims includes plural referents unless the suffix is specifically limited to singular. Thus, for example, a laminate comprising a medicament comprises a mixture of two or more medicaments, an adhesive means one or more adhesives, and a sorbitan ester comprises a mixture of two or more sorbitan esters. do.

In describing and claiming the invention, the following terms will be used in accordance with the definitions set out below.

Penetration enhancement or permeation enhancement refers to an increase in the permeability of the skin to a pharmacologically active agent (ie to increase the rate of penetration of an agent through the skin). Permeation enhancer means a material that achieves such a penetration enhancer. The permeation enhancing amount of the penetration enhancer used means an amount effective to promote the passage of the skin to a desired degree of the selected agent.

Used in the traditional sense in transdermal drug delivery. That is, it refers to the delivery of medicine by the route through the skin and into the bloodstream. Transmucosal drug delivery refers to the delivery of medicine to the bloodstream through the mucosa. Topical medication delivery refers to the topical administration of topical medications used in the treatment of various skin diseases. These terms will sometimes be used interchangeably. That is, one aspect of the invention described in the context of transdermal drug delivery may also be applied to transmucosal or topical delivery, unless otherwise specified.

In other words, the configurations, systems, and methods of the present invention may be equally applicable to any one of these three methods of drug delivery, unless specifically stated otherwise.

The term drug or pharmacologically active agent refers to any complex or mixture of substances, which, when administered to an organism (human or animal), is characterized by pharmacological and / or systemic action as desired by local and / or systemic action. Refers to complexes or mixtures of substances that induce physiological effects. In general, these terms include therapeutic or prophylactic agents in all major therapeutic / prophylactic fields of medicine.

Examples of medicaments useful in connection with the present invention include anti-inflammatory drugs such as antibiotics and antiviral drugs; Analgesics and analgesic compounds; Loss of appetite, antiperspirant; Antiarthritis drugs; Anti-asthmatic agents; Anticholinergic agents; Antiemetic agent; Antidepressants; Antidiabetic agents; Antidiarrheal; Antihypertensives; Anti-inflammatory; Antimigraine drugs; Anti-inflammatory drugs; Anti-seasoning agents; Antitumor agents; Anti-Pakison's disease; Antipruritic drugs; Antipsychotics; fever remedy; sedative; Anticholinergic agents; Sympathetic nervous system; Xanthine derivatives; Cardiovascular drugs; Antiarrhythmic agents; Antisolid pressure agents; diuretic; Whole body coronary. Peripheral. Vasodilators for the cerebrum; Decongestants; steroid; soporific; Immunosuppressants; Muscle relaxants; Parasympathetic blockers; Psychostimulants, sedatives; There are things like mental stabilizers. The medicaments used herein for the purpose of the definitions of the foregoing terms also include topically administered topical medications, such as those of antimicrobial agents, antifungal agents, antibacterial agents, skin growth promoters, anti-psoriasis agents, anti-acne medications.

Carriers or vehicles as used herein refer to delivery materials that are suitable for administration in conjunction with a mixture currently found and claimed, and which have no pharmaceutical activity.

Such carriers or excipients are liquids, gels, solvents, liquid diluents, solubilizers, and the like.

Suitable carriers or excipients herein are pharmaceutically acceptable because they are nontoxic, do not interfere with drug delivery, and are not biologically or otherwise undesirable for any reason. Examples of specific suitable carriers or excipients for use herein include water, mineral oil, silicone, inorganic gels, liquid emulsions, liquid sugar, wax, petroleum jelly, and various other oils and polymers. .

A therapeutically effective amount of a medicament or pharmaceutical active means a nontoxic but sufficient amount of the medicament or agent to give the desired therapeutic effect.

Nitroglycerine means 1,2,3-propanetriol trinitrate.

That is, it is a mixture which has the following structural formula.

The present invention thus refers to a method of promoting the rate of passage of the pharmaceutically active agent through the skin, wherein the method is through the predetermined site of the skin, the drug and mainly sorbitan esters, sorbitan esters and C ₁ for a predetermined time. -C ₄ A combination method of penetration accelerator consisting of a combination of aliphatic alcohols. Sorbitan esters useful in connection with the present invention have the following structure.

Wherein the substituent R ₁ has a structure —O (CO) R ′ wherein R ′ is a saturated, monounsaturated, bisaturated, triunsaturated aliphatic hydrocarbon substituent (with 7-21 carbon atoms, preferably 11-21 carbon atoms). Is selected from the group containing. R 'may be substituted with 1-3 hydroxyl groups. The substituents R and R may be the same or different. And hydroxyl and -O (CO) R '. R ₁ , R ₂ , R ₃ can be, for example, lauryl, myristyl, palmityl, stearyl, palmitoleyl, oleyl, linoleyl, linolelenyl, or ricinoleyl ester, or the like. Typical sorbitan esters are long chain sorbitan monoesters.

Wherein R ₁ is as defined above, R 'is a hydrocarbon group of 11-21 carbon, and R ₂ and R ₃ are both of a hydroxyl group. Particularly preferred compounds within the sorbitan monoester class are sorbitan monooleate and sorbitan monolaurate.

In addition to the sorbitan esters, the penetration enhancer mixtures of the present invention may comprise an aliphatic alcohol component.

Preferred aliphatic alcohols are C ₁ -C ₄ alcohols such as ethanol, n-propanol, isopropanol, t-butanol, and mixtures thereof. However, the more long chain alcohols such as oleyl alcohol (typically a C _{2 8} -2) can also be used in the present application (see e.g. Examples 8 and 9).

The method of delivery of the mixtures herein may vary, but essentially entails applying the medications and promoters to selected surfaces of the skin or other tissues for a time sufficient to provide an appropriate blood level of medication. The method is preferably administered in a single mixture of the medicament and the promoter. Here a homogeneous mixture is made into an ointment, gel, cream or the like. Or the use of a medicament delivery device as shown in US Pat. Nos. 4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.

When the drug to be administered and the penetration enhancer described above are applied in the form of an ointment, gel, cream or the like, the amount of drug contained in the mixture will be determined by various factors.

These factors include the desired rate of delivery, the desired single dose, the disease being treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of the drug selected to reach its intended goal, and the patient and physician's specific knowledge. There are other factors within. The amount of promoter is typically in the range of 0.1-40 (% by weight) relative to the total composition, and more preferably in the range of 2.5-15 (% by weight). In addition to medications and accelerators, the mixture may contain one or more selected carriers and excipients and / or various medications and ingredients commonly used in dermatological ointments or lotions. For example, fragrances, opacifiers, preservatives, antioxidants, gelling agents, perfumes, thickeners, stabilizers, surfactants, thickeners, colorants, and the like, these are pharmaceutically acceptable and their pharmaceuticals and accelerators. If it is compatible with, it can exist.

Percutaneous delivery devices for the administration of medications are made of a mixture of medications / promoters described above. Preferred percutaneous drug delivery systems for use herein are mixtures of laminations, which comprise one or more medication / penetration accelerator reservoirs and a backing layer and optionally one or more additional layers (eg additional medications). And / or accelerator reservoirs. This is readily understood by those skilled in percutaneous drug delivery. 1 depicts a typical system 10, which, when applied to the skin, is administered a selected pharmaceutical active as described above. System 10 is a mixture of layers, where upper layer 12 is a backing layer, the face of which is the upper surface of the mixture. Medication reservoirs include the medications and accelerators described in the text, and optional carriers or excipients adjacent immediately below the backing layer as indicated in 14.

Seen before use, the layer also has a removable peeling liner for removal. Preferably, as described in Application No. 07 / 625,906, filed on October 10, 1990, of a method and apparatus for administering nitroglycerin percutaneously at the same and concurrently assigned jointly assigned improved percutaneous flux. The peeling liner is in the form of two plates 16a and 16b. However, the first plate 16a partially overlaps the second plate 16b.

Additional structural layers and / or additional medication / promoter reservoirs may also be placed.

The pharmaceutical reservoir is preferably composed of a pressure-sensitive adhesive adhesive suitable for long-term skin contact. As used herein, including the claims, the term 'pressure sensitive' or 'pressure sensitive adhesive' means a property that is well adhered by pressing above. The medication reservoir should also be able to be physically and chemically parallel to the medicaments and accelerators used and the carriers and excipients applied to the medicament / promoter mixtures. In addition, the adhesive selected for use as the reservoir layer must be at least slightly soluble in the medicament and the promoter. Medicine reservoirs typically range in thickness from 2-4 mm. Suitable adhesives to be used as medicament reservoirs are sticky rubbers such as polysiloxane, polyacrylic, polyurethane, polyisobutylene and the like. A particularly preferred adhesive for use as a pharmaceutical reservoir is acrylic crosslinked as a hydrophobic adhesive, available under the tradename Durotak of National Strach Chemical, New York, NY, or Gelva, Monsanto, St. Louis, MO. Do.

As shown in the figure, the backing layer is attached to the medicament reservoir and, during use, serves as the upper layer of the device and functions as the main structural element of the device. The backing layer consists of a flexible elastomeric material of one plate or film that is fairly impermeable to the drug / promoter mixture. The backing layer is generally about 1-4 mm thick, preferably made of a material that allows such a device to follow the contours of the skin so that it can be comfortably used in any part of the skin, such as joints or other bends.

In this way, there is little or no chance of the device leaving the skin due to differences in flexibility or elasticity between the skin and the device in response to normal mechanical deformation. Examples of polymers useful in the backing layer herein are polyethylene, polypropylene, polyester, polyurethane, polyethylene, vinyl acetate, polyvinylidene chloride, block interpolymers such as PEBAX, and the like. The backing layer may also consist of one or more layers of the aforementioned polymers.

The peeling liner is a disposable part that can be discarded after use, which serves only to protect the device before use. Generally, the peeling liner is made of an impermeable material for medicine, excipients, and adhesives. And, this peeling liner can be easily peeled off from the adhesive agent which serves as the medicine reservoir layer. Preferred release liners to be used herein are generally suitable for use with pressure sensitive adhesives. Currently silanized polyester films are preferred.

As mentioned above, as an example of a preferred embodiment, a two-part peeling liner is preferably used, in which the first detachable shroud (as shown in FIG. 16a in FIG. 1) is second. The overlapping of the removable guard plate is partially overlapped, which creates a hand strap extending from the base surface of the stack, to facilitate removal of the detachable plate from the reservoir layer.

A preferred stack of mixtures of the present invention is shown in Figure 1, which consists of a support, a medicine reservoir, and a two-piece peeling liner. Wherein the medication reservoir has a medication / promoter mixture as described above, which contains some amount of medication, and the remainder of the medication reservoir is an adhesive, an optional carrier, an excipient or the like.

In order to use this mixture of layers, it is attached directly to the patient's skin to release the drug / promoter mixture to the skin, allowing the drug to penetrate into the circulation.

The adhesive layer, which acts as a medication reservoir, should be in contact with the skin.

In general, these devices are made using standard technical methods. That is, all components of the drug / promoter mixture are mixed with an adhesive that acts as a drug reservoir and made using a solvent-evaporation film casting method that is deposited on a substrate, which is a backing layer or a release liner.

The other layers are then laminated to this initial structure.

Alternatively, as an example of the embodiment, a mixture of laminations comprising a medicament may be used, as described in US Pat. No. 4,849,224. As described in the patent, such a device, generally shown as 18 in FIG. 2, consists of a top layer of a heat sealable backing 20, which acts as a reservoir 22 for the drug-promoting formula. It has an inverted cup-shaped recess. At the bottom of the outer edge of the backing membrane is the annular layer 24 of the pressure-sensitive adhesive in the periphery of the reservoir. Under the reservoir there is a membrane layer 26 through which the medicament-promoter formula can permeate, just inside the perimeter of the adhesive. Peel sealable innerliner 28 is located under the membrane 26 and part of the backing membrane 20. The double sealable peeling liner 30 covers the entire bottom of the assembly and forms the base surface of the device.

The device 18 has a heat seal 32 between the membrane and the backing layer and a non-removable (temporary) heat seal between the backing film and the inner liner 28. Alternative liquid reservoir type devices that can be used in connection with the present compounds are described in US Pat. No. 4,983,395, which is also incorporated herein by reference.

Preferred doses vary depending on the medication being administered. The daily dose will depend on the individual being treated, the symptoms indicated, the length of time the individual has been using the drug, and the like.

Now, in more detail regarding the administration of nitroglycerin, it is preferred that the medicament and the selected penetration enhancer or promoter are administered to the individual simultaneously, in a single mixture. However, like other medications, the preferred method of administration is to use a transdermal patch. Below will be summarized the preferred amounts of the various elements.

In a preferred embodiment, the nitroglycerin and the selected penetration accelerator or promoter are increased by at least 50% relative to that obtained in the absence of the penetration accelerator, and the flux is generally at least about 10 μg / cm 2 / hr, preferably Preferably 20 µg / cm 2 / hr, more preferably about 30 µg / cm 2 / hr. Those skilled in the percutaneous drug delivery art will understand that the numbers mentioned above are approximate. This is because the skin penetration rate may vary depending on the patient being treated and the particular skin location selected for percutaneous drug delivery.

In addition, the time zone for nitroglycerin administration is preferably 12-36 hours, with 12-24 hours being optimal, during which time the drug delivery is generally continuous.

Preferred daily dosages obtained in the methods and systems of the present invention are generally in the range of 2.5-50 mg, more generally in the range of 2.5-20 mg relative to nitroglycerin.

However, the daily target dose will depend on the particular drug being administered, the individual being treated, the indications present, the length of time of the individual who has used the drug, and the like. As mentioned above, the methods and systems of the present invention provide for diseases in which the percutaneous flux of nitroglycerin is faster than most conventional percutaneous nitroglycerin systems and therefore requires a higher daily dose than conventional ones (eg congestion). Sexual heart disease) or patients who develop some resistance to the drug.

The present invention can also use small patches of convenient size.

Percutaneous delivery of the penetration promoter and nitroglycerin of the present invention ranges from 1 cm 2 to about 100 cm 2 of skin area for drug administration. At higher fluxes, the skin area becomes smaller within the aforementioned ranges. That is, it is 25 cm <2> or less, More preferably, it is 10 cm <2> or less.

Experiment

The following examples are completely open to the ordinary skilled in the art and describe how the composition and system of the present invention are constructed, and are not intended to limit the scope of how the present inventors regard the present invention. Efforts have been made to ensure accuracy with respect to numbers used (eg amounts, temperature, etc.), but some experimental errors and deviations are inevitable.

Unless stated otherwise, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Estradiol, noethyne drone acetate, progesterone and pindorol were purchased from Sigma Chemical (St. Louis, MO), and polyacrylic adhesive solutions were obtained from National Starch Chemical (New Jersey, Durotak). 880-1194, 80-1054, 80-1070) and Monsanto (St. Louis, MO, Gelva) 737). Sorbitan monooleate, sorbitan monolaurate, and sorbitan trioleate were all purchased from ICI Americas. Ethanol (USP 95%) was purchased from Fisher Scientific.

The adhesive layer is obtained after mixing the selected polyacrylic solution with the medicament and / or the promoter and then evaporating the solvent. The concentrated solution is cast on the silanized surface of a polyester release liner (Release Technologies, 2-EST-A-S242M) using a 10 mm gap Gardner knife.

The cast adhesive is then dried at 80 ° C. for 15 minutes to give a final 0.05 inch thick adhesive coating in a convection oven. A 0.0075-inch-thick, low-density polyethylene film (Schoeller Technical Paper Co., New York) then created a three-layered percutaneous matrix system structure on the dried adhesive surface. In vitro skin fluxes of certain drugs tested as described by Merritt and Cooper using HPLC analysis in J. Controlled Release (1984) 1: 161 were evaluated through human body skin. One percutaneous matrix structure was removed from the previously cut site. The matrix was then placed on the surface of the stratum corneum of the human epidermis separated by heat.

The skin was then immediately fixed onto the diffusion vessel, with the transdermal system in place.

The steady state flux of the drug (µg / cm 2 / hr) was determined by linear regression analysis as a function of time the cumulative amount of drug passing through the skin (µg / cm 2).

Example 1

The aforementioned procedure was used to measure the effect of increasing sorbitan ester levels on the estradiol flux from the acrylic adhesive. The sorbitan ester used was sorbitan monolaurate (SML), and the acrylic adhesive used was Durotak. 80-1194 (1194).

As shown in Table 1, it was found that the obtained flux increased with the amount of sorbitan monolaurate.

Example 2

According to the procedure of Example 1 Durotak, three different acrylic adhesive substrates of sorbitan monooleate (SMO) and sorbitan monolaurate 80-1194 (1194), Durotak 80-1054 (1054) and Durotak The effect on the flux of estradiol of 80-1070 (1070) was measured.

All systems tested included 4 wt% estradiol. As can be inferred from the results in the following table, two sorbitan esters have been shown to significantly increase flux in all three types of adhesive substrates.

Example 3

Following the above procedure, an acrylic adhesive substrate (with and without sorbitan esters) was further prepared to determine the effect of medicinal loading on estradiol flux. Used acrylic adhesive is Durotak 80-1070, and the sorbitan ester used was sorbitan 1 oleate. Table 3 shows the results.

Sorbitan 1 oleate has been shown to increase estradiol flux in two systems tested.

Example 4

Following this procedure, an acrylic adhesive substrate containing estradiol (Durotak) 80-1194) was further prepared. One system was prepared with sorbitan trioleate (STO) as promoter, and another system was prepared without sorbitan trioleate.

The flux obtained using the sorbitan 3 oleate system was about 52% higher than the flux obtained from the control system (ie, the system without sorbitan trioleate).

Table 4 shows the results.

Example 5

Acrylic adhesive substrate containing 10% by weight noethyne drone acetate following the above procedure (Durotak) 80-1194 80-1054) was prepared. Systems with and without 15 wt% sorbitan esters were prepared and sorbitan 1 oleate and sorbitan 1 laurate were tested as shown in Table 5. As can be concluded from the results summarized in the table, sorbitan oleate and sorbitan monolaurate significantly increased noethine drone acetate in both adhesion systems.

Example 6

Gelva containing 5% by weight pindorol following the above procedure An acrylic adhesive substrate using 737 was prepared. A system containing 15 wt% sorbitan monooleate, 15 wt% sorbitan monolaurate, and 15 wt% sorbitan trioleate was prepared and compared to a system that did not contain any sorbitan esters. . Again, the flux of the medicament was found to be much higher than for all systems comprising sorbitan esters otherwise (i.e. control systems). The results are shown in Table 6.

Example 7

The progesterone flux from the ethanol solution of the drug was measured as follows.

Ethanol / water / glycerine / sorbitan ester ointment was prepared as summarized in Table 7, from which the flux of the drug was measured.

The data summarized in Table 7 clearly shows a synergistic improvement for progesterone when ethanol is combined with sorbitan monolaurate or sorbitan oleate.

Example 8

Nitroglycerin (10% by volume) contained in ethanol was purchased from ICI Americas (Delaware), a polyacrylic adhesive solution (Durotak). 80-1194) was purchased from National Starch Chemical (New Jersey). Oleyl alcohol was purchased from Henkel (La Grange, Illinois; HD ethanol, ultrapure). The final solution is prepared by mixing the polyacrylic adhesive solution, the nitroglycerin solution, and the oleyl alcohol in the required proportions. do. The solution was rotovap as a way to increase the viscosity of the solution to facilitate casting as a film. The concentrated solution was poured onto the silanized surface of a polyester release liner (Release Technologies, 2-EST-A-S242M) using a 10 mm gap Gardner knife. This cast adhesive was then dried at 80 ° C. for 15 minutes to make a final 0.0025 inch thick adhesive coating in a convection oven. A 0.0025 inch thick low density polyethylene film (Schoeller Thchnical Paper Co., New York) was then covered with a thin film on the dried adhesive surface, resulting in a three-layered percutaneous matrix system. Following the procedure, another transdermal matrix system was prepared having a final composition of 35 wt% nitroglycerin and 65 wt% polyacrylic. This matrix did not include any accelerators.

Nitroglycerin patches (NtroDur II, Key Pharma-ceuticals) without accelerators as controls and nitroglycerin patches (Minitran) with accelerators Riker Pharmaceuticals) was measured in parallel.

Table 9 shows the skin flux in two different experiments obtained by preparing the control system and percutaneous matrix patches, according to the method described above. The flux from the oleyl alcohol substrate was much higher than the flux from the NitroDur II control patch without promoter and nitroglycerin patch without accelerator prepared as described above. Moreover, oleyl alcohol substrates gave much higher nitroglycerin skin flux than control patches (Minitran) with accelerators.

Example 9

National Starch Dorotak from Nitroglycerin and Atlas Powder 80-1194 polyacrylamide was mixed to prepare a final solution containing 22.1 wt% nitroglycerin, 35.8 wt% solid acrylic adhesive, and 42.1 wt% exclusive solvent. Oleyl alcohol (Henkel) or sorbitan 1 oleate (Arlacel 80; ICI Americas) was dissolved in various levels in the nitroglycerin / adhesive solution. The mixture of final substrates ranged from 0 to 7.5% by weight of accelerator after drying. It was. Thereafter, the solutions were poured into a silanized release liner and dried at 80 ° C. for 15 minutes, finally covering the solutions with a thin film on a polyethylene backing film as described in the previous examples. Percutaneous nitroglycerin delivery was then determined as a function of promoter load, as described in Example 8 using Minitran patches (Riker Labs) as the control system. The results are shown in Table 3.

In general, the nitroglycerin flux is a promoter (oleyl alcohol or Arlacel). As the amount of 80) increased, it increased accordingly. In addition, all cases containing accelerators in the experimental matrix mixture showed higher nitroglycerin flux values than in the case of Minitran controls.

Example 10

The procedure of Example 9 was repeated but instead of sorbitan monooleate, sorbitan monolaurate (Arlacel from ICI Americas) 20) was used. An improved transdermal flux was obtained when compared to nitroglycerin systems without accelerators.

Example 11

The procedure of Example 9 was repeated but sorbitan 1 palmitate (Arlacel from ICI Americas) instead of sorbitan monooleate 40) was used. A relatively improved transdermal flux was obtained compared to that obtained in a nitroglycerin system containing no accelerator.

Example 12

The procedure of Example 9 was repeated except that sorbitan trioleate (Arlacel from ICI Americas) instead of sorbitan 1 oleate 85) was used. As in the previous examples, the percutaneous flux obtained was higher than the value obtained for nitroglycerin patches containing no promoter.

Example 13

5% by weight of accelerator (oleyl alcohol or Arlacel Promoted transdermal delivery of nitroglycerin from acrylic substrates containing 80) was measured using the skins of three different donors.

An accelerated nitroglycerin substrate was prepared as described in Example 9.

Nitroglycerin skin flux was determined as described in Example 8 using NitroDur II and Minitran as controls. The skin flux results in the body are shown in Table 10.

Ole Alcohol and Arlacel The flux obtained from the substrate containing 80 accelerators was nearly twice that obtained with the NitroDur II control patch without the accelerator.

In addition, both substrates, including accelerators, produced uniformly higher nitroglycerin dermal flux than control patches (Minitran) containing accelerators.

Example 14

To easily open the release loop, you can stack the two-part release liner by about 1/8 inch. Thereafter, the adhesive / medicament / promoter solution is poured onto the first release liner, dried and then covered with a thin film on the backing film as described in the above examples. Then, the first peeling liner is removed and the overlapping peeling liner in place is covered with a thin film on the adhesive surface. The final laminated patch is then die cut while overlapping the release liner portion spatially in the final patch. Alternatively, the first release liner may be a control depth slit followed by laminating the backing film. Then, one part of the slit liner is removed and the new part is relaminated over the exposed adhesive part. Here the new liner portion overlaps the remaining slit prior linner, which has not been removed from the original stack.

Claims (31)

A composition for promoting the rate of penetration of a pharmaceutically active agent through the skin, the composition comprising (a) a therapeutically effective amount of the pharmaceutically active agent and (b) an effective amount of sorbitan ester, wherein the amount of sorbitan ester is 0.1 wt% to 40 wt% with respect to the composition comprising a pharmaceutically active agent and sorbitan ester, wherein the sorbitan ester has the following structural formula. Wherein R ₁ has a structure —O (CO) R ′ wherein R ′ is a saturated, mono-unsaturated, double-unsaturated, tri-unsaturated aliphatic hydrocarbon group or 1 to 3 hydroxyl groups having 7 to 21 carbon atoms And R ₂ and R ₃ are independently selected from the group consisting of a receiver and —O (CO) R ′. The compound of claim 1, wherein R 'is selected from the group consisting of saturated, mono-unsaturated, double-unsaturated, triple-unsaturated aliphatic hydrocarbon groups having 11 to 21 carbon atoms containing 1 to 3 hydroxyl groups, and R ₂ and R ₃ is all a hydroxyl group, The composition characterized by the above-mentioned. The composition of claim 1 wherein the sorbitan ester is selected from the group consisting of sorbitan 1 oleate, sorbitan monolaurate, and mixtures thereof. The composition of claim ₁ further comprising a C ₁ -C ₄ aliphatic alcohol. 5. The composition of claim 4, wherein the C ₁ -C ₄ aliphatic alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, t-butanol and mixtures thereof. 6. The composition of claim 1, wherein the pharmaceutical active and the sorbitan ester are present in a single pharmaceutical composition, the composition further comprising a pharmaceutically inert excipient. . 6. The composition of claim 1, wherein the pharmaceutically active agent is a steroid. 7. 7. The composition of claim 6, wherein the pharmaceutically active agent is a steroid. 8. The composition of claim 7, wherein said steroid is selected from the group consisting of estradiol, progesterone, noretin drone acetate, and mixtures thereof. The composition of claim 8, wherein the steroid is selected from the group consisting of estradiol, progesterone, noretin drone acetate, and mixtures thereof. 6. The composition of claim 1, wherein the pharmaceutically active agent is nitroglycerin. 7. 7. The composition of claim 6, wherein said pharmaceutically active agent is nitroglycerin. A laminated composite for administering a pharmaceutically active agent through a selected area of skin over a period of time, comprising: (a) a backing layer impermeable to the pharmaceutically active agent, (b) its base surface suitable for adhesion to the skin And, (c) a therapeutically effective amount of the pharmaceutically active agent, and (d) a sorbitan ester, wherein the amount of the sorbitan ester comprises a pharmaceutically active agent and a sorbitan ester. 0.1 wt% to 40 wt% with respect to the composition to be laminated, wherein the sorbitan ester has the following structural formula. Wherein R ₁ has a structure —O (CO) R ′ wherein R ′ is a saturated, mono-unsaturated, double-unsaturated, tri-unsaturated aliphatic hydrocarbon group or 1 to 3 hydroxyl groups having 7 to 21 carbon atoms It is selected from the group consisting of these substituents, and R ₂ and R ₃ are independently selected from the group consisting of a hydroxyl group and -O (CO) R '. 14. A compound according to claim 13, wherein R 'is selected from the group consisting of saturated, mono-unsaturated, double-unsaturated, triple-unsaturated aliphatic hydrocarbon groups having 11 to 21 carbon atoms comprising 1 to 3 hydroxyl groups, and R ₂ and R ₃ is a laminated composite, wherein all are hydroxyl groups. 14. The laminated composite of claim 13, wherein said sorbitan ester is selected from the group consisting of sorbitan 1 oleate, sorbitan monolaurate, and mixtures thereof. The laminated composite of claim 13, further comprising a C ₁ -C ₄ aliphatic alcohol. 17. The laminated composite of claim 16, wherein said C ₁ -C ₄ aliphatic alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, t-butanol and mixtures thereof. 18. Lamination according to any one of claims 13 and 14 to 17, wherein said pharmaceutical active agent and said sorbitan ester are present in a single pharmaceutical composition, said composition further comprising a pharmaceutically inert excipient. Complex. 18. The laminated composite according to any one of claims 13 and 14 to 17, wherein the pharmaceutically active agent is a steroid. 19. The laminate of claim 18 wherein said pharmaceutically active agent is a steroid. 20. The laminated composite of claim 19, wherein said steroid is selected from the group consisting of estradiol, progesterone, noretin drone acetate, and mixtures thereof. 21. The laminated composite of claim 20, wherein said steroid is selected from the group consisting of estradiol, progesterone, noretin drone acetate, and mixtures thereof. 18. The laminated composite according to any one of claims 13 and 14 to 17, wherein the pharmaceutically active agent is nitroglycerin. 19. The laminated composite of claim 18, wherein said pharmaceutically active agent is nitroglycerin. The laminated composite according to any one of claims 13 and 14 to 17, wherein the hydrophobic pressure-sensitive adhesive polymer is a crosslinked hydrophobic pressure-sensitive adhesive polymer. 20. The laminated composite of claim 19, wherein the hydrophobic pressure-sensitive adhesive polymer is a crosslinked hydrophobic pressure-sensitive adhesive polymer. 23. The laminated composite of claim 22, wherein said hydrophobic pressure-sensitive adhesive polymer is a crosslinked hydrophobic pressure-sensitive adhesive polymer. The laminated composite of claim 23, wherein the hydrophobic pressure-sensitive adhesive polymer is a crosslinked hydrophobic pressure-sensitive adhesive polymer. 25. The laminated composite of claim 24, wherein said hydrophobic pressure-sensitive adhesive polymer is a crosslinked hydrophobic pressure-sensitive adhesive polymer. The laminate composite according to any one of claims 13 and 14 to 17, wherein the adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylic lakes, polyurethanes and tacky rubbers. 20. The laminated composite of claim 19, wherein said adhesive polymer is selected from the group consisting of polysiloxanes, polyacrylic lakes, polyurethanes, and tacky rubbers.